WO2024251855A1 - Heteroaryl derivatives as ddrs inhibitors - Google Patents

Heteroaryl derivatives as ddrs inhibitors Download PDF

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WO2024251855A1
WO2024251855A1 PCT/EP2024/065550 EP2024065550W WO2024251855A1 WO 2024251855 A1 WO2024251855 A1 WO 2024251855A1 EP 2024065550 W EP2024065550 W EP 2024065550W WO 2024251855 A1 WO2024251855 A1 WO 2024251855A1
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azaspiro
heptan
methyl
carbonyl
urea
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French (fr)
Inventor
Laura Carzaniga
Fabio Rancati
Jonathan Andrew SPENCER
Benjamin Paul WHITTAKER
Zuzana HAMASOVA
Andrea Rizzi
Roberta MAZZUCATO
Stefano LEVANTO
Robert Stuart Laurie CHAPMAN
Gabriele FUMAGALLI
Nicolò IOTTI
Marta GIULIANI
Dean Alfie STIMPSON
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Chiesi Farmaceutici SpA
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Chiesi Farmaceutici SpA
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Priority to AU2024284017A priority Critical patent/AU2024284017A1/en
Priority to CN202480037172.8A priority patent/CN121285552A/en
Priority to EP24731930.4A priority patent/EP4724439A1/en
Priority to KR1020267000329A priority patent/KR20260022383A/en
Publication of WO2024251855A1 publication Critical patent/WO2024251855A1/en
Priority to MX2025014449A priority patent/MX2025014449A/en
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
    • C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D205/04—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • the present invention relates to compounds inhibiting Discoidin Domain Receptors (DDR inhibitors), methods of preparing such compounds, intermediate compounds useful in such preparations, pharmaceutical compositions containing them and therapeutic use thereof.
  • DDR inhibitors Discoidin Domain Receptors
  • the compounds of the invention may be useful for instance in the treatment of many disorders associated with DDR mechanisms.
  • DDRs Discoidin Domain Receptors
  • RTKs transmembrane receptor tyrosine kinase
  • DDRs are unique receptors among the other members of the RTK superfamily, in that DDRs are activated by collagen whereas other members of the RTK superfamily are typically activated by soluble peptide-like growth factors (see Vogel, W. (1997) Mol. Cell 1, 13-23; Shrivastava A. Mol Cell. 1997; 1 :25-34). Moreover, DDRs are unusual RTKs also because they form ligandindependent stable dimers that are non-covalently linked (see Noordeen, N. A. (2006) J. Biol. Chem. 281, 22744-22751; Mihai C. J Mol Biol. 2009; 385:432-445).
  • the DDR1 subfamily is composed of five membrane-anchored isoforms, and the DDR2 subfamily is represented by a single protein.
  • the five DDR1 isoforms all have in common the extracellular and transmembrane domains but differ in the cytoplasmic region (see Valiathan, R. R. (2012) Cancer Metastasis Rev. 31, 295-321; Alves, F. (2001) FASEB J. 15, 1321-1323).
  • DDR receptor family has been found involved in a series of fibrotic diseases, such as pulmonary fibrosis, and in particular idiopathic pulmonary fibrosis (IPF), or kidney fibrosis.
  • pulmonary fibrosis and in particular idiopathic pulmonary fibrosis (IPF), or kidney fibrosis.
  • IPF idiopathic pulmonary fibrosis
  • the first evidence for a protective role of DDR1 deletion in lung fibrosis was generated in 2006 by the research group of Dr. Vogel (see Avivi-Green C, Am J Respir Crit Care Med 2006;174:420-427). The authors demonstrated that DDRl-null mice were largely protected against bleomycin (BLM)- induced injury. Furthermore, myofibroblast expansion and apoptosis were much lower in these animals compared with their wild-type counterparts. Absence of inflammation in knockout mice was confirmed by lavage cell count and cytokines ELISA. These results indicated that DDR1 expression is a prerequisite for the
  • DDR2 deficiency or downregulation reduces bleomycin-induced lung fibrosis (see Zhao H, Bian H, Bu X, Zhang S, Zhang P, Yu J, et al Mol Ther 2016; 24: 1734-1744).
  • Zhao et al demonstrated that DDR2 plays a critical role in the induction of fibrosis and angiogenesis in the lung, in particular that DDR2 synergizes with transforming growth factor (TGF)-P to induce myofibroblast differentiation. Furthermore, they showed that treatment of injured mice with specific siRNA against DDR2 exhibited therapeutic efficacy against lung fibrosis.
  • TGF transforming growth factor
  • DDR1 Discoidin Domain Receptor 1
  • MCP-1 and TGF- ⁇ are also a key factor of renal disease by promoting inflammation and fibrosis, and blocking the expression of DDR1 after the initiation of renal disease can delay or arrest the progression of this pathology.
  • DDR1 contributes to acute and chronic kidney injury by regulating BCR and STAT3 phosphorylation and in turn the production of MCP-1 and TGF- ⁇ .
  • a DDR1-null mice model had reduced acute tubular injury, inflammation and tubulointerstitial fibrosis with overall decreased renal monocyte chemoattractant protein (MCP-1) levels and STAT3 activation.
  • MCP-1 renal monocyte chemoattractant protein
  • US 2018/148450 A1 discloses triaza-spirodecanones as DDR1 inhibitors.
  • US 2019/374526 A1 discloses inhibitors of PR domain-containing protein 9. It discloses the conversion of 1-(3,5-dichlorophenyl)-3-(2-azaspiro[3.3]heptan-6-yl)urea HCl salt into 1-(3,5- dichlorophenyl)-3-(2-(2-methylpyridin-4-yl)-2-azaspiro[3.3]heptan-6-yl)urea (compound 239).
  • WO2023064370A1 discloses epoxide hydrolase (sEH) inhibitors.
  • both receptors DDR1 and DDR2 useful for the treatment of diseases, disorders or conditions associated with a dysregulation of DDR receptors, in the respiratory field, in particular idiopathic pulmonary fibrosis (IPF), and in the field of fibrosis diseases in general, in particular kidney fibrosis.
  • New selective inhibitors of both receptors DDR1 and DDR2 could be administered by the inhalation route when characterized by a good inhalatory profile, corresponding to a good activity in the lung, a good lung retention and to a low metabolic stability in order to minimize the systemic exposure and correlated safety issues.
  • new inhibitors could be administered by the oral route when charachterized by a good oral profile, high oral bioavailability and low clearance with suitable physical-chemical properties.
  • a new series of compounds of general formula (I), as herebelow reported, has been surprisingly found, which solves the problem of providing inhibitors for receptors DDR1 and DDR2 for administration by inhalation, which act as selective inhibitors of DDR1 and DDR2 receptors with respect to other human protein kinases.
  • Such compounds show high potency, good inhalatory profile, low metabolic stability, low systemic exposure, improved safety and tolerability.
  • the present invention relates to a compound of formula (I) wherein A is a ring selected from the group consisting of: wherein indicates a direct bond to NH; W1, W2 and W3 are substituents of ring A independently selected from the group consisting of hydrogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )halohydroxyalkyl, (C 1 -C 4 )alkoxy, (C 1 - C4)alkoxy-(C1-C4)alkyl, (C1-C4)haloalkoxy, (C1-C4)hydroxyalkyl, halogen, cyano, SF5, NR1R2- (C 1 -C 4 )alkyl, CONR1R2, NHCOR1, NR1R2, heterocycloalkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 4 )
  • the invention refers to a pharmaceutical composition comprising a compound of formula (I), or pharmaceutically acceptable salts thereof, in admixture with at least one or more pharmaceutically acceptable carrier and/or excipient.
  • the invention refers to a compound of formula (I), or pharmaceutically acceptable salts thereof, or to a pharmaceutical composition comprising a compound of formula (I), or pharmaceutically acceptable salts thereof, for use as a medicament.
  • the invention refers to a compound of formula (I), or pharmaceutically acceptable salts thereof, or to a pharmaceutical composition comprising a compound of formula (I), or pharmaceutically acceptable salts thereof, for use in preventing and/or treating a disease, disorder or condition associated with dysregulation of DDR.
  • the invention refers to a compound of formula (I), or pharmaceutically acceptable salts thereof, or to a pharmaceutical composition comprising a compound of formula (I), or pharmaceutically acceptable salts thereof, for use in preventing and/or treating fibrosis and/or diseases, disorders or conditions that involve fibrosis.
  • the invention refers to a compound of formula (I), or pharmaceutically acceptable salts thereof, or to a pharmaceutical composition comprising a compound of formula (I), or pharmaceutically acceptable salts thereof, for use in preventing and/or treating idiopathic pulmonary fibrosis (IPF).
  • IPF idiopathic pulmonary fibrosis
  • the invention refers to processes for the preparation of compounds of formula (I) and to intermediate compounds that are useful in their preparation.
  • the compounds of formula (I) of the present invention are intended to include stereoisomers, tautomers, solvates and pharmaceutically acceptable salts thereof.
  • the compounds of formula (I) of the present invention are intended to include the compounds of formula (la), (lb), (Ic), (Id) and (le).
  • salts refers to derivatives of compounds of formula (I) wherein the parent compound is suitably modified by converting any of the free acid or basic groups, if present, into the corresponding addition salt with any base or acid conventionally intended as being pharmaceutically acceptable.
  • Suitable examples of said salts may thus include mineral or organic acid addition salts of basic residues such as amino groups, as well as mineral or organic basic addition salts of acid residues such as carboxylic groups.
  • Cations of inorganic bases which can be suitably used to prepare salts comprise ions of alkali or alkaline earth metals, such as potassium, sodium, calcium or magnesium.
  • the salts obtained by reacting the main compound, functioning as a base, with an inorganic or organic acid comprise, for example, salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, acetic acid, oxalic acid, maleic acid, fumaric acid, succinic acid and citric acid.
  • the term "stereoisomer” refers to isomers of identical constitution that differ in the arrangement of their atoms in space. Enantiomers and diastereomers are examples of stereoisomers.
  • the term “enantiomer” refers to one of a pair of molecular species that are mirror images of each other and are not superimposable.
  • racemate or “racemic mixture” refers to a composition composed of equimolar quantities of two enantiomeric species, wherein the composition is devoid of optical activity.
  • the compounds of formula (I) of the present invention comprise one or more stereogenic carbons, all stereoisomers thereof are included in the scope of the invention, both as racemic mixtures and as other stereoisomer mixtures in all proportions.
  • halogen or “halogen atoms” or “halo” as used herein includes fluorine (F), chlorine (Cl), bromine and iodine atom.
  • (C 1 -C 4 )alkyl refers to a straight or branched chain alkyl group having from 1 to 4 carbon atoms.
  • Said term comprises methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, and t-butyl.
  • groups are herein indicated also by their atoms arrangement, i.e. as CH3, CH 2 CH 3 , etc.
  • (C1-C4)haloalkyl refers to a straight or branched chain alkyl group having from 1 to 4 carbon atoms, comprising at least one halogen substituent.
  • the term comprises CF 3 and C(CH 3 ) 2 CF 3 .
  • (C 1 -C 4 )alkoxy refers to a straight or branched chain alkyl group having from 1 to 4 carbon atoms, comprising at least one oxygen atom, in particular, but not only, an oxygen atom directly linked to ring A or ring B, i.e. when W1, W2, W3, Y1 or Y2, respectively and independently, are (C 1 -C 4 )alkoxy. Examples include OCH 3 and OCH 2 CH 3 .
  • (C1-C4)haloalkoxy refers to a (C1-C4)alkoxy comprising at least one halogen substituent. Examples include OCF3 and OCF2H.
  • (C 1 -C 4 )hydroxyalkyl refers to a (C 1 -C 4 )alkyl comprising at least one hydroxy substituent. Examples include CH2OH, CH(OH)CH3 and CH2CH2OH.
  • (C3-C7)cycloalkyl refers to a saturated hydrocarbon ring comprising a number of ring carbon atoms from 3 to 7. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
  • oxy refers to an oxygen atom as the point of attachment to ring A or ring B of the substituent indicated right before “oxy”.
  • heterocycloalkyl-oxy refers to a heterocycloalkyl substituent attached to ring A or ring B through an oxygen atom.
  • deuterated refers to a substituent wherein one or more hydrogen atoms are replaced with deuterium, like for instance CDs.
  • mono- or bi-cyclic heteroaryl refers to a mono- or bi-cyclic aromatic group, comprising a number of ring atoms from 5 to 10 and comprising from 1 to 4, or 1 to 3, heteroatoms independently selected from N, S and O, and includes groups having two such monocyclic rings, or one such monocyclic ring and one monocyclic aryl ring, such as a phenyl ring, which are fused through a common bond or linked by a single bond.
  • the mono- or bi-cyclic heteroaryl rings comprise pyrazolyl, furanyl, tiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, imidazolyl, benzofuranyl, lH-benzo[d]imidazolyl, IH-indazolyl, benzothiophenyl, benzo[c]thiophenyl, quinazolinyl, pteridinyl, lH-pyrazolo[5,l-c][l,2,4]triazolyl, pyrrolizinyl, indolizinyl, benzothiazolyl, pyrazolo[5,l-b]thiazolyl, lH-imidazo[l,2-b]pyrazolyl, 1H- pyrazolo[3,4-b]pyridinyl, lH-pyrazolo[3,4-d]pyrimidinyl, l,6
  • bi-cyclic semisaturated heteroaryl ring refers to a bicyclic group, comprising a number of ring atoms from 7 to 11, and comprising from 1 to 4, or 1 to 3, heteroatoms independently selected from N, S and O, and comprising a mono-cyclic heteroaryl or phenyl ring condensed to a mono-cyclic heterocycloalkyl or (C3-C7)cycloalkyl.
  • bi-cyclic semisaturated heteroaryl ring examples include, for instance, 2,3-dihydro-lH-pyrrolo[2,3-b]pyridinyl, 6,7- dihydro-5H-pyrrolo[2,3-b]pyrazinyl, 4,5,6,7-tetrahydrooxazolo[4,5-c]pyridinyl, 4, 5,6,7- tetrahydro-lH-pyrazolo[4,3-b]pyridinyl, 2,3,4,5-tetrahydro-lH-pyrrolo[2,3-b]pyrazinyl, 5,6- dihydro-8H-imidazo[2,l-c][l,4]oxazinyl, 6,7-dihydro-5H-pyrazolo[5,l-b][l,3]thiazinyl and 1- (4, 5 ,6, 7 -tetrahy dropyrazolof 1 , 5 -a]pyridinyl) .
  • heterocycloalkyl refers to a saturated or partly unsaturated mono-, bi- or spiro- cyclic ring system of 3 to 12 ring atoms comprising one or more, for instance 1 to 3, heteroatoms independently selected from N, S and O.
  • S may be in different oxidation states, such as for instance S, SO or SO2.
  • S may be in different oxidation states, such as for instance S, SO or SO2.
  • any ring carbon atom may be in different oxidation states, such as for instance CH2, CH(OH) or CO.
  • heterocycloalkyl examples include piperazinyl, pyrrolidinyl, azetidinyl, morpholinyl, S,S-dioxido-thiomorpholinyl, oxopiperazinyl and piperidinyl.
  • spiro-cyclic ring system refers to a saturated or partly unsaturated bi-cyclic ring system of 5 to 12 ring atoms, comprising one or more, for instance 1 to 3, heteroatoms selected from N, S and O, wherein the two rings have only one common carbon atom.
  • spiro- cyclic ring systems include spiro[3.5]nonanyl, spiro[2.3]hexanyl, spiro[2.4]heptanyl, 2- azaspiro[3.3]heptanyl, 71 2 -azaspiro[3.5]nonanyl and 21 2 -azaspiro[3.5]nonanyl.
  • any composite term like for instance “(Ci-C4)alkyl-heterocycloalkyl-carbonyl”, should be intended as conventionally construed by the groups from which it derives; in this example, it has to be construed by a (Ci-C4)alkyl, a heterocycloalkyl and a carbonyl group which are linked together in the indicated sequence, and wherein the last group in the sequence, the carbonyl group in this example, is the point of attachment to the residual part of the compound of formula (I).
  • the carbonyl group when not indicated in words, is herein represented as CO.
  • physiologically acceptable anions may be present, selected among chloride, bromide, iodide, trifluoroacetate, formate, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate, p-toluenesulfonate, pamoate and naphthalene disulfonate.
  • corresponding physiological cations may be present as well, for instance including alkaline or alkaline earth metal ions.
  • Ki indicates the dissociation constant for the enzyme-inhibitor complex, expressed in molar units. It is an indicator of the binding affinity between inhibitor and DDR1 or DDR2 receptors.
  • the present invention refers to a series of compounds represented by the general formula (I) as herein below described in detail, which are endowed with an inhibitory activity on receptors DDR1 and DDR2.
  • Antagonizing receptors DDR1 and DDR2 can be particularly effective in the treatment of those diseases where the DDR receptors play a role, such as fibrosis and any other disease, disorder or condition related to fibrosis.
  • the compounds of formula (I) of the present invention are able to act as inhibitors of both DDR1 and DDR2 receptors in a substantive and effective way.
  • Table 44 further below shows that for representative compounds of the present invention the inhibitory activity against either DDR1 and/or DDR2 receptors, expressed as Ki, is lower than 100 nM in the binding assay.
  • Ki the inhibitory activity against either DDR1 and/or DDR2 receptors
  • the compounds of formula (I) are able to inhibit the two isoforms of DDR receptor mainly involved in fibrosis and diseases resulting from fibrosis.
  • the compounds of formula (I) can be used in the treatment of fibrosis, in particular pulmonary fibrosis or kidney fibrosis, when DDR1 and DDR2 are involved.
  • comparative compounds section in particular in Table 7, conversely to compounds Cl and C2, characterized by having different linkers replacing the - NH-CO-L1- linker of the compounds of the invention, and conversely to compound C3, characterized by a flipped central core, the presence of said -NH-CO-L1- linker and of a central core as defined above in the compounds of the present invention unexpectedly and remarkably determines a high inhibitory activity on the DDR1 and DDR2 receptors.
  • the compounds of the present invention are endowed with a very high potency and could be administered in humans at very low dosages, thus potentially reducing the adverse events that typically may occur when administering drugs.
  • the compounds of the present invention are also characterized by being selective inhibitors of DDR1 and DDR2 receptors with respect to other human protein kinases, and by a good inhalatory profile, that allows to act effectively on the lung compartment and have, at the same time, a low metabolic stability, that allows to minimize the drawbacks associated with systemic exposure, such as safety and tolerability issues.
  • the compounds of the present invention may be particularly appreciated when looking at suitable and efficacious compounds useful for the treatment of fibrosis, in particular idiopathic pulmonary fibrosis, administered by the inhalation route and characterized by a good inhalatory profile, that corresponds to a good activity on the lung, a good lung retention and a low metabolic stability, that minimizes the systemic exposure and correlated safety issues.
  • the compounds of the present invention may be administered by the oral route for the treatment of fibrosis, when charachterized by a good oral profile, high oral bioavailability and low clearance with suitable physical-chemical properties.
  • the present invention relates to a compound of formula (I) wherein A is a ring selected from the group consisting of: wherein indicates a direct bond to NH; W1, W2 and W3 are substituents of ring A independently selected from the group consisting of hydrogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)halohydroxyalkyl, (C1-C4)alkoxy, (C1- C4)alkoxy-(C1-C4)alkyl, (C1-C4)haloalkoxy, (C1-C4)hydroxyalkyl, halogen, cyano, SF5, NR1R2- (C 1 -C 4 )alkyl, CONR1R2, NHCOR1, NR1R2, heterocycloalkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 4 )alkyl- heterocycloalkyl, (C 1 -C 4 )alkyl--
  • R1 and R2 are independently selected from the group consisting of hydrogen, (C 1 -C 4 )alkyl, (C1-C4)hydroxyalkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkylamino-(C1-C4)alkyl, di-(C1- C4)alkylamino-(C1-C4)alkyl, optionally substituted (C3-C7)cycloalkyl, optionally substituted heterocycloalkyl and optionally substituted heterocycloalkyl-(C 1 -C 4 )alkoxy, wherein optional substituents are from 1 to 3 and are selected from the group consisting of (C 1 -C 4 )alkyl, (C 1 - C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy and carbamoyl; optional substituents are preferably selected from the group consisting of CH 3 , OCH 3 ,
  • R3 is selected from the group consisting of (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )alkyl- phenyl and monocyclic heteroaryl; preferably, R3 is CH 3 or p-tolyl; or a stereoisomer, tautomer, solvate and pharmaceutically acceptable salt thereof; wherein the compound of formula (I) is not 1-(3,5-dichlorophenyl)-3-(2-(2-methylpyridin-4-yl)-2-azaspiro[3.3]heptan-6-yl)urea.
  • variable moieties A, B, L, L1, R, W1, W2, W3, Y1, Y2, R1, R2, R3 and Rs of the compound of formula (I) of the invention have to be intended as alternatives and may be combined with each other in embodiments which are included in the scope of the invention.
  • Preferred halogens, as such and in groups comprising them, such as, for instance, (C1- C 4 )haloalkyl and (C 1 -C 4 )haloalkoxy substituents, are fluorine and chlorine, wherein fluorine is more preferred.
  • W1, W2 and W3 are substituents of ring A which can be attached to A at any available position. Ortho and meta are preferred positions.
  • W1, W2 and W3 are independently selected from the group consisting of hydrogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1- C4)halohydroxyalkyl, (C1-C4)alkoxy, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)haloalkoxy, (C1- C 4 )hydroxyalkyl, fluorine, bromine, iodine, cyano, SF 5 , NR1R2-(C 1 -C 4 )alkyl, CONR1R2, NHCOR1, NR1R2, heterocycloalkyl, (C3-C7)cycloalkyl, (C1-C4)alkyl-heterocycloalkyl, (C1- C4)alkyl-heterocycloalkyl-(C1-C4)alkyl, (C1-C4)
  • W1, W2 and W3 are independently selected from the group consisting of hydrogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)halohydroxyalkyl, (C1-C4)alkoxy, (C 1 -C 4 )alkoxy-(C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkoxy, (C 1 -C 4 )hydroxyalkyl, fluorine, bromine, iodine, cyano, SF5, NR1R2-(C1-C4)alkyl, CONR1R2, NHCOR1, NR1R2, heterocycloalkyl, (C3- C7)cycloalkyl, (C1-C4)alkyl-heterocycloalkyl, (C1-C4)alkyl-heterocycloalkyl-(C1-C4)alkyl, (C1- C 4 )haloalkyl-cycloal
  • L is a linker and may be selected from CO and CH 2 or is absent.
  • L1 is a linker and may be selected from NR, CH2 and O, wherein R is preferably selected from the group consisting of hydrogen, CD3, cyclopropylmethyl, cyclopropyl, CH2CF3, CH2CH3 and CH 3 .
  • Rs is hydrogen or methyl when L1 is NR;
  • RS is hydrogen when L1 is CH2 or O.
  • B is preferably selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, pyrazolo[1,5-a]pyrazinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[3,4-d]pyrimidinyl, pyrazolo[1,5-a]pyrimidinyl, 1H-pyrazolo[3,4-b]pyridinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, 1H-imidazo[1,2-b]pyrazolyl, imidazo[2,1- b]thiazolyl, pyrrolo[2,3-c]pyrimidinyl, pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, pyrazol
  • Any ring B may be attached to the L moiety at any available position of its mono- or bi-cyclic ring system.
  • Y1 is a substituent of ring B which can be attached to B at any available position.
  • Y1 is preferably selected from the group consisting of hydrogen, CH3, OCH3, OCF3, CF3, C(CH3)3, C(CH3)2CF3, CONH2, OCF2H, CF2H, CF2CH3, CF2CF3, CH2CF3, CH2OH, CH2CH2OH, CH 2 CH 2 OCH 3 , CH 2 CH 2 SCH 3 , CH 2 CH 2 F, CH 2 SCH 3 , SCF 3 , SO 2 CF 3 , CD 3 , cyano, NHCOCH 3 , NH 2, (C 1 -C 4 )alkyl-piperazinyl, 4-methylpiperazin-1-yl, piperazinyl, morpholinyl, pyrrolidinyl, hydroxypyrrolidinyl, N-methyl-
  • Y2 is a substituent of ring B which can be attached to B at any available position. Y2 may have the same preferred meanings as Y1, independently. In more preferred embodiments Y2 is hydrogen. R1 and R2 are preferably independently selected from the group consisting of hydrogen, (C1-C4)alkyl and optionally substituted heterocycloalkyl; more preferably, R1 and R2 are independently selected from the group consisting of hydrogen, methyl and oxetanyl.
  • R3 is selected from the group consisting of (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )alkyl- phenyl and monocyclic heteroaryl, being preferably CH 3 or p-tolyl.
  • the invention relates to a compound of formula (I) wherein A is a ring selected from the group consisting of : ; even more preferably, A is selected from the group consisting of phenyl, 3-pyridinyl, 2- pyridinyl, 3-pyridazinyl, 3-isoxazolyl and pyrazolyl, wherein R3 is CH 3 or p-tolyl; W1, W2 and W3 are selected from the group consisting of hydrogen, CH 3 , OCH 3 , OCF 3 , CF3, CHF2, C(CH3)3, CH2CF3, CF2CH3, CF2CF3, C(CH3)2CF3, OCF2H, CH2OH, cyano, CF3SO2, SCF 3 , SF 5 , F, Br, I, cyclopropyl, morpholino-N-ethoxy, N-acetylpiperidinyl-oxy, N- acetylazetidinyl
  • L is selected from CO and CH 2 or is absent, being preferably CO;
  • L1 is selected from NR, CH2 and O, being preferably NR, wherein R is preferably selected from the group consisting of hydrogen, CD3, cyclopropylmethyl, cyclopropyl, CH2CF3, CH2CH3 and CH 3 ;
  • B is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, pyrazolo[1,5-a]pyrazinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[3,4- d]pyrimidinyl, pyrazolo[1,5-a]pyrimidinyl, 1H-pyrazolo[3,4-b]pyridinyl, imidazo[1,2- b]pyridazinyl, imidazo[1,2-a]pyrazinyl
  • the present invention relates to a compound of formula (I) wherein L is CO and L1 is NR, which is represented by formula (Ia) wherein Wl, W2, W3, A, B, R, Rs, Y1 and Y2 are as defined above.
  • the present invention relates to a compound of formula (I), wherein L is CH2 and LI is NR, which is represented by formula (lb) wherein Wl, W2, W3, A, B, R, Rs, Y1 and Y2 are as defined above.
  • the present invention relates to a compound of formula (I), wherein L is absent and LI is NR, which is represented by formula (Ic) wherein Wl, W2, W3, A, B, R, Rs, Y1 and Y2 are as defined above.
  • the present invention relates to a compound of formula (I), wherein LI is CH2, which is represented by formula (Id) wherein Wl, W2, W3, A, B, L, Y1 and Y2 are as defined above and Rs is hydrogen.
  • the present invention relates to a compound of formula (Id) wherein L is CO.
  • the present invention relates to a compound of formula (I), wherein LI is O, which is represented by formula (le) wherein Wl, W2, W3, A, B, L, Y1 and Y2 are as defined above and Rs is hydrogen.
  • the present invention relates to a compound of formula (le) wherein L is CO.
  • Particularly preferred embodiments of the invention are the compounds of formula (la) listed in Table 1 below, and pharmaceutically acceptable salts thereof. These compounds are particularly active on receptors DDR1 and DDR2, as shown in Table 44 further below.
  • Particularly preferred embodiments of the invention are the compounds of formula (lb) as defined above, wherein A is optionally substituted phenyl, LI is NH and B is selected from imidazo[l,2-a]pyrazinyl and lH-pyrazolo[3,4-b]pyridinyl.
  • Further particularly preferred compounds of formula (lb) are those listed in Table 2 below, and pharmaceutically acceptable salts thereof. These compounds are particularly active on receptors DDR1 and DDR2, as shown in Table 44 further below.
  • Table 2 List of representative compounds of Formula (lb) Additional particularly preferred embodiments of the invention are the compounds of formula (Ic) as defined above, wherein A is optionally substituted phenyl or pyridinyl and B is selected from lH-pyrazolo[3,4-b]pyridinyl, imidazo[l,5-a]pyrazinyl and lH-pyrrolo[2,3- b]pyridinyl, and wherein R is preferably hydrogen or CH3.
  • More particularly preferred compounds of formula (Ic) are those listed in Table 3 below, and pharmaceutically acceptable salts thereof. These compounds are particularly active on receptors DDR1 and DDR2, as shown in Table 44 further below.
  • Additional particularly preferred embodiments of the invention are the compounds of formula (Id) as defined above, wherein A is optionally substituted phenyl or pyridinyl, L is CO and B is selected from pyrazolo[5,l-b]thiazolyl, imidazo[l,2-a]pyridinyl, pyrazolo[l,5- a]pyrazinyl, imidazo[l,5-a]pyrazinyl, thieno[3,2-b]pyridinyl, lH-imidazo[l,2-b]pyrazolyl and pyrazolo[5,l-b]thiazolyl.
  • Also particularly preferred embodiments of the invention are the compounds of formula (le) as defined above, wherein A is selected from the group consisting of optionally substituted phenyl, optionally substituted pyridinyl and optionally substituted isoxazolyl, L is CO and B is selected from pyrazolo[5,l-b]thiazolyl and lH-imidazo[l,2-b]pyrazolyl.
  • A is selected from the group consisting of optionally substituted phenyl, optionally substituted pyridinyl and optionally substituted isoxazolyl
  • L is CO
  • B is selected from pyrazolo[5,l-b]thiazolyl and lH-imidazo[l,2-b]pyrazolyl.
  • Further particularly preferred compounds of formula (le) are those listed in Table 5 below, and pharmaceutically acceptable salts thereof. These compounds are particularly active on receptors DDR1 and DDR2, as shown in Table 44 further below.
  • Table 5 List of representative compounds of Formula (le)
  • the compounds of the invention including all the compounds here above listed, can be prepared from readily available starting materials using the following general methods and procedures or by using slightly modified processes readily available to those of ordinary skill in the art. Although a particular embodiment of the present invention may be shown or described herein, those skilled in the art will recognize that all embodiments or aspects of the present invention can be obtained using the methods described herein or by using other known methods, reagents and starting materials. When typical or preferred process conditions (i.e. reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated.
  • PG protective groups
  • intermediate urea III may be prepared from amine II, wherein Rs is hydrogen or methyl, by reaction with the isocyanate X in a suitable solvent, such as DCM, at rt.
  • Intermediate compound IVa may then be obtained from intermediate III by Boc-deprotection in acidic conditions, for instance by using TFA in a suitable solvent, such as DCM, at rt.
  • intermediate urea III may be prepared from amine II by reaction with the suitable 2,2,2-trichloroethyl carbamate (Troc carbamate) XXII, which can be obtained from the suitable amine XV and 2,2,2-trichloroethyl chloroformate, in a suitable solvent mixture, such as ACN, in the presence of a base, such as DIPEA, and at a temperature varying from 80 °C to 150 °C in a microwave oven.
  • a suitable solvent mixture such as ACN
  • a base such as DIPEA
  • carboxylic acid XI and intermediate compound IVa may be reacted to give a compound of formula (la) under suitable amide coupling reaction conditions, in the presence of an activating agent, such as for instance HATU or TBTU, with an organic base, such as DIPEA or TEA, in a suitable organic solvent, such as DCM or DMF, at a temperature generally around rt for a time ranging from a few hours to overnight.
  • an activating agent such as for instance HATU or TBTU
  • organic base such as DIPEA or TEA
  • suitable organic solvent such as DCM or DMF
  • a compound of formula (la) may be prepared from amine IVa and acyl chloride XIV, which can be obtained from carboxylic acid XI in the presence of an appropriate chlorinating reagent, such as POCh, thionyl chloride or oxalyl chloride, in a solvent, such as DCM and, if needed, in the presence of a catalytic amount of DMF, at a temperature ranging from 5 °C to 50 °C.
  • an appropriate chlorinating reagent such as POCh, thionyl chloride or oxalyl chloride
  • a compound of formula (la) may be prepared via direct amidation of carboxylic acid XI, by conversion into the transient activated acylimidazolinium intermediate in the presence of TCFH and 1 -methylimidazole and subsequent reaction with the amine IVa in a solvent, such as DMF, generally around RT.
  • a compound of formula (la), wherein Y1 is bromine, may be converted into a different compound of formula (la), wherein Y1 is optionally substituted phenyl or optionally substituted heteroaryl, by reaction with a phenyl or heteroaryl boronic ester/acid by a palladium-catalyzed cross-coupling.
  • the reaction may be carried out by the usual Suzuki protocol, in a suitable organic solvent, such as dioxane, in the presence of an inorganic base, such as potassium carbonate, with an appropriate palladium catalytic system, such as Pd(dppf)C12, at high temperature (around 100°C) for few hours.
  • a compound of formula (la), wherein Y1 is bromine, may be converted into a different compound of formula (la), wherein Y1 is heterocycloalkyl, by reaction with an heterocycloalkylamine (i.e. a heterocycloalkyl wherein a group NH is part of the ring) by means of an electrochemical reaction, in the presence of dibromonickel and an electrolyte, such as TBAB, in an appropriate solvent, such as DMA.
  • an heterocycloalkylamine i.e. a heterocycloalkyl wherein a group NH is part of the ring
  • intermediate compound IVa may be converted into a compound of formula (lb) by applying reductive amination conditions with the appropriate aldehyde XII, with a suitable reducing agent, such as STAB or NaCNBH?, in a suitable solvent, such as DCM or EtOH, in the presence of an acid, such as acetic acid, and in the presence of a dehydrating agent, such as magnesium sulfate, if needed, at a temperature ranging from rt to 50 °C.
  • a suitable reducing agent such as STAB or NaCNBH?
  • a suitable solvent such as DCM or EtOH
  • an acid such as acetic acid
  • a dehydrating agent such as magnesium sulfate
  • a palladium catalyst such as Pd(dppf)C12
  • organic solvent such as DMA
  • a suitable base such as CS2CO3.
  • a compound of formula (I) may be obtained after an additional step of removal of the protecting group in the required conditions, such as acidic conditions, by using TFA or HC1 in 4-di oxane, or with TBAF.
  • intermediate compound XXIII can be obtained by protection of amine II, as defined above, with phenyl chloroformate, in a suitable solvent, such as for instance DCM or EtOAc and/or water, at a temperature varying from -5 °C to rt, optionally in the presence of TEA.
  • a suitable solvent such as for instance DCM or EtOAc and/or water
  • N-(benzyloxycarbonyloxy)succinimide or 4-nitrophenyl chloroformate may be used for protection of amine II.
  • Intermediate compound XXIV may then be prepared from intermediate compound XXIII by Boc-deprotection in acidic conditions, for instance by using TFA in a suitable solvent, such as DCM, at rt.
  • Intermediate compound XXIV may be converted into intermediate compound XXV by cross-coupling reactions, like for instance Buchwald coupling, with a suitable aryl halide XIIF, in the presence of a palladium catalyst, such as Pd-175 or Pd(dppf)C12, or another palladium source/phosphine-based ligand, at high temperature (around 100 °C) for a few hours, in an organic solvent, such as DMA or Me-THF, with a suitable base, such as CS2CO3, and wherein Y17Y2’ may be Y1/Y2 or may bear protecting groups, such as Boc or SEM, and wherein the halide X is preferably bromide.
  • a palladium catalyst such as Pd-175 or Pd(dppf)C12
  • another palladium source/phosphine-based ligand at high temperature (around 100 °C) for a few hours
  • organic solvent such as DMA or Me-THF
  • compounds of formula XXVI may be prepared by amine deprotection reaction of the intermediate compound XXV in the presence of a palladium catalyst and tri ethylsilane or Pd/C 10% and hydrogen, in a suitable solvent, such as ethanol, at a temperature generally around rt for a few hours, optionally followed by deprotection of any protecting group on the Y substituents, if present, in acidic conditions, for instance by using TFA in a suitable solvent, such as DCM, or using TBAF in THF, at rt.
  • a suitable solvent such as ethanol
  • compounds of formula (Ic) may be prepared by reaction of the intermediate compound XXVI either with the suitable 2,2,2-trichloroethyl carbamate (Troc carbamate) XXII, which can be obtained from the suitable amine XV and 2,2,2-trichloroethyl chloroformate, or with intermediate compound XVI, which can be obtained from the suitable amine XV and phenyl chloroformate, in a suitable solvent mixture, such as ACN or THF, in the presence of a base, such as DIPEA, and at a temperature varying from rt to 150 °C, in a few cases in a microwave oven, followed by deprotection of any protecting group on the Wl, W2 or W3 substituents.
  • a suitable solvent mixture such as ACN or THF
  • a base such as DIPEA
  • acidic conditions may be used for cleavage of SEM protecting group, such as TFA in DCM or TBAF in THF, at rt.
  • Intermediate VI may be prepared from amine V and acyl chloride XIV (as defined in SCHEME 1), which can be obtained from carboxylic acid XI (as defined in SCHEME 1) in the presence of an appropriate chlorinating reagent, such as POCh, thionyl chloride or oxalyl chloride, in a solvent, such as DCM and, if needed, in the presence of a catalytic amount of DMF at a temperature ranging from 5 °C to 50 °C; the amine V and the acyl chloride XIV may undergo an amide coupling in the presence of a suitable base, such as TEA, in a suitable solvent, such as DCM, at rt.
  • a suitable base such as TEA
  • intermediate VI may be prepared via direct amidation of carboxylic acid XI, by conversion into the transient activated acylimidazolinium intermediate in the presence of TCFH and 1 -methylimidazole and subsequent reaction with the amine V in a solvent, such as DMF, generally at rt.
  • Intermediate VII may then be obtained from intermediate VI by Boc-deprotection in acidic conditions, for instance by using TFA in a suitable solvent, such as DCM, at rt.
  • Compounds of formula (la) may be prepared from intermediate VII by reaction with the isocyanate X (see SCHEME 1) in a suitable solvent, such as DCM, at rt.
  • compounds of formula (la) may be prepared from intermediate VII by reaction with amine XV (see SCHEME 1) and triphosgene in a suitable solvent, such as DCM, at a temperature varying from 0 °C to rt.
  • compounds of formula (Ic) may be prepared according to SCHEME 3a as described hereinafter.
  • Intermediate compound XXVIII may then be obtained from intermediate XXVII by Boc-deprotection in acidic conditions, for instance by using TFA in a suitable solvent, such as DCM, at rt.
  • Compounds of formula (Ic) may be prepared from intermediate XXVIII by reaction with the suitable 2,2,2-trichloroethyl carbamate (Troc carbamate) XXII, which can be obtained from the suitable amine XV (see SCHEME 1) and 2,2,2-trichloroethyl chloroformate, in a suitable solvent mixture, such as ACN, in the presence of a base, such as DIPEA, and at a temperature varying from 80 °C to 150 °C in a micro wave oven.
  • a suitable solvent mixture such as ACN
  • a base such as DIPEA
  • Compounds of formula (la) may be prepared from intermediate VII by reaction with the suitable phenyl carbamate XVI, which can be obtained from the suitable amine XV (see SCHEME 1) and phenyl chloroformate in a suitable solvent mixture, such as a mixture of EtOAc, DCM and water, at a temperature varying from 0 °C to rt.
  • a suitable solvent mixture such as a mixture of EtOAc, DCM and water
  • the suitable amine XV may be reacted with N-(benzyloxycarbonyloxy)succinimide, in a suitable solvent, such as DCM, at a temperature varying from -5 °C to rt, in the presence of TEA to afford the benzyloxycarbonyl protected amine XV.
  • Compounds of formula (la) may also be prepared from intermediate VII by reaction with the suitable 2, 2, 2-tri chloroethyl carbamate (Troc carbamate) XXII (see SCHE
  • compounds of formula (la) may be prepared by reaction of the suitable amine XV with intermediate VIII, which may be obtained from intermediate VII and phenyl chloroformate in a suitable solvent mixture, such as a mixture of EtOAc, DCM and water, at a temperature varying from 0 °C to rt.
  • a suitable solvent mixture such as a mixture of EtOAc, DCM and water
  • intermediate XVIII may be prepared from commercially available carboxylic acid XVII, wherein Rs is hydrogen, by reaction with the suitable amine XV (see SCHEME 1) under suitable amide coupling reaction conditions, in the presence of an activating agent, such as for instance HATU or TBTU, and an organic base, such as DIPEA or TEA, in a suitable organic solvent, such as DCM or DMF, and at a temperature generally around rt for a time ranging from a few hours to overnight.
  • an activating agent such as for instance HATU or TBTU
  • an organic base such as DIPEA or TEA
  • a suitable organic solvent such as DCM or DMF
  • a compound XVIII may be prepared via direct amidation of carboxylic acid XVII, i.e. by its conversion into the transient activated acylimidazolinium intermediate in the presence of TCFH and 1 -methylimidazole and subsequent reaction with the amine XV in a solvent, such as
  • Intermediate compound IVb may then be obtained from intermediate XVIII by Boc- deprotection in acidic conditions, for instance by using TFA in a suitable solvent, such as DCM, at rt. Subsequently, intermediate compound IVb may be reacted with either a carboxylic acid XI, as described for SCHEME 1, or an aldehyde XII or an aryl halide XIII, as described for SCHEME 2, to obtain a compound of formula (Id), wherein L is CO, or CH2, or absent, respectively.
  • a carboxylic acid XI as described for SCHEME 1
  • an aldehyde XII or an aryl halide XIII as described for SCHEME 2
  • Intermediate compound IVb may also be reacted with an aryl halide XIIF, followed by a deprotection reaction, as described for the synthetic pathway of SCHEME 2a, wherein XIIF is defined, to finally provide a compound of formula (Id).
  • compounds of formula (le) may be prepared from intermediate compound XIX by reaction with isocyanate X (see SCHEME 1) in a suitable solvent, such as DCM, and in the presence of a base, such as DIPEA, at rt.
  • compound XX may be reacted with isocyanate X in a suitable solvent, such as DCM, and in the presence of a base, such as DIPEA, at rt, or compound XX may be reacted with a suitable chloroformate and amine XV, in the presence of a base, such as pyridine, in a suitable solvent, such as DCM, at rt, thus affording intermediate compound XXI.
  • Intermediate IVc may then be obtained from intermediate XXI by Boc-deprotection in acidic conditions, for instance by using TFA in a suitable solvent, such as DCM, at rt.
  • intermediate IVc may be reacted with either a carboxylic acid XI or an aldehyde XII or an aryl halide XIII, as described for SCHEME 1 and 2, to obtain a compound of formula (le), wherein L is CO, or CH2, or absent, respectively.
  • Intermediate compound IVc may also be reacted with an aryl halide XIII’, followed by a deprotection reaction, as described for the synthetic pathway of SCHEME 2a, wherein XIII’ is defined, to finally provide a compound of formula (le).
  • the present invention provides an intermediate compound IV wherein A is a ring selected from the group consisting of: wherein indicates a direct bond to NH; W1, W2 and W3 are substituents of ring A independently selected from the group consisting of hydrogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )halohydroxyalkyl, (C 1 -C 4 )alkoxy, (C 1 - C 4 )alkoxy-(C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkoxy, (C 1 -C 4 )hydroxyalkyl, halogen, cyano, SF 5 , NR1R2- (C1-C4)alkyl, CONR1R2, NHCOR1, NR1R2, heterocycloalkyl, (C3-C7)cycloalkyl, (C1-C4)alkyl- heterocycloalkyl, (C3-
  • the intermediate compound IV is not 1-(2-azaspiro[3.3]heptan-6-yl)-3-(4- (trifluoromethoxy)phenyl)urea.
  • the intermediate compound IV corresponds to an intermediate compound IVa when L1 is NR, to an intermediate compound IVb when L1 is CH 2 and to an intermediate compound IVc when L1 is O.
  • substituents W1, W2 and W3 (indicated also as W substituents) in the intermediate compound IV occupy ortho and/or meta positions on ring A. More preferred W substituents are hydrogen, CH 3 , OCH 3 , OCF 3 , CF 3, CHF 2 , CH 2 CF 3 , OCF 2 H, CH 2 OH, SF 5 , F, Br and I.
  • substituents occupy ortho and/or meta positions.
  • W1 and W2 are both hydrogen and W3 is OCF3, W3 preferably occupies ortho or meta position.
  • W3 is not para-OCF3.
  • a ring is phenyl, L1 is NH and W1 is hydrogen, W2 and W3 are not both Cl in meta positions.
  • W1, W2 and W3 are independently selected from the group consisting of hydrogen, (C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkyl, (C 1 -C 4 )halohydroxyalkyl, (C 1 -C 4 )alkoxy, (C 1 -C 4 )alkoxy-(C 1 -C 4 )alkyl, (C 1 -C 4 )haloalkoxy, (C 1 - C4)hydroxyalkyl, fluorine, bromine, iodine, cyano, SF5, NR1R2-(C1-C4)alkyl, CONR1R2, NHCOR1, NR1R2, heterocycloalkyl, (C 3 -C 7 )cycloalkyl, (C 1 -C 4 )alkyl-heterocycloalkyl, (C 1 - C 4 )alkyl-
  • the invention further provides the use of the intermediate compound IV as defined above in the preparation of a compound of formula (I), or pharmaceutically acceptable salts thereof.
  • the present invention provides a process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof, comprising the step of: a) reacting an intermediate compound IV with either a carboxylic acid XI or an aldehyde XII or an aryl halide XIII, as defined above, to obtain a compound of formula (I), as defined above, wherein A, L1, Rs, W1, W2 and W3 are as defined above and wherein X in the aryl halide XIII is a halogen, preferably bromine.
  • the process may comprise an additional deprotection step in case any substituent on A or B rings bears a protecting group, which the skilled in the art would envisage to use to accomplish the synthesis of a compound of formula (I).
  • the present invention provides intermediate compounds III, IV, IVa, IVb, IVc, VI, VII, VIII, XVIII, XIX, XXI, XXIII, XXIV, XXV, XXVI, XXVII and XXVIII, as defined above, and their use in the preparation of compounds of formula (I).
  • the compounds of formula (I) of the present invention have surprisingly been found to effectively inhibit both receptor DDR1 and DDR2.
  • the inhibition of receptors DDR1 and DDR2 may result in efficacious treatment of the diseases or conditions wherein the DDR receptors are involved.
  • the compounds of formula (I) of the present invention have a very high antagonist drug potency on DDR1 and DDR2.
  • Table 44 in the present experimental part reports such potency expressed as inhibition constant Ki for representative compounds of formula (I) of the invention.
  • Preferred compounds of the invention have a Ki on DDR1 and DDR2 which is lower than 100 nM. More preferred compounds have a Ki between 25 and 5 nM. Even more preferred compounds of the invention have a Ki on DDR1 and DDR2 lower than 5 nM.
  • the present invention refers to a compound of formula (I) according to any of the embodiments disclosed above for use as a medicament.
  • the invention refers to a compound of formula (I), and pharmaceutically acceptable salts thereof, for use in treating diseases, disorders, or conditions associated with dysregulation of DDR.
  • the invention refers to the use of a compound of formula (I) as above described, and pharmaceutically acceptable salts thereof, in the preparation of a medicament for the treatment of disorders associated with dysregulation of DDR.
  • the invention refers to a compound of formula (I), and pharmaceutically acceptable salts thereof, for use in the prevention and/or treatment of a disease, disorder or condition associated with DDR receptor mechanism.
  • the present invention refers to a compound of formula (I) for use in the prevention and/or treatment of fibrosis and/or diseases, disorders or conditions that involve fibrosis.
  • fibrosis refers to conditions that are associated with the abnormal accumulation of cells and/or fibronectin and/or collagen and/or increased fibroblast recruitment and include, but are not limited to, fibrosis of individual organs or tissues such as the heart, kidney, liver, joints, lung, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal and digestive tract.
  • the compounds of formula (I) as above described are useful for the treatment and/or prevention of fibrosis, such as pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), hepatic fibrosis, progressive pulmonary fibrosis, sarcoidosis, familiar pulmonary fibrosis, chronic hypersensitivity pneumonitis (CHP), kidney or renal fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis and systemic sclerosis. More preferably, the compounds of formula (I) as above described are useful for the treatment of idiopathic pulmonary fibrosis (IPF).
  • IPF idiopathic pulmonary fibrosis
  • the compounds of formula (I) as above described are useful for the treatment of kidney fibrosis.
  • the invention refers to a compound of formula (I) or its pharmaceutical composition for use in the prevention and/or treatment of IPF.
  • the invention refers to the use of the compounds of formula (I) or its pharmaceutical composition for the preparation of a medicament for the treatment and/or prevention of IPF.
  • the invention refers to a method for the treatment and/or prevention of IPF, the method comprising administering a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I) and one or more pharmaceutically acceptable carriers and/or excipients.
  • the invention refers to a compound of formula (I) or its pharmaceutical composition for use in the prevention and/or treatment of kidney fibrosis.
  • the invention refers to the use of the compounds of formula (I) or its pharmaceutical composition for the preparation of a medicament for the treatment and/or prevention of kidney fibrosis.
  • the invention refers to a method for the treatment and/or prevention of kidney fibrosis, the method comprising administering a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I) and one or more pharmaceutically acceptable carriers and/or excipients.
  • the invention also refers to a method for the prevention and/or treatment of diseases, disorders or conditions associated with DDR receptors mechanisms, said method comprising the step of administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) as above described.
  • the invention refers to the use of a compound of formula (I) as above described for the treatment of diseases, disorders or conditions associated with DDR receptors mechanism.
  • the invention refers to the use of a compound of formula (I) as above described in the preparation of a medicament for the treatment of diseases, disorders or conditions associated with DDR receptors mechanism.
  • the invention refers to a method for the prevention and/or treatment of a disease, disorder or condition associated with the dysregulation of DDR receptors 1 and 2, said method comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I) as above described.
  • the present invention refers to the use of a compound of formula (I) as above described for the treatment of a disease, disorder or condition associated with dysregulation of DDR receptors 1 and 2.
  • safety and effective amount in reference to a compound of formula (I) or a pharmaceutically acceptable salt thereof or other pharmaceutically active agent means an amount of the compound sufficient to treat the patient's condition but low enough to avoid serious side effects and that can nevertheless be routinely determined by the skilled artisan.
  • the compounds of formula (I) may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. Typical daily dosages may vary depending upon the route of administration chosen.
  • the present invention also refers to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) according to any of its embodiment in admixture with at least one or more pharmaceutically acceptable carrier and/or excipient.
  • the invention refers to a pharmaceutical composition of compounds of formula (I) in admixture with at least one or more pharmaceutically acceptable carrier and/or excipient, for example those described in Remington’s Pharmaceutical Sciences Handbook, XVII Ed., Mack Pub., N.Y., U.S.A.
  • Administration of the compounds of the invention and their pharmaceutical compositions may be accomplished according to patient needs, for example, orally, nasally, parenterally (subcutaneously, intravenously, intramuscularly, intrasternally and by infusion) and by inhalation.
  • the compounds of the present invention are administered orally or by inhalation.
  • the pharmaceutical composition comprising the compound of formula (I) is a solid oral dosage form such as tablets, gelcaps, capsules, caplets, granules, lozenges and bulk powders.
  • the pharmaceutical composition comprising the compound of formula (I) is a tablet.
  • the compounds of the invention can be administered alone or combined with various pharmaceutically acceptable carriers, diluents (such as sucrose, mannitol, lactose, starches) and known excipients, including suspending agents, solubilizers, buffering agents, binders, disintegrants, preservatives, colorants, flavorants, lubricants and the like.
  • diluents such as sucrose, mannitol, lactose, starches
  • excipients including suspending agents, solubilizers, buffering agents, binders, disintegrants, preservatives, colorants, flavorants, lubricants and the like.
  • the pharmaceutical composition comprising a compound of formula (I) is a liquid oral dosage form such as aqueous and non-aqueous solutions, emulsions, suspensions, syrups, and elixirs.
  • a liquid oral dosage form such as aqueous and non-aqueous solutions, emulsions, suspensions, syrups, and elixirs.
  • Such liquid dosage forms can also contain suitable known inert diluents such as water and suitable known excipients such as preservatives, wetting agents, sweeteners, flavorants, as well as agents for emulsifying and/or suspending the compounds of the invention.
  • the pharmaceutical composition comprising the compound of formula (I) is an inhalable preparation such as inhalable powders, propellant-containing metering aerosols or propellant-free inhalable formulations.
  • the powder may be filled in gelatine, plastic or other capsules, cartridges or blister packs or in a reservoir.
  • a diluent or carrier chemically inert to the compounds of the invention e.g. lactose or any other additive suitable for improving the respirable fraction may be added to the powdered compounds of the invention.
  • Inhalation aerosols containing propellant gas such as hydrofluoroalkanes may contain the compounds of the invention either in solution or in dispersed form.
  • the propellant-driven formulations may also contain other ingredients such as co-solvents, stabilizers and optionally other excipients.
  • the propellant-free inhalable formulations comprising the compounds of the invention may be in form of solutions or suspensions in an aqueous, alcoholic or hydroalcoholic medium and they may be delivered by jet or ultrasonic nebulizers known from the prior art or by soft-mist nebulizers.
  • the compounds of the invention can be administered as the sole active agent or in combination with other pharmaceutical active ingredients.
  • the dosages of the compounds of the invention depend upon a variety of factors including among others the particular disease to be treated, the severity of the symptoms, the route of administration and the like.
  • the invention is also directed to a device comprising a pharmaceutical composition comprising a compound of Formula (I) according to the invention, in form of a single- or multidose dry powder inhaler or a metered dose inhaler.
  • UPLC Ultra Performance Liquid Chromatography
  • TBAF tetrabutylammonium fluoride
  • TBAB Tetrabutylammonium bromide
  • DBU 1,8- diazabiciclo[5.4.0]undec-7-ene
  • CPME cyclopentyl methyl ether
  • mCPBA 3- Chloroperbenzoic acid
  • CDI l,l'-Carbonyldiimidazole
  • Xantphos 4,5-
  • signals NH from amide bond or amine bond are not visible. In a few cases, some signals could be hidden or partly covered by the signal of water or under the DMSO peak or other residual solvents.
  • Method 1 Agilent Zorbax column 4.6x50mm, 3.5 pm, maintained at 40 °C. Mobile phase: MeCN (0.1% formic acid) in water (0.1% formic acid), from 5% to 95% within 2 min. Flow rate: 3.0 ml/min. Wavelength: 210-400 nm DAD. WatersTM 2795/2695 separations module + WatersTM DAD + Micromass ZQ, single quadrupole LCMS.
  • Method 2 WatersTM Acquity UPLC HSS C18 column, 100 * 2.1mm, 1.8 pm (Plus guard cartridge), maintained at 40°C.
  • Mobile phase MeCN (0.1% formic acid) in water (0.1% formic acid) from 5% to 95% within 5.6 min.
  • Flow rate 0.4 ml/min.
  • Wavelength 210-400 nm DAD.
  • Method 3 WatersTM Acquity UPLC BEH Shield RP 18 column, 100 * 2.1mm, 1.72pm (Plus guard cartridge), maintained at 40 °C.
  • Mobile phase MeCN in water + 10 nM ammonium bicarbonate from 5% to 95% within 5.6 min.
  • Wavelength 210-400 nm DAD.
  • Method 4 WatersTM Sunfire C18 column, 4.6x50mm, 3.5 pm, maintained at 40 °C. Mobile phase MeCN in water + lOmM ammonium bicarbonate, from 5 to 95% within 2.5 min. Flow rate: 2.0 mL/min. Wavelength: 210-400 nm DAD. WatersTM 2795 separations module + WatersTM DAD + Micromass ZQ, single quadrupole LCMS.
  • Method 6 WatersTM Acquity QSM, Acquity UPLC CSH Cl 8 column 50mm x 2.1mm 1.7 pm, maintained at 50°C; Mobile Phase: Eluent A (HCOONH4 0.025M pH 3), Eluent B (ACN+0.1% FA). Gradient mode: from 0 to 5.50 min. eluent B is increased from 20% to 80%, from 5.50 to 7.50 min. is kept at 80%, from 7.50 to 8 min. is decreased from 80% to 20%, and from 8 min. it is kept at 20% till the end at 10 min. Flow rate: 0.35 mL/min. Wavelength: 210- 400 nm DAD. UPLC + WatersTM PDA + Xevo TQS MS instrument.
  • Method 7 Acquity CSH C18 column 50mm x 2.1mm 1.7pm, maintained at 40°C; Mobile Phase: Eluent B (ACN) in Eluent A (water +0.1% HCOOH) from 1% to 99.9% within 1.5 min. Flow rate: 1 mL/min. Wavelength: 210-400 nm DAD. UPLC + Waters PDA + Waters QDA.
  • Method 8 Kinetex® XB-C18 column, 4.6x50 mm, 2.6 pm maintained at 25 °C.
  • Mobile phase water (0.1% formic acid) in MeCN (0.1% formic acid), from 80% to 5% within 3.90 min;
  • Flow rate 1.0 ml/min; wavelength: 190-340 nm DAD.
  • Method 9 Kinetex® XB-C18 column, 4.6x50 mm, 2.6 pm maintained at 25 °C.
  • Mobile phase water (0.1% formic acid) in MeCN (0.1% formic acid), from 90% to 5% within 3.90 min;
  • Flow rate 1.0 ml/min; wavelength: 190-340 nm DAD.
  • Method 10 Acquity UPLC BEH - Waters, 1.7 pm Cl 8 (2.1 x 100 mm), 130 A, maintained at 25 °C. Mobile phase: water (0.1% formic acid) in MeCN (0.1% formic acid), from 80% to 5% within 2.70 min; Flow rate: 0.5 ml/min; wavelength: 254 nm. Shimadzu LCMS-2020 Single Quadrupole Liquid Chromatograph Mass Spectrometer.
  • Method 11 Waters Acquity UPLC BEH C18 column 2.1x100mm, 1.7um, (Plus guard cartridge), maintained at 40 °C.
  • Mobile phase MeCN (0.1% formic acid) in water (0.1% formic acid), from 5% to 95% within 8 min.
  • Flow rate 0.4 ml/min.
  • Wavelength 200-400 nm DAD, Waters Aquity PDA, separations module + Waters PDA + Micromass ZQ, single quadrapole LCMS.
  • Method 12 Waters Acquity UPLC BEH C18 column 2.1x100mm, 1.7um, (Plus guard cartridge), maintained at 40 °C.
  • Mobile phase MeCN (0.1% Ammonium Hydroxide) in water (0.1% Ammonium Hydroxide), from 5% to 95% within 8 min.
  • Flow rate 0.4 ml/min.
  • Wavelength 200-400 nm DAD, Waters Acquity PDA, separations module + Waters PDA + Micromass ZQ, single quadrapole LC-MS.
  • Method 13 Acquity CSH C18 column 50mm x 2.1mm 1.7pm, maintained at 40°C; Mobile Phase: Eluent B (ACN) in Eluent A (water +0.1% HCOOH) from 1% to 99.9% within 3.5 min. Flow rate: 1 mL/min. Wavelength: 210-400 nm DAD. UPLC + Waters PDA + Waters QDA.g
  • Method 15 Phenomenex Kinetex EVO C18 HPLC column, 4.6x50 mm, 5 pm, operating at room temperature: Mobile phase: MeCN (0.1% NH4OH) in water (0.1% NH4OH), from 5 to 95% within 2.5 min. Flow rate: 1.5 mL/min. Wavelength: 210-400 nm DAD. Acquity H-Class UPLC with PDA detector and QDa.
  • Method 18 Waters Aquity UPLC BEH Cl 8 column 2.1x100 mm, 1.7 pm, (Plus guard cartridge), maintained at 40 °C. Mobile phase: MeCN (0.1% FA) in water (0.1% FA), from 10% to 50% within 8 min. Flow rate: 0.4 mL/min. Wavelength: 200-400 nm DAD, Waters Aquity PDA, separations module + Waters PDA + Micromass ZQ, single quadrapole LCMS.
  • Method 20 YMC Amylose-C MeOH, WATERS VIRIDIS 2-EP 20x250 mm, 5 pm 5-15% MeOH (0.1% NH4OH) / CO2, 100 mL/min, 120 bar, 40 °C, DAD 235 nm.
  • Flash chromatography was performed on Biotage® Isol eraTM system or similar instruments.
  • Example 1 l-(2-(imidazo [1,2-a] pyridine-3-carbonyl)-2-azaspiro [3.3] heptan-6-yl)-3-(3- (trifluoromethyl)phenyl)urea
  • Step 1 tert-butyl 6-(3-(3-(trifluoromethyl)phenyl)ureido)-2-azaspiro[3.3] heptane-2- carboxylate (Intermediate 6)
  • Example 16 1-(3-fluoro-5-(trifluoromethyl)phenyl)-3-(2-(pyrazolo[1,5-a]pyrazine-3- carbonyl)-2-azaspiro [3.3]heptan-6-yl)urea
  • Step 1 - tert-butyl (2-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-2-azaspiro[3.3] heptan-6- yl)carbamate (Intermediate 9)
  • a solution of pyrazolo[1,5-a]pyrazine-3-carboxylic acid (384 mg, 2.36 mmol) and thionyl chloride (1.7 mL, 23.6 mmol) was stirred at reflux for 6 h.
  • Example 18 1-(5-(tert-butyl)isoxazol-3-yl)-3-(2-(pyrazolo[1,5-a]pyrazine-3-carbonyl)- 2-azaspiro[3.3]heptan-6-yl)urea
  • Example 18 A solution of Intermediate 10 (50 mg, 0.194 mmol) and Intermediate 3 (51 mg, 0.194 mmol) in pyridine (1.00 mL) was stirred at 80 °C for 6 h.
  • reaction mixture was concentrated in vacuo and purified by preparative HPLC (Sunfire C1819x150 mm, 10 ⁇ m 5-60% ACN/H2O (10 mM NH 4 CO 3 ), 20 mL/min, RT) to give the title compound (19 mg, 0.0458 mmol, 24 % yield).
  • Example 20 1-(5-(tert-butyl)isoxazol-3-yl)-3-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)- 2-azaspiro[3.3]heptan-6-yl)urea
  • Example 20 Step 1 tert-butyl (2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3] heptan-6- yl)carbamate (Intermediate 11) To a solution of tert-butyl (2-azaspiro[3.3]heptan-6-yl)carbamate (350 mg, 1.65 mmol), pyrazolo[5,1-b]thiazole-7-carboxylic acid (277 mg, 1.65 mmol) and TCFH (463 mg, 1.65 mmol) in DMF (2.00 mL) 1-methyl-1
  • Example 21 1-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3- (3-(trifluoromethoxy) phenyl)urea Step 1 - phenyl (2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6- 15 yl)carbamate (Intermediate 13) To a suspension of Intermediate 12 (250 mg, 0.953 mmol) and Na 2 CO 3 (61 mg, 0.572 mmol) in EtOAc (20.00 mL), THF (4.00 mL) and water (4.00 mL) cooled to 0 °C, phenyl chloroformate (0.13 mL, 1.05 mmol) was added dropwise.
  • Example 25 was prepared by following the procedure described for the synthesis of Example 1, step 3.
  • Example 27 was prepared by following the procedure described for the synthesis of Example 1, step 3.
  • Example 146 2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl (5-(trifluoromethyl)pyridin-3-yl)carbamate
  • Example 146 Intermediate 56 (120 mg, 0.46 mmol) was dissolved in DCM (2 mL) and added to 4- nitrophenyl chloroformate (112 mg, 0.553 mmol) and pyridine (0.056 mL). Solution was stirred at rt for 2 h, then solvent was removed under vacuum.
  • Intermediate 154 (benzyl (2-(1-(2-methoxyethyl)-1H-imidazo[1,2-b]pyrazole-7- carbonyl)-2-azaspiro[3.3]heptan-6-yl)(methyl)carbamate)
  • Intermediate 154 was prepared by following the procedure for Intermediate 30, starting from Intermediate 132 (860 mg, 3.6 mmol) and 2-bromoethyl methyl ether (0.3 ml, 5.5 mmol).
  • reaction mixture was stirred at rt until completion, then it was washed with sol. NH4Cl and HCl 0.5N, the organic layer was dried over MgSO4, filtered and essicated to afford title compound (48 g, 139 mmol, 98 % yield).
  • Example 202 1-(2-(1-(2-methoxyethyl)-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-1-methyl-3-(4-(trifluoromethoxy)pyridin-2-yl)urea
  • Intermediate 155 was dissolved in DMF (1 mL) then DIPEA (0.235 mL, 1.34 mmol) was added, followed by addition of phenyl (4-(trifluoromethoxy)pyridin-2-yl)carbamate (66.8 mg, 0.22 mmol) at 0° C. The reaction was stirred at rt for 12h.
  • Example 182 1-(2-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)- 2-azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea
  • Example 182 In a reactor, Intermediate 53 (0.100 g, 0.19 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole (0.040 g, 0.19 mmol) and K2CO3 (0.066 g, 0.48 mmol) were placed and dioxane (0.55 mL) was added via syringe under argon atmosphere.
  • Example 192 1-(2-(1-methyl-3-morpholino-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea
  • An ElectraSyn vial (5 mL) with a stir bar was charged with dibromonickel;1-methoxy-2-(2- methoxyethoxy)ethane (84 mg, 0.24 mmol), 2,2'-bipyridine (111 mg, 0.71 mmol), TBAB (2.38 ml, 0.48 mmol), Intermediate 52 (250 mg, 0.48 mmol), morpholine (0.062 ml, 0.71 mmol), DBU (0.143 ml, 0.95 mmol) and DMA (6 mL).
  • the vial was closed with an ElectraSyn 2.0 vial cap equipped with anode ((+)RVC, 47 mm x 8 mm x 2 mm) and cathode ((-)Ni foam, 0.8 cm x 4.7 x 0.1 cm) inserted into the mixture.
  • the vial was then evacuated and backfilled with an argon balloon.
  • the reaction mixture was electrolyzed under a constant current of 4 mA until complete consumption of the starting material as judged by LC-MS.
  • Example 227 1-(2-(6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine- 3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-1-methyl-3-(5-(trifluoromethyl)pyridin-3-yl)urea
  • Intermediate 129 70 mg, 0.13 mmol
  • 1-(2-methoxyethyl)-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole 49.3 mg, 0.195 mmol
  • Me-THF 1.5 mL
  • potassium phosphate tribasic 69 mg, 0.33 mmol
  • Comparative newly synthesized compounds C1, C2 and C3 were prepared as described below.
  • C1 is characterized by having a -CO-NH- linker replacing the -NH-CO-L1- linker of the compounds of the invention.
  • C2 is characterized by having a -CH 2 -CO-NH- linker replacing the -NH-CO-L1- linker of the compounds of the invention.
  • C3 is characterized by having a structure XXIII wherein the central core of the compounds of formula (I) has been flipped (for Rs being hydrogen).
  • Compound C2 (N-(2-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-2-azaspiro[3.3] heptan-6- yl)-2-(3-(trifluoromethyl)phenyl)acetamide) was prepared analogously to what described for Compound C1 by starting from commercially available 2-(3-(trifluoromethyl)phenyl)acetic acid (see Table 43).
  • the compounds were incubated with 5 nM DDR1 (Carna Biosciences) or 5 nM DDR2 (Life Technologies) for 1 h at rt in white 384-well OptiPlate (PerkinElmer), containing 20 nM or 10 nM Kinase Tracer 178 respectively and 2 nM Europium labelled anti-GST antibody (Life Technologies) in assay buffer (50 mM HEPES pH 7.5, 10 mM MgCI 2 , 1 mM EGTA and 0.01% BRIJ35). The ratio of fluorescence emission 665 nm/ 615 nm after excitation at 340 nm was obtained using the Tecan Spark 20M plate reader.
  • the results for representative compounds of the invention are provided in Table 44, wherein the compounds are classified in term of potency (Ki, nM) in binding with respect to their inhibitory activity on DDR1 and DDR2: Table 44 -: Ki higher than 100 nM +: Ki between 25 and 100 nM ++: Ki between 5 nM and 25 nM +++: Ki lower than 5 nM
  • the compounds of Table 44 i.e.
  • the compounds according to the invention show a good activity as antagonist of DDR1 and DDR2. Accordingly, the compounds of the invention can be effectively used for treating diseases, disorders or conditions associated with DDR receptors, such as fibrosis, e.g. pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), hepatic fibrosis, progressive pulmonary fibrosis, sarcoidosis, familiar pulmonary fibrosis, chronic hypersensitivity pneumonitis (CHP), kidney or renal fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis and systemic sclerosis.
  • fibrosis e.g. pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), hepatic fibrosis, progressive pulmonary fibrosis, sarcoidosis, familiar pulmonary fibrosis, chronic hypersensitivity pneumonitis (CHP), kidney or renal fibrosis, ocular fibrosis, cardiac fibros
  • Comparative Compounds Compounds C1, C2 and C3 were tested in the same binding assay described above and their Ki(nM) is reported in Table 45.
  • Table 45 The compounds of the present invention whose activity is reported in Table 44 have a binding affinity for DDR1 and DDR2 receptors, expressed as Ki, which is lower than 100 nM, in several cases lower than 25 nM or even lower than 5 nM. To the contrary, as it can be seen in Table 45, the comparative compounds C1, C2 and C3 did not show a binding affinity for DDR1 and DDR2 receptors, being their Ki over the detectable limit of the binding assay.

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Abstract

The present invention relates to compounds of formula (I) inhibiting Discoidin Domain Receptors (DDR inhibitors), methods of preparing such compounds, intermediate compounds useful in such preparations, pharmaceutical compositions containing them and therapeutic use thereof. The compounds of the invention may be useful for instance in the treatment of many disorders associated with DDR mechanisms.

Description

HETEROARYL DERIVATIVES AS DDRs INHIBITORS
FIELD OF THE INVENTION
The present invention relates to compounds inhibiting Discoidin Domain Receptors (DDR inhibitors), methods of preparing such compounds, intermediate compounds useful in such preparations, pharmaceutical compositions containing them and therapeutic use thereof.
The compounds of the invention may be useful for instance in the treatment of many disorders associated with DDR mechanisms.
BACKGROUND OF THE INVENTION
Discoidin Domain Receptors (DDRs) are type I transmembrane receptor tyrosine kinase (RTKs). The DDR family comprises two distinct members, DDR1 and DDR2.
DDRs are unique receptors among the other members of the RTK superfamily, in that DDRs are activated by collagen whereas other members of the RTK superfamily are typically activated by soluble peptide-like growth factors (see Vogel, W. (1997) Mol. Cell 1, 13-23; Shrivastava A. Mol Cell. 1997; 1 :25-34). Moreover, DDRs are unusual RTKs also because they form ligandindependent stable dimers that are non-covalently linked (see Noordeen, N. A. (2006) J. Biol. Chem. 281, 22744-22751; Mihai C. J Mol Biol. 2009; 385:432-445).
The DDR1 subfamily is composed of five membrane-anchored isoforms, and the DDR2 subfamily is represented by a single protein. The five DDR1 isoforms all have in common the extracellular and transmembrane domains but differ in the cytoplasmic region (see Valiathan, R. R. (2012) Cancer Metastasis Rev. 31, 295-321; Alves, F. (2001) FASEB J. 15, 1321-1323).
DDR receptor family has been found involved in a series of fibrotic diseases, such as pulmonary fibrosis, and in particular idiopathic pulmonary fibrosis (IPF), or kidney fibrosis. The first evidence for a protective role of DDR1 deletion in lung fibrosis was generated in 2006 by the research group of Dr. Vogel (see Avivi-Green C, Am J Respir Crit Care Med 2006;174:420-427). The authors demonstrated that DDRl-null mice were largely protected against bleomycin (BLM)- induced injury. Furthermore, myofibroblast expansion and apoptosis were much lower in these animals compared with their wild-type counterparts. Absence of inflammation in knockout mice was confirmed by lavage cell count and cytokines ELISA. These results indicated that DDR1 expression is a prerequisite for the development of lung inflammation and fibrosis.
DDR2 deficiency or downregulation reduces bleomycin-induced lung fibrosis (see Zhao H, Bian H, Bu X, Zhang S, Zhang P, Yu J, et al Mol Ther 2016; 24: 1734-1744). Zhao et al, demonstrated that DDR2 plays a critical role in the induction of fibrosis and angiogenesis in the lung, in particular that DDR2 synergizes with transforming growth factor (TGF)-P to induce myofibroblast differentiation. Furthermore, they showed that treatment of injured mice with specific siRNA against DDR2 exhibited therapeutic efficacy against lung fibrosis. In a second publication, Jia et al showed that mice lacking DDR2 are protected from bleomycin-induced lung fibrosis (see Jia S, Am J Respir Cell Mol Biol 2018;59:295–305). In addition, DDR2-null fibroblasts are significantly more prone to apoptosis than wild-type fibroblasts, supporting a paradigm in which fibroblast resistance to apoptosis is critical for progression of fibrosis. Discoidin Domain Receptor 1 (DDR1) is also a key factor of renal disease by promoting inflammation and fibrosis, and blocking the expression of DDR1 after the initiation of renal disease can delay or arrest the progression of this pathology (Kerroch et al., Sci Rep 6, 21262, 2016). DDR1 contributes to acute and chronic kidney injury by regulating BCR and STAT3 phosphorylation and in turn the production of MCP-1 and TGF-β. A DDR1-null mice model had reduced acute tubular injury, inflammation and tubulointerstitial fibrosis with overall decreased renal monocyte chemoattractant protein (MCP-1) levels and STAT3 activation. These findings identify DDR1 as an attractive therapeutic target for ameliorating both proinflammatory and profibrotic signaling in kidney disease (C.M. Borza et al., JCI Insight.2022;7(3):e150887). Some compounds have been described in the literature as DDR1 or DDR2 antagonists. Expert Opin. Ther. Patents 2020, Vol. 30, No. 5, 341-350, by Guo Jing et al., is a review article of Discoidin Domain Receptor 1 (DDR1) modulators. WO2023021278 and WO2023079291 disclose compounds as DDRl and DDR2 inhibitors, useful in the treatment of cancer and fibrotic diseases, in particular in lung and kidney. US 2018/148450 A1 discloses triaza-spirodecanones as DDR1 inhibitors. US 2019/374526 A1 discloses inhibitors of PR domain-containing protein 9. It discloses the conversion of 1-(3,5-dichlorophenyl)-3-(2-azaspiro[3.3]heptan-6-yl)urea HCl salt into 1-(3,5- dichlorophenyl)-3-(2-(2-methylpyridin-4-yl)-2-azaspiro[3.3]heptan-6-yl)urea (compound 239). WO2023064370A1 discloses epoxide hydrolase (sEH) inhibitors. It discloses 1-(2- azaspiro[3.3]heptan-6-yl)-3-(4-(trifluoromethoxy)phenyl)urea at page 53, paragraph 219. Of note, antagonizing the DDR receptors may be useful for the treatment of fibrosis and diseases, disorders or conditions that result from fibrosis. Even more, antagonizing both receptors DDR1 and DDR2 may be particularly efficacious in the treatment of the above-mentioned diseases, disorders or conditions. Several efforts have been done in the past years to develop novel DDR1 and DDR2 receptor antagonists useful for the treatment of several diseases and some of those compounds have shown efficacy also in humans. However, there remains a potential for developing selective inhibitors of both receptors DDR1 and DDR2 useful for the treatment of diseases, disorders or conditions associated with a dysregulation of DDR receptors, in the respiratory field, in particular idiopathic pulmonary fibrosis (IPF), and in the field of fibrosis diseases in general, in particular kidney fibrosis. New selective inhibitors of both receptors DDR1 and DDR2 could be administered by the inhalation route when characterized by a good inhalatory profile, corresponding to a good activity in the lung, a good lung retention and to a low metabolic stability in order to minimize the systemic exposure and correlated safety issues. Alternatively, new inhibitors could be administered by the oral route when charachterized by a good oral profile, high oral bioavailability and low clearance with suitable physical-chemical properties.  In this direction, a new series of compounds of general formula (I), as herebelow reported, has been surprisingly found, which solves the problem of providing inhibitors for receptors DDR1 and DDR2 for administration by inhalation, which act as selective inhibitors of DDR1 and DDR2 receptors with respect to other human protein kinases. Such compounds show high potency, good inhalatory profile, low metabolic stability, low systemic exposure, improved safety and tolerability. SUMMARY OF THE INVENTION In a first aspect the present invention relates to a compound of formula (I)
Figure imgf000004_0001
wherein A is a ring selected from the group consisting of:
Figure imgf000004_0002
wherein indicates a direct bond to NH; W1, W2 and W3 are substituents of ring A independently selected from the group consisting of hydrogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)halohydroxyalkyl, (C1-C4)alkoxy, (C1- C4)alkoxy-(C1-C4)alkyl, (C1-C4)haloalkoxy, (C1-C4)hydroxyalkyl, halogen, cyano, SF5, NR1R2- (C1-C4)alkyl, CONR1R2, NHCOR1, NR1R2, heterocycloalkyl, (C3-C7)cycloalkyl, (C1-C4)alkyl- heterocycloalkyl, (C1-C4)alkyl-heterocycloalkyl-(C1-C4)alkyl, (C1-C4)haloalkyl-cycloalkyl, (C1- C4)alkyl-(C3-C7)cycloalkyl, heterocycloalkyl-(C1-C4)alkyl, heterocycloalkyl-NH-(C1-C4)alkyl, (C3-C7)cycloalkyl-(C1-C4)alkyl, heterocycloalkyl-(C1-C4)alkoxy, (C1-C4)alkyl-CO- heterocycloalkyl-oxy, (C3-C7)cycloalkyl-(C1-C4)alkoxy, heterocycloalkyl-oxy, (C3- C7)cycloalkyl-oxy, (C1-C4)alkyl-heterocycloalkyl-carbonyl, monocyclic (C1-C4)alkyl-heteroaryl, (C1-C4)alkyl-sulfonyl, (C1-C4)haloalkyl-sulfonyl, (C1-C4)haloalkyl-sulfonylamino, (C1- C4)haloalkyl-sulfinyl, (C1-C4)haloalkyl-thio, (C1-C4)alkyl-thio-(C1-C4)alkyl, (C1-C4)alkyl- sulfonyl-(C1-C4)alkyl and (C1-C4)alkyl-sulfinyl-(C1-C4)alkyl, and are preferably selected from the group consisting of hydrogen, CH3, OCH3, OCF3, CF3, CHF2, C(CH3)3, CH2CF3, CF2CH3, CF2CF3, C(CH3)2CF3, OCF2H, CH2OH, cyano, CF3SO2, SCF3, SF5, F, Cl, Br, I, cyclopropyl, morpholino-N-ethoxy, N-acetylpiperidinyl-oxy, N-acetylazetidinyl-oxy, 2,2,2-trifluoro-1- hydroxyethyl, oxetanyloxy, CH2N(CH3)2 and 4-methylpiperazin-1-yl; or, wherein W1 and W2 are in adjacent positions on ring A, W1 and W2 form a (C5-C6)cycloalkyl or a 5- or 6-membered heterocycloalkyl, wherein the (C5-C6)cycloalkyl or the 5- or 6-membered heterocycloalkyl are optionally substituted with 1 to 3 halogen atoms; and wherein preferably the 6-membered heterocycloalkyl is a pyranyl ring; L is selected from CO and CH2 or is absent; L1 is selected from NR, CH2 and O, wherein R is selected from the group consisting of hydrogen, (C1-C4)alkyl, (C1-C4)hydroxyalkyl, (C1-C4)haloalkyl, (C3-C7)cycloalkyl, (C3- C7)cycloalkyl-(C1-C4)alkyl and deuterated (C1-C4)alkyl, preferably selected from the group consisting of hydrogen, CD3, cyclopropylmethyl, cyclopropyl, CH2CF3, CH2CH3 and CH3; RS is selected from hydrogen and methyl, when L1 is NR; RS is hydrogen, when L1 is CH2 or O; B is mono- or bi-cyclic heteroaryl ring or bi-cyclic semisaturated heteroaryl ring, preferably selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, pyrazolo[1,5-a]pyrazinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[3,4-d]pyrimidinyl, pyrazolo[1,5-a]pyrimidinyl, 1H-pyrazolo[3,4-b]pyridinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, 1H-imidazo[1,2-b]pyrazolyl, imidazo[2,1-b]thiazolyl, pyrrolo[2,3- c]pyrimidinyl, pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, pyrazolo[5,1-b]thiazolyl, imidazo[1,5-a]pyrazinyl, 5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazinyl, thieno[3,2-d]pyrimidinyl, thieno[3,2-b]pyridinyl, thieno[2,3-d]pyrimidinyl, pyrazolo[5,1-b][1,3]thiazinyl, pyrrolo[3,2- d]pyrimidinyl, pyrrolo[2,3-d]pyrimidinyl and imidazo[1,2-a]pyridinyl; Y1 and Y2 are substituents of ring B independently selected from the group consisting of hydrogen, (C1-C4)alkyl, deuterated (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1- C4)haloalkoxy, (C1-C4)hydroxyalkyl, halogen, cyano, SF5, (C1-C4)cyanoalkyl, (C1-C4)alkyl- sulfonyl, (C1-C4)haloalkyl-sulfonyl, CONR1R2, NHCOR1, NR1R2, NR1R2-(C1-C4)alkyl, heterocycloalkyl optionally substituted with 1 to 3 halogens, heterocycloalkyl-NH-(C1-C4)alkyl, (C3-C7)cycloalkyl, (C1-C4)alkyl-heterocycloalkyl, (C1-C4)alkyl-(C3-C7)cycloalkyl, heterocycloalkyl-(C1-C4)alkyl, (C3-C7)cycloalkyl-(C1-C4)alkyl, heterocycloalkyl-(C1-C4)alkoxy, (C3-C7)cycloalkyl-(C1-C4)alkoxy, heterocycloalkyl-oxy, (C3-C7)cycloalkyl-oxy, phenyl, (C1- C4)alkoxy substituted phenyl, (C1-C4)alkyl-thio-(C1-C4)alkyl, (C1-C4)alkyl-sulfonyl-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)haloalkyl-cycloalkyl, (C1-C4)alkyl-heterocycloalkyl-carbonyl and monocyclic heteroaryl, optionally substituted with 1 to 3 groups selected from the group consisting of (C1-C4)alkyl, (C1-C4)alkoxy and (C1-C4)alkoxy-(C1-C4)alkyl; wherein Y1 is preferably selected from the group consisting of hydrogen, CH3, OCH3, OCF3, CF3, C(CH3)3, C(CH3)2CF3, CONH2, OCF2H, CF2H, CF2CH3, CF2CF3, CH2CF3, CH2OH, CH2CH2OH, CH2CH2OCH3, CH2CH2SCH3, CH2CH2F, CH2SCH3, SCF3, SO2CF3, CD3, cyano, NHCOCH3, NH2, (C1-C4)alkyl-piperazinyl, 4-methylpiperazin-1-yl, piperazinyl, morpholinyl, pyrrolidinyl, hydroxypyrrolidinyl, N-methyl-oxopiperazinyl, S,S-dioxido-thiomorpholinyl, oxetanyl-methyl, oxetanyl, (oxetanylamino)methyl, 1H-pyrazol-4-yl, oxazol-5-yl, pyridin-3-yl, pyrimidin-5-yl, pyridin-4-yl, dimethoxyphenyl, thiazol-5-yl, 3-isoxazol-5-yl and 1-methyl-1H-pyrazol-4-yl, and wherein Y2 is preferably hydrogen; R1 and R2 are independently selected from the group consisting of hydrogen, (C1-C4)alkyl, (C1-C4)hydroxyalkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkylamino-(C1-C4)alkyl, di-(C1- C4)alkylamino-(C1-C4)alkyl, optionally substituted (C3-C7)cycloalkyl, optionally substituted heterocycloalkyl and optionally substituted heterocycloalkyl-(C1-C4)alkoxy, wherein optional substituents are from 1 to 3 and are selected from the group consisting of (C1-C4)alkyl, (C1- C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy and carbamoyl; preferably, R1 and R2 are independently selected from the group consisting of hydrogen, (C1-C4)alkyl and optionally substituted heterocycloalkyl; more preferably, R1 and R2 are independently selected from the group consisting of hydrogen, methyl and oxetanyl; R3 is selected from the group consisting of (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkyl- phenyl and monocyclic heteroaryl; preferably, R3 is CH3 or p-tolyl; or a stereoisomer, tautomer, solvate and pharmaceutically acceptable salt thereof; wherein the compound of formula (I) is not 1-(3,5-dichlorophenyl)-3-(2-(2-methylpyridin- 4-yl)-2-azaspiro[3.3]heptan-6-yl)urea. In a second aspect, the invention refers to a pharmaceutical composition comprising a compound of formula (I), or pharmaceutically acceptable salts thereof, in admixture with at least one or more pharmaceutically acceptable carrier and/or excipient. In a third aspect, the invention refers to a compound of formula (I), or pharmaceutically acceptable salts thereof, or to a pharmaceutical composition comprising a compound of formula (I), or pharmaceutically acceptable salts thereof, for use as a medicament.
In a further aspect, the invention refers to a compound of formula (I), or pharmaceutically acceptable salts thereof, or to a pharmaceutical composition comprising a compound of formula (I), or pharmaceutically acceptable salts thereof, for use in preventing and/or treating a disease, disorder or condition associated with dysregulation of DDR.
In another aspect, the invention refers to a compound of formula (I), or pharmaceutically acceptable salts thereof, or to a pharmaceutical composition comprising a compound of formula (I), or pharmaceutically acceptable salts thereof, for use in preventing and/or treating fibrosis and/or diseases, disorders or conditions that involve fibrosis.
In yet another aspect, the invention refers to a compound of formula (I), or pharmaceutically acceptable salts thereof, or to a pharmaceutical composition comprising a compound of formula (I), or pharmaceutically acceptable salts thereof, for use in preventing and/or treating idiopathic pulmonary fibrosis (IPF).
In a further aspect, the invention refers to processes for the preparation of compounds of formula (I) and to intermediate compounds that are useful in their preparation.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
Unless otherwise specified, the compounds of formula (I) of the present invention are intended to include stereoisomers, tautomers, solvates and pharmaceutically acceptable salts thereof.
Unless otherwise specified, the compounds of formula (I) of the present invention are intended to include the compounds of formula (la), (lb), (Ic), (Id) and (le).
The term “pharmaceutically acceptable salts”, as used herein, refers to derivatives of compounds of formula (I) wherein the parent compound is suitably modified by converting any of the free acid or basic groups, if present, into the corresponding addition salt with any base or acid conventionally intended as being pharmaceutically acceptable. Suitable examples of said salts may thus include mineral or organic acid addition salts of basic residues such as amino groups, as well as mineral or organic basic addition salts of acid residues such as carboxylic groups.
Cations of inorganic bases which can be suitably used to prepare salts comprise ions of alkali or alkaline earth metals, such as potassium, sodium, calcium or magnesium.
The salts obtained by reacting the main compound, functioning as a base, with an inorganic or organic acid comprise, for example, salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, camphorsulfonic acid, acetic acid, oxalic acid, maleic acid, fumaric acid, succinic acid and citric acid. The term "stereoisomer" refers to isomers of identical constitution that differ in the arrangement of their atoms in space. Enantiomers and diastereomers are examples of stereoisomers. The term "enantiomer" refers to one of a pair of molecular species that are mirror images of each other and are not superimposable. The term "racemate" or "racemic mixture" refers to a composition composed of equimolar quantities of two enantiomeric species, wherein the composition is devoid of optical activity. Wherein the compounds of formula (I) of the present invention comprise one or more stereogenic carbons, all stereoisomers thereof are included in the scope of the invention, both as racemic mixtures and as other stereoisomer mixtures in all proportions. The term “halogen” or “halogen atoms” or “halo” as used herein includes fluorine (F), chlorine (Cl), bromine and iodine atom. The term "(C1-C4)alkyl" refers to a straight or branched chain alkyl group having from 1 to 4 carbon atoms. Said term comprises methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- butyl, and t-butyl. Such groups are herein indicated also by their atoms arrangement, i.e. as CH3, CH2CH3, etc. The term "(C1-C4)haloalkyl" refers to a straight or branched chain alkyl group having from 1 to 4 carbon atoms, comprising at least one halogen substituent. For example, the term comprises CF3 and C(CH3)2CF3. The term "(C1-C4)alkoxy" refers to a straight or branched chain alkyl group having from 1 to 4 carbon atoms, comprising at least one oxygen atom, in particular, but not only, an oxygen atom directly linked to ring A or ring B, i.e. when W1, W2, W3, Y1 or Y2, respectively and independently, are (C1-C4)alkoxy. Examples include OCH3 and OCH2CH3. The term "(C1-C4)haloalkoxy" refers to a (C1-C4)alkoxy comprising at least one halogen substituent. Examples include OCF3 and OCF2H. The term "(C1-C4)hydroxyalkyl" refers to a (C1-C4)alkyl comprising at least one hydroxy substituent. Examples include CH2OH, CH(OH)CH3 and CH2CH2OH. The term "(C3-C7)cycloalkyl” refers to a saturated hydrocarbon ring comprising a number of ring carbon atoms from 3 to 7. Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The term “oxy” refers to an oxygen atom as the point of attachment to ring A or ring B of the substituent indicated right before “oxy”. For instance, “heterocycloalkyl-oxy” refers to a heterocycloalkyl substituent attached to ring A or ring B through an oxygen atom. The term “deuterated” refers to a substituent wherein one or more hydrogen atoms are replaced with deuterium, like for instance CDs.
The term “mono- or bi-cyclic heteroaryl (ring)” refers to a mono- or bi-cyclic aromatic group, comprising a number of ring atoms from 5 to 10 and comprising from 1 to 4, or 1 to 3, heteroatoms independently selected from N, S and O, and includes groups having two such monocyclic rings, or one such monocyclic ring and one monocyclic aryl ring, such as a phenyl ring, which are fused through a common bond or linked by a single bond. The mono- or bi-cyclic heteroaryl rings comprise pyrazolyl, furanyl, tiophenyl, oxazolyl, isoxazolyl, isothiazolyl, thiazolyl, imidazolyl, benzofuranyl, lH-benzo[d]imidazolyl, IH-indazolyl, benzothiophenyl, benzo[c]thiophenyl, quinazolinyl, pteridinyl, lH-pyrazolo[5,l-c][l,2,4]triazolyl, pyrrolizinyl, indolizinyl, benzothiazolyl, pyrazolo[5,l-b]thiazolyl, lH-imidazo[l,2-b]pyrazolyl, 1H- pyrazolo[3,4-b]pyridinyl, lH-pyrazolo[3,4-d]pyrimidinyl, l,6-dihydropyrrolo[2,3-b]pyrrolyl, 1,4- dihydropyrrolo[3,2-b]pyrrolyl, 4H-thieno[3,2-b]pyrrolyl, thieno[3,2-b]pyridinyl, isobenzofuranyl, 1,2,4-triazolyl, 1,2,5 oxadiazolyl, 1,2,3 oxadiazolyl, 1,2,5 thiadiazolyl, 1,2,3 thiadiazolyl, tetrazolyl, 6H-furo[2,3-b]pyrrolyl, 6H-thieno[2,3-b]pyrrolyl, 4H-furo[3,2-b]pyrrolyl, benzo[d]isothiazolyl, thiazolo[4,5-b]pyridinyl, 1,3,5-triazinyl, 1,2,3,4-thiatriazolyl, 1, 2,3,4- oxatriazolyl, 1,2,3,4-tetrazinyl, 1,2,4,5-tetrazinyl, 1,2,3,5-tetrazinyl, lH-imidazo[4,5-b]pyridinyl, 7H-purinyl, IH-pyrrolyl, 1 -methyl- IH-pyrrolyl, 1 -methyl- 1H- 1,2,4-triazolyl, 1 -methyl- 1H- tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazo[l,2-b]pyridazinyl, pyrazolo[l,5-a]pyrazinyl, imidazo[l,2-a]pyrazinyl, imidazo[l,2-a]pyrazinyl, imidazo[l,2- a]pyridinyl, pyrazolo[l,5-a]pyridinyl, pyrazolo[l,5-a]pyrimidinyl, lH-pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-d]pyrimidinyl, pyrrolo[3,2-d]pyrimidinyl, pyrrolo[2,3-c]pyridinyl, thieno[3,2- d]pyrimidinyl, imidazo[2,l-b]thiazolyl and imidazo[l,5-a]pyrazinyl.
The term "bi-cyclic semisaturated heteroaryl ring" refers to a bicyclic group, comprising a number of ring atoms from 7 to 11, and comprising from 1 to 4, or 1 to 3, heteroatoms independently selected from N, S and O, and comprising a mono-cyclic heteroaryl or phenyl ring condensed to a mono-cyclic heterocycloalkyl or (C3-C7)cycloalkyl. Examples of suitable bi-cyclic semisaturated heteroaryl ring include, for instance, 2,3-dihydro-lH-pyrrolo[2,3-b]pyridinyl, 6,7- dihydro-5H-pyrrolo[2,3-b]pyrazinyl, 4,5,6,7-tetrahydrooxazolo[4,5-c]pyridinyl, 4, 5,6,7- tetrahydro-lH-pyrazolo[4,3-b]pyridinyl, 2,3,4,5-tetrahydro-lH-pyrrolo[2,3-b]pyrazinyl, 5,6- dihydro-8H-imidazo[2,l-c][l,4]oxazinyl, 6,7-dihydro-5H-pyrazolo[5,l-b][l,3]thiazinyl and 1- (4, 5 ,6, 7 -tetrahy dropyrazolof 1 , 5 -a]pyridinyl) .
The term “heterocycloalkyl” refers to a saturated or partly unsaturated mono-, bi- or spiro- cyclic ring system of 3 to 12 ring atoms comprising one or more, for instance 1 to 3, heteroatoms independently selected from N, S and O. This definition includes ring systems wherein S may be in different oxidation states, such as for instance S, SO or SO2. This definition also includes ring systems wherein any ring carbon atom may be in different oxidation states, such as for instance CH2, CH(OH) or CO. Examples of heterocycloalkyl include piperazinyl, pyrrolidinyl, azetidinyl, morpholinyl, S,S-dioxido-thiomorpholinyl, oxopiperazinyl and piperidinyl.
The term “spiro-cyclic ring system” refers to a saturated or partly unsaturated bi-cyclic ring system of 5 to 12 ring atoms, comprising one or more, for instance 1 to 3, heteroatoms selected from N, S and O, wherein the two rings have only one common carbon atom. Examples of spiro- cyclic ring systems include spiro[3.5]nonanyl, spiro[2.3]hexanyl, spiro[2.4]heptanyl, 2- azaspiro[3.3]heptanyl, 712-azaspiro[3.5]nonanyl and 212-azaspiro[3.5]nonanyl.
Any composite term, like for instance “(Ci-C4)alkyl-heterocycloalkyl-carbonyl”, should be intended as conventionally construed by the groups from which it derives; in this example, it has to be construed by a (Ci-C4)alkyl, a heterocycloalkyl and a carbonyl group which are linked together in the indicated sequence, and wherein the last group in the sequence, the carbonyl group in this example, is the point of attachment to the residual part of the compound of formula (I).
When referring to substituents, a dash
Figure imgf000010_0001
that is not between two letters, words, or symbols is meant to represent the point of attachment for such substituents.
The carbonyl group, when not indicated in words, is herein represented as CO.
Whenever basic amino groups are present in the compounds of formula (I), physiologically acceptable anions may be present, selected among chloride, bromide, iodide, trifluoroacetate, formate, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate, p-toluenesulfonate, pamoate and naphthalene disulfonate. Likewise, in the presence of acidic groups, corresponding physiological cations may be present as well, for instance including alkaline or alkaline earth metal ions.
The term “Ki” indicates the dissociation constant for the enzyme-inhibitor complex, expressed in molar units. It is an indicator of the binding affinity between inhibitor and DDR1 or DDR2 receptors.
As above indicated, the present invention refers to a series of compounds represented by the general formula (I) as herein below described in detail, which are endowed with an inhibitory activity on receptors DDR1 and DDR2. Antagonizing receptors DDR1 and DDR2 can be particularly effective in the treatment of those diseases where the DDR receptors play a role, such as fibrosis and any other disease, disorder or condition related to fibrosis.
Indeed, as detailed in the experimental part below, the compounds of formula (I) of the present invention are able to act as inhibitors of both DDR1 and DDR2 receptors in a substantive and effective way. In particular, Table 44 further below shows that for representative compounds of the present invention the inhibitory activity against either DDR1 and/or DDR2 receptors, expressed as Ki, is lower than 100 nM in the binding assay. This confirms that the compounds of formula (I) are able to inhibit the two isoforms of DDR receptor mainly involved in fibrosis and diseases resulting from fibrosis. Accordingly, the compounds of formula (I) can be used in the treatment of fibrosis, in particular pulmonary fibrosis or kidney fibrosis, when DDR1 and DDR2 are involved.
As indicated in the experimental part, comparative compounds section, in particular in Table 7, conversely to compounds Cl and C2, characterized by having different linkers replacing the - NH-CO-L1- linker of the compounds of the invention, and conversely to compound C3, characterized by a flipped central core, the presence of said -NH-CO-L1- linker and of a central core as defined above in the compounds of the present invention unexpectedly and remarkably determines a high inhibitory activity on the DDR1 and DDR2 receptors.
Advantageously, the compounds of the present invention are endowed with a very high potency and could be administered in humans at very low dosages, thus potentially reducing the adverse events that typically may occur when administering drugs.
In addition to being notably potent with respect to their inhibitory activity on both receptors DDR1 and DDR2, the compounds of the present invention are also characterized by being selective inhibitors of DDR1 and DDR2 receptors with respect to other human protein kinases, and by a good inhalatory profile, that allows to act effectively on the lung compartment and have, at the same time, a low metabolic stability, that allows to minimize the drawbacks associated with systemic exposure, such as safety and tolerability issues.
Therefore, the compounds of the present invention may be particularly appreciated when looking at suitable and efficacious compounds useful for the treatment of fibrosis, in particular idiopathic pulmonary fibrosis, administered by the inhalation route and characterized by a good inhalatory profile, that corresponds to a good activity on the lung, a good lung retention and a low metabolic stability, that minimizes the systemic exposure and correlated safety issues.
Alternatively, the compounds of the present invention may be administered by the oral route for the treatment of fibrosis, when charachterized by a good oral profile, high oral bioavailability and low clearance with suitable physical-chemical properties.
Accordingly, the present invention relates to a compound of formula (I)
Figure imgf000011_0001
wherein A is a ring selected from the group consisting of:
Figure imgf000012_0001
wherein indicates a direct bond to NH; W1, W2 and W3 are substituents of ring A independently selected from the group consisting of hydrogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)halohydroxyalkyl, (C1-C4)alkoxy, (C1- C4)alkoxy-(C1-C4)alkyl, (C1-C4)haloalkoxy, (C1-C4)hydroxyalkyl, halogen, cyano, SF5, NR1R2- (C1-C4)alkyl, CONR1R2, NHCOR1, NR1R2, heterocycloalkyl, (C3-C7)cycloalkyl, (C1-C4)alkyl- heterocycloalkyl, (C1-C4)alkyl-heterocycloalkyl-(C1-C4)alkyl, (C1-C4)haloalkyl-cycloalkyl, (C1- C4)alkyl-(C3-C7)cycloalkyl, heterocycloalkyl-(C1-C4)alkyl, heterocycloalkyl-NH-(C1-C4)alkyl, (C3-C7)cycloalkyl-(C1-C4)alkyl, heterocycloalkyl-(C1-C4)alkoxy, (C1-C4)alkyl-CO- heterocycloalkyl-oxy, (C3-C7)cycloalkyl-(C1-C4)alkoxy, heterocycloalkyl-oxy, (C3- C7)cycloalkyl-oxy, (C1-C4)alkyl-heterocycloalkyl-carbonyl, monocyclic (C1-C4)alkyl-heteroaryl, (C1-C4)alkyl-sulfonyl, (C1-C4)haloalkyl-sulfonyl, (C1-C4)haloalkyl-sulfonylamino, (C1- C4)haloalkyl-sulfinyl, (C1-C4)haloalkyl-thio, (C1-C4)alkyl-thio-(C1-C4)alkyl, (C1-C4)alkyl- sulfonyl-(C1-C4)alkyl and (C1-C4)alkyl-sulfinyl-(C1-C4)alkyl, and are preferably selected from the group consisting of hydrogen, CH3, OCH3, OCF3, CF3, CHF2, C(CH3)3, CH2CF3, CF2CH3, CF2CF3, C(CH3)2CF3, OCF2H, CH2OH, cyano, CF3SO2, SCF3, SF5, F, Cl, Br, I, cyclopropyl, morpholino-N-ethoxy, N-acetylpiperidinyl-oxy, N-acetylazetidinyl-oxy, 2,2,2-trifluoro-1- hydroxyethyl, oxetanyloxy, CH2N(CH3)2 and 4-methylpiperazin-1-yl; or, wherein W1 and W2 are in adjacent positions on ring A, W1 and W2 form a (C5-C6)cycloalkyl or a 5- or 6-membered heterocycloalkyl, wherein the (C5-C6)cycloalkyl or the 5- or 6-membered heterocycloalkyl are optionally substituted with 1 to 3 fluorine atoms; and wherein preferably the 6-membered heterocycloalkyl is a pyranyl ring; L is selected from CO and CH2 or is absent; L1 is selected from NR, CH2 and O, wherein R is selected from the group consisting of hydrogen, (C1-C4)alkyl, (C1-C4)hydroxyalkyl, (C1-C4)haloalkyl, (C3-C7)cycloalkyl, (C3- C7)cycloalkyl-(C1-C4)alkyl and deuterated (C1-C4)alkyl, preferably selected from the group consisting of hydrogen, CD3, cyclopropylmethyl, CH2CF3, CH2CH3 and CH3; RS is selected from hydrogen and methyl, when L1 is NR; RS is hydrogen when L1 is CH2 or O; B is mono- or bi-cyclic heteroaryl ring or bi-cyclic semisaturated heteroaryl ring; Y1 and Y2 are substituents of ring B independently selected from the group consisting of hydrogen, (C1-C4)alkyl, deuterated (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1- C4)haloalkoxy, (C1-C4)hydroxyalkyl, halogen, cyano, SF5, (C1-C4)cyanoalkyl, (C1-C4)alkyl- sulfonyl, (C1-C4)haloalkyl-sulfonyl, CONR1R2, NHCOR1, NR1R2, NR1R2-(C1-C4)alkyl, heterocycloalkyl optionally substituted with 1 to 3 halogens, heterocycloalkyl-NH-(C1-C4)alkyl, (C3-C7)cycloalkyl, (C1-C4)alkyl-heterocycloalkyl, (C1-C4)alkyl-(C3-C7)cycloalkyl, heterocycloalkyl-(C1-C4)alkyl, (C3-C7)cycloalkyl-(C1-C4)alkyl, heterocycloalkyl-(C1-C4)alkoxy, (C3-C7)cycloalkyl-(C1-C4)alkoxy, heterocycloalkyl-oxy, (C3-C7)cycloalkyl-oxy, phenyl, (C1- C4)alkoxy substituted phenyl, (C1-C4)alkyl-thio-(C1-C4)alkyl, (C1-C4)alkyl-sulfonyl-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)haloalkyl-cycloalkyl, (C1-C4)alkyl-heterocycloalkyl-carbonyl and monocyclic heteroaryl, optionally substituted with 1 to 3 groups selected from the group consisting of (C1-C4)alkyl, (C1-C4)alkoxy and (C1-C4)alkoxy-(C1-C4)alkyl; wherein Y1 is preferably selected from the group consisting of hydrogen, CH3, OCH3, OCF3, CF3, C(CH3)3, C(CH3)2CF3, CONH2, OCF2H, CF2H, CF2CH3, CF2CF3, CH2CF3, CH2OH, CH2CH2OH, CH2CH2OCH3, CH2CH2SCH3, CH2CH2F, CH2SCH3, SCF3, SO2CF3, CD3, cyano, NHCOCH3, NH2, (C1-C4)alkyl-piperazinyl, 4-methylpiperazin-1-yl, piperazinyl, morpholinyl, pyrrolidinyl, hydroxypyrrolidinyl, N-methyl-oxopiperazinyl, S,S-dioxido-thiomorpholinyl, oxetanyl-methyl, oxetanyl, (oxetanylamino)methyl, 1H-pyrazol-4-yl, oxazol-5-yl, pyridin-3-yl, pyrimidin-5-yl, pyridin-4-yl, dimethoxyphenyl, thiazol-5-yl, 3-isoxazol-5-yl and 1-methyl-1H-pyrazol-4-yl, and wherein Y2 is preferably hydrogen; in a preferred embodiment, Y1 is selected from the group consisting of hydrogen, CH3 and 1-methyl-1H-pyrazol-4-yl, and Y2 is hydrogen; in another preferred embodiment, both Y1 and Y2 are hydrogen. R1 and R2 are independently selected from the group consisting of hydrogen, (C1-C4)alkyl, (C1-C4)hydroxyalkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkylamino-(C1-C4)alkyl, di-(C1- C4)alkylamino-(C1-C4)alkyl, optionally substituted (C3-C7)cycloalkyl, optionally substituted heterocycloalkyl and optionally substituted heterocycloalkyl-(C1-C4)alkoxy, wherein optional substituents are from 1 to 3 and are selected from the group consisting of (C1-C4)alkyl, (C1- C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy and carbamoyl; optional substituents are preferably selected from the group consisting of CH3, OCH3, OCF3, CF3, C(CH3)3, C(CH3)2CF3, CONH2, OCF2H and CF2H. R3 is selected from the group consisting of (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkyl- phenyl and monocyclic heteroaryl; preferably, R3 is CH3 or p-tolyl; or a stereoisomer, tautomer, solvate and pharmaceutically acceptable salt thereof; wherein the compound of formula (I) is not 1-(3,5-dichlorophenyl)-3-(2-(2-methylpyridin-4-yl)-2-azaspiro[3.3]heptan-6-yl)urea. All the listed meanings of each of the variable moieties A, B, L, L1, R, W1, W2, W3, Y1, Y2, R1, R2, R3 and Rs of the compound of formula (I) of the invention have to be intended as alternatives and may be combined with each other in embodiments which are included in the scope of the invention. Preferred halogens, as such and in groups comprising them, such as, for instance, (C1- C4)haloalkyl and (C1-C4)haloalkoxy substituents, are fluorine and chlorine, wherein fluorine is more preferred. W1, W2 and W3 are substituents of ring A which can be attached to A at any available position. Ortho and meta are preferred positions. In one embodiment, when A ring is phenyl and L1 is NH, W1, W2 and W3 are independently selected from the group consisting of hydrogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1- C4)halohydroxyalkyl, (C1-C4)alkoxy, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)haloalkoxy, (C1- C4)hydroxyalkyl, fluorine, bromine, iodine, cyano, SF5, NR1R2-(C1-C4)alkyl, CONR1R2, NHCOR1, NR1R2, heterocycloalkyl, (C3-C7)cycloalkyl, (C1-C4)alkyl-heterocycloalkyl, (C1- C4)alkyl-heterocycloalkyl-(C1-C4)alkyl, (C1-C4)haloalkyl-cycloalkyl, (C1-C4)alkyl-(C3- C7)cycloalkyl, heterocycloalkyl-(C1-C4)alkyl, heterocycloalkyl-NH-(C1-C4)alkyl, (C3- C7)cycloalkyl-(C1-C4)alkyl, heterocycloalkyl-(C1-C4)alkoxy, (C1-C4)alkyl-CO-heterocycloalkyl- oxy, (C3-C7)cycloalkyl-(C1-C4)alkoxy, heterocycloalkyl-oxy, (C3-C7)cycloalkyl-oxy, (C1- C4)alkyl-heterocycloalkyl-carbonyl, monocyclic (C1-C4)alkyl-heteroaryl, (C1-C4)alkyl-sulfonyl, (C1-C4)haloalkyl-sulfonyl, (C1-C4)haloalkyl-sulfonylamino, (C1-C4)haloalkyl-sulfinyl, (C1- C4)haloalkyl-thio, (C1-C4)alkyl-thio-(C1-C4)alkyl, (C1-C4)alkyl-sulfonyl-(C1-C4)alkyl and (C1- C4)alkyl-sulfinyl-(C1-C4)alkyl; or, wherein W1 and W2 are in adjacent positions on ring A, W1 and W2 form a (C5-C6)cycloalkyl or a 5- or 6-membered heterocycloalkyl, wherein the (C5- C6)cycloalkyl or the 5- or 6-membered heterocycloalkyl are optionally substituted with 1 to 3 halogen atoms; and wherein preferably the 6-membered heterocycloalkyl is a pyranyl ring; W1, W2 and W3 are preferably selected from the group consisting of hydrogen, CH3, OCH3, OCF3, CF3, CHF2, C(CH3)3, CH2CF3, CF2CH3, CF2CF3, C(CH3)2CF3, OCF2H, CH2OH, cyano, CF3SO2, SCF3, SF5, F, Br, I, cyclopropyl, morpholino-N-ethoxy, N-acetylpiperidinyl-oxy, N- acetylazetidinyl-oxy, 2,2,2-trifluoro-1-hydroxyethyl, oxetanyloxy, CH2N(CH3)2, and 4- methylpiperazin-1-yl; more preferably, W1, W2 and W3 are selected from the group consisting of H, CH3, OCH3, OCF3, CF3, OCF2H, cyano, SF5, F, Br, I, CH2OH, CF2CF3 and CH2CF3. In another embodiment, W1, W2 and W3 are independently selected from the group consisting of hydrogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)halohydroxyalkyl, (C1-C4)alkoxy, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)haloalkoxy, (C1-C4)hydroxyalkyl, fluorine, bromine, iodine, cyano, SF5, NR1R2-(C1-C4)alkyl, CONR1R2, NHCOR1, NR1R2, heterocycloalkyl, (C3- C7)cycloalkyl, (C1-C4)alkyl-heterocycloalkyl, (C1-C4)alkyl-heterocycloalkyl-(C1-C4)alkyl, (C1- C4)haloalkyl-cycloalkyl, (C1-C4)alkyl-(C3-C7)cycloalkyl, heterocycloalkyl-(C1-C4)alkyl, heterocycloalkyl-NH-(C1-C4)alkyl, (C3-C7)cycloalkyl-(C1-C4)alkyl, heterocycloalkyl-(C1- C4)alkoxy, (C1-C4)alkyl-CO-heterocycloalkyl-oxy, (C3-C7)cycloalkyl-(C1-C4)alkoxy, heterocycloalkyl-oxy, (C3-C7)cycloalkyl-oxy, (C1-C4)alkyl-heterocycloalkyl-carbonyl, monocyclic (C1-C4)alkyl-heteroaryl, (C1-C4)alkyl-sulfonyl, (C1-C4)haloalkyl-sulfonyl, (C1- C4)haloalkyl-sulfonylamino, (C1-C4)haloalkyl-sulfinyl, (C1-C4)haloalkyl-thio, (C1-C4)alkyl-thio- (C1-C4)alkyl, (C1-C4)alkyl-sulfonyl-(C1-C4)alkyl and (C1-C4)alkyl-sulfinyl-(C1-C4)alkyl; or, wherein W1 and W2 are in adjacent positions on ring A, W1 and W2 form a (C5-C6)cycloalkyl or a 5- or 6-membered heterocycloalkyl, wherein the (C5-C6)cycloalkyl or the 5- or 6-membered heterocycloalkyl are optionally substituted with 1 to 3 halogen atoms; and wherein preferably the 6-membered heterocycloalkyl is a pyranyl ring; W1, W2 and W3 are preferably selected from the group consisting of hydrogen, CH3, OCH3, OCF3, CF3, CHF2, C(CH3)3, CH2CF3, CF2CH3, CF2CF3, C(CH3)2CF3, OCF2H, CH2OH, cyano, CF3SO2, SCF3, SF5, F, Br, I, cyclopropyl, morpholino-N-ethoxy, N-acetylpiperidinyl-oxy, N-acetylazetidinyl-oxy, 2,2,2-trifluoro-1- hydroxyethyl, oxetanyloxy, CH2N(CH3)2, and 4-methylpiperazin-1-yl; more preferably, W1, W2 and W3 are selected from the group consisting of H, CH3, OCH3, OCF3, CF3, OCF2H, cyano, SF5, F, Br, I, CH2OH, CF2CF3 and CH2CF3. L is a linker and may be selected from CO and CH2 or is absent. L1 is a linker and may be selected from NR, CH2 and O, wherein R is preferably selected from the group consisting of hydrogen, CD3, cyclopropylmethyl, cyclopropyl, CH2CF3, CH2CH3 and CH3. Rs is hydrogen or methyl when L1 is NR; RS is hydrogen when L1 is CH2 or O. B is preferably selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, pyrazolo[1,5-a]pyrazinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[3,4-d]pyrimidinyl, pyrazolo[1,5-a]pyrimidinyl, 1H-pyrazolo[3,4-b]pyridinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, 1H-imidazo[1,2-b]pyrazolyl, imidazo[2,1- b]thiazolyl, pyrrolo[2,3-c]pyrimidinyl, pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, pyrazolo[5,1-b]thiazolyl, imidazo[1,5-a]pyrazinyl, 5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazinyl, thieno[3,2-d]pyrimidinyl, thieno[3,2-b]pyridinyl, thieno[2,3-d]pyrimidinyl, pyrazolo[5,1- b][1,3]thiazinyl, pyrrolo[3,2-d]pyrimidinyl, pyrrolo[2,3-d]pyrimidinyl and imidazo[1,2- a]pyridinyl. Any ring B may be attached to the L moiety at any available position of its mono- or bi-cyclic ring system. Y1 is a substituent of ring B which can be attached to B at any available position. Y1 is preferably selected from the group consisting of hydrogen, CH3, OCH3, OCF3, CF3, C(CH3)3, C(CH3)2CF3, CONH2, OCF2H, CF2H, CF2CH3, CF2CF3, CH2CF3, CH2OH, CH2CH2OH, CH2CH2OCH3, CH2CH2SCH3, CH2CH2F, CH2SCH3, SCF3, SO2CF3, CD3, cyano, NHCOCH3, NH2, (C1-C4)alkyl-piperazinyl, 4-methylpiperazin-1-yl, piperazinyl, morpholinyl, pyrrolidinyl, hydroxypyrrolidinyl, N-methyl-oxopiperazinyl, S,S-dioxido-thiomorpholinyl, oxetanyl-methyl, oxetanyl, (oxetanylamino)methyl, 1H-pyrazol-4-yl, oxazol-5-yl, pyridin-3-yl, pyrimidin-5-yl, pyridin-4-yl, dimethoxyphenyl, thiazol-5-yl, 3-isoxazol-5-yl and 1-methyl-1H-pyrazol-4-yl; more preferably, Y1 is selected from the group consisting of hydrogen, CH3 and 1-methyl-1H-pyrazol- 4-yl. Y2 is a substituent of ring B which can be attached to B at any available position. Y2 may have the same preferred meanings as Y1, independently. In more preferred embodiments Y2 is hydrogen. R1 and R2 are preferably independently selected from the group consisting of hydrogen, (C1-C4)alkyl and optionally substituted heterocycloalkyl; more preferably, R1 and R2 are independently selected from the group consisting of hydrogen, methyl and oxetanyl. R3 is selected from the group consisting of (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkyl- phenyl and monocyclic heteroaryl, being preferably CH3 or p-tolyl. Accordingly, in a preferred embodiment, the invention relates to a compound of formula (I) wherein A is a ring selected from the group consisting of :
Figure imgf000016_0001
; even more preferably, A is selected from the group consisting of phenyl, 3-pyridinyl, 2- pyridinyl, 3-pyridazinyl, 3-isoxazolyl and pyrazolyl, wherein R3 is CH3 or p-tolyl; W1, W2 and W3 are selected from the group consisting of hydrogen, CH3, OCH3, OCF3, CF3, CHF2, C(CH3)3, CH2CF3, CF2CH3, CF2CF3, C(CH3)2CF3, OCF2H, CH2OH, cyano, CF3SO2, SCF3, SF5, F, Br, I, cyclopropyl, morpholino-N-ethoxy, N-acetylpiperidinyl-oxy, N- acetylazetidinyl-oxy, 2,2,2-trifluoro-1-hydroxyethyl, oxetanyloxy and CH2N(CH3)2; more preferably, W1, W2 and W3 are selected from the group consisting of H, CH3, OCH3, OCF3, CF3, OCF2H, cyano, SF5, F, Br, I, CH2OH, CF2CF3 and CH2CF3. L is selected from CO and CH2 or is absent, being preferably CO; L1 is selected from NR, CH2 and O, being preferably NR, wherein R is preferably selected from the group consisting of hydrogen, CD3, cyclopropylmethyl, cyclopropyl, CH2CF3, CH2CH3 and CH3; B is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, pyrazolo[1,5-a]pyrazinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[3,4- d]pyrimidinyl, pyrazolo[1,5-a]pyrimidinyl, 1H-pyrazolo[3,4-b]pyridinyl, imidazo[1,2- b]pyridazinyl, imidazo[1,2-a]pyrazinyl, 1H-imidazo[1,2-b]pyrazolyl, imidazo[2,1-b]thiazolyl, pyrrolo[2,3-c]pyrimidinyl, pyrrolo[3,2-b]pyridinyl, 1H-pyrrolo[2,3-b]pyridinyl, pyrazolo[5,1- b]thiazolyl, imidazo[1,5-a]pyrazinyl, 5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazinyl, thieno[3,2- d]pyrimidinyl, thieno[3,2-b]pyridinyl, thieno[2,3-d]pyrimidinyl, pyrazolo[5,1-b][1,3]thiazinyl, pyrrolo[3,2-d]pyrimidinyl, pyrrolo[2,3-d]pyrimidinyl and imidazo[1,2-a]pyridinyl; Y1 is selected from the group consisting of hydrogen, CH3, OCH3, OCF3, CF3, C(CH3)3, C(CH3)2CF3, CONH2, OCF2H, CF2H, CF2CH3, CF2CF3, CH2CF3, CH2CH2OH, CH2CH2OCH3, CH2CH2SCH3, CH2CH2F, CH2SCH3, SCF3, SO2CF3, CD3, cyano, NHCOCH3, NH2, (C1-C4)alkyl- piperazinyl, 4-methylpiperazin-1-yl, piperazinyl, morpholinyl, pyrrolidinyl, hydroxypyrrolidinyl, N-methyl-oxopiperazinyl, S,S-dioxido-thiomorpholinyl, oxetanyl-methyl, oxetanyl, (oxetanylamino)methyl, 1H-pyrazol-4-yl, oxazol-5-yl, pyridin-3-yl, pyrimidin-5-yl, pyridin-4-yl, dimethoxyphenyl, thiazol-5-yl, 3-isoxazol-5-yl and 1-methyl-1H-pyrazol-4-yl, and Y2 is hydrogen; and R1 and R2 are preferably independently selected from the group consisting of hydrogen, (C1-C4)alkyl and optionally substituted heterocycloalkyl; more preferably, R1 and R2 are independently selected from the group consisting of hydrogen, methyl and optionally substituted oxetanyl, wherein optional substituents, when present, are selected from the group consisting of CH3, OCH3, OCF3, CF3, C(CH3)3, C(CH3)2CF3, CONH2, OCF2H and CF2H; or a stereoisomer, tautomer, solvate and pharmaceutically acceptable salt thereof. In another preferred embodiment, the present invention relates to a compound of formula (I) wherein L is CO and L1 is NR, which is represented by formula (Ia)
Figure imgf000018_0001
wherein Wl, W2, W3, A, B, R, Rs, Y1 and Y2 are as defined above.
In yet another preferred embodiment, the present invention relates to a compound of formula (I), wherein L is CH2 and LI is NR, which is represented by formula (lb)
Figure imgf000018_0002
wherein Wl, W2, W3, A, B, R, Rs, Y1 and Y2 are as defined above.
In a further preferred embodiment, the present invention relates to a compound of formula (I), wherein L is absent and LI is NR, which is represented by formula (Ic)
Figure imgf000018_0003
wherein Wl, W2, W3, A, B, R, Rs, Y1 and Y2 are as defined above.
In another preferred embodiment, the present invention relates to a compound of formula (I), wherein LI is CH2, which is represented by formula (Id)
Figure imgf000018_0004
wherein Wl, W2, W3, A, B, L, Y1 and Y2 are as defined above and Rs is hydrogen. In a particularly preferred embodiment, the present invention relates to a compound of formula (Id) wherein L is CO. In another preferred embodiment, the present invention relates to a compound of formula (I), wherein LI is O, which is represented by formula (le)
Figure imgf000019_0001
wherein Wl, W2, W3, A, B, L, Y1 and Y2 are as defined above and Rs is hydrogen. In a particularly preferred embodiment, the present invention relates to a compound of formula (le) wherein L is CO.
Particularly preferred embodiments of the invention are the compounds of formula (la) listed in Table 1 below, and pharmaceutically acceptable salts thereof. These compounds are particularly active on receptors DDR1 and DDR2, as shown in Table 44 further below.
Table 1: List of representative compounds of Formula (la)
Figure imgf000019_0002
Figure imgf000020_0001
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
Figure imgf000024_0001
Figure imgf000025_0001
Figure imgf000026_0001
Figure imgf000027_0001
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
Figure imgf000031_0001
Figure imgf000032_0001
Figure imgf000033_0001
Figure imgf000034_0001
Figure imgf000035_0001
Figure imgf000036_0001
Figure imgf000037_0001
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
Figure imgf000041_0001
Figure imgf000042_0001
Figure imgf000043_0001
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000046_0001
Figure imgf000047_0001
Figure imgf000048_0001
Figure imgf000049_0001
Figure imgf000050_0001
Figure imgf000051_0001
Figure imgf000052_0001
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
Figure imgf000058_0001
Figure imgf000059_0001
Figure imgf000060_0001
Particularly preferred embodiments of the invention are the compounds of formula (lb) as defined above, wherein A is optionally substituted phenyl, LI is NH and B is selected from imidazo[l,2-a]pyrazinyl and lH-pyrazolo[3,4-b]pyridinyl. Further particularly preferred compounds of formula (lb) are those listed in Table 2 below, and pharmaceutically acceptable salts thereof. These compounds are particularly active on receptors DDR1 and DDR2, as shown in Table 44 further below.
Table 2: List of representative compounds of Formula (lb)
Figure imgf000061_0001
Additional particularly preferred embodiments of the invention are the compounds of formula (Ic) as defined above, wherein A is optionally substituted phenyl or pyridinyl and B is selected from lH-pyrazolo[3,4-b]pyridinyl, imidazo[l,5-a]pyrazinyl and lH-pyrrolo[2,3- b]pyridinyl, and wherein R is preferably hydrogen or CH3.
More particularly preferred compounds of formula (Ic) are those listed in Table 3 below, and pharmaceutically acceptable salts thereof. These compounds are particularly active on receptors DDR1 and DDR2, as shown in Table 44 further below.
Table 3: List of representative compounds of Formula (Ic)
Figure imgf000061_0002
Figure imgf000062_0001
Figure imgf000063_0001
Additional particularly preferred embodiments of the invention are the compounds of formula (Id) as defined above, wherein A is optionally substituted phenyl or pyridinyl, L is CO and B is selected from pyrazolo[5,l-b]thiazolyl, imidazo[l,2-a]pyridinyl, pyrazolo[l,5- a]pyrazinyl, imidazo[l,5-a]pyrazinyl, thieno[3,2-b]pyridinyl, lH-imidazo[l,2-b]pyrazolyl and pyrazolo[5,l-b]thiazolyl.
Further particularly preferred compounds of formula (Id) are those listed in Table 4 below, and pharmaceutically acceptable salts thereof. These compounds are particularly active on receptors DDR1 and DDR2, as shown in Table 44 further below.
Table 4: List of representative compounds of Formula (Id)
Figure imgf000063_0002
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0002
Also particularly preferred embodiments of the invention are the compounds of formula (le) as defined above, wherein A is selected from the group consisting of optionally substituted phenyl, optionally substituted pyridinyl and optionally substituted isoxazolyl, L is CO and B is selected from pyrazolo[5,l-b]thiazolyl and lH-imidazo[l,2-b]pyrazolyl. Further particularly preferred compounds of formula (le) are those listed in Table 5 below, and pharmaceutically acceptable salts thereof. These compounds are particularly active on receptors DDR1 and DDR2, as shown in Table 44 further below.
Table 5: List of representative compounds of Formula (le)
Figure imgf000066_0001
Figure imgf000067_0001
Figure imgf000068_0001
The compounds of the invention, including all the compounds here above listed, can be prepared from readily available starting materials using the following general methods and procedures or by using slightly modified processes readily available to those of ordinary skill in the art. Although a particular embodiment of the present invention may be shown or described herein, those skilled in the art will recognize that all embodiments or aspects of the present invention can be obtained using the methods described herein or by using other known methods, reagents and starting materials. When typical or preferred process conditions (i.e. reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, other process conditions can also be used unless otherwise stated. While the optimal reaction conditions may vary depending on the particular reactants or solvent used, such conditions can be readily determined by those skilled in the art by routine optimization procedures. Thus, processes described below should not be viewed as limiting the scope of the synthetic methods available for the preparation of the compounds of the invention.
In some cases, generally known protective groups (PG) may be employed when needed to mask or protect sensitive or reactive moieties, in accordance to general principles of chemistry (Protective group in organic syntheses, 3rd ed. T. W. Greene, P. G. M. Wuts).
Compounds of formula (I) may be prepared as described hereinafter in SCHEME 1 to SCHEME 6, wherein at least one non-limiting synthetic route is provided for the preparation of the exemplified compounds (i.e. the Examples).
Compounds of formula (I), in particular compounds of formula (la), wherein L is CO and LI is NR, may be prepared, for instance, according to SCHEME 1 as described below.
SCHEME 1
Figure imgf000070_0001
According to SCHEME 1, intermediate urea III may be prepared from amine II, wherein Rs is hydrogen or methyl, by reaction with the isocyanate X in a suitable solvent, such as DCM, at rt. Intermediate compound IVa may then be obtained from intermediate III by Boc-deprotection in acidic conditions, for instance by using TFA in a suitable solvent, such as DCM, at rt.
Alternatively, intermediate urea III may be prepared from amine II by reaction with the suitable 2,2,2-trichloroethyl carbamate (Troc carbamate) XXII, which can be obtained from the suitable amine XV and 2,2,2-trichloroethyl chloroformate, in a suitable solvent mixture, such as ACN, in the presence of a base, such as DIPEA, and at a temperature varying from 80 °C to 150 °C in a microwave oven.
Subsequently, carboxylic acid XI and intermediate compound IVa may be reacted to give a compound of formula (la) under suitable amide coupling reaction conditions, in the presence of an activating agent, such as for instance HATU or TBTU, with an organic base, such as DIPEA or TEA, in a suitable organic solvent, such as DCM or DMF, at a temperature generally around rt for a time ranging from a few hours to overnight. Alternatively, a compound of formula (la) may be prepared from amine IVa and acyl chloride XIV, which can be obtained from carboxylic acid XI in the presence of an appropriate chlorinating reagent, such as POCh, thionyl chloride or oxalyl chloride, in a solvent, such as DCM and, if needed, in the presence of a catalytic amount of DMF, at a temperature ranging from 5 °C to 50 °C. Alternatively, a compound of formula (la) may be prepared via direct amidation of carboxylic acid XI, by conversion into the transient activated acylimidazolinium intermediate in the presence of TCFH and 1 -methylimidazole and subsequent reaction with the amine IVa in a solvent, such as DMF, generally around RT.
A compound of formula (la), wherein Y1 is bromine, may be converted into a different compound of formula (la), wherein Y1 is optionally substituted phenyl or optionally substituted heteroaryl, by reaction with a phenyl or heteroaryl boronic ester/acid by a palladium-catalyzed cross-coupling. The reaction may be carried out by the usual Suzuki protocol, in a suitable organic solvent, such as dioxane, in the presence of an inorganic base, such as potassium carbonate, with an appropriate palladium catalytic system, such as Pd(dppf)C12, at high temperature (around 100°C) for few hours. A compound of formula (la), wherein Y1 is bromine, may be converted into a different compound of formula (la), wherein Y1 is heterocycloalkyl, by reaction with an heterocycloalkylamine (i.e. a heterocycloalkyl wherein a group NH is part of the ring) by means of an electrochemical reaction, in the presence of dibromonickel and an electrolyte, such as TBAB, in an appropriate solvent, such as DMA.
Compounds of formula (I), in particular compounds of formula (lb), wherein L is CH2 and LI is NR, or compounds of formula (Ic), wherein L is absent and LI is NR, may be prepared, for instance, according to SCHEME 2 as described below.
SCHEME 2
Figure imgf000072_0001
As depicted in SCHEME 2, intermediate compound IVa may be converted into a compound of formula (lb) by applying reductive amination conditions with the appropriate aldehyde XII, with a suitable reducing agent, such as STAB or NaCNBH?, in a suitable solvent, such as DCM or EtOH, in the presence of an acid, such as acetic acid, and in the presence of a dehydrating agent, such as magnesium sulfate, if needed, at a temperature ranging from rt to 50 °C.
Otherwise, intermediate compound IVa may be converted into a compound of formula (Ic) by cross-coupling reactions, like for instance Buchwald coupling, in the presence of a palladium catalyst, such as Pd(dppf)C12, or another palladium source/phosphine-based ligand at high temperature (around 100 °C) for a few hours with a suitable aryl halide XIII, preferably an aryl bromide (X = Br), in an organic solvent, such as DMA, with a suitable base, such as CS2CO3.
In case a protecting group is present on aryl halide XIII or intermediate compound IVa, a compound of formula (I) may be obtained after an additional step of removal of the protecting group in the required conditions, such as acidic conditions, by using TFA or HC1 in 4-di oxane, or with TBAF.
Compounds of formula (Ic) may also be prepared according to SCHEME 2a as described hereinafter. SCHEME 2a
Figure imgf000073_0001
2) TFA/TBAF
According to SCHEME 2a, intermediate compound XXIII can be obtained by protection of amine II, as defined above, with phenyl chloroformate, in a suitable solvent, such as for instance DCM or EtOAc and/or water, at a temperature varying from -5 °C to rt, optionally in the presence of TEA. Similarly, N-(benzyloxycarbonyloxy)succinimide or 4-nitrophenyl chloroformate may be used for protection of amine II. Intermediate compound XXIV may then be prepared from intermediate compound XXIII by Boc-deprotection in acidic conditions, for instance by using TFA in a suitable solvent, such as DCM, at rt. Intermediate compound XXIV may be converted into intermediate compound XXV by cross-coupling reactions, like for instance Buchwald coupling, with a suitable aryl halide XIIF, in the presence of a palladium catalyst, such as Pd-175 or Pd(dppf)C12, or another palladium source/phosphine-based ligand, at high temperature (around 100 °C) for a few hours, in an organic solvent, such as DMA or Me-THF, with a suitable base, such as CS2CO3, and wherein Y17Y2’ may be Y1/Y2 or may bear protecting groups, such as Boc or SEM, and wherein the halide X is preferably bromide. Then compounds of formula XXVI may be prepared by amine deprotection reaction of the intermediate compound XXV in the presence of a palladium catalyst and tri ethylsilane or Pd/C 10% and hydrogen, in a suitable solvent, such as ethanol, at a temperature generally around rt for a few hours, optionally followed by deprotection of any protecting group on the Y substituents, if present, in acidic conditions, for instance by using TFA in a suitable solvent, such as DCM, or using TBAF in THF, at rt.
Then, compounds of formula (Ic) may be prepared by reaction of the intermediate compound XXVI either with the suitable 2,2,2-trichloroethyl carbamate (Troc carbamate) XXII, which can be obtained from the suitable amine XV and 2,2,2-trichloroethyl chloroformate, or with intermediate compound XVI, which can be obtained from the suitable amine XV and phenyl chloroformate, in a suitable solvent mixture, such as ACN or THF, in the presence of a base, such as DIPEA, and at a temperature varying from rt to 150 °C, in a few cases in a microwave oven, followed by deprotection of any protecting group on the Wl, W2 or W3 substituents. For instance, acidic conditions may be used for cleavage of SEM protecting group, such as TFA in DCM or TBAF in THF, at rt.
Compounds of formula (la) may also be prepared according to SCHEME 3 as described hereinafter.
Figure imgf000074_0001
Intermediate VI may be prepared from amine V and acyl chloride XIV (as defined in SCHEME 1), which can be obtained from carboxylic acid XI (as defined in SCHEME 1) in the presence of an appropriate chlorinating reagent, such as POCh, thionyl chloride or oxalyl chloride, in a solvent, such as DCM and, if needed, in the presence of a catalytic amount of DMF at a temperature ranging from 5 °C to 50 °C; the amine V and the acyl chloride XIV may undergo an amide coupling in the presence of a suitable base, such as TEA, in a suitable solvent, such as DCM, at rt. Alternatively, intermediate VI may be prepared via direct amidation of carboxylic acid XI, by conversion into the transient activated acylimidazolinium intermediate in the presence of TCFH and 1 -methylimidazole and subsequent reaction with the amine V in a solvent, such as DMF, generally at rt. Intermediate VII may then be obtained from intermediate VI by Boc-deprotection in acidic conditions, for instance by using TFA in a suitable solvent, such as DCM, at rt. Compounds of formula (la) may be prepared from intermediate VII by reaction with the isocyanate X (see SCHEME 1) in a suitable solvent, such as DCM, at rt. Alternatively, compounds of formula (la) may be prepared from intermediate VII by reaction with amine XV (see SCHEME 1) and triphosgene in a suitable solvent, such as DCM, at a temperature varying from 0 °C to rt. Additionally, compounds of formula (Ic) may be prepared according to SCHEME 3a as described hereinafter.
SCHEME 3a
Figure imgf000075_0001
Intermediate compound XXVII may be obtained by cross-coupling reactions, like for instance Buchwald coupling, starting from amine V in the presence of a palladium catalyst, such as Pd(dppf)C12, or another palladium source/phosphine-based ligand at high temperature (around 100 °C) for a few hours with a suitable aryl halide XIII, preferably an aryl bromide (X = Br), in an organic solvent, such as DMA, with a suitable base, such as CS2CO3. Intermediate compound XXVIII may then be obtained from intermediate XXVII by Boc-deprotection in acidic conditions, for instance by using TFA in a suitable solvent, such as DCM, at rt. Compounds of formula (Ic) may be prepared from intermediate XXVIII by reaction with the suitable 2,2,2-trichloroethyl carbamate (Troc carbamate) XXII, which can be obtained from the suitable amine XV (see SCHEME 1) and 2,2,2-trichloroethyl chloroformate, in a suitable solvent mixture, such as ACN, in the presence of a base, such as DIPEA, and at a temperature varying from 80 °C to 150 °C in a micro wave oven.
Compounds of formula (la) may also be prepared according to SCHEME 4 as described hereinafter.
Figure imgf000076_0001
Compounds of formula (la) may be prepared from intermediate VII by reaction with the suitable phenyl carbamate XVI, which can be obtained from the suitable amine XV (see SCHEME 1) and phenyl chloroformate in a suitable solvent mixture, such as a mixture of EtOAc, DCM and water, at a temperature varying from 0 °C to rt. Alternatively, the suitable amine XV may be reacted with N-(benzyloxycarbonyloxy)succinimide, in a suitable solvent, such as DCM, at a temperature varying from -5 °C to rt, in the presence of TEA to afford the benzyloxycarbonyl protected amine XV. Compounds of formula (la) may also be prepared from intermediate VII by reaction with the suitable 2, 2, 2-tri chloroethyl carbamate (Troc carbamate) XXII (see SCHEME 1), which can be obtained as described above.
Alternatively, compounds of formula (la) may be prepared by reaction of the suitable amine XV with intermediate VIII, which may be obtained from intermediate VII and phenyl chloroformate in a suitable solvent mixture, such as a mixture of EtOAc, DCM and water, at a temperature varying from 0 °C to rt.
Compounds of formula (Id), which are compounds of formula (I) wherein LI is CH2, may be prepared, for instance, according to SCHEME 5 as described below. SCHEME 5
Figure imgf000077_0001
According to SCHEME 5, intermediate XVIII may be prepared from commercially available carboxylic acid XVII, wherein Rs is hydrogen, by reaction with the suitable amine XV (see SCHEME 1) under suitable amide coupling reaction conditions, in the presence of an activating agent, such as for instance HATU or TBTU, and an organic base, such as DIPEA or TEA, in a suitable organic solvent, such as DCM or DMF, and at a temperature generally around rt for a time ranging from a few hours to overnight. Alternatively, a compound XVIII may be prepared via direct amidation of carboxylic acid XVII, i.e. by its conversion into the transient activated acylimidazolinium intermediate in the presence of TCFH and 1 -methylimidazole and subsequent reaction with the amine XV in a solvent, such as DMF, generally around rt.
Intermediate compound IVb may then be obtained from intermediate XVIII by Boc- deprotection in acidic conditions, for instance by using TFA in a suitable solvent, such as DCM, at rt. Subsequently, intermediate compound IVb may be reacted with either a carboxylic acid XI, as described for SCHEME 1, or an aldehyde XII or an aryl halide XIII, as described for SCHEME 2, to obtain a compound of formula (Id), wherein L is CO, or CH2, or absent, respectively. Intermediate compound IVb may also be reacted with an aryl halide XIIF, followed by a deprotection reaction, as described for the synthetic pathway of SCHEME 2a, wherein XIIF is defined, to finally provide a compound of formula (Id).
Compounds of formula (le), which are compounds of formula (I) wherein LI is O, may be prepared, for instance, according to SCHEME 6 as described below. SCHEME 6
Figure imgf000078_0001
According to SCHEME 6, commercially available compound IX, wherein Rs is hydrogen, may be reacted with either a carboxylic acid XI (see SCHEME 1) or an aldehyde XII or an aryl halide XIII (see SCHEME 2) to obtain intermediate compound XIX, wherein L is CO, or CH2, or absent, respectively. Compounds of formula (le) may be prepared from intermediate compound XIX by reaction with a chloroformate, such as 4-nitrophenyl chloroformate, and the suitable amine XV (see SCHEME 1) in the presence of a base, such as pyridine, in a suitable solvent, such as DCM, at rt. Alternatively, compounds of formula (le) may be prepared from intermediate compound XIX by reaction with isocyanate X (see SCHEME 1) in a suitable solvent, such as DCM, and in the presence of a base, such as DIPEA, at rt.
According to another synthetic approach, commercially available compound XX may be reacted with isocyanate X in a suitable solvent, such as DCM, and in the presence of a base, such as DIPEA, at rt, or compound XX may be reacted with a suitable chloroformate and amine XV, in the presence of a base, such as pyridine, in a suitable solvent, such as DCM, at rt, thus affording intermediate compound XXI. Intermediate IVc may then be obtained from intermediate XXI by Boc-deprotection in acidic conditions, for instance by using TFA in a suitable solvent, such as DCM, at rt. Then intermediate IVc may be reacted with either a carboxylic acid XI or an aldehyde XII or an aryl halide XIII, as described for SCHEME 1 and 2, to obtain a compound of formula (le), wherein L is CO, or CH2, or absent, respectively. Intermediate compound IVc may also be reacted with an aryl halide XIII’, followed by a deprotection reaction, as described for the synthetic pathway of SCHEME 2a, wherein XIII’ is defined, to finally provide a compound of formula (le). Accordingly, the present invention provides an intermediate compound IV
Figure imgf000079_0001
wherein A is a ring selected from the group consisting of:
Figure imgf000079_0002
wherein indicates a direct bond to NH; W1, W2 and W3 are substituents of ring A independently selected from the group consisting of hydrogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)halohydroxyalkyl, (C1-C4)alkoxy, (C1- C4)alkoxy-(C1-C4)alkyl, (C1-C4)haloalkoxy, (C1-C4)hydroxyalkyl, halogen, cyano, SF5, NR1R2- (C1-C4)alkyl, CONR1R2, NHCOR1, NR1R2, heterocycloalkyl, (C3-C7)cycloalkyl, (C1-C4)alkyl- heterocycloalkyl, (C1-C4)alkyl-heterocycloalkyl-(C1-C4)alkyl, (C1-C4)haloalkyl-cycloalkyl, (C1- C4)alkyl-(C3-C7)cycloalkyl, heterocycloalkyl-(C1-C4)alkyl, heterocycloalkyl-NH-(C1-C4)alkyl, (C3-C7)cycloalkyl-(C1-C4)alkyl, heterocycloalkyl-(C1-C4)alkoxy, (C1-C4)alkyl-CO- heterocycloalkyl-oxy, (C3-C7)cycloalkyl-(C1-C4)alkoxy, heterocycloalkyl-oxy, (C3- C7)cycloalkyl-oxy, (C1-C4)alkyl-heterocycloalkyl-carbonyl, monocyclic (C1-C4)alkyl-heteroaryl, (C1-C4)alkyl-sulfonyl, (C1-C4)haloalkyl-sulfonyl, (C1-C4)haloalkyl-sulfonylamino, (C1- C4)haloalkyl-sulfinyl, (C1-C4)haloalkyl-thio, (C1-C4)alkyl-thio-(C1-C4)alkyl, (C1-C4)alkyl- sulfonyl-(C1-C4)alkyl and (C1-C4)alkyl-sulfinyl-(C1-C4)alkyl, and are preferably selected from the group consisting of hydrogen, CH3, OCH3, OCF3, CF3, CHF2, C(CH3)3, CH2CF3, CF2CH3, CF2CF3, C(CH3)2CF3, OCF2H, CH2OH, cyano, CF3SO2, SCF3, SF5, F, Br, I, cyclopropyl, morpholino-N-ethoxy, N-acetylpiperidinyl-oxy, N-acetylazetidinyl-oxy, 2,2,2-trifluoro-1- hydroxyethyl, oxetanyloxy, CH2N(CH3)2 and 4-methylpiperazin-1-yl; or, wherein W1 and W2 are in adjacent positions on ring A, W1 and W2 form a (C5-C6)cycloalkyl or a 5- or 6-membered heterocycloalkyl, wherein the (C5-C6)cycloalkyl or the 5- or 6-membered heterocycloalkyl are optionally substituted with 1 to 3 halogen atoms; and wherein preferably the 6-membered heterocycloalkyl is a pyranyl ring; L1 is selected from NR, CH2 and O, wherein R is selected from the group consisting of hydrogen, (C1-C4)alkyl, (C1-C4)hydroxyalkyl, (C1-C4)haloalkyl, (C3-C7)cycloalkyl, (C3- C7)cycloalkyl-(C1-C4)alkyl and deuterated (C1-C4)alkyl, preferably selected from the group consisting of hydrogen, CD3, cyclopropylmethyl, cyclopropyl, CH2CF3, CH2CH3 or CH3; Rs is selected from hydrogen and methyl when L1 is NR; RS is hydrogen when L1 is CH2 or O; R1 and R2 are independently selected from the group consisting of hydrogen, (C1-C4)alkyl, (C1-C4)hydroxyalkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkylamino-(C1-C4)alkyl, di-(C1- C4)alkylamino-(C1-C4)alkyl, optionally substituted (C3-C7)cycloalkyl, optionally substituted heterocycloalkyl and optionally substituted heterocycloalkyl-(C1-C4)alkoxy, wherein optional substituents are from 1 to 3 and are selected from the group consisting of (C1-C4)alkyl, (C1- C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy and carbamoyl; preferably, R1 and R2 are independently selected from the group consisting of hydrogen, (C1-C4)alkyl and optionally substituted heterocycloalkyl, wherein optional substituents, when present, are selected from the group consisting of CH3, OCH3, OCF3, CF3, C(CH3)3, C(CH3)2CF3, CONH2, OCF2H and CF2H; more preferably, R1 and R2 are independently selected from the group consisting of hydrogen, methyl and optionally substituted oxetanyl; and R3 is selected from the group consisting of (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkyl- phenyl and monocyclic heteroaryl; or a stereoisomer, tautomer, solvate and pharmaceutically acceptable salt thereof; wherein the intermediate compound IV is not 1-(3,5-dichlorophenyl)-3-(2- azaspiro[3.3]heptan-6-yl)urea; and wherein, when A ring is phenyl, L1 is NH and W1 and W2 are hydrogen, W3 is not para-OCF3. The intermediate compound IV is not 1-(2-azaspiro[3.3]heptan-6-yl)-3-(4- (trifluoromethoxy)phenyl)urea. The intermediate compound IV corresponds to an intermediate compound IVa when L1 is NR, to an intermediate compound IVb when L1 is CH2 and to an intermediate compound IVc when L1 is O. Preferably, substituents W1, W2 and W3 (indicated also as W substituents) in the intermediate compound IV occupy ortho and/or meta positions on ring A. More preferred W substituents are hydrogen, CH3, OCH3, OCF3, CF3, CHF2, CH2CF3, OCF2H, CH2OH, SF5, F, Br and I. More preferably, such substituents occupy ortho and/or meta positions. When W1 and W2 are both hydrogen and W3 is OCF3, W3 preferably occupies ortho or meta position. When A ring is phenyl, L1 is NH and W1 and W2 are hydrogen, W3 is not para-OCF3. When A ring is phenyl, L1 is NH and W1 is hydrogen, W2 and W3 are not both Cl in meta positions. In one preferred embodiment, when A ring is phenyl and L1 is NH, W1, W2 and W3 are independently selected from the group consisting of hydrogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)halohydroxyalkyl, (C1-C4)alkoxy, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)haloalkoxy, (C1- C4)hydroxyalkyl, fluorine, bromine, iodine, cyano, SF5, NR1R2-(C1-C4)alkyl, CONR1R2, NHCOR1, NR1R2, heterocycloalkyl, (C3-C7)cycloalkyl, (C1-C4)alkyl-heterocycloalkyl, (C1- C4)alkyl-heterocycloalkyl-(C1-C4)alkyl, (C1-C4)haloalkyl-cycloalkyl, (C1-C4)alkyl-(C3- C7)cycloalkyl, heterocycloalkyl-(C1-C4)alkyl, heterocycloalkyl-NH-(C1-C4)alkyl, (C3- C7)cycloalkyl-(C1-C4)alkyl, heterocycloalkyl-(C1-C4)alkoxy, (C1-C4)alkyl-CO-heterocycloalkyl- oxy, (C3-C7)cycloalkyl-(C1-C4)alkoxy, heterocycloalkyl-oxy, (C3-C7)cycloalkyl-oxy, (C1- C4)alkyl-heterocycloalkyl-carbonyl, monocyclic (C1-C4)alkyl-heteroaryl, (C1-C4)alkyl-sulfonyl, (C1-C4)haloalkyl-sulfonyl, (C1-C4)haloalkyl-sulfonylamino, (C1-C4)haloalkyl-sulfinyl, (C1- C4)haloalkyl-thio, (C1-C4)alkyl-thio-(C1-C4)alkyl, (C1-C4)alkyl-sulfonyl-(C1-C4)alkyl and (C1- C4)alkyl-sulfinyl-(C1-C4)alkyl; or, wherein W1 and W2 are in adjacent positions on ring A, W1 and W2 form a (C5-C6)cycloalkyl or a 5- or 6-membered heterocycloalkyl, wherein the (C5- C6)cycloalkyl or the 5- or 6-membered heterocycloalkyl are optionally substituted with 1 to 3 halogen atoms. The invention further provides the use of the intermediate compound IV as defined above in the preparation of a compound of formula (I), or pharmaceutically acceptable salts thereof. Accordingly, the present invention provides a process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof, comprising the step of: a) reacting an intermediate compound IV
Figure imgf000081_0001
with either a carboxylic acid XI or an aldehyde XII or an aryl halide XIII, as defined above, to obtain a compound of formula (I), as defined above, wherein A, L1, Rs, W1, W2 and W3 are as defined above and wherein X in the aryl halide XIII is a halogen, preferably bromine. The process may comprise an additional deprotection step in case any substituent on A or B rings bears a protecting group, which the skilled in the art would envisage to use to accomplish the synthesis of a compound of formula (I).
Accordingly, the present invention provides intermediate compounds III, IV, IVa, IVb, IVc, VI, VII, VIII, XVIII, XIX, XXI, XXIII, XXIV, XXV, XXVI, XXVII and XXVIII, as defined above, and their use in the preparation of compounds of formula (I).
The compounds of formula (I) of the present invention have surprisingly been found to effectively inhibit both receptor DDR1 and DDR2. Advantageously, the inhibition of receptors DDR1 and DDR2 may result in efficacious treatment of the diseases or conditions wherein the DDR receptors are involved.
In this respect, it has been found that the compounds of formula (I) of the present invention have a very high antagonist drug potency on DDR1 and DDR2. Table 44 in the present experimental part reports such potency expressed as inhibition constant Ki for representative compounds of formula (I) of the invention. Preferred compounds of the invention have a Ki on DDR1 and DDR2 which is lower than 100 nM. More preferred compounds have a Ki between 25 and 5 nM. Even more preferred compounds of the invention have a Ki on DDR1 and DDR2 lower than 5 nM.
In one aspect, the present invention refers to a compound of formula (I) according to any of the embodiments disclosed above for use as a medicament.
In a preferred aspect, the invention refers to a compound of formula (I), and pharmaceutically acceptable salts thereof, for use in treating diseases, disorders, or conditions associated with dysregulation of DDR.
In another aspect, the invention refers to the use of a compound of formula (I) as above described, and pharmaceutically acceptable salts thereof, in the preparation of a medicament for the treatment of disorders associated with dysregulation of DDR.
In another preferred aspect, the invention refers to a compound of formula (I), and pharmaceutically acceptable salts thereof, for use in the prevention and/or treatment of a disease, disorder or condition associated with DDR receptor mechanism. In a preferred embodiment, the present invention refers to a compound of formula (I) for use in the prevention and/or treatment of fibrosis and/or diseases, disorders or conditions that involve fibrosis.
The terms "fibrosis" or "fibrosing disorder," as used herein, refer to conditions that are associated with the abnormal accumulation of cells and/or fibronectin and/or collagen and/or increased fibroblast recruitment and include, but are not limited to, fibrosis of individual organs or tissues such as the heart, kidney, liver, joints, lung, pleural tissue, peritoneal tissue, skin, cornea, retina, musculoskeletal and digestive tract. Preferably, the compounds of formula (I) as above described are useful for the treatment and/or prevention of fibrosis, such as pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), hepatic fibrosis, progressive pulmonary fibrosis, sarcoidosis, familiar pulmonary fibrosis, chronic hypersensitivity pneumonitis (CHP), kidney or renal fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis and systemic sclerosis. More preferably, the compounds of formula (I) as above described are useful for the treatment of idiopathic pulmonary fibrosis (IPF).
In another preferred embodiment, the compounds of formula (I) as above described are useful for the treatment of kidney fibrosis.
Thus in a preferred embodiment, the invention refers to a compound of formula (I) or its pharmaceutical composition for use in the prevention and/or treatment of IPF.
In another preferred embodiment, the invention refers to the use of the compounds of formula (I) or its pharmaceutical composition for the preparation of a medicament for the treatment and/or prevention of IPF.
In another preferred embodiment, the invention refers to a method for the treatment and/or prevention of IPF, the method comprising administering a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I) and one or more pharmaceutically acceptable carriers and/or excipients.
In another preferred embodiment, the invention refers to a compound of formula (I) or its pharmaceutical composition for use in the prevention and/or treatment of kidney fibrosis.
In another aspect, the invention refers to the use of the compounds of formula (I) or its pharmaceutical composition for the preparation of a medicament for the treatment and/or prevention of kidney fibrosis.
In another preferred embodiment, the invention refers to a method for the treatment and/or prevention of kidney fibrosis, the method comprising administering a compound of formula (I) or a pharmaceutical composition comprising a compound of formula (I) and one or more pharmaceutically acceptable carriers and/or excipients.
In one aspect, the invention also refers to a method for the prevention and/or treatment of diseases, disorders or conditions associated with DDR receptors mechanisms, said method comprising the step of administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) as above described.
In a further aspect, the invention refers to the use of a compound of formula (I) as above described for the treatment of diseases, disorders or conditions associated with DDR receptors mechanism. In another aspect, the invention refers to the use of a compound of formula (I) as above described in the preparation of a medicament for the treatment of diseases, disorders or conditions associated with DDR receptors mechanism.
In a further aspect, the invention refers to a method for the prevention and/or treatment of a disease, disorder or condition associated with the dysregulation of DDR receptors 1 and 2, said method comprising administering to a patient in need of such treatment a therapeutically effective amount of a compound of formula (I) as above described.
In a further aspect, the present invention refers to the use of a compound of formula (I) as above described for the treatment of a disease, disorder or condition associated with dysregulation of DDR receptors 1 and 2.
As used herein, "safe and effective amount" in reference to a compound of formula (I) or a pharmaceutically acceptable salt thereof or other pharmaceutically active agent means an amount of the compound sufficient to treat the patient's condition but low enough to avoid serious side effects and that can nevertheless be routinely determined by the skilled artisan.
The compounds of formula (I) may be administered once or according to a dosing regimen wherein a number of doses are administered at varying intervals of time for a given period of time. Typical daily dosages may vary depending upon the route of administration chosen.
The present invention also refers to a pharmaceutical composition comprising a compound of formula (I) according to any of its embodiment in admixture with at least one or more pharmaceutically acceptable carrier and/or excipient.
In one embodiment, the invention refers to a pharmaceutical composition of compounds of formula (I) in admixture with at least one or more pharmaceutically acceptable carrier and/or excipient, for example those described in Remington’s Pharmaceutical Sciences Handbook, XVII Ed., Mack Pub., N.Y., U.S.A.
Administration of the compounds of the invention and their pharmaceutical compositions may be accomplished according to patient needs, for example, orally, nasally, parenterally (subcutaneously, intravenously, intramuscularly, intrasternally and by infusion) and by inhalation.
Preferably, the compounds of the present invention are administered orally or by inhalation.
In one preferred embodiment, the pharmaceutical composition comprising the compound of formula (I) is a solid oral dosage form such as tablets, gelcaps, capsules, caplets, granules, lozenges and bulk powders.
In one embodiment, the pharmaceutical composition comprising the compound of formula (I) is a tablet.
The compounds of the invention can be administered alone or combined with various pharmaceutically acceptable carriers, diluents (such as sucrose, mannitol, lactose, starches) and known excipients, including suspending agents, solubilizers, buffering agents, binders, disintegrants, preservatives, colorants, flavorants, lubricants and the like.
In a further embodiment, the pharmaceutical composition comprising a compound of formula (I) is a liquid oral dosage form such as aqueous and non-aqueous solutions, emulsions, suspensions, syrups, and elixirs. Such liquid dosage forms can also contain suitable known inert diluents such as water and suitable known excipients such as preservatives, wetting agents, sweeteners, flavorants, as well as agents for emulsifying and/or suspending the compounds of the invention.
In a further embodiment, the pharmaceutical composition comprising the compound of formula (I) is an inhalable preparation such as inhalable powders, propellant-containing metering aerosols or propellant-free inhalable formulations.
For administration as a dry powder, single- or multi-dose inhalers known from the prior art may be utilized. In that case the powder may be filled in gelatine, plastic or other capsules, cartridges or blister packs or in a reservoir.
A diluent or carrier chemically inert to the compounds of the invention, e.g. lactose or any other additive suitable for improving the respirable fraction may be added to the powdered compounds of the invention.
Inhalation aerosols containing propellant gas such as hydrofluoroalkanes may contain the compounds of the invention either in solution or in dispersed form. The propellant-driven formulations may also contain other ingredients such as co-solvents, stabilizers and optionally other excipients.
The propellant-free inhalable formulations comprising the compounds of the invention may be in form of solutions or suspensions in an aqueous, alcoholic or hydroalcoholic medium and they may be delivered by jet or ultrasonic nebulizers known from the prior art or by soft-mist nebulizers.
The compounds of the invention can be administered as the sole active agent or in combination with other pharmaceutical active ingredients.
The dosages of the compounds of the invention depend upon a variety of factors including among others the particular disease to be treated, the severity of the symptoms, the route of administration and the like.
The invention is also directed to a device comprising a pharmaceutical composition comprising a compound of Formula (I) according to the invention, in form of a single- or multidose dry powder inhaler or a metered dose inhaler.
All preferred groups or embodiments described above for compounds of formula (I) may be combined with each other and apply as well mutatis mutandis. The various aspects of the invention described in this application are illustrated by the following examples which are not meant to limit the invention in any way.
PREPARATION OF INTERMEDIATES AND EXAMPLES
Chemical Names of the compounds were generated with Structure-To-Name tool of PerkinElmer ChemDraw® Professional application (v. 20.0.0.41.) or are common chemical names, unless otherwise stated. All reagents, for which the synthesis is not described in the experimental part, are either commercially available, or are known compounds or may be formed from known compounds by known methods by a person skilled in the art.
In the procedures that follow, some of the starting materials are identified through an “Intermediate” or “Example” number with indications on step number. This is provided merely for assistance to the skilled chemist.
When reference is made to the use of a “similar” or “analogous” procedure, as it will be appreciated by those skilled in the art, such a procedure may involve minor variations, for example reaction temperature, reagent/solvent amount, reaction time, work-up conditions or chromatographic purification conditions, that will be appreciated by those skilled in the art. All final compounds were obtained as a free base, unless stated otherwise.
Abbreviations
AcOH = acetic acid; Acetone-t/6 = deuterated acetone; ACN = acetonitrile; ACN-t/3 = deuterated acetonitrile; CDCh = deuterated chloroform; cHex = cyclohexane; CV = Column Volumes; DCM = dichloromethane; DIPEA = diisopropylethylamine; DMA = N,N- dimethylacetamide; DMF = dimethylformamide; DMSO = dimethyl sulfoxide; DMSO-t/6 = deuterated dimethyl sulfoxide; ee = enantiomeric excess; Et2O = diethyl ether; EtOAc = ethyl acetate; eq = equivalents; FCC = flash column chromatography; h = hour/s; HATU = 1- [Bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; HCOOH = formic acid; HPLC = High Performance Liquid Chromatography; LCMS = Liquid Chromatography /Mass Spectrometry; MeOH = methyl alcohol; Me-THF = 2-Methyltetrahydrofuran; min = minute/s; NMR = nuclear magnetic resonance; Pd2(dba)3 = tris(dibenzylideneacetone)dipalladium(0); XPhos Pd G3 = 2-Dicyclohexylphosphino- 2',4',6'-triisopropyl-l,r-biphenyl)[2-(2'-amino-l,r-biphenyl)]palladium(II) methanesulfonate; RT/rt = room temperature; RuPhos = 2-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl; SCX = strong cation exchange; SFC = supercritical fluid chromatography; STAB = sodium triacetoxyborohydride; SM = starting material; tBu = tert-Butyl; tBuOK = Potassium tert-butoxide; TCFH = chloro-7V,7V,7V',7V' -tetramethylformamidinium hexafluorophosphate; TEA = triethylamine; TFA = trifluoroacetic acid; THF = tetrahydrofuran; TLC = Thin Layer Chromatography; tz? = retention time; UPLC = Ultra Performance Liquid Chromatography; TBAF = tetrabutylammonium fluoride; TBAB = Tetrabutylammonium bromide; DBU = 1,8- diazabiciclo[5.4.0]undec-7-ene; CPME = cyclopentyl methyl ether; mCPBA = 3- Chloroperbenzoic acid; CDI = l,l'-Carbonyldiimidazole; Xantphos = 4,5-
Bis(diphenylphosphino)-9,9-dimethylxanthene; Mel = methyl iodide; SEM = 2- (Trimethylsilyl)ethoxymethyl; Boc = tert-Butyloxycarbonyl; Troc = 2,2,2-trichloroethyl carbamate; LiOH = lithium hydroxyde.
General Experimental details
NMR characterization:
JH NMR spectra were recorded on Bruker instrument operating at 400 MHz (proton frequency), using the stated solvent at around rt unless otherwise stated. In all cases, NMR data were consistent with the proposed structures. Characteristic chemical shifts are reported as 5 values in ppm (parts-per-million). Coupling constants (J values) are given in hertz (Hz) and multiplicities are reported using the following conventional abbreviations for designation of major peaks: s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, dt = doublet of triplets, m = multiplet, br = broad, nd = not determined.
In some cases, signals NH from amide bond or amine bond (exchangeable protons) are not visible. In a few cases, some signals could be hidden or partly covered by the signal of water or under the DMSO peak or other residual solvents.
LC/UV/MS Analytical Methods
LC/MS retention times are estimated to be affected by an experimental error of ± 0.5 min.
Method 1: Agilent Zorbax column 4.6x50mm, 3.5 pm, maintained at 40 °C. Mobile phase: MeCN (0.1% formic acid) in water (0.1% formic acid), from 5% to 95% within 2 min. Flow rate: 3.0 ml/min. Wavelength: 210-400 nm DAD. Waters™ 2795/2695 separations module + Waters™ DAD + Micromass ZQ, single quadrupole LCMS.
Method 2: Waters™ Acquity UPLC HSS C18 column, 100 * 2.1mm, 1.8 pm (Plus guard cartridge), maintained at 40°C. Mobile phase: MeCN (0.1% formic acid) in water (0.1% formic acid) from 5% to 95% within 5.6 min. Flow rate: 0.4 ml/min. Wavelength: 210-400 nm DAD. UPLC + Waters™ DAD + Waters™ SQD2, single quadrupole UPLCMS
Method 3: Waters™ Acquity UPLC BEH Shield RP 18 column, 100 * 2.1mm, 1.72pm (Plus guard cartridge), maintained at 40 °C. Mobile phase: MeCN in water + 10 nM ammonium bicarbonate from 5% to 95% within 5.6 min. Flow rate: 0.4 ml/min. Wavelength: 210-400 nm DAD. UPLC + Waters™ DAD + Waters™ SQD2, single quadrupole UPLCMS
Method 4: Waters™ Sunfire C18 column, 4.6x50mm, 3.5 pm, maintained at 40 °C. Mobile phase MeCN in water + lOmM ammonium bicarbonate, from 5 to 95% within 2.5 min. Flow rate: 2.0 mL/min. Wavelength: 210-400 nm DAD. Waters™ 2795 separations module + Waters™ DAD + Micromass ZQ, single quadrupole LCMS.
Method 5: Waters Acquity QSM, Kinetex C8 column 100mm x 2.1mm 1.7pm, maintained at 55°C; Mobile Phase: Eluent A (HCOONH40.025M pH 3), Eluent B (ACN+0.1% FA). Gradient mode: from 0 to 3 min. eluent B is increased from 1% to 30%, from 3 to 6.50 min. is increased from 30% to 50%, from 6.50 to 7.50 min. is increased from 50% to 80%, from 7.50 to 8 min is kept at 80%, from 8 to 8.10 min. is decreased from 80% to 1% and from 8.10 it is kept at 1% till the end at 10 min. Flow rate: 0.5 mL/min. Wavelength: 210-400 nm PAD. UPLC + Waters PDA + Xevo TQS MS instrument.
Method 6: Waters™ Acquity QSM, Acquity UPLC CSH Cl 8 column 50mm x 2.1mm 1.7 pm, maintained at 50°C; Mobile Phase: Eluent A (HCOONH4 0.025M pH 3), Eluent B (ACN+0.1% FA). Gradient mode: from 0 to 5.50 min. eluent B is increased from 20% to 80%, from 5.50 to 7.50 min. is kept at 80%, from 7.50 to 8 min. is decreased from 80% to 20%, and from 8 min. it is kept at 20% till the end at 10 min. Flow rate: 0.35 mL/min. Wavelength: 210- 400 nm DAD. UPLC + Waters™ PDA + Xevo TQS MS instrument.
Method 7: Acquity CSH C18 column 50mm x 2.1mm 1.7pm, maintained at 40°C; Mobile Phase: Eluent B (ACN) in Eluent A (water +0.1% HCOOH) from 1% to 99.9% within 1.5 min. Flow rate: 1 mL/min. Wavelength: 210-400 nm DAD. UPLC + Waters PDA + Waters QDA.
Method 8: Kinetex® XB-C18 column, 4.6x50 mm, 2.6 pm maintained at 25 °C. Mobile phase: water (0.1% formic acid) in MeCN (0.1% formic acid), from 80% to 5% within 3.90 min; Flow rate: 1.0 ml/min; wavelength: 190-340 nm DAD. Dionex UHPLC Ultimate 3000 with DAD detector/Thermo Scientific ISQ EC mass spectrometer.
Method 9: Kinetex® XB-C18 column, 4.6x50 mm, 2.6 pm maintained at 25 °C. Mobile phase: water (0.1% formic acid) in MeCN (0.1% formic acid), from 90% to 5% within 3.90 min; Flow rate: 1.0 ml/min; wavelength: 190-340 nm DAD. Dionex UHPLC Ultimate 3000 with DAD detector/Thermo Scientific ISQ EC mass spectrometer.
Method 10: Acquity UPLC BEH - Waters, 1.7 pm Cl 8 (2.1 x 100 mm), 130 A, maintained at 25 °C. Mobile phase: water (0.1% formic acid) in MeCN (0.1% formic acid), from 80% to 5% within 2.70 min; Flow rate: 0.5 ml/min; wavelength: 254 nm. Shimadzu LCMS-2020 Single Quadrupole Liquid Chromatograph Mass Spectrometer.
Method 11: Waters Acquity UPLC BEH C18 column 2.1x100mm, 1.7um, (Plus guard cartridge), maintained at 40 °C. Mobile phase: MeCN (0.1% formic acid) in water (0.1% formic acid), from 5% to 95% within 8 min. Flow rate: 0.4 ml/min. Wavelength: 200-400 nm DAD, Waters Aquity PDA, separations module + Waters PDA + Micromass ZQ, single quadrapole LCMS. Method 12: Waters Acquity UPLC BEH C18 column 2.1x100mm, 1.7um, (Plus guard cartridge), maintained at 40 °C. Mobile phase: MeCN (0.1% Ammonium Hydroxide) in water (0.1% Ammonium Hydroxide), from 5% to 95% within 8 min. Flow rate: 0.4 ml/min. Wavelength: 200-400 nm DAD, Waters Acquity PDA, separations module + Waters PDA + Micromass ZQ, single quadrapole LC-MS.
Method 13: Acquity CSH C18 column 50mm x 2.1mm 1.7pm, maintained at 40°C; Mobile Phase: Eluent B (ACN) in Eluent A (water +0.1% HCOOH) from 1% to 99.9% within 3.5 min. Flow rate: 1 mL/min. Wavelength: 210-400 nm DAD. UPLC + Waters PDA + Waters QDA.g
Method 14: Acquity UPLC BEH - Waters, 1.7 pm C18 (2.1 x 100 mm), 130A, maintained at 25 °C. Mobile phase: water (0.1% formic acid) in MeCN (0.1% formic acid), from 80% to 5% within 3.9 min; Flow rate: 0.5 mL/min; wavelenght: 220 nm and 254 nm. Shimadzu LCMS-2020 Single Quadrupole Liquid Chromatograph Mass Spectrometer.
Method 15: Phenomenex Kinetex EVO C18 HPLC column, 4.6x50 mm, 5 pm, operating at room temperature: Mobile phase: MeCN (0.1% NH4OH) in water (0.1% NH4OH), from 5 to 95% within 2.5 min. Flow rate: 1.5 mL/min. Wavelength: 210-400 nm DAD. Acquity H-Class UPLC with PDA detector and QDa.
Method 16: Waters Aquity UPLC HSS Cl 8 column, 2.1x5 0mm, 1.8 pm, maintained at 40 °C: MeCN (0.1% FA) in water (0.1% FA), from 5 to 95% within 2.5 min. Flow rate: 1.5 mL/min. Wavelength: 210-400 nm DAD. Acquity H-Class UPLC with PDA detector and QDa.
Method 17: Waters Aquity UPLC BEH Cl 8 column 2.1x100 mm, 1.7 pm, (Plus guard cartridge), maintained at 40 °C. Mobile phase: MeCN (0.1% FA) in water (0.1% FA), from 5% to 50% within 8 min. Flow rate: 0.4 mL/min. Wavelength: 200-400 nm DAD, Waters Aquity PDA, separations module + Waters PDA + Micromass ZQ, single quadrapole LCMS.
Method 18: Waters Aquity UPLC BEH Cl 8 column 2.1x100 mm, 1.7 pm, (Plus guard cartridge), maintained at 40 °C. Mobile phase: MeCN (0.1% FA) in water (0.1% FA), from 10% to 50% within 8 min. Flow rate: 0.4 mL/min. Wavelength: 200-400 nm DAD, Waters Aquity PDA, separations module + Waters PDA + Micromass ZQ, single quadrapole LCMS.
The purification of some compounds was achieved by Achiral Supercritical Fluid Chromatography (SFC) using a Waters™ Thar PreplOO preparative SFC system.
Method 19: (TORUS DEA 20x150 mm, 5 pm 10-20% MeOH (0.1% NH4OH)/CO2, 100 ml/min, 120 bar, 40 °C
Method 20: YMC Amylose-C MeOH, WATERS VIRIDIS 2-EP 20x250 mm, 5 pm 5-15% MeOH (0.1% NH4OH) / CO2, 100 mL/min, 120 bar, 40 °C, DAD 235 nm.
Other compounds were purified by reverse phase HPLC using a Waters™ Fractionlynx™ preparative HPLC system or equivalent system, both in basic conditions (ACN+0.1% NH3, H2O+0.1% NEE) and in acidic conditions (ACN+0.1% HCOOH, H2O+0.1% HCOOH), wherein, in the last case, the fractions containing the required product (identified by TLC and/or LCMS analysis) were pooled and the solvent either removed under reduced pressure or lyophilised; or alternatively extracted by SCX (NH) to obtain the free base of the product, unless differently stated.
Flash chromatography (FCC) was performed on Biotage® Isol era™ system or similar instruments.
For reverse phase FCC (RF FCC) the following gradient/eluent were used: gradient eluent A:eluent B from 100:0 to 0: 10 in 12 CV eluent A: H2O/ACN/HCOOH 95:5:0.1 Eluent B: H2O/ACN/HCOOH 5:95:0.1. After purification, SCX (NH) was utilized to obtain free base of the product, unless differently stated.
All solvents were purchased from commercial sources and were used without additional purification.
General Synthetic procedures
Intermediate 1: 6-(4-methylpiperazin-l-yl)imidazo[l,2-a]pyridine-3-carboxylic acid
Figure imgf000090_0001
Step 1 - Methyl 6-(4-methylpiperazin-l-yl)imidazo[l,2-a]pyridine-3-carboxylate (Intermediate 2)
Figure imgf000090_0002
To a solution of ethyl 6-bromoimidazo[l,2-a]pyridine-3 -carboxylate (807 mg, 3.00 mmol) in toluene (10 mL) Pd2(dba)s (275 mg, 0.300 mmol), BINAP (560 mg, 0.900 mmol) and sodium tert-butoxide (403 mg, 4.20 mmol) were added. The reaction mixture was sparged with nitrogen then 1 -methylpiperazine (0.37 mL, 3.30 mmol) was added and the reaction mixture was stirred at 100°C for 3 h. The reaction mixture was allowed to cool to rt and filtered through a pad of Celite®, which was then washed with MeOH. The combined organic phases were concentrated in vacuo, the residue was purified by FCC (0-100% EtOAc in cHex followed by 0-100 % MeOH in EtOAc). The material was taken on to the next step without further purification, as a mixture of methyl and ethyl esters.
LCMS (ESI): Method 1, tz? = 0.65 min, m/z (M+l) = 275 (Methyl ester);
LCMS (ESI): Method 1, tz? = 0.75 min, m/z (M+l) = 289 (Ethyl ester) Analogously the following Intermediates were prepared, using the suitable amine, bromointermediate, the catalyst shown in the Table 6 and, in a few cases, dioxane or Me-THF as a solvent and CS2CO3 as a base.
Table 6
Figure imgf000091_0001
Figure imgf000092_0001
Step 2 - 6-(4-methylpiperazin-l-yl)imidazo[l,2-a]pyridine-3-carboxylic acid
(Intermediate 1)
LiOH (314 mg, 13.1 mmol) in water (1 mL) was added to Intermediate 2 (1200 mg, 4.37 mmol) in THF (1 mL) at 0°C. The reaction mixture was allowed to warm to RT and stirred for 18 h. The reaction mixture was concentrated in vacuo. The residue was washed with water and the aqueous phase was adjusted to pH 7 with IM HCl(aq) and washed with DCM. The aqueous fractions were concentrated in vacuo to yield a mixture of product and inorganic salts. The material was taken on to the next step without further purification.
LCMS (ESI): Method 1, tR = 0.87 min, m/z (M+l) = 261 Analogously the following Intermediates, as carboxylic acids or as salts, were prepared (see Table 7 below).
Table 7
Figure imgf000092_0002
Figure imgf000093_0001
Figure imgf000094_0002
Intermediate 3: phenyl (5-(tert-butyl)isoxazol-3-yl)carbamate
Figure imgf000094_0001
To a suspension of 5-(tert-butyl)isoxazol-3-amine (321 mg, 2.29 mmol) and Na2COs (171 mg, 1.61 mmol) in EtOAc (20.00 mL), THF (4.00 mL) and water (4.00 mL) at 0 °C, phenyl chloroformate (0.37 mL, 2.95 mmol) was added dropwise. The reaction mixture was stirred at 0 °C for 20 min, then warmed up to rt and stirred for 18 h. The reaction was concentrated in vacuo , EtOAc (20 mL) added and washed with water (30 mL). The organic phase was dried over a hydrophobic frit and concentrated in vacuo to give the title compound (487 mg, 1.25 mmol, 55 % yield). LCMS (ESI): Method 4, ta = 1.69 min, m/z (M+l) = 261
Analogously the following Intermediates were prepared (see Table 8 below).
Table 8
Figure imgf000094_0003
Figure imgf000095_0003
Intermediate 114: (3-amino-2-methoxy-5-(trifluoromethoxy)phenyl)methanol
Figure imgf000095_0001
(2-methoxy-3-nitro-5-(trifluoromethoxy)phenyl)methanol (2.64 g, 9.88 mmol) was prepared by following the procedure described in US 10280145. Intermediate 5: 4-bronio-l-((2-(trinietliylsilyl)etlioxy)niethyl)-l//-pyrazolo|3.4-
/>]pyridine
Figure imgf000095_0002
To a solution of 4-bromo-U/-pyrazolo[3,4-b]pyridine (1160 mg, 5.86 mmol) and /BuOK (986 mg, 8.79 mmol) in DMF (15.00 mL), 2-(trimethylsilyl)ethoxymethyl chloride (1.2 mL, 7.03 mmol) was added dropwise at 0 °C and the mixture was allowed to warm to rt and stirred overnight.
The reaction mixture was quenched with sat. aq. NH4CI and extracted with EtOAc. The organic phase was washed with water and brine, dried over MgSCh and concentrated in vacuo. The residue was purified by FCC (0 - 60 % EtOAc in cHex) to give the title compound (959 mg, 2.92 mmol, 50 % yield). LCMS (ESI): Method 4, tR = 1.96 min, m/z (M+1) =328.0; 330.0 ¹H NMR (400 MHz, DMSO-d6) δ 8.58 (d, J=4.9 Hz, 1H), 8.40 (s, 1H), 7.72 (d, J=4.9 Hz, 1H), 5.90 (s, 2H), 3.71 (t, J=8.0 Hz, 2H), 0.93 (t, J=8.0 Hz, 2H), 0.01 (s, 9H). Analogously the following Intermediate was prepared, using sodium hydride as a base (see Table 9). Table 9
Figure imgf000096_0002
Intermediate 29: 2,2,2-trichloroethyl (3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5- yl)carbamate
Figure imgf000096_0001
A solution of 3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-amine (100 mg, 0.436 mmol) and NaOH (1M aq., 1.3 mL, 1.31 mmol) in EtOAc (3 mL) was cooled in an ice/water bath, 2,2,2- trichloroethyl chloroformate (0.066 mL, 0.480 mmol) was added dropwise and the reaction mixture was stirred at rt for 1.5 h, then concentrated in vacuo to give the title compound (100 mg, 0.247 mmol, 57% yield) and it was used as crude in the next reaction. LCMS (ESI): Method 1, tR =1.86 min, m/z (M+1) = 404.0, 406.0 ¹H NMR (400 MHz, CDCl3) δ 7.36 - 7.26 (m, 4H), 6.82 (br s, 1H), 6.41 (s, 1H), 4.81 (s, 2H), 2.41 (s, 3H), 1.34 (s, 9H). All the following Troc carbamates were prepared by using the same procedure; sometimes DIPEA was used as a base and THF or pyridine as a solvent, starting from the suitable amine (see Table 10) Table 10
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0002
Intermediate 30: Ethyl l-(oxetan-3-yl)-lH-imidazo[l,2-b]pyrazole-7-carboxylate
Figure imgf000099_0001
To a solution of ethyl LH-imidazo[l,2-b]pyrazole-7-carboxylate (150 mg, 0.837 mmol) and 3-iodooxetane (0.22 mL, 2.51 mmol) in DMF (3.5 mL), stirring under nitrogen, potassium carbonate (231 mg, 1.67 mmol), was added in one portion. The reaction was stirred at 50 °C for 18 h. The reaction was allowed to cool down to rt and diluted with EtOAc. The organic layer was washed with saturated aqueous NaHCCh solution, brine, dried over MgSCh, filtered and solvent removed in vacuo. The crude material was purified by FCC (0-100% 3:1 EtOAc:EtOH in cHex) to yield the title compound (126 mg, 0.536 mmol, 64% yield). LCMS (ESI): Method 4, ta =1.26 min, m/z (M+l) = 236.2
Analogously to Intermediate 30, the following intermediates were prepared (see Table 11). Table 11
Figure imgf000100_0001
Figure imgf000101_0002
Intermediate 32: l-(oxetan-3-yl)-LH-imidazo[ l,2-b]pyrazole-7-carboxylic acid
Figure imgf000101_0001
To a solution of ethyl l-(oxetan-3-yl)-lH-imidazo[l,2-b]pyrazole-7-carboxylate (120 mg, 0.51 mmol) in THF (10 mL) sodium hydroxide (204 mg, 5.10 mmol) and MeOH (5.0 mL) were added and the mixture was heated to 50°C for 24 h. The reaction mixture was allowed to cool down to rt, pH reduced to about 2 with 2 N HC1 aqueous solution and extracted with EtOAc. Combined organic layers were washed with brine, dried over MgSCh, filtered and solvents removed in vacuo. The title compound (100 mg, 0.48 mmol, 95% yield) was used in the next step without further purification. LCMS (ESI): Method 1 min, tz? =1.02 min, m/z (M+l) = 208.0
The following compounds were prepared according to the same synthetic procedure (table
12).
Table 12
Figure imgf000101_0003
Figure imgf000102_0002
Intermediate 34: methyl 6-((oxetan-3-ylamino)methyl)pyrazolo[l,5-a]pyridine-3- carboxylate
Figure imgf000102_0001
To a solution of methyl 6-formylpyrazolo[l,5-a]pyridine-3-carboxylate (85 mg, 0.416 mmol) and oxetan-3 -amine (0.037 mL, 0.520 mmol) in DCM (2 mL) AcOH (20 pL) was added; after 10 min NaBH(OAc)3 (176 mg, 0.833 mmol) was added and the mixture was stirred at rt for 3 h. The reaction mixture was then diluted with DCM and washed with NaHCCh and water. The organic phase was dried over MgSCh and concentrated in vacuo to give the title compound (95 mg, 0.364 mmol, 87% yield). LCMS (ESI): Method 7, tR =1.01 min, m/z (M+l) = 262.0 Intermediate 35: lithium 6-((oxetan-3-ylamino)methyl)pyrazolo[l,5-a]pyndine-3- carboxylate
Figure imgf000103_0001
Intermediate 35 was prepared by following the procedure for Intermediate 1, step 2, to give the title compound (66 mg, 0.268 mmol, quantitative).
LCMS (ESI): Method 4 min, ty? =0.60 min, m/z (M+l) = 248.2
Intermediate 36: 4-(2,2,2-trifluoroethyl)pyridin-2-amine
Figure imgf000103_0002
Step 1 - 2-chloro-4-(2,2,2-trifluoroethyl)pyridine (Intermediate 37)
Figure imgf000103_0003
To a solution of 2-chloro-isonicotinaldehyde (250 mg, 1.77 mmol) in MeOH (2.0 mL) hydrazine monohydrate (0.10 mL, 2.12 mmol) was added and the reaction stirred at rt for 1 h under nitrogen. The solvent was removed in vacuo and 1 -(trifluoromethyl)- IX3- benzo[d][l,2]iodaoxol-3(177)-one (Togni reagent II, 1.023 g, 1.94 mmol) was added to the solid crude. The vial containing the two solids and a stirrer bar was subjected to vacuum/nitrogen cycles before DMSO (2.0 mL) and TFA (0.14 mL, 1.77 mmol) were added and the reaction mixture heated to 50 °C for 72 h. The reaction was allowed to cool back down to rt and it was diluted with water, extracted with Et2O and organic layer was washed with water and brine, and then dried over MgSCh. The organic layers were concentrated in vacuo. The residue was purified by FCC (0-50% EtOAc in cHex) to provide title compound (60 mg, 0.307 mmol, 17% yield).
LCMS (ESI): Method 1 min, ty? =1.57 min, m/z (M+l) = 196.0, 198.0
Step 2 - 4-(2,2,2-trifluoroethyl)pyridin-2-amine (Intermediate 36)
Intermediate 37 (60 mg, 0.307 mmol), tert-butyl carbamate (93 mg, 0.798 mmol), caesium carbonate (130 mg, 0.399 mmol), Xantphos (30 mg, 0.0522 mmol), Pd2(dba)s (25 mg, 0.0276 mmol) and CPME (3.0 mL) were added to a reaction vessel and the mixture sparged with nitrogen for 20 minutes. The vessel was sealed and the reaction mixture was heated at 130 °C for 18 h. The reaction was allowed to cool down to rt and filtered through Celite® washing with EtOAc. Solvents were removed in vacuo. The crude mixture was redissolved in DCM (3.0 mL) and TFA (1.0 mL) then the reaction was stirred for 3 h. The reaction was concentrated to dryness and the crude residue was dissolved in MeOH and passed through an SCX Isolute column, eluting with 7 N methanolic NH3. The ammonia solution was evaporated at reduced pressure and the title compound was used in the next step without further purification (44 mg, 31 %). LCMS (ESI): Method 1 min, tR =1.32 min, m/z (M+1) = 177.1 Intermediate 124: lithium 2-(2-methoxyethyl)-1-methyl-1H-imidazo[1,2-b]pyrazole-7- carboxylate
Figure imgf000104_0001
Step 1: ethyl 2-(2-methoxyethyl)-1H-imidazo[1,2-b]pyrazole-7-carboxylate (Intermediate 125)
Figure imgf000104_0002
Ethyl 5-amino-1H-pyrazole-4-carboxylate (1.48 g, 9.5 mmol) was dissolved in dry ACN (20 mL), then DIPEA (1.28 ml, 7.3 mmol), tetrabutylammonium bromide (2.36 g, 7.3 mmol) and 1- chloro-4-methoxybutan-2-one (1 g, 7.3 mmol) were added and the reaction was stirred overnight at 90° C. The solvent was removed and the crude was purified by RF FCC affording title compound (0.57 g, 2.4 mmol, 33 % yield). 1H NMR (600 MHz, DMSO-d6) δ ppm 11.88 (1 H, br s), 7.82 (1 H, s), 7.47 (1 H, s), 4.21 (2 H, q, J=7.09 Hz), 3.60 (2 H, t, J=6.75 Hz), 3.26 (3 H, s), 2.85 (2 H, m), 1.28 (3 H, t, J=7.12 Hz) Step 2: ethyl 2-(2-methoxyethyl)-1-methyl-1H-imidazo[1,2-b]pyrazole-7-carboxylate (Intermediate 126)
Figure imgf000104_0003
To a solution of Intermediate 125 (380 mg, 1.6 mmol), MeI (0.10 ml, 1.60 mmol) and NaH 95% w/w (40.5 mg, 1.60 mmol) were added and the mixture was stirred overnight at 50 °C. The solvent was removed and the crude was purified by RF FCC affording title compound (50 mg, 0.20 mmol, 12 % yield). LCMS (ESI): Method 7, tR =0.8 min, m/z (M+1) = 252.0 Step 3: lithium 2-(2-methoxyethyl)-1-methyl-1H-imidazo[1,2-b]pyrazole-7- carboxylate (Intermediate 124) Intermediate 124 was prepared by following the procedure for Intermediate 1, step 2, to give the title compound (45 mg, 98% yield). LCMS (ESI): Method 7, tR =0.54 min, m/z (M+1) = 224 Intermediate 127: lithium 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine- 3-carboxylate
Figure imgf000105_0001
Step 1: methyl 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3- carboxylate (Intermediate 128)
Figure imgf000105_0002
To a suspension of methyl 6-bromopyrazolo[1,5-a]pyridine-3-carboxylate (185 mg, 0.725 mmol) and (1-methylpyrazol-4-yl)boronic acid (137 mg, 1.088 mmol) in Me-THF (1.5 mL), Potassium phosphate tribasic (385 mg, 1.813 mmol) was added. After applying three N2/vacuum cycles XPhos Pd G3 (61.4 mg, 0.073 mmol) was added and the vial was sealed. The reaction was heated at 75 °C for 12h. EtOAc and brine were added and the organic layer was concentrated under vacuum.The crude was purified by FCC (Sfar NH, gradient of EtOAc/EtOH 3:1 in heptane from 0% to 60%) to afford title compound (61 mg, 0.24 mmol, 33 % yield) LCMS (ESI): Method 7, tR =0.77 min, m/z (M+1) = 256.99 Step 2: lithium 6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3- carboxylate (Intermediate 127) Intermediate 127 was prepared by following the procedure for Intermediate 1, step 2 to give the title compound (59 mg, 100% yield). LCMS (ESI): Method 7, tR =0.54 min, m/z (M+1) = 224 Intermediate 177: 4-(perfluoroethyl)pyridin-2-amine
Figure imgf000105_0003
In a microwave vial, 2-chloro-4-(pernuoroethyl)pyndine (250 mg, 1.08 mmol) was suspended in 35% aqueous ammonia (4.0 mL, 72.3 mmol). The vial was capped and heated in a microwave to 150 °C for 8 h, then the contents were transferred in a separating funnel and diluted with water and EtOAc. Phases were separated and the aqueous layer was extracted with EtOAc. Combined organics were washed with brine, dried over MgSO4, filtered and solvents removed in vacuo to yield the title compound (450 mg, 2.54 mmol, quantitative) which was used without further purification.
LCMS (ESI): Method 16, tz? =1.50 min, m/z (M+l) = 213.1
Intermediate 178: (3-amino-2-methoxy-5-(trifluoromethyl)phenyl)methanol
Figure imgf000106_0001
Intermediate 178 was prepared by following the procedure decribed in WO2017038873.
Intermediate 179: (3-amino-2-methoxy-5-(trifluoromethoxy)Dhenyl)methanol
Figure imgf000106_0002
Intermediate 179, was prepared by following the procedure decribed in WO2017038873.
Example 1 : l-(2-(imidazo [1,2-a] pyridine-3-carbonyl)-2-azaspiro [3.3] heptan-6-yl)-3-(3- (trifluoromethyl)phenyl)urea
Figure imgf000106_0003
Step 1 - tert-butyl 6-(3-(3-(trifluoromethyl)phenyl)ureido)-2-azaspiro[3.3] heptane-2- carboxylate (Intermediate 6)
Figure imgf000106_0004
To a solution of tert-butyl 6-amino-2-azaspiro[3.3]heptane-2-carboxylate (500 mg, 2.36 mmol) in DCM (15.00 mL) cooled to 0 °C, l-isocyanato-3-(trifluoromethyl)benzene (0.32 mL, 2.36 mmol) was added and the reaction mixture was warmed to rt after 5 min and stirred for 2 h. It was then concentrated in vacuo to give the title compound (1 g, 2.50 mmol, quantitative yield) as a clear oil. LCMS (ESI): Method 1, tR = 1.70 min, m/z (M+1-tBu) = 344.0 ¹H NMR (400 MHz, DMSO-d6) δ 8.65 (s, 1H), 7.86 (s, 1H), 7.44 - 7.34 (m, 2H), 7.14 (d, J=7.5 Hz, 1H), 6.45 (d, J=7.5 Hz, 1H), 3.97 - 3.85 (m, 1H), 3.81 (s, 2H), 3.70 (s, 2H), 2.42 - 2.35 (m, 2H), 2.02 - 1.91 (m, 2H), 1.29 (s, 9H). The following Intermediates were prepared according to the same synthetic procedure, starting from commercially available compounds or previously described intermediates (see Table 13). Table 13
Figure imgf000107_0001
Figure imgf000108_0003
Step 2 – 1-(2-azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Intermediate 7, compound IVa)
Figure imgf000108_0001
A solution of Intermediate 6 (900 mg, 2.25 mmol) and TFA (2.6 mL, 33.8 mmol) in DCM (15.00 mL) was stirred at rt for 1 h, then concentrated in vacuo. The residue was loaded onto an Isolute SCX cartridge, washed with 1:1 DCM:MeOH (50 mL) and 100% MeOH (20 mL), and released with 1:17 N NH3 in MeOH:DCM (50 mL) and 100% 7 N NH3 in MeOH (20 mL). The ammonia eluent was concentrated in vacuo to give the title compound (550 mg, 1.84 mmol, 82 % yield). LCMS (ESI): Method 1, tR =1.29 min, m/z (M+1) = 300.0 ¹H NMR (400 MHz, CDCl3) δ 7.60 - 7.55 (m, 1H), 7.53 - 7.49 (m, 1H), 7.36 (t, J=8.0 Hz, 1H), 7.28 - 7.23 (m, 1H), 7.17 (s, 1H), 5.24 (d, J=7.3 Hz, 1H), 4.15 - 4.05 (m, 1H), 3.62 (s, 2H), 3.52 (s, 2H), 2.63 - 2.56 (m, 2H), 1.94 - 1.83 (m, 2H). The following compounds were prepared according to the same synthetic procedure of Intermediate 7 (see Table 14). Table 14
Figure imgf000108_0002
Figure imgf000109_0001
Step 3 – 1-(2-(imidazo[1,2-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3- (trifluoromethyl)phenyl)urea (Example 1) To a solution of Intermediate 7 (75 mg, 0.251 mmol, 1.00 eq), imidazo[1,2-a]pyridine-3- carboxylic acid (41 mg, 0.251 mmol) and DIPEA (0.13 mL, 0.752 mmol) in DMF (2.00 mL), HATU (124 mg, 0.326 mmol) was added and the reaction mixture was stirred at rt overnight. It was then diluted with EtOAc, washed with K2CO3 (semi sat. aq.) and brine. The organic phase was dried MgSO4 and concentrated in vacuo. The residue was purified by achiral SFC (method 19) to give the title compound (3.0 mg, 6.70 µmol, 3 % yield). LCMS (ESI): Method 2, tR = 3.41 min, m/z (M+1) = 444.2 ¹H NMR (400 MHz, DMSO-d6) δ 9.45 (d, J=6.8 Hz, 1H), 8.84 (s, 1H), 8.06 (s, 1H), 7.94 (s, 1H), 7.74 (d, J=8.8 Hz, 1H), 7.53 - 7.41 (m, 3H), 7.24 - 7.20 (m, 1H), 7.15 - 7.11 (m, 1H), 6.67 (d, J=7.6 Hz, 1H), 4.58 - 4.03 (m, 5H), 2.60 - 2.52 (m, 2H), 2.20 - 2.13 (m, 2H). The following Examples were prepared analogously to what described for Example 1, step 3, by starting from the suitable, commercially available carboxylic acid intermediate or, alternatively, previously described acid intermediate or corresponding lithium salt (see Table 15). Table 15
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
Figure imgf000115_0001
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Figure imgf000121_0001
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0002
Example 11: l-(2-(imidazo[l,2-a]pyrazin-3-ylmethyl)-2-azaspiro[3.3]heptan-6-yl)-3-
(3-(trifluoromethyl)phenyl)urea
Figure imgf000125_0001
Example 11
A solution of Intermediate 7 (115 mg, 0.384 mmol), imidazo[l,2-a]pyrazine-3-carbaldehyde (62 mg, 0.423 mmol), STAB (122 mg, 0.576 mmol) and AcOH (2 drops) in DCM (3.00 mL) and MeOH (0.50 mL) was stirred at rt overnight. The reaction mixture was concentrated in vacuo and the residue was purified by achiral SFC (Method 19) to give the title compound (33 mg, 0.0766 mmol, 20 % yield). LCMS (ESI): Method 3, tR = 3.65 min, m/z (M+1) = 431.27 ¹H NMR (400 MHz, DMSO-d6) δ 9.03 (d, J=1.5 Hz, 1H), 8.72 (s, 1H), 8.45 (dd, J=1.5, 4.8 Hz, 1H), 7.93 - 7.90 (m, 2H), 7.72 (s, 1H), 7.49 - 7.40 (m, 2H), 7.20 (d, J=7.6 Hz, 1H), 6.55 (d, J=7.6 Hz, 1H), 4.02 - 3.91 (m, 1H), 3.89 (s, 2H), 3.21 (s, 2H), 3.09 (s, 2H), 2.41 - 2.34 (m, 2H), 2.00 - 1.93 (m, 2H). The following Examples were prepared analogously to what described for Example 11 by starting from the suitable, commercially available aldehyde (see Table 16). Table 16
Figure imgf000126_0001
Example 15: 1-(2-(1H-pyrazolo[3,4-b]pyridin-4-yl)-2-azaspiro[3.3]heptan-6-yl)-3-(3- (trifluoromethyl) phenyl)urea
Figure imgf000127_0001
Example 15 Step 1 – 1-(3-(trifluoromethyl)phenyl)-3-(2-(1-((2-(trimethylsilyl)ethoxy) methyl)-1H- pyrazolo[3,4-b]pyridin-4-yl)-2-azaspiro[3.3]heptan-6-yl)urea (Intermediate 8)
Figure imgf000127_0002
A suspension of Intermediate 5 (165 mg, 0.501 mmol), Intermediate 7 (150 mg, 0.501 mmol), RuPhos (47 mg, 0.100 mmol) and Cs2CO3 (490 mg, 1.50 mmol) in THF (5.00 mL) was degassed with N2 for 10 min, then Pd2(dba)3 (46 mg, 0.0501 mmol) was added and the reaction mixture was stirred at 80 °C overnight. It was then cooled to rt, filtered through a pad of Celite®, washed with EtOAc (50 mL) and concentrated in vacuo. The residue was purified by FCC, (gradient of 20-100% EtOAc in cHex) to give the title compound (274 mg, 0.501 mmol, 100%). LCMS (ESI): Method 4, tR = 1.77 min, m/z (M+1) = 547.6 The following Examples and Intermediates were prepared using the procedure described for Intermediate 8, using the suitable commercially available bromo or chloro derivative or already described intermediates (see Table 17). Table 17
Figure imgf000127_0003
Figure imgf000128_0001
Step 2 – 1-(2-(1H-pyrazolo[3,4-b]pyridin-4-yl)-2-azaspiro[3.3]heptan-6-yl)-3-(3- (trifluoromethyl)phenyl)urea (Example 15) A solution of Intermediate 8 (274 mg, 0.501 mmol) and HCl (4 M in 1,4-dioxane, 3.0 mL) in 1,4-dioxane (4.00 mL) was stirred at rt for 4 h, then concentrated in vacuo. The residue was 5 purified by achiral SFC (Method 19) to give the title compound (67 mg, 0.161 mmol, 29% yield). LCMS (ESI): Method 2, tR = 3.32 min, m/z (M+1) = 417.2 ¹H NMR (400 MHz, DMSO-d6) δ 13.11 (s, 1H), 8.82 (s, 1H), 8.00 - 7.94 (m, 3H), 7.54 - 7.42 (m, 2H), 7.24 - 7.20 (m, 1H), 6.69 - 6.64 (m, 1H), 5.86 (d, J=5.6 Hz, 1H), 4.34 - 4.03 (m, 5H), 2.63 - 2.56 (m, 2H), 2.24 - 2.17 (m, 2H). Example 163: 1-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)-2-azaspiro[3.3]heptan-6-yl)-3-(5- (trifluoro methyl)pyridin-2-yl)urea
Figure imgf000129_0001
Example 163 Intermediate 54 (0.07 g, 0.13 mmol) was charged in a vial and diluted with TBAF 1M solution in THF (3.5 mL, 3.5 mmol). The solution was heated up to 70 °C for 8h. Mixture was cooled down and organic mixture was diluted in EtOAc and washed with aq KHCO32% and then brine/water 1:4. Organic layer was evaporated to dryness and crude dissolved in DMF/CH3CN 2:1 and purified by RF FCC. Fractions containing the products were combined and evaporated to dryness to give the title compound (0.025 g, 0.06 mmol, 47 % yield). LC-MS (ESI): Method 5, tR = 5.50 min, m/z (M+1) = 418.30 1H NMR (400 MHz, DMSO-d6) δ ppm 13.27 (1 H, s), 9.45 (1 H, s), 8.46 (1 H, d, J=5.26 Hz), 7.92 (3 H, m), 7.69 (1 H, br d, J=7.23 Hz), 7.27 (1 H, dd, J=5.26, 0.88 Hz), 7.09 (1 H, d, J=2.41 Hz), 4.12 (1 H, d, J=7.89 Hz), 3.93 (2 H, s), 3.83 (2 H, s), 2.57 (2 H, m), 2.16 (2 H, m) The following Examples and Intermediates were prepared using the procedure described for Example 163 (see Table 18). Table 18
Figure imgf000129_0002
Example 16: 1-(3-fluoro-5-(trifluoromethyl)phenyl)-3-(2-(pyrazolo[1,5-a]pyrazine-3- carbonyl)-2-azaspiro [3.3]heptan-6-yl)urea
Figure imgf000130_0001
Example 16 Step 1 - tert-butyl (2-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-2-azaspiro[3.3] heptan-6- yl)carbamate (Intermediate 9)
Figure imgf000130_0002
A solution of pyrazolo[1,5-a]pyrazine-3-carboxylic acid (384 mg, 2.36 mmol) and thionyl chloride (1.7 mL, 23.6 mmol) was stirred at reflux for 6 h. The reaction mixture was concentrated in vacuo and dissolved in DCM (2.00 mL). This solution was added dropwise to a solution of tert- butyl N-(2-azaspiro[3.3]heptan-6-yl)carbamate (500 mg, 2.36 mmol) and TEA (0.98 mL, 7.07 mmol) in DCM (2.00 mL) and the reaction was stirred at rt for 16 h. Water was added and the organic phase was separated. The organic phase was dried over a hydrophobic frit and concentrated in vacuo to give the title compound (750 mg, 2.10 mmol, 89 % yield). LCMS (ESI): Method 1, tR = 1.34 min, m/z (M+1) = 358 ¹H NMR (400 MHz, DMSO-d6) δ 9.55 (d, J=1.4 Hz, 1H), 8.91 (dd, J=1.4, 4.6 Hz, 2H), 8.44 (s, 1H), 8.11 (d, J=4.7 Hz, 1H), 7.16 (d, J=8.2 Hz, 1H), 4.50 (d, J=50.8 Hz, 2H), 4.04 (d, J=48.4 Hz, 2H), 3.91 - 3.79 (m, 1H), 2.48 - 2.43 (m, 2H), 2.15 - 2.07 (m, 2H), 1.38 (s, 9H). Analogously, the following Examples and Intermediates were prepared starting from the suitable analogue and carboxylic acid (see Table 19).Table19
Figure imgf000130_0003
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0002
Step 2 - (6-amino-2-azaspiro[3.3]heptan-2-yl)(pyrazolo[1,5-a]pyrazin-3-yl) methanone (Intermediate 10)
Figure imgf000134_0001
Intermediate 10 was prepared by following the procedure described for Intermediate 7. SM: Intermediate 9: 750 mg (1 eq); TFA: 3.4 mL (20 eq) Amount/yield: 460 mg, 1.79 mmol, 80 % LCMS (ESI): Method 1, tR = 0.94 min, m/z (M+1) = 258 The following Intermediates were prepared analogously to what described for Intermediate 10, by starting from the suitable precursor (see Table 20). Table 20
Figure imgf000134_0003
Figure imgf000135_0001
Step 3 - 1-(3-fluoro-5-(trifluoromethyl)phenyl)-3-(2-(pyrazolo[1,5-a]pyrazine-3- carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 16) To a solution of Intermediate 10 (50 mg, 0.194 mmol) in DCM (1.00 mL) 1-fluoro-3- isocyanato-5-(trifluoromethyl)benzene (0.028 mL, 0.194 mmol) was added and the reaction mixture was stirred at rt for 4 h, then concentrated in vacuo. The residue was purified by preparative HPLC (Sunfire C1819x150 mm, 10 μm 20-80% ACN/H2O (10 mM NH4CO3), 20 mL/min, RT) to give the title compound (7.5 mg, 0.0162 mmol, 8% yield). LCMS (ESI): Method 2, tR = 4.04 min, m/z (M+1) = 463.2 ¹H NMR (400 MHz, DMSO-d6) δ 9.55 - 9.54 (m, 1H), 9.06 (s, 1H), 8.91 (dd, J=1.1, 4.7 Hz, 1H), 8.44 (s, 1H), 8.11 (d, J=4.8 Hz, 1H), 7.62 (s, 1H), 7.57 (d, J=11.6 Hz, 1H), 7.14 - 7.10 (m, 1H), 6.83 - 6.79 (m, 1H), 4.58 (s, 1H), 4.48 (s, 1H), 4.15 (s, 1H), 4.07 - 4.02 (m, 2H), 2.60 - 2.54 (m, 2H), 2.22 - 2.14 (m, 2H). The following Examples and Intermediates were prepared analogously to what described for Example 16, step 3, by starting from the suitable Intermediate and the suitable, commercially available isocyanate (see Table 21). Table 21
Figure imgf000135_0002
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0002
Example 18: 1-(5-(tert-butyl)isoxazol-3-yl)-3-(2-(pyrazolo[1,5-a]pyrazine-3-carbonyl)- 2-azaspiro[3.3]heptan-6-yl)urea
Figure imgf000138_0001
Example 18 A solution of Intermediate 10 (50 mg, 0.194 mmol) and Intermediate 3 (51 mg, 0.194 mmol) in pyridine (1.00 mL) was stirred at 80 °C for 6 h. The reaction mixture was concentrated in vacuo and purified by preparative HPLC (Sunfire C1819x150 mm, 10 µm 5-60% ACN/H2O (10 mM NH4CO3), 20 mL/min, RT) to give the title compound (19 mg, 0.0458 mmol, 24 % yield). LCMS (ESI): Method 2, tR = 3.75 min, m/z (M+1) = 424.2 ¹H NMR (400 MHz, DMSO-d6) δ 9.55 (d, J=1.5 Hz, 1H), 9.26 (s, 1H), 8.91 (dd, J=1.3, 4.8 Hz, 1H), 8.44 (s, 1H), 8.11 (d, J=4.8 Hz, 1H), 6.74 (d, J=7.3 Hz, 1H), 6.33 (s, 1H), 4.59 - 4.44 (m, 2H), 4.15 - 4.01 (m, 3H), 2.59 - 2.52 (m, 2H), 2.19 - 2.11 (m, 2H), 1.27 - 1.26 (m, 9H). The following Examples were prepared analogously to what described for Example 18 by starting from the suitable Intermediates (see Table 22). Table 22
Figure imgf000138_0003
Figure imgf000139_0003
Example 20: 1-(5-(tert-butyl)isoxazol-3-yl)-3-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)- 2-azaspiro[3.3]heptan-6-yl)urea
Figure imgf000139_0001
Example 20 Step 1 tert-butyl (2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3] heptan-6- yl)carbamate (Intermediate 11)
Figure imgf000139_0002
To a solution of tert-butyl (2-azaspiro[3.3]heptan-6-yl)carbamate (350 mg, 1.65 mmol), pyrazolo[5,1-b]thiazole-7-carboxylic acid (277 mg, 1.65 mmol) and TCFH (463 mg, 1.65 mmol) in DMF (2.00 mL) 1-methyl-1H-imidazole (0.13 mL, 1.65 mmol) was added and the reaction mixture was stirred at rt overnight. Water was added and the product was extracted into EtOAc. The organic phase was dried over a hydrophobic frit and concentrated in vacuo to give the title compound (467 mg, 1.29 mmol, 78 % yield). LCMS (ESI): Method 4, tR = 1.39 min, m/z (M+1) = 363.1 The following Examples and Intermediate were prepared analogously to what described for Intermediate 11 by starting from the suitable Intermediates (see Table 23). Table 23
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0002
Step 2 - (6-amino-2-azaspiro[3.3]heptan-2-yl)(pyrazolo[5,1-b]thiazol-7-yl)methanone (Intermediate 12)
Figure imgf000146_0001
Intermediate 12 was prepared by following the procedure described for the synthesis of 5 Intermediate 7. SM: Intermediate 11: 467 mg (1 eq); TFA: 0.99 mL (10 eq) Amount/yield: 314 mg, 1.20 mmol, 93 % LCMS (ESI): Method 4, tR = 0.98 min, m/z (M+1) = 263.1 The following Intermediates were prepared analogously to what described for Intermediate , starting from suitable intermediate (see Table 24).
Table 24
Figure imgf000147_0001
Figure imgf000148_0002
Step 3 - 1-(5-(tert-butyl)isoxazol-3-yl)-3-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)urea (Example 20) Example 20 was prepared by following the procedure described for the synthesis of Intermediate 18. 5 SM: Intermediate 12: 50 mg (1 eq) ; Intermediate 3: 50 mg (1 eq) Amount/yield: 34 mg, 0.0799 mmol, 42 % LCMS (ESI): Method 2, tR = 3.97 min, m/z (M+1) = 429.3 ¹H NMR (400 MHz, DMSO-d6) δ 9.26 (s, 1H), 8.31 (d, J=4.3 Hz, 1H), 8.06 (s, 1H), 7.52 (dd, J=1.4, 4.2 Hz, 1H), 6.74 (d, J=7.6 Hz, 1H), 6.33 (s, 1H), 4.44 (d, J=44.9 Hz, 2H), 4.09 - 3.94 10 (m, 3H), 2.58 - 2.53 (m, 2H), 2.17 - 2.07 (m, 2H), 1.26 (s, 9H). Example 21: 1-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3- (3-(trifluoromethoxy) phenyl)urea
Figure imgf000148_0001
Step 1 - phenyl (2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6- 15 yl)carbamate (Intermediate 13)
Figure imgf000149_0001
To a suspension of Intermediate 12 (250 mg, 0.953 mmol) and Na2CO3 (61 mg, 0.572 mmol) in EtOAc (20.00 mL), THF (4.00 mL) and water (4.00 mL) cooled to 0 °C, phenyl chloroformate (0.13 mL, 1.05 mmol) was added dropwise. The resulting suspension was stirred at 0 °C for 20 min, then warmed up to rt. DMF (4 mL) was added and the reaction stirred for a further 16 h at rt. Water was added and product extracted into EtOAc. The organic phase was dried over a hydrophobic frit and concentrated in vacuo to give the title compound (420 mg, 0.769 mmol, 81 % yield). LCMS (ESI): Method 4, tR = 1.37 min, m/z (M+1) = 383.1 The following compounds were prepared analogously to what described for Intermediate 13, starting from suitable intermediates (see Table 25). Table 25
Figure imgf000149_0002
Step 2 - 1-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3- (trifluoromethoxy)phenyl)urea (Example 21) A solution of 3-(Trifluoromethoxy)aniline (0.035 mL, 0.261 mmol) and Intermediate 13 (100 mg, 0.261 mmol) in pyridine (1.00 mL) was stirred for 16 h at 120 °C. The reaction mixture was concentrated in vacuo. The residue was loaded onto an Isolute SCX-II cartridge and released with MeOH. The MeOH eluent was concentrated in vacuo and the residue purified by preparative HPLC (Sunfire C1819x150 mm, 10 µm 5-60% ACN/H2O (10 mM NH4CO3), 20 mL/minute) to give the title compound (5.7 mg, 0.0122 mmol, 5% yield). LCMS (ESI): Method 2, tR = 4.24 min, m/z (M+1) = 466.2 ¹H NMR (400 MHz, DMSO-d6) δ 8.76 (s, 1H), 8.31 (d, J=4.3 Hz, 1H), 8.07 (s, 1H), 7.63 (s, 1H), 7.52 (dd, J=1.3, 4.0 Hz, 1H), 7.32 (t, J=8.2 Hz, 1H), 7.21 (dd, J=1.6, 7.7 Hz, 1H), 6.87 - 6.84 (m, 1H), 6.61 (d, J=7.6 Hz, 1H), 4.55 - 4.34 (m, 1H), 4.10 - 4.00 (m, 3H), 2.58 - 2.53 (m, 2H), 2.17 - 2.10 (m, 2H). The following Examples and Intermediates were prepared analogously to what described for Example 21, step 2, by starting from the corresponding aniline/amine and suitable Intermediates (Table 26). Table 26
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0002
Example 25: 1-methyl-1-(2-(pyrazolo [1,5-a]pyrazine-3-carbonyl) -2- azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl) phenyl)urea
Figure imgf000153_0001
Step 1 – tert-butyl 6-(1-methyl-3-(3-(trifluoromethyl)phenyl)ureido)-2- 5 azaspiro[3.3]heptane-2-carboxylate (Intermediate 14)
Figure imgf000154_0001
Intermediate 14 was prepared by following the same procedure reported for the synthesis of Intermediate 6. SM: tert-butyl 6-(methylamino)-2-azaspiro[3.3]heptane-2-carboxylate: 300 mg (1 eq); 1-isocyanato-3-(trifluoromethyl)benzene (1 eq) Amount/yield: 478 mg, 1.16 mmol, 87 % LCMS (ESI): Method 4, tR = 1.76 min, m/z (M+1) = 414.1 Step 2 - 1-methyl-1-(2-azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Intermediate 15, compound IVa)
Figure imgf000154_0002
Intermediate 15 was prepared by following the procedure described for the synthesis of Intermediate 7. SM: Intermediate 14: 467 mg (1 eq); TFA: 0.99 mL (10 eq) Amount/yield: 314 mg, 1.20 mmol, 93 % LCMS (ESI): Method 4, tR = 1.40 min, m/z (M+1) = 314.1 ¹H NMR (400 MHz, DMSO-d6) δ 8.58 – 8.55 (m, 1H), 7.88 (s, 1H), 7.72 – 7.68 (m, 1H), 7.45 (t, J=8.0 Hz, 1H), 7.27 – 7.24 (m, 1H), 4.52 – 3.96 (m, 5H), 2.84 (s, 3H), 2.34 – 2.26 (m, 2H), 2.23 – 2.14 (m, 2H). Step 3 – 1-methyl-1-(2-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-2-azaspiro [3.3]heptan-6- yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 25) Example 25 was prepared by following the procedure described for the synthesis of Example 1, step 3. SM: Intermediate 15: 100 mg (1 eq); pyrazolo[1,5-a]pyrazine-3-carboxylic acid: 52 mg mL (1 eq) Amount/yield: 36 mg, 0.0790 mmol, 25 % LCMS (ESI): Method 4, tR = 4.11 min, m/z (M+1) = 459.6 ¹H NMR (400 MHz, DMSO-d6) δ 9.55 (d, J=1.5 Hz, 1H), 8.91 (dd, J=1.3, 4.8 Hz, 1H), 8.60 (s, 1H), 8.45 – 8.44 (m, 1H), 8.11 (d, J=4.8 Hz, 1H), 7.91 (s, 1H), 7.77 – 7.74 (m, 1H), 7.46 (t, J=8.0 Hz, 1H), 7.28 – 7.25 (m, 1H), 4.63 – 4.47 (m, 3H), 4.21 – 4.02 (m, 2H), 2.90 (s, 3H), 2.47 – 2.38 (m, 4H). The following Examples and Intermediates were prepared analogously to what described for Example 25, step 3, by starting from corresponding Intermediate and the suitable carboxylic acid (see Table 27). Table 27
Figure imgf000155_0001
Figure imgf000156_0001
Intermediate 77: 1-(2-azaspiro[3.3]heptan-6-yl)-1-(2,2,2-trifluoroethyl)-3-(3- (trifluoromethyl)phenyl)urea
Figure imgf000157_0001
Step 1- tert-butyl 6-((2,2,2-trifluoroethyl)amino)-2-azaspiro[3.3]heptane-2-carboxylate (Intermediate 78)
Figure imgf000157_0002
A solution of 2,2,2-trifluoroethan-1-amine (0.14 mg, 1.42 mmol, 1.20 eq) and tert-butyl 6- oxo-2-azaspiro[3.3]heptane-2-carboxylate (250 mg, 1.18 mmol) in MeOH (1.5 mL) was stirred at rt for 18 h. The reaction cooled to 0 °C and NaBH4 (0.067 mg, 1.8 mmol) was added and stirring continued at rt for 3 h. The reaction mixture was concentrated in vacuo and the residue partitioned between DCM and saturated Na2CO3. The organic extract was filtered through a hydrophobic frit and concentrated in vacuo. The title compound was used without further purification (350 mg, 1.18 mmol, quantitative). LCMS (ESI): Method 4, tR =1.57 min, m/z (M+1-tBu) = 239.2 The following Intermediate was prepared analogously to what described for Intermediate 78, by starting from corresponding Intermediate (see Table 28). Table 28
Figure imgf000157_0003
Step 2 - tert-butyl 6-(1-(2,2,2-trifluoroethyl)-3-(3-(trifluoromethyl)phenyl)ureido)-2- azaspiro[3.3]heptane-2-carboxylate (Intermediate 80)
Figure imgf000158_0001
Intermediate 80 was prepared by following the same procedure reported for the synthesis of Intermediate 6. SM: Intermediate 78: 350 mg (1 eq); 1-isocyanato-3-(trifluoromethyl)benzene: 0.163 mL (1 eq) Amount/yield: 127 mg, 22 % LCMS (ESI): Method 4, tR = 1.85 min, m/z (M+1-tBu) = 426.2 The following compound was prepared analogously to what described for Intermediate 80, by starting from suitable Intermediate (see Table 29). Table 29
Figure imgf000158_0002
Step 3 - 1-(2-azaspiro[3.3]heptan-6-yl)-1-(2,2,2-trifluoroethyl)-3-(3-(trifluoromethyl) phenyl)urea (Intermediate 77) Intermediate 77 was prepared by following the same procedure reported for the synthesis of Intermediate 7. SM: Intermediate 80: 127 mg (1 eq) Amount/yield: 100 mg, quantitative LCMS (ESI): Method 4, tR = 1.57 min, m/z (M+1) = 382.1 The following compound was prepared analogously to what described for Intermediate 77, by starting from suitable Intermediates (see Table 30). Table 30
Figure imgf000159_0003
Example 27: 2-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-N- (3-(trifluoromethyl)phenyl)acetamide
Figure imgf000159_0001
Step 1 - tert-butyl 6-(2-oxo-2-((3-(trifluoromethyl)phenyl)amino)ethyl)-2- azaspiro[3.3]heptane-2-carboxylate (Intermediate 16)
Figure imgf000159_0002
Intermediate 16 was prepared by following the procedure described for the synthesis of Example 1, step 3. SM: 2-(2-tert-butoxycarbonyl-2-azaspiro[3.3]heptan-6-yl)acetic acid: 300 mg (1 eq.); 3- (trifluoromethyl)aniline: 0.15 mL, (1 eq.) Amount/yield: 430 mg, 1.08 mmol, 92 % LC-MS (ESI): Method 1, tR = 1.75 min, m/z (M +H-tBu) = 343.0 The following compounds were prepared analogously to what described for Intermediate 16, by starting from suitable Intermediates (see Table 31). Table 31
Figure imgf000159_0004
Figure imgf000160_0002
Step 2 – 2-(2-azaspiro[3.3]heptan-6-yl)-N-[3-(trifluoromethyl) phenyl] acetamide (Intermediate 17, compound IVb)
Figure imgf000160_0001
Intermediate 17 was prepared by following the procedure described for the synthesis of Intermediate 7. SM: Intermediate 16: 430 mg (1 eq.); TFA: 1.7 ml, (20 eq) Amount/yield: 230 mg, 0.270 mmol, 25 % LC-MS (ESI): Method 1 tR = 1.30 min, m/z (M+1) = 299.0 The following compounds were prepared analogously to what described for Intermediate 17, by starting from suitable Intermediates (see Table 32). Table 32
Figure imgf000160_0003
Figure imgf000161_0001
Step 3 – 2-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-N-(3- (trifluoromethyl)phenyl)acetamide (Example 27) Example 27 was prepared by following the procedure described for the synthesis of Example 1, step 3. SM: Intermediate 17: 230 mg (1 eq.); pyrazolo[5,1-b]thiazole-7-carboxylic acid: 45 mg, (1 eq.) Amount/yield: 31 mg, 0.0694 mmol, 26 % LC-MS (ESI): Method 3 tR = 4.35 min, m/z (M+1) = 449.2 ¹H NMR (400 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.31 (d, J=4.3 Hz, 1H), 8.08 (d, J=10.8 Hz, 2H), 7.76 (d, J=8.8 Hz, 1H), 7.56 - 7.51 (m, 2H), 7.38 (d, J=7.8 Hz, 1H), 4.49 - 4.37 (m, 2H), 4.06 - 3.96 (m, 2H), 2.61 - 2.52 (m, 1H), 2.46 (d, J=7.6 Hz, 2H), 2.42 - 2.34 (m, 2H), 2.01 - 1.94 (m, 2H). The following compounds were prepared as described for Example 27, step 3, by starting from Intermediate 17 and the suitable carboxylic acid (see Table 33). Table 33
Figure imgf000162_0002
Example 47: 1-methyl-1-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea
Figure imgf000162_0001
Example 47 To a stirred solution of triphosgene (258 mg, 0.87 mmol) in DCM (2 mL) at 0 °C was added a solution of 5-(trifluoromethyl)pyridin-3-amine (94 mg, 0.579 mmol, 2.00 eq) and Et3N (0.12 mL, 0.87 mmol) in DCM (2 mL) dropwise, the reaction was then stirred at 0 °C for 1 h. Intermediate 68 (80 mg, 0.289 mmol, 1.00 eq) and Et3N (0.16 mL, 1.15 mmol) in DCM were added dropwise, then after addition the reaction was allowed to warm to rt and the reaction was stirred overnight. The reaction mixture was diluted with DCM and washed with NaHCO3 and brine. The organic phase was dried over MgSO4 and concentrated in vacuo. The crude residue was purified by FCC (0 – 10% MeOH in DCM) to give the title compound (20.7 mg, 0.045 mmol, 15%). LCMS (ESI): Method 3, tR =3.72 min, m/z (M+1) = 465.2 ¹H NMR (400 MHz, DMSO-d6) δ 8.94 (d, J=2.3 Hz, 1H), 8.84 (s, 1H), 8.52 (d, J=1.0 Hz, 1H), 8.31 (dd, J=3.8, 3.8 Hz, 2H), 8.07 (s, 1H), 7.53 (dd, J=1.4, 4.2 Hz, 1H), 4.62 – 4.36 (m, 3H), 4.17 – 3.96 (m, 2H), 2.92 (s, 3H), 2.47 – 2.39 (m, 4H). Analogously, the following Examples were prepared as described for Example 47 by starting from suitable Intermediate (see Table 34). Table 34
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0002
Example 146: 2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl (5-(trifluoromethyl)pyridin-3-yl)carbamate
Figure imgf000165_0001
Example 146 Intermediate 56 (120 mg, 0.46 mmol) was dissolved in DCM (2 mL) and added to 4- nitrophenyl chloroformate (112 mg, 0.553 mmol) and pyridine (0.056 mL). Solution was stirred at rt for 2 h, then solvent was removed under vacuum. The solid was dissolved in 1 mL pyridine and added of 5-(trifluoromethyl)pyridin-3-amine (90 mg, 0.55 mmol) and solution was stirred at 60 °C. Then solvent was removed under vacuum. The solid was dissolved in DCM and washed with NaHCO3 sat. solution. After purification by RF FCC, appropriate fractions were combined and concentrated, aqueous phase was quenched with NaHCO3 sat solution and extracted with DCM and MeTHF. Organic layer was evaporated to give title product (45 mg, 0.10 mmol, 22 % yield). LCMS (ESI): Method 5, tR =5.23 min, m/z (M+1) = 449.30 1H NMR (400 MHz, DMSO-d6) δ ppm 10.33 (1 H, s), 8.84 (1 H, d, J=2.19 Hz), 8.60 (1 H, s), 8.27 (1 H, br s), 7.76 (1 H, d, J=1.10 Hz), 7.66 (1 H, d, J=2.19 Hz), 7.26 (1 H, dd, J=1.97, 1.10 Hz), 4.92 (1 H, m), 4.32 (4 H, m), 3.96 (3 H, s), 2.70 (2 H, td, J=6.96, 3.62 Hz), 2.32 (2 H, m). The following Example was prepared analogously to what described for Example 146 by starting from suitable Intermediate (see Table 35).
Table 35
Figure imgf000167_0003
Intermediate 154: (benzyl (2-(1-(2-methoxyethyl)-1H-imidazo[1,2-b]pyrazole-7- carbonyl)-2-azaspiro[3.3]heptan-6-yl)(methyl)carbamate)
Figure imgf000167_0001
Intermediate 154 was prepared by following the procedure for Intermediate 30, starting from Intermediate 132 (860 mg, 3.6 mmol) and 2-bromoethyl methyl ether (0.3 ml, 5.5 mmol). Amount/yield: 430 mg, 0.95 mmol mmol, 44 % LC-MS (ESI): Method 7, tR = 0.95 min, m/z (M+1) = 452.25 Intermediate 155: (1-(2-methoxyethyl)-1H-imidazo[1,2-b]pyrazol-7-yl)(6- (methylamino)-2-azaspiro[3.3]heptan-2-yl)methanone
Figure imgf000167_0002
In a screwable two-chamber glass sytem, Intermediate 154 was dissolved in ethanol (5 mL) then Pd/C (50% wet) (10.13 mg, 0.05 mmol) was splitted in both chambers.The vessel was closed and 3 cycle vacuum-N2 was performed to set the reaction. Triethylsilane (1.52 ml, 9.5 mmol) was added slowly to chamber 1 and then the reaction was stirred at rt for 2h. The reaction mixture was filtered on a paper filter to removed the catalyst,washing with EtOH and then the organic phase was concentrated under vaccum to afford the title product (260 mg, 0.82 mmol, 86 %). LCMS (ESI): Method 7, tR =0.31 min, m/z (M+1) = 318.17 The following compound was prepared according to the same synthetic procedure (see Table 36). Table 36
Figure imgf000168_0003
Intermediate 157: tert-butyl 6-(((benzyloxy)carbonyl)(methyl)amino)-2- azaspiro[3.3]heptane-2-carboxylate
Figure imgf000168_0001
To a stirred solution of tert-butyl 6-(((benzyloxy)carbonyl)amino)-2-azaspiro[3.3]heptane- 2-carboxylate (30.7 g, 89 mmol) in DMF (296 mL) was added NaH (60% in mineral oil) (7.10 g, 178 mmol). After 15 min of stirring the MeI (16.58 ml, 266 mmol) was added and the reaction mixture was stirred at rt for 1h. Then the mixture was diluted with water and extracted with AcOEt. Organic layer was dried over Na2SO4 and concentrated, to give title compound (33.6 g, quantitative). LC-MS (ESI): Method 10 tR = 2.56 min, m/z (M+1) = 361.15 1H NMR (300 MHz, Chloroform-d) δ 7.35 (s, 5H), 5.11 (s, 2H), 3.94 (s, 2H), 3.83 (s, 2H), 2.83 (s, 3H), 2.37 (ddt, J = 10.2, 7.7, 2.6 Hz, 2H), 2.26 (td, J = 9.6, 2.7 Hz, 2H), 1.42 (s, 9H). Intermediate 83: (1-methyl-1H-imidazo[1,2-b]pyrazol-7-yl)(6-((methyl-d3)amino)-2- azaspiro[3.3]heptan-2-yl)methanone
Figure imgf000168_0002
Step 1 - benzyl (methyl-d3)(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3] heptan-6-yl)carbamate (Intermediate 84)
Figure imgf000169_0001
A solution of Intermediate 51 (250 mg, 0.635 mmol) in THF (2.0 mL) was added dropwise under a nitrogen atmosphere to a slurry of sodium hydride (60% suspension in mineral oil, 51 mg, 1.3 mmol) in THF (0.50 mL). The mixture was stirred at rt for 2 h, then iodomethane-d3 (0.40 mL, 6.4 mmol) was added dropwise. The reaction was then stirred at rt for 18 h. The mixture was carefully quenched with water and was diluted with brine and partitioned with EtOAc. Organic layer was washed with brine, dried over MgSO4, filtered and solvents removed in vacuo. The crude was purified by FCC (40 g silica gel, 0-10% MeOH in DCM) to yield the title compound (247 mg, 0.60 mmol, 95%). LC-MS (ESI): Method 1, tR = 1.44 min, m/z (M+1) = 411.3 The following compound was prepared analogously to what described for Intermediate 84, by starting from suitable Intermediate (see Table 37). Table 37
Figure imgf000169_0002
Step 2 – (1-methyl-1H-imidazo[1,2-b]pyrazol-7-yl)(6-((methyl-d3)amino)-2- azaspiro[3.3]heptan-2-yl)methanone (Intermediate 83) A suspension of Intermediate 84 (247 mg, 0.602 mmol) and palladium (10% on carbon, 64 mg, 0.0602 mmol) in EtOH (5.0 mL) was subjected to cycles of vacuum/nitrogen, followed by cycles of vacuum/hydrogen before being subjected to 1 atmosphere of hydrogen gas. The reaction was stirred at rt for 18 h. The mixture was filtered on Celite® washing with EtOAc and solvents were removed in vacuo to yield the title compound (161 mg, 0.583 mmol, 97 %) which was used without any further purification. LC-MS (ESI): Method 1 tR = 1.04 min, m/z (M+1) =277.2 Intermediate 86: 1-(2-methoxy-5-(trifluoromethoxy)phenyl)-3-(2azaspiro[3.3]heptan- 6-yl)urea
Figure imgf000170_0001
Step 1 - tert-butyl 6-(3-(2-methoxy-5-(trifluoromethoxy)phenyl)ureido)-2- azaspiro[3.3]heptane-2-carboxylate (Intermediate 87)
Figure imgf000170_0002
A solution of 2,2,2-trichloroethyl (2-methoxy-5-(trifluoromethoxy)phenyl)carbamate (649 mg, 1.70 mmol), tert-butyl 6-amino-2-azaspiro[3.3]heptane-2-carboxylate (300 mg, 1.41 mmol) and DIPEA (0.74 mL, 4.24 mmol) in ACN (5.0 mL) was stirred under microwave radiation at 150 °C for 30 minutes, then cooled and concentrated in vacuo to give the title compound (882 mg, 1.98 mmol, quant.). LC-MS (ESI): Method 1 tR = 1.76 min, m/z (M+1-tBu) = 390.1 The following Intermediates were prepared analogously to the procedure described for Intermediate 87 (see Table 38). Table 38
Figure imgf000170_0003
Figure imgf000171_0001
Figure imgf000172_0001
Step 2 - l-(2-methoxy-5-(trifluoromethoxy)phenyl)-3-(2-azaspiro[3.3]heptan-6- yl)urea (Intermediate 86)
Intermediate 86 was prepared by following the procedure described for Intermediate 7.
SM: Previous Intermediate: 882 mg (1 eq); TFA: 3.0 mL (20 eq) Amount/yield: 450 mg, 1.79 mmol, 66 %
LC-MS (ESI): Method 1 tR = 1.32 min, m/z (M+1-) = 346.0
The following compounds were prepared analogously to what described for Intermediate 86, starting from previously described intermediates (see Table 39).
Table 39
Figure imgf000172_0002
Figure imgf000173_0001
Figure imgf000174_0002
Intermediate 172: benzyl methyl(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)- 2-azaspiro[3.3]heptan-6-yl)carbamate
Figure imgf000174_0001
1-methyl-1H-imidazo[1,2-b]pyrazole-7-carboxylic acid (0.866 g, 5.2 mmol) was dissolved in DMF (25 mL) and then added of CDI. Solution was stirred a rt until formation of activated ester then Intermediate 167 (1.3 g, 5 mmol) was added to the solution and stirred at rt on. Solution was then diluted with EtOAc and washed with NaHCO3 sat solution. Organic phase was then evaporated under vacuum and purified by FCC (Sfar NH, from 100% of n-heptane to 40% of EtOac/EtOH 3:1). Appropriate fractions were combined and evaporated under vacuum to give title compound (550 mg, 1.3 mmol, 27 % yield). LCMS (ESI): Method 2, tR =0.92 min, m/z (M+1) = 408.19 Intermediate 173: tert-butyl 6-(((benzyloxy)carbonyl)amino)-2-azaspiro[3.3]heptane- 2-carboxylate
Figure imgf000175_0001
Tert-butyl 6-amino-2-azaspiro[3.3]heptane-2-carboxylate (30 g, 141 mmol)) and triethylamine (21.7 ml, 155 mmol) were dissolved in DCM (70 mL), the solution was cooled at - 5°C and stirred for 10 min, then N-(benzyloxycarbonyloxy)succinimide (37.0 g, 148 mmol) was added carefully. The reaction mixture was stirred at rt until completion, then it was washed with sol. NH4Cl and HCl 0.5N, the organic layer was dried over MgSO4, filtered and essicated to afford title compound (48 g, 139 mmol, 98 % yield). LCMS (ESI): Method 2, tR =0.92 min, m/z (M+1) = 408.19 Example 52: 3-(2-methoxy-5-(trifluoromethoxy)phenyl)-1-methyl-1-(2-(1-methyl-1H- imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea
Figure imgf000175_0002
Example 52 To a stirred solution of Intermediate 57 (70 mg, 0.26 mmol) and 2,2,2-trichloroethyl (2- methoxy-5-(trifluoromethoxy)phenyl)carbamate (147 mg, 0.38 mmol) in ACN (3 mL) DIPEA (0.13 mL, 0.77 mmol) was added and the reaction mixture was heated to 150 °C in the microwave for 30 min. The reaction mixture was concentrated in vacuo to dryness. The crude residue was purified by preparative HPLC (Sunfire C1819x150 mm, 10 µm 20-80% ACN/H2O (0.1% FA), 20 mL/minute) to give the title compound (73 mg, 0.144 mmol, 56% yield). LCMS (ESI): Method 2, tR =4.42 min, m/z (M+1) = 507.2 ¹H NMR (400 MHz, DMSO-d6) δ 8.00 (d, J=2.0 Hz, 1H), 7.83 (s, 1H), 7.72 (d, J=2.0 Hz, 1H), 7.51 (s, 1H), 7.32 (d, J=1.3 Hz, 1H), 7.13 (d, J=8.8 Hz, 1H), 7.01 (dd, J=2.3, 8.8 Hz, 1H), 4.58 - 4.48 (m, 1H), 4.39 - 4.08 (m, 4H), 4.02 (s, 3H), 3.94 (s, 3H), 2.94 (s, 3H), 2.54 - 2.37 (m, 4H). The following Examples and intermediates were prepared analogously to what described for Example 52 using ACN or DMF as solvent, at a temperature varying from 80 to 150 °C, starting from suitable Troc carbamates and Intermediate (see Table 40) Table 40
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
Figure imgf000189_0001
Figure imgf000190_0001
Figure imgf000191_0001
Figure imgf000192_0001
Figure imgf000193_0001
Figure imgf000194_0001
Figure imgf000195_0001
Figure imgf000196_0001
Figure imgf000197_0001
Figure imgf000198_0001
Figure imgf000199_0001
Figure imgf000200_0001
Figure imgf000201_0001
Figure imgf000202_0001
Figure imgf000203_0001
Figure imgf000204_0002
Example 292: 2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl(6- (trifluoromethyl)pyrimidin-4-yl)carbamate
Figure imgf000204_0001
To a stirred solution of (6-hydroxy-2-azaspiro[3.3]heptan-2-yl)(pyrazolo[5,1-b]thiazol-7- yl)methanone (100 mg, 0.380 mmol) in DMF (1 mL) sodium hydride (45 mg, 1.1 mmol) was added and the mixture was stirred for 20 minutes, then 2,2,2-trichloroethyl (6- (trifluoromethyl)pyrimidin-4-yl)carbamate (231 mg, 0.684 mmol) was added and the mixture was stirred overnight. The crude was purified by preparative HPLC (Xbridge C1819x150mm, 10um 20-80% ACN / H2O (10 mM NH4CO3), 20 mL/min, r.t.) to give the title compound (48 mg, 0.105 mmol, 28% yield). LCMS (ESI): Method 11, tR = 3.84 min, m/z (M+1) = 453.4 ¹H NMR (400 MHz, DMSO-d6) δ 11.37 (bs, 1H), 9.02 (s, 1H), 8.31 (d, J=4.1 Hz, 1H), 8.20 – 8.18 (m, 1H), 8.07 – 8.05 (m, 1H), 7.54 – 7.51 (m, 1H), 4.99 - 4.92 (m, 1H), 4.49 - 4.49 (m, 2H), 4.07 - 4.07 (m, 2H), 2.76 - 2.68 (m, 2H), 2.39 - 2.31 (m, 2H). The following Examples were prepared analogously to what described for Example 292 (Table 41). Table 41
Figure imgf000205_0001
Figure imgf000206_0002
Example 202: 1-(2-(1-(2-methoxyethyl)-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-1-methyl-3-(4-(trifluoromethoxy)pyridin-2-yl)urea
Figure imgf000206_0001
Intermediate 155 was dissolved in DMF (1 mL) then DIPEA (0.235 mL, 1.34 mmol) was added, followed by addition of phenyl (4-(trifluoromethoxy)pyridin-2-yl)carbamate (66.8 mg, 0.22 mmol) at 0° C. The reaction was stirred at rt for 12h. The reaction was diluted with EtOAc and then washed with brine. The organic layer was concentrated under vacuum. The crude was purified by RF FCC to give the title compound (20 mg, 0.04 mmol, 17% yield). LCMS (ESI): Method 5, tR =5.88 min, m/z (M+1) = 522.50 1H NMR (400 MHz, DMSO-d6) δ ppm 9.31 (1 H, s), 8.34 (1 H, d, J=5.70 Hz), 7.83 (1 H, s), 7.77 (1 H, s), 7.65 (1 H, d, J=2.19 Hz), 7.27 (1 H, m), 6.98 (1 H, m), 4.60 (3 H, m), 4.13 (4 H, m), 3.60 (2 H, t, J=5.15 Hz), 3.21 (3 H, s), 2.89 (3 H, s), 2.38 (4 H, m). Example 182: 1-(2-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)- 2-azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea
Figure imgf000207_0001
Example 182 In a reactor, Intermediate 53 (0.100 g, 0.19 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrazole (0.040 g, 0.19 mmol) and K2CO3 (0.066 g, 0.48 mmol) were placed and dioxane (0.55 mL) was added via syringe under argon atmosphere. Solution was filled with argon, next Pd(dppf)Cl2 (0.014 g, 0.019 mmol) was added. The tube was sealed and heated overnight at 110 °C. The reaction mixture was diluted with water and extracted with DCM. Organic layer was washed with water, brine, dried over Na2SO4 and concentrated on rotary evaporator. The crude material was purified via FCC (DCM/MeOH from 100/0 to 90/10) to give the title compound (20 mg, 0.038 mmol, 20% yield). LCMS (ESI): Method 8, tR =3.45 min, m/z (M+1) = 524.23 1H NMR (400 MHz, DMSO-d6) δ 9.10 (t, J = 1.3 Hz, 1H), 8.75 (s, 1H), 8.27 (d, J = 10.3 Hz, 2H), 8.17 (dd, J = 9.1, 1.0 Hz, 1H), 8.03 (d, J = 0.8 Hz, 1H), 7.94 (d, J = 2.2 Hz, 1H), 7.75 (dd, J = 9.2, 1.6 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 7.44 (t, J = 7.9 Hz, 1H), 7.22 (d, J = 7.6 Hz, 1H), 6.58 (d, J = 7.6 Hz, 1H), 4.48 (d, J = 47.4 Hz, 2H), 4.06 (td, J = 17.7, 17.3, 9.3 Hz, 3H), 2.59 – 2.52 (m, 2H), 2.15 (dd, J = 12.0, 8.7 Hz, 2H). Example 192: 1-(2-(1-methyl-3-morpholino-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea
Figure imgf000207_0002
An ElectraSyn vial (5 mL) with a stir bar was charged with dibromonickel;1-methoxy-2-(2- methoxyethoxy)ethane (84 mg, 0.24 mmol), 2,2'-bipyridine (111 mg, 0.71 mmol), TBAB (2.38 ml, 0.48 mmol), Intermediate 52 (250 mg, 0.48 mmol), morpholine (0.062 ml, 0.71 mmol), DBU (0.143 ml, 0.95 mmol) and DMA (6 mL). The vial was closed with an ElectraSyn 2.0 vial cap equipped with anode ((+)RVC, 47 mm x 8 mm x 2 mm) and cathode ((-)Ni foam, 0.8 cm x 4.7 x 0.1 cm) inserted into the mixture. The vial was then evacuated and backfilled with an argon balloon. The reaction mixture was electrolyzed under a constant current of 4 mA until complete consumption of the starting material as judged by LC-MS. Then, the ElectraSyn vial cap was removed and electrodes were rinsed with a mixture of EtOAc:hexanes = 1:1, which was combined with the crude mixture. Aqueous sat. NH4Cl was then added to the combined solutions; the resulting solution was extracted with a mixture of EtOAc:hexanes = 1:1. The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The crude material was purified by RF FCC to give the desired product (4 mg, 0.008 mmol, 2 % yield). LCMS (ESI): Method 5, tR =5.82 min, m/z (M+1) = 532.40 1H NMR (600 MHz, DMSO-d6) δ ppm 8.88 (1 H, br s), 7.94 (1 H, s), 7.75 (1 H, m), 7.51 (1 H, m), 7.43 (1 H, t, J=7.92 Hz), 7.21 (1 H, br d, J=7.63 Hz), 6.69 (1 H, br d, J=7.34 Hz), 6.62 (1 H, d, J=1.03 Hz), 4.03 (2 H, m), 3.89 (2 H, s), 4.16 (4 H, m), 3.76 (3 H, m), 3.10 (3 H, m), 2.52 (2 H, m), 2.12 (2 H, td, J=9.13, 2.71 Hz). Example 227: 1-(2-(6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine- 3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-1-methyl-3-(5-(trifluoromethyl)pyridin-3-yl)urea
Figure imgf000208_0001
To a suspension of Intermediate 129 (70 mg, 0.13 mmol) and 1-(2-methoxyethyl)-4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (49.3 mg, 0.195 mmol) in Me-THF (1.5 mL), potassium phosphate tribasic (69 mg, 0.33 mmol) was added. After applying three N2/vacuum cycles, tetrakis(triphenylphosphine)palladium(0) polymer bound (15.05 mg, 0.013 mmol) was added and the vial was sealed. The reaction was heated at 75 °C for 12h. EtOAc and brine were added and the organic layer was concentrated under vacuum.The crude was purified by RF FCC to give title compound (28 mg, 0.05 mmol, 37 % yield). LCMS (ESI): Method 5, tR =5.66 min, m/z (M+1) = 583.50 1H NMR (400 MHz, DMSO-d6) δ ppm 9.12 (1 H, s), 8.94 (1 H, d, J=2.41 Hz), 8.85 (1 H, s), 8.52 (1 H, s), 8.32 (1 H, s), 8.31 (1 H, t, J=1.97 Hz), 8.26 (1 H, s), 8.18 (1 H, d, J=9.17 Hz), 8.06 (1 H, s), 7.77 (1 H, dd, J=9.32, 1.43 Hz), 4.56 (3 H, m), 4.29 (2 H, t, J=5.26 Hz), 4.05 (2 H, m), 3.72 (2 H, t, J=5.26 Hz), 3.25 (3 H, s), 2.93 (3 H, s), 2.43 (4 H, m) The following Examples were prepared analogously to what described for Example 227, using XPhos Pd G3, starting from corresponding intermediate (see Table 42). Table 42
Figure imgf000209_0001
Figure imgf000210_0001
Figure imgf000211_0001
Figure imgf000212_0001
The following compounds of formula (I) were prepared by applying the experimental conditions described above: 1-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(2-(pyrazolo[5,1- b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea; 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(4- (2-morpholinoethoxy)-3-(trifluoromethyl)phenyl)urea; 1-(2-(6,7-dihydro-5H-pyrrolo[1,2-a]imidazole-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3- (3-(trifluoromethyl) phenyl)urea; 1-(3-fluorophenyl)-3-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6- yl)urea; 1-(2-(2,3-dihydro-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3- (3-(trifluoromethyl)phenyl)urea; 1-(2-(1-methyl-2,3-dihydro-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea; 1-(3-fluorophenyl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)urea; 1-(2-(pyrazolo[1,5-a]pyrimidine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoro- methyl)phenyl)urea; 1-(2-(pyrazolo[1,5-a]pyrimidine-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoro- methyl)phenyl)urea; 1-(3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7- carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea; 1-(5-(tert-butyl)-1-methyl-1H-pyrazol-3-yl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7- carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea; 1-(5-cyclopropylpyridin-3-yl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)urea; 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(2- (trifluoromethyl)pyridin-4-yl)urea; 1-(5-cyanopyridin-3-yl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)urea; 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(4- (trifluoromethyl)pyrimidin-2-yl)urea; 1-(2-(5-oxo-4,5-dihydropyrazolo[1,5-a]pyrimidine-3-carbonyl)-2-azaspiro[3.3]heptan-6- yl)-3-(3-(trifluoromethyl)phenyl)urea; 1-(3-(tert-butyl)-1-(pyridin-3-yl)-1H-pyrazol-5-yl)-3-(2-(1-methyl-1H-imidazo[1,2- b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea; 1-(2-(1-(2-(dimethylamino)ethyl)-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea; 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3- (4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)urea; 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3- (methylsulfonyl)-5-(trifluoromethyl)phenyl)urea; 1-(2-((1-acetylazetidin-3-yl)oxy)-5-(trifluoromethyl)phenyl)-3-(2-(1-methyl-1H- imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea; 1-(2-((1-acetylpiperidin-4-yl)oxy)-5-(trifluoromethyl)phenyl)-3-(2-(1-methyl-1H- imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea; 1-(2-(pyrazolo[1,5-a]pyrazin-3-yl)-2-azaspiro[3.3]heptan-6-yl)-3-(3- (trifluoromethyl)phenyl)urea; 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3- (2,2,2-trifluoro-1-hydroxyethyl)phenyl)urea; 1-(2-(2,3-dihydropyrazolo[5,1-b]oxazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3- (trifluoromethyl)phenyl)urea; 1-(2-(imidazo[2,1-b]thiazole-2-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3- (trifluoromethyl)phenyl)urea; 1-(2-(7-methylthieno[3,2-d]pyrimidine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3- (trifluoromethyl)phenyl)urea; 1-(2-(1-methyl-1H-pyrrolo[2,3-c]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3- (trifluoromethyl)phenyl)urea; 1-(2-(pyrazolo[1,5-a]pyrimidin-6-yl)-2-azaspiro[3.3]heptan-6-yl)-3-(3- (trifluoromethyl)phenyl)urea; 1-(2-(pyrazolo[1,5-a]pyridin-3-yl)-2-azaspiro[3.3]heptan-6-yl)-3-(3- (trifluoromethyl)phenyl)urea; 1-(2-(thieno[3,2-b]pyridin-6-yl)-2-azaspiro[3.3]heptan-6-yl)-3-(3- (trifluoromethyl)phenyl)urea; 1-(2-(imidazo[2,1-b]thiazole-6-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3- (trifluoromethyl)phenyl)urea; 1-(5-isopropylpyridin-3-yl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)urea; 1-(cyclopropylmethyl)-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea; 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(6- (trifluoromethyl)pyrazin-2-yl)urea; 1-(5-(difluoromethyl)pyridin-3-yl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7- carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea; 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3- (S-(trifluoromethyl)sulfonimidoyl)phenyl)urea; 1-(5-(tert-butyl)pyridin-3-yl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)urea; 1-(3-(hydroxymethyl)-2-methoxy-5-(trifluoromethyl)phenyl)-3-(2-(1-methyl-1H- imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea; 1-(2-(1H-pyrazolo[3,4-b]pyridine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(2-methyl-5- (trifluoromethyl)pyridin-3-yl)urea; 1-methyl-3-(2-methyl-5-(trifluoromethyl)pyridin-3-yl)-1-(2-(pyrazolo[5,1-b]thiazole-7- carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea; 1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6- yl)-3-(2-methyl-5-(trifluoromethyl)pyridin-3-yl)urea; 1-isobutyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan- 6-yl)-3-(3-(trifluoromethyl)phenyl)urea; 1-methyl-1-(2-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(6- (trifluoromethyl)pyrimidin-4-yl)urea; 1-(5-(1,1-difluoroethyl)pyridin-3-yl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7- carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea; 1-(2-(1H-pyrazolo[3,4-b]pyridine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-1-methyl-3-(5- (trifluoromethyl)pyridin-3-yl)urea; 1-(2-(1H-pyrazolo[3,4-b]pyridine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-1-methyl-3-(6- (trifluoromethyl)pyrimidin-4-yl)urea; 1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6- yl)-3-(5-(trifluoromethoxy)pyridin-2-yl)urea; 1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6- yl)-3-(6-(trifluoromethoxy)pyridin-3-yl)urea; 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(5- (trifluoromethoxy)pyridin-2-yl)urea; 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(6- (trifluoromethoxy)pyridin-3-yl)urea; 1-(2-(1-(cyanomethyl)-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6- yl)-3-(3-(trifluoromethyl)phenyl)urea; 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(6- (trifluoromethyl)pyridazin-4-yl)urea; 1-methyl-3-(2-methyl-5-(trifluoromethoxy)phenyl)-1-(2-(pyrazolo[1,5-a]pyrazine-3- carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea; 1-(2-(1H-pyrazolo[3,4-b]pyridine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-1-methyl-3-(5- (trifluoromethoxy)pyridin-3-yl)urea; 1-(6-methyl-2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6- yl)-3-(3-(trifluoromethyl)phenyl)urea; 1-(2-(1H-pyrazolo[3,4-b]pyridine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-1-methyl-3-(4- (trifluoromethyl)pyridin-2-yl)urea; 1-methyl-1-(2-(pyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(6- (trifluoromethyl)pyrimidin-4-yl)urea; 1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6- yl)-3-(1-methyl-2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)urea; 1-(2-(1-((methylsulfonyl)methyl)-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea; 1-(2-(1-(2-hydroxyethyl)-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6- yl)-1-methyl-3-(3-(trifluoromethyl)phenyl)urea; 1-(2-(1-((2-methoxyethoxy)methyl)-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-1-methyl-3-(5-(trifluoromethyl)pyridin-3-yl)urea; 3-(2-methoxy-5-(trifluoromethyl)phenyl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2- b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea; 1-(2-(6-aminopyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-1-methyl- 3-(5-(trifluoromethyl)pyridin-3-yl)urea; 3-(3-cyclopropylisoxazol-5-yl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7- carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea; 1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6- yl)-3-(3-(trifluoromethyl)isoxazol-5-yl)urea; 1-methyl-1-(2-(thieno[3,2-d]pyrimidine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(5- (1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea; 1-methyl-1-(2-(pyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(5- (1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea; 1-methyl-3-(1-methyl-2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)-1-(2- (pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea; 3-(3-fluoro-4-(trifluoromethyl)pyridin-2-yl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2- b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea; 1-methyl-1-(2-(thieno[3,2-d]pyrimidine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(6- (trifluoromethyl)pyrimidin-4-yl)urea; 1-(2-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(4- bromopyridin-2-yl)-1-methylurea; 1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6- yl)-3-(1-methyl-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-3-yl)urea; 2-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-N-(6- (trifluoromethyl)pyrimidin-4-yl)acetamide; 2-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-N-(4- (trifluoromethoxy)pyridin-2-yl)propanamide; 2-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-N-(4- (trifluoromethoxy)pyridin-2-yl)propanamide; 2-methyl-2-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6- yl)-N-(4-(trifluoromethoxy)pyridin-2-yl)propanamide; 1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6- yl)-3-(1-methyl-5-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-3-yl)urea; 1-methyl-1-(2-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine-3-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(4-(trifluoromethyl)pyridin-2-yl)urea; 1-(2-(5-fluoro-1H-pyrrolo[2,3-b]pyridine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-1- methyl-3-(3-(trifluoromethyl)phenyl)urea; 3-(5-bromopyridazin-3-yl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7- carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea; 1-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)-2-azaspiro[3.3]heptan-6-yl)-3-(4-bromopyridin-2- yl)urea; 1-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)-2-azaspiro[3.3]heptan-6-yl)-3-(6- (trifluoromethyl)pyrimidin-4-yl)urea; 1-(2-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-1-methyl-3-(4- (trifluoromethyl)pyridin-2-yl)urea; 1-methyl-3-(2-methyl-6-(trifluoromethyl)pyrimidin-4-yl)-1-(2-(thieno[3,2-d]pyrimidine-4- carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea; 1-methyl-3-(5-(perfluoroethyl)pyridazin-3-yl)-1-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)- 2-azaspiro[3.3]heptan-6-yl)urea and 1-methyl-1-(2-(thieno[3,2-d]pyrimidine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(5- (trifluoromethyl)pyridazin-3-yl)urea. Comparative newly synthesized compounds C1, C2 and C3 were prepared as described below. C1 is characterized by having a -CO-NH- linker replacing the -NH-CO-L1- linker of the compounds of the invention. C2 is characterized by having a -CH2-CO-NH- linker replacing the -NH-CO-L1- linker of the compounds of the invention. C3 is characterized by having a structure XXIII
Figure imgf000218_0001
wherein the central core
Figure imgf000218_0002
of the compounds of formula (I) has been flipped (for Rs being hydrogen). Compound C1: N-(2-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-2-azaspiro[3.3] heptan-6- yl)-3-(trifluoromethyl) benzamide
Figure imgf000218_0003
Compound C1 was prepared by following the procedure described for the synthesis of Example 1, step 3. SM: Intermediate 10: 50 mg (1 eq); 3-(trifluoromethyl)benzoic acid: 37 mg (1 eq) Amount/yield: 23 mg, 0.0544 mmol, 28 % LCMS (ESI): Method 3, tR 3.73 min, m/z (M+1) = 430.2 ¹H NMR (400 MHz, DMSO-d6) δ 9.55 (d, J=1.5 Hz, 1H), 8.92 - 8.87 (m, 2H), 8.46 (s, 1H), 8.19 (s, 1H), 8.15 (d, J=8.1 Hz, 1H), 8.11 (d, J=4.8 Hz, 1H), 7.91 (d, J=7.6 Hz, 1H), 7.72 (t, J=7.7 Hz, 1H), 4.56 (d, J=52.8 Hz, 1H), 4.38 - 4.33 (m, 1H), 4.13 (d, J=50.2 Hz, 1H), 2.68 - 2.58 (m, 2H), 2.39 - 2.31 (m, 2H). Compound C2 (N-(2-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-2-azaspiro[3.3] heptan-6- yl)-2-(3-(trifluoromethyl)phenyl)acetamide) was prepared analogously to what described for Compound C1 by starting from commercially available 2-(3-(trifluoromethyl)phenyl)acetic acid (see Table 43). Table 43
Figure imgf000219_0004
Compound C3: N-(2-((3-(trifluoromethyl)phenyl)carbamoyl)-2-azaspiro [3.3]heptan- 6-yl)pyrazolo[1,5-a]pyrazine-3-carboxamide (compound of formula XX, wherein L is CO and L1 is NR, wherein R is hydrogen)
Figure imgf000219_0001
Step 1 - tert-butyl (2-((3-(trifluoromethyl)phenyl)carbamoyl)-2-azaspiro [3.3]heptan-6- yl)carbamate (Intermediate 18)
Figure imgf000219_0002
Intermediate 18 was prepared by following the same procedure reported for the synthesis of Intermediate 6. SM: tert-butyl (2-azaspiro[3.3]heptan-6-yl)carbamate: 200 mg (1 eq); 1-isocyanato-3- (trifluoromethyl)benzene (1 eq) Amount/yield: 376 mg, 0.941 mmol, 100 % LCMS (ESI): Method 4, tR =1.67 min, m/z (M+1) = 400.2 Step 2 - 6-amino-N-(3-(trifluoromethyl)phenyl)-2-azaspiro[3.3]heptane-2-carboxa mide (Intermediate 19)
Figure imgf000219_0003
Intermediate 19 was prepared by following the same procedure reported for the synthesis of Intermediate 7. SM: Intermediate 18: 376 mg (1 eq) TFA: 1.4 mL (20 eq) Amount/yield: 270 mg, 0.902 mmol, 96 % LCMS (ESI): Method 4, tR=1.34 min, m/z (M+1) = 300 Step 3 - N-(2-((3-(trifluoromethyl)phenyl)carbamoyl)-2-azaspiro[3.3]heptan-6- yl)pyrazolo[1,5-a]pyrazine-3-carboxamide (Compound C3) Compound C3 was prepared by following the procedure described for the synthesis of Example 1, step 3. SM: Intermediate 19: 100 mg (1 eq); pyrazolo[1,5-a]pyrazine-3-carboxylic acid: 55 mg (1 eq) Amount/yield: 34 mg, 0.0755 mmol, 23 % LCMS (ESI): Method 3, tR =3.82 min, m/z (M+1) = 445.2 ¹H NMR (400 MHz, DMSO-d6) δ 9.55 (d, J=1.3 Hz, 1H), 8.87 (dd, J=1.4, 4.7 Hz, 1H), 8.75 (s, 1H), 8.66 - 8.59 (m, 2H), 8.07 (d, J=4.8 Hz, 1H), 7.96 (s, 1H), 7.78 - 7.74 (m, 1H), 7.46 (t, J=8.0 Hz, 1H), 7.27 - 7.23 (m, 1H), 4.40 - 4.32 (m, 1H), 4.08 (s, 2H), 3.97 (s, 2H), 2.62 - 2.55 (m, 2H), 2.33 - 2.26 (m, 2H). PHARMACOLOGICAL ACTIVITY OF THE COMPOUNDS OF THE INVENTION In vitro Assays Binding Assays DDR1 and DDR2 binding assays were performed using Life Technologies LanthaScreen™ Europium Kinase Binding assay. The compounds were incubated with 5 nM DDR1 (Carna Biosciences) or 5 nM DDR2 (Life Technologies) for 1 h at rt in white 384-well OptiPlate (PerkinElmer), containing 20 nM or 10 nM Kinase Tracer 178 respectively and 2 nM Europium labelled anti-GST antibody (Life Technologies) in assay buffer (50 mM HEPES pH 7.5, 10 mM MgCI2, 1 mM EGTA and 0.01% BRIJ35). The ratio of fluorescence emission 665 nm/ 615 nm after excitation at 340 nm was obtained using the Tecan Spark 20M plate reader. IC50 values were determined in GraphPad Prism 7.0 software, using 4 parameter model: log(inhibitor) vs. response. IC50 values were converted in Ki using the Cheng-Prusoff equation (Ki=IC50/(1+[Tracer]/Kd). The results for representative compounds of the invention are provided in Table 44, wherein the compounds are classified in term of potency (Ki, nM) in binding with respect to their inhibitory activity on DDR1 and DDR2: Table 44
Figure imgf000221_0001
-: Ki higher than 100 nM +: Ki between 25 and 100 nM ++: Ki between 5 nM and 25 nM +++: Ki lower than 5 nM As it can be appreciated, the compounds of Table 44, i.e. compounds according to the invention, show a good activity as antagonist of DDR1 and DDR2. Accordingly, the compounds of the invention can be effectively used for treating diseases, disorders or conditions associated with DDR receptors, such as fibrosis, e.g. pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), hepatic fibrosis, progressive pulmonary fibrosis, sarcoidosis, familiar pulmonary fibrosis, chronic hypersensitivity pneumonitis (CHP), kidney or renal fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis and systemic sclerosis. Comparative Compounds Compounds C1, C2 and C3 were tested in the same binding assay described above and their Ki(nM) is reported in Table 45. Table 45
Figure imgf000222_0001
The compounds of the present invention whose activity is reported in Table 44 have a binding affinity for DDR1 and DDR2 receptors, expressed as Ki, which is lower than 100 nM, in several cases lower than 25 nM or even lower than 5 nM. To the contrary, as it can be seen in Table 45, the comparative compounds C1, C2 and C3 did not show a binding affinity for DDR1 and DDR2 receptors, being their Ki over the detectable limit of the binding assay. Thus, the presence of the -NH-CO-L1- linker, wherein L1 is NR, CH2 or O, of the linker L, being -CO-, -CH2- or absent, and of the central core in the compounds of formula (I) of the present invention unexpectedly and noteworthy determine a remarkable inhibitory activity on the DDR1 and DDR2 receptors.

Claims

CLAIMS 1. A compound of formula (I)
Figure imgf000223_0001
wherein A is a ring selected from the group consisting of :
Figure imgf000223_0002
wherein indicates a direct bond to NH; W1, W2 and W3 are substituents of ring A independently selected from the group consisting of hydrogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)halohydroxyalkyl, (C1- C4)alkoxy, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)haloalkoxy, (C1-C4)hydroxyalkyl, halogen, cyano, SF5, NR1R2-(C1-C4)alkyl, CONR1R2, NHCOR1, NR1R2, heterocycloalkyl, (C3- C7)cycloalkyl, (C1-C4)alkyl-heterocycloalkyl, (C1-C4)alkyl-heterocycloalkyl-(C1-C4)alkyl, (C1-C4)haloalkyl-cycloalkyl, (C1-C4)alkyl-(C3-C7)cycloalkyl, heterocycloalkyl-(C1- C4)alkyl, heterocycloalkyl-NH-(C1-C4)alkyl, (C3-C7)cycloalkyl-(C1-C4)alkyl, heterocycloalkyl-(C1-C4)alkoxy, (C1-C4)alkyl-CO-heterocycloalkyl-oxy, (C3- C7)cycloalkyl-(C1-C4)alkoxy, heterocycloalkyl-oxy, (C3-C7)cycloalkyl-oxy, (C1-C4)alkyl- heterocycloalkyl-carbonyl, monocyclic (C1-C4)alkyl-heteroaryl, (C1-C4)alkyl-sulfonyl, (C1- C4)haloalkyl-sulfonyl, (C1-C4)haloalkyl-sulfonylamino, (C1-C4)haloalkyl-sulfinyl, (C1- C4)haloalkyl-thio, (C1-C4)alkyl-thio-(C1-C4)alkyl, (C1-C4)alkyl-sulfonyl-(C1-C4)alkyl and (C1-C4)alkyl-sulfinyl-(C1-C4)alkyl; or, wherein W1 and W2 are in adjacent positions on ring A, W1 and W2 form a (C5-C6)cycloalkyl or a 5- or 6-membered heterocycloalkyl, wherein the (C5-C6)cycloalkyl or the 5- or 6-membered heterocycloalkyl are optionally substituted with 1 to 3 halogen atoms; L is selected from CO and CH2 or is absent; L1 is selected from NR, CH2 and O, wherein R is selected from the group consisting of hydrogen, (C1-C4)alkyl, (C1-C4)hydroxyalkyl, (C1-C4)haloalkyl, (C3-C7)cycloalkyl, (C3- C7)cycloalkyl-(C1-C4)alkyl and deuterated (C1-C4)alkyl; RS is selected from hydrogen and methyl, when L1 is NR; RS is hydrogen, when L1 is CH2 or O; B is mono- or bi-cyclic heteroaryl ring or bi-cyclic semisaturated heteroaryl ring; Y1 and Y2 are substituents of ring B independently selected from the group consisting of hydrogen, (C1-C4)alkyl, deuterated (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1- C4)haloalkoxy, (C1-C4)hydroxyalkyl, halogen, cyano, SF5, (C1-C4)cyanoalkyl, (C1-C4)alkyl- sulfonyl, (C1-C4)haloalkyl-sulfonyl, CONR1R2, NHCOR1, NR1R2, NR1R2-(C1-C4)alkyl, heterocycloalkyl optionally substituted with 1 to 3 halogens, heterocycloalkyl-NH-(C1- C4)alkyl, (C3-C7)cycloalkyl, (C1-C4)alkyl-heterocycloalkyl, (C1-C4)alkyl-(C3-C7)cycloalkyl, heterocycloalkyl-(C1-C4)alkyl, (C3-C7)cycloalkyl-(C1-C4)alkyl, heterocycloalkyl-(C1- C4)alkoxy, (C3-C7)cycloalkyl-(C1-C4)alkoxy, heterocycloalkyl-oxy, (C3-C7)cycloalkyl-oxy, phenyl, (C1-C4)alkoxy substituted phenyl, (C1-C4)alkyl-thio-(C1-C4)alkyl, (C1-C4)alkyl- sulfonyl-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)haloalkyl-cycloalkyl, (C1- C4)alkyl-heterocycloalkyl-carbonyl and monocyclic heteroaryl, optionally substituted with 1 to 3 groups selected from the group consisting of (C1-C4)alkyl, (C1-C4)alkoxy and (C1- C4)alkoxy-(C1-C4)alkyl; R1 and R2 are independently selected from the group consisting of hydrogen, (C1- C4)alkyl, (C1-C4)hydroxyalkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkylamino-(C1- C4)alkyl, di-(C1-C4)alkylamino-(C1-C4)alkyl, optionally substituted (C3-C7)cycloalkyl, optionally substituted heterocycloalkyl and optionally substituted heterocycloalkyl-(C1- C4)alkoxy, wherein optional substituents are from 1 to 3 and are selected from the group consisting of (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy and carbamoyl; R3 is selected from the group consisting of (C1-C4)alkyl, (C1-C4)haloalkyl, (C1- C4)alkyl-phenyl and monocyclic heteroaryl; or a stereoisomer, tautomer, solvate and pharmaceutically acceptable salt thereof; wherein the compound of formula (I) is not 1-(3,5-dichlorophenyl)-3-(2-(2- methylpyridin-4-yl)-2-azaspiro[3.3]heptan-6-yl)urea. 2. The compound according to claim 1, wherein, when A ring is phenyl and L1 is NH, W1, W2 and W3 are substituents of ring A independently selected from the group consisting of hydrogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)halohydroxyalkyl, (C1- C4)alkoxy, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)haloalkoxy, (C1-C4)hydroxyalkyl, fluorine, bromine, iodine, cyano, SF5, NR1R2-(C1-C4)alkyl, CONR1R2, NHCOR1, NR1R2, heterocycloalkyl, (C3-C7)cycloalkyl, (C1-C4)alkyl-heterocycloalkyl, (C1-C4)alkyl- heterocycloalkyl-(C1-C4)alkyl, (C1-C4)haloalkyl-cycloalkyl, (C1-C4)alkyl-(C3- C7)cycloalkyl, heterocycloalkyl-(C1-C4)alkyl, heterocycloalkyl-NH-(C1-C4)alkyl, (C3- C7)cycloalkyl-(C1-C4)alkyl, heterocycloalkyl-(C1-C4)alkoxy, (C1-C4)alkyl-CO- heterocycloalkyl-oxy, (C3-C7)cycloalkyl-(C1-C4)alkoxy, heterocycloalkyl-oxy, (C3- C7)cycloalkyl-oxy, (C1-C4)alkyl-heterocycloalkyl-carbonyl, monocyclic (C1-C4)alkyl- heteroaryl, (C1-C4)alkyl-sulfonyl, (C1-C4)haloalkyl-sulfonyl, (C1-C4)haloalkyl- sulfonylamino, (C1-C4)haloalkyl-sulfinyl, (C1-C4)haloalkyl-thio, (C1-C4)alkyl-thio-(C1- C4)alkyl, (C1-C4)alkyl-sulfonyl-(C1-C4)alkyl and (C1-C4)alkyl-sulfinyl-(C1-C4)alkyl; or, wherein W1 and W2 are in adjacent positions on ring A, W1 and W2 form a (C5- C6)cycloalkyl or a 5- or 6-membered heterocycloalkyl, wherein the (C5-C6)cycloalkyl or the 5- or 6-membered heterocycloalkyl are optionally substituted with 1 to 3 halogen atoms; and wherein preferably the 6-membered heterocycloalkyl is a pyranyl ring; or a stereoisomer, tautomer, solvate and pharmaceutically acceptable salt thereof. 3. The compound according to claim 1 or 2, wherein W1, W2 and W3 are substituents of ring A independently selected from the group consisting of hydrogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)halohydroxyalkyl, (C1- C4)alkoxy, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)haloalkoxy, (C1-C4)hydroxyalkyl, fluorine, bromine, iodine, cyano, SF5, NR1R2-(C1-C4)alkyl, CONR1R2, NHCOR1, NR1R2, heterocycloalkyl, (C3-C7)cycloalkyl, (C1-C4)alkyl-heterocycloalkyl, (C1-C4)alkyl- heterocycloalkyl-(C1-C4)alkyl, (C1-C4)haloalkyl-cycloalkyl, (C1-C4)alkyl-(C3- C7)cycloalkyl, heterocycloalkyl-(C1-C4)alkyl, heterocycloalkyl-NH-(C1-C4)alkyl, (C3- C7)cycloalkyl-(C1-C4)alkyl, heterocycloalkyl-(C1-C4)alkoxy, (C1-C4)alkyl-CO- heterocycloalkyl-oxy, (C3-C7)cycloalkyl-(C1-C4)alkoxy, heterocycloalkyl-oxy, (C3- C7)cycloalkyl-oxy, (C1-C4)alkyl-heterocycloalkyl-carbonyl, monocyclic (C1-C4)alkyl- heteroaryl, (C1-C4)alkyl-sulfonyl, (C1-C4)haloalkyl-sulfonyl, (C1-C4)haloalkyl- sulfonylamino, (C1-C4)haloalkyl-sulfinyl, (C1-C4)haloalkyl-thio, (C1-C4)alkyl-thio-(C1- C4)alkyl, (C1-C4)alkyl-sulfonyl-(C1-C4)alkyl and (C1-C4)alkyl-sulfinyl-(C1-C4)alkyl; or, wherein W1 and W2 are in adjacent positions on ring A, W1 and W2 form a (C5- C6)cycloalkyl or a 5- or 6-membered heterocycloalkyl, wherein the (C5-C6)cycloalkyl or the 5- or 6-membered heterocycloalkyl are optionally substituted with 1 to 3 halogen atoms; and wherein preferably the 6-membered heterocycloalkyl is a pyranyl ring; or a stereoisomer, tautomer, solvate and pharmaceutically acceptable salt thereof. 4. The compound according to any one of claims 1 to 3, wherein A is a ring selected from the group consisting of :
Figure imgf000226_0001
; more preferably A is selected from the group consisting of phenyl, 3-pyridinyl,
2- pyridinyl, 3-pyridazinyl,
3-isoxazolyl and pyrazolyl, wherein R3 is CH3 or p-tolyl; W1, W2 and W3 are selected from the group consisting of hydrogen, CH3, OCH3, OCF3, CF3, CHF2, C(CH3)3, CH2CF3, CF2CH3, CF2CF3, C(CH3)2CF3, OCF2H, CH2OH, cyano, CF3SO2, SCF3, SF5, F, Br, I, cyclopropyl, morpholino-N-ethoxy, N- acetylpiperidinyl-oxy, N-acetylazetidinyl-oxy, 2,2,2-trifluoro-1-hydroxyethyl, oxetanyloxy and CH2N(CH3)2; L is selected from CO and CH2 or is absent, being preferably CO; L1 is selected from NR, CH2 and O, wherein R is selected from the group consisting of hydrogen, CD3, cyclopropylmethyl, cyclopropyl, CH2CF3, CH2CH3 and CH3; B is selected from the group consisting of pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, pyrazolo[1,5-a]pyrazinyl, pyrazolo[1,5-a]pyridinyl, pyrazolo[3,4-d]pyrimidinyl, pyrazolo[1,5-a]pyrimidinyl, 1H-pyrazolo[3,
4-b]pyridinyl, imidazo[1,2-b]pyridazinyl, imidazo[1,2-a]pyrazinyl, 1H-imidazo[1,2-b]pyrazolyl, imidazo[2,1-b]thiazolyl, pyrrolo[2,3-c]pyrimidinyl, pyrrolo[3,2-b]pyridinyl, 1H- pyrrolo[2,3-b]pyridinyl, pyrazolo[5,1-b]thiazolyl, imidazo[1,5-a]pyrazinyl,
5,
6-dihydro- 8H-imidazo[2,1-c][1,4]oxazinyl, thieno[3,2-d]pyrimidinyl, thieno[3,2-b]pyridinyl, thieno[2,3-d]pyrimidinyl, pyrazolo[5,1-b][1,3]thiazinyl, pyrrolo[3,2-d]pyrimidinyl, pyrrolo[2,3-d]pyrimidinyl and imidazo[1,2-a]pyridinyl; Y1 is selected from the group consisting of hydrogen, CH3, OCH3, OCF3, CF3, C(CH3)3, C(CH3)2CF3, CONH2, OCF2H, CF2H, CF2CH3, CF2CF3, CH2CF3, CH2OH, CH2CH2OH, CH2CH2OCH3, CH2CH2SCH3, CH2CH2F, CH2SCH3, SCF3, SO2CF3, CD3, cyano, NHCOCH3, NH2, (C1-C4)alkyl-piperazinyl, 4-methylpiperazin-1-yl, piperazinyl, morpholinyl, pyrrolidinyl, hydroxypyrrolidinyl, N-methyl-oxopiperazinyl, S,S-dioxido- thiomorpholinyl, oxetanyl-methyl, oxetanyl, (oxetanylamino)methyl, 1H-pyrazol-4-yl, oxazol-5-yl, pyridin-3-yl, pyrimidin-5-yl, pyridin-4-yl, dimethoxyphenyl, thiazol-5-yl, 3- isoxazol-5-yl and 1-methyl-1H-pyrazol-4-yl, and Y2 is hydrogen; R1 and R2 are independently selected from the group consisting of hydrogen, (C1- C4)alkyl and optionally substituted heterocycloalkyl, wherein optional substituents are selected from the group consisting of CH3, OCH3, OCF3, CF3, C(CH3)3, C(CH3)2CF3, CONH2, OCF2H and CF2H; or a stereoisomer, tautomer, solvate and pharmaceutically acceptable salt thereof. 5. The compound according to any one of claims 1 to 4, wherein L is CO and L1 is NR, which is represented by formula (Ia)
Figure imgf000227_0001
6. The compound according to any one of claims 1 to 4, wherein L is CH2 and L1 is NR, which is represented by formula (Ib)
Figure imgf000227_0002
7. The compound according to any one of claims 1 to 4, wherein L is absent and L1 is NR, which is represented by formula (Ic)
Figure imgf000227_0003
8. The compound according to any one of claims 1 to 4, wherein L1 is CH2, which is represented
Figure imgf000227_0004
and wherein Rs is hydrogen.
9. The compound according to any one of claims 1 to 4, wherein L1 is O, which is represented by formula (Ie)
Figure imgf000228_0001
and wherein Rs is hydrogen.
10. The compound of formula (I) according to claim 1 selected from the group consisting of: 1-(2-(imidazo[1,2-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3- (trifluoromethyl)phenyl)urea (Example 1); 1-(2-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3- (trifluoromethyl)phenyl)urea (Example 2); 1-(2-(1H-pyrrolo[2,3-b]pyridine-5-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3- (trifluoromethyl)phenyl)urea (Example 3); 1-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3- (trifluoromethyl)phenyl)urea (Example 4); 1-(2-(6-(4-methylpiperazin-1-yl)imidazo[1,2-a]pyridine-3-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 5); 1-(2-(5,6-dihydro-8H-imidazo[2,1-c][1,4]oxazine-3-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 6); 1-(2-(imidazo[1,2-b]pyridazine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3- (trifluoromethyl)phenyl)urea (Example 7); 1-(2-(1-methyl-1H-imidazole-5-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3- (trifluoromethyl)phenyl)urea (Example 8); 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)- 3-(3-(trifluoromethyl)phenyl)urea (Example 9); 1-(2-(imidazo[1,2-a]pyrazin-3-ylmethyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3- (trifluoromethyl)phenyl)urea (Example 11); 1-(2-((1H-pyrazolo[3,4-b]pyridin-5-yl)methyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3- (trifluoromethyl)phenyl)urea (Example 12); 1-(2-(1H-pyrazolo[3,4-b]pyridin-4-yl)-2-azaspiro[3.3]heptan-6-yl)-3-(3- (trifluoromethyl)phenyl)urea (Example 15); 1-(3-fluoro-5-(trifluoromethyl)phenyl)-3-(2-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-2- azaspiro[3.3]heptan-6-yl)urea (Example 16); 1-(2-fluoro-5-(trifluoromethyl)phenyl)-3-(2-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-2- azaspiro[3.3]heptan-6-yl)urea (Example 17); 1-(5-(tert-butyl)isoxazol-3-yl)-3-(2-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-2- azaspiro[3.3]heptan-6-yl)urea (Example 18); 1-(3-cyano-5-(trifluoromethyl)phenyl)-3-(2-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-2- azaspiro[3.3]heptan-6-yl)urea (Example 19); 1-(5-(tert-butyl)isoxazol-3-yl)-3-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)urea (Example 20); 1-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3- (trifluoromethoxy)phenyl)urea (Example 21); 1-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(5- (trifluoromethyl)pyridin-3-yl)urea (Example 22); 1-(2-methoxy-5-(trifluoromethoxy)phenyl)-3-(2-(pyrazolo[5,1-b]thiazole-7- carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 23); 1-(4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl)-3-(2-(pyrazolo[5,1- b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 24); 1-methyl-1-(2-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3- (3-(trifluoromethyl)phenyl)urea (Example 25); 1-(2-(imidazo[1,2-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-1-methyl-3-(3- (trifluoromethyl)phenyl)urea (Example 26); 2-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-N-(3- (trifluoromethyl)phenyl)acetamide (Example 27); 2-(2-(imidazo[1,2-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-N-(3- (trifluoromethyl)phenyl)acetamide (Example 28); 2-(2-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-N-(3- (trifluoromethyl)phenyl)acetamide (Example 29); 1-(2-(1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3- (trifluoromethyl)phenyl)urea (Example 30); 1-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3-(2,2,2- trifluoroethyl)phenyl)urea (Example 31); 1-(2-(4-aminopyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3- (trifluoromethyl)phenyl)urea (Example 32); 1-(3-methoxyphenyl)-3-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)urea (Example 33); 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)- 3-(3-(2,2,2-trifluoroethyl)phenyl)urea (Example 34); 1-(5-isopropylpyridin-3-yl)-3-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)urea (Example 35); 1-(2-methoxy-5-(trifluoromethoxy)phenyl)-3-(2-(1-methyl-1H-imidazo[1,2- b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 36); 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)- 3-(5-(trifluoromethyl)pyridin-3-yl)urea (Example 37); 1-(5-chloro-2-methoxyphenyl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7- carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 38); 1-(3-cyano-5-(trifluoromethyl)phenyl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7- carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 39); 1-(2-(pyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3- (trifluoromethyl)phenyl)urea (Example 40); 1-(3-(hydroxymethyl)-5-(trifluoromethyl)phenyl)-3-(2-(pyrazolo[5,1-b]thiazole-7- carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 41); 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)- 3-(3-(pentafluoro-l6-sulfaneyl)phenyl)urea (Example 42); 1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(2-(1-methyl-1H-imidazo[1,2- b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 43); 1-(2-isonicotinoyl-2-azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 44); 1-(2-chloro-5-(trifluoromethyl)phenyl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole- 7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 45); 1-(2-(1H-pyrrolo[3,2-b]pyridine-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3- (trifluoromethyl)phenyl)urea (Example 46); 1-methyl-1-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3- (5-(trifluoromethyl)pyridin-3-yl)urea (Example 47); 1-(2-methoxy-5-(trifluoromethoxy)phenyl)-3-(2-(thieno[3,2-b]pyridine-7-carbonyl)- 2-azaspiro[3.3]heptan-6-yl)urea (Example 48); 1-(2-(thieno[3,2-b]pyridine-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(5- (trifluoromethyl)pyridin-3-yl)urea (Example 49); 1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(3-(2,2,2-trifluoroethyl)phenyl)urea (Example 50); 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)- 3-(5-(trifluoromethoxy)pyridin-3-yl)urea (Example 51); 3-(2-methoxy-5-(trifluoromethoxy)phenyl)-1-methyl-1-(2-(1-methyl-1H- imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 52); 3-(3-cyano-5-(trifluoromethyl)phenyl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2- b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 53); 1-(2-(imidazo[1,2-b]pyridazine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(2- methoxy-5-(trifluoromethoxy)phenyl)urea (Example 54); 1-(2-methoxy-5-(trifluoromethoxy)phenyl)-3-(2-(pyrazolo[1,5-a]pyrimidine-3- carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 55); 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)- 3-(2-(2-morpholinoethoxy)-5-(trifluoromethyl)phenyl)urea (Example 56); 1-(2-(imidazo[1,2-a]pyrazine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(2-methoxy- 5-(trifluoromethoxy)phenyl)urea (Example 57); 1-(1-methyl-2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)-3-(2-(pyrazolo[5,1- b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 58); 1-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(4- (trifluoromethyl)pyridin-2-yl)urea (Example 59); 3 3-(3-fluoro-5-(trifluoro methyl)phenyl)-1-methyl-1-(2-(pyrazolo[5,1-b]thiazole-7- carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 60); 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)- 3-(2-methyl-5-(trifluoromethoxy)phenyl)urea (Example 61); -(2-methoxy-5-(trifluoromethoxy)phenyl)-3-(2-(thieno[3,2-d]pyrimidine-4- carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 62); 1-(3-(difluoromethyl)phenyl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7- carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 63); 3-(3-fluoro-5-(trifluoromethyl)phenyl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2- b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 64); 1-(2-methoxy-5-(trifluoromethyl)phenyl)-3-(2-(1-methyl-1H-imidazo[1,2- b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 65); 1-(4-(difluoromethyl)pyridin-2-yl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7- carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 66); 1-(3-(difluoromethoxy)phenyl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7- carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 67); 1-(2-methoxy-5-(trifluoromethoxy)phenyl)-3-(2-(pyrazolo[1,5-a]pyridine-3- carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 68); 1-(2-methoxy-5-(trifluoromethoxy)phenyl)-3-(2-(5-(4-methylpiperazin-1- yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 69); 1-(2-(1-ethyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3- (3-(trifluoromethyl)phenyl)urea (Example 70); 1-(3-cyano-5-(trifluoromethoxy)phenyl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole- 7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 71); 1-(2-fluoro-5-(trifluoromethoxy)phenyl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole- 7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 72); 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)- 3-(4-(trifluoromethoxy)pyridin-2-yl)urea (Example 73); 1-(4-(difluoromethyl)pyridin-2-yl)-3-(2-(thieno[3,2-d]pyrimidine-4-carbonyl)-2- azaspiro[3.3]heptan-6-yl)urea (Example 74); 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)- 3-(4-(trifluoromethyl)pyridin-2-yl)urea (Example 75); 1-(2-(thieno[3,2-d]pyrimidine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(5- (trifluoromethyl)pyridin-3-yl)urea (Example 76); 3-(2-methoxy-5-(trifluoromethoxy)phenyl)-1-methyl-1-(2-(thieno[3,2-d]pyrimidine- 4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 77); 1-(3-(hydroxymethyl)-2-methoxy-5-(trifluoromethoxy)phenyl)-3-(2-(1-methyl-1H- imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 78); 1-(2-(thieno[3,2-d]pyrimidine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3- (trifluoromethyl)phenyl)urea (Example 79); 1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(2-(pyrazolo[5,1-b]thiazole-7- carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 80); 3-(2-methoxy-5-(trifluoromethoxy)phenyl)-1-methyl-1-(2-(5-(4-methylpiperazin-1- yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 81); 1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(2-(thieno[3,2-d]pyrimidine-4- carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 82); 1-(5-chloro-2-methoxypyridin-3-yl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7- carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 83); 1-(2-(5-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 84); 1-ethyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 85); 1-ethyl-3-(3-fluoro-5-(trifluoromethyl)phenyl)-1-(2-(1-methyl-1H-imidazo[1,2- b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 86); 1-(3-cyano-5-(trifluoromethyl)phenyl)-3-(2-(5-(4-methylpiperazin-1-yl)pyrazolo[1,5- a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 87); 1-(2-(thieno[2,3-d]pyrimidine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3- (trifluoromethyl)phenyl)urea (Example 88); 1-(3-(difluoromethoxy)phenyl)-3-(2-(thieno[3,2-d]pyrimidine-4-carbonyl)-2- azaspiro[3.3]heptan-6-yl)urea (Example 89); 1-(2-(thieno[3,2-d]pyrimidine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(4- (trifluoromethyl)pyridin-2-yl)urea (Example 90); 1-(5-(difluoromethoxy)-2-methoxyphenyl)-3-(2-(1-methyl-1H-imidazo[1,2- b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 91); 1-(2-chloro-5-(trifluoromethoxy)phenyl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole- 7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 92); 1-(2-(1H-pyrazolo[3,4-b]pyridine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3- (trifluoromethyl)phenyl)urea (Example 93); 3-(3-(hydroxymethyl)-5-(trifluoromethyl)phenyl)-1-methyl-1-(2-(pyrazolo[5,1- b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 94); 1-(3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)-3-(2-(thieno[3,2-d]pyrimidine-4- carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 95); 1-(2-(imidazo[2,1-b]thiazole-5-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3- (trifluoromethyl)phenyl)urea (Example 96); 1-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(4- (trifluoromethoxy)pyridin-2-yl)urea (Example 97); 1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(3-(pentafluoro-l6-sulfaneyl)phenyl)urea (Example 98); 1-(2-(6-methylthieno[3,2-d]pyrimidine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3- (3-(trifluoromethyl)phenyl)urea (Example 99); 1-(5-(tert-butyl)-1-methyl-1H-pyrazol-3-yl)-3-(2-(thieno[3,2-d]pyrimidine-4- carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 100); 1-(2-(thieno[3,2-d]pyrimidine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(4- (trifluoromethoxy)pyridin-2-yl)urea (Example 101); 1-(2-(1-(2-hydroxyethyl)-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 102); 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)- 3-(6-(trifluoromethyl)pyrimidin-4-yl)urea (Example 103); 1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(2-methyl-5-(trifluoromethoxy)phenyl)urea (Example 104); 1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(4-(trifluoromethoxy)pyridin-2-yl)urea (Example 105); 1-(3-fluoro-5-(trifluoromethyl)phenyl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7- carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 106); 1-(2-methoxy-5-(trifluoromethyl)pyridin-3-yl)-3-(2-(1-methyl-1H-imidazo[1,2- b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 107); 1-(4-chloro-3-(trifluoromethyl)phenyl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole- 7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 108); 1-(2-methoxy-5-(pentafluoro-l6-sulfaneyl)phenyl)-3-(2-(1-methyl-1H-imidazo[1,2- b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 109); 1-(3-(hydroxymethyl)-5-(trifluoromethyl)phenyl)-3-(2-(thieno[3,2-d]pyrimidine-4- carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 110); 3-(3-cyano-5-(trifluoromethoxy)phenyl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2- b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 111); 1-(4-((dimethylamino)methyl)-3-(trifluoromethyl)phenyl)-3-(2-(thieno[3,2- d]pyrimidine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 112); 1-(2-(6-(hydroxymethyl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan- 6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 113); 1-methyl-1-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3- (4-(trifluoromethoxy)pyridin-2-yl)urea (Example 114); 1-(2-(1H-pyrrolo[2,3-b]pyridine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3- (trifluoromethyl)phenyl)urea (Example 115); 1-(2-(6-((oxetan-3-ylamino)methyl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 116); 1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(3-(perfluoroethyl)phenyl) urea (Example 117); 1-(4-fluoro-3-(trifluoromethoxy)phenyl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole- 7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 118); 1-(3-cyano-5-(pentafluoro-l6-sulfaneyl)phenyl)-3-(2-(1-methyl-1H-imidazo[1,2- b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 119); 1-(2-(1H-pyrazolo[3,4-b]pyridine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3- (pentafluoro-l6-sulfaneyl)phenyl)urea (Example 120); 1-(4-fluoro-3-(trifluoromethyl)phenyl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7- carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 121); 1-(2-(1H-pyrazolo[3,4-d]pyrimidine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3- (trifluoromethyl)phenyl)urea (Example 122); 1-(2-fluoro-5-(trifluoromethyl)phenyl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7- carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 123); 1-(3-fluoro-5-(trifluoromethoxy)phenyl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole- 7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 124); 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)- 3-(3-((trifluoromethyl)thio)phenyl)urea (Example 125); 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)- 3-(2-(oxetan-3-yloxy)-5-(trifluoromethyl)phenyl)urea (Example 126); 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)- 3-(3-(perfluoroethyl)phenyl)urea (Example 127); 1-(2-(1H-pyrazolo[3,4-b]pyridine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-1-methyl- 3-(3-(trifluoromethyl)phenyl)urea (Example 128); 1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(4-(trifluoromethyl)pyridin-2-yl)urea (Example 129); 1-methyl-1-(2-(thieno[3,2-d]pyrimidine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3- (5-(trifluoromethyl)pyridin-3-yl)urea (Example 130); 3-(4-fluoro-3-(trifluoromethyl)phenyl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2- b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 131); 3-(2-fluoro-5-(trifluoromethoxy)phenyl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2- b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 132); 1-methyl-1-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3- (3-(trifluoromethyl)phenyl)urea (Example 133); 1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 134); 1-(2-(2,3-dihydropyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3- (3-(trifluoromethyl)phenyl)urea (Example 135); 1-(2-(6,7-dihydro-5H-pyrazolo[5,1-b][1,3]thiazine-3-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 136); 1-(2-(thieno[3,2-b]pyridine-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3- (trifluoromethyl)phenyl)urea (Example 137); 1-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)-2-azaspiro[3.3]heptan-6-yl)-3-(3- (trifluoromethyl)phenyl)urea (Example 138); N-(2-methoxy-5-(trifluoromethoxy)phenyl)-2-(2-(thieno[3,2-b]pyridine-7-carbonyl)- 2-azaspiro[3.3]heptan-6-yl)acetamide (Example 139); 2-(2-(thieno[3,2-b]pyridine-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-N-(3- (trifluoromethyl)phenyl)acetamide (Example 140); 2-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)- N-(3-(trifluoromethyl)phenyl)acetamide (Example 141); N-(2-methoxy-5-(trifluoromethoxy)phenyl)-2-(2-(1-methyl-1H-imidazo[1,2- b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)acetamide (Example 142); 2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl(3- (trifluoromethyl)phenyl)carbamate (Example 143); 2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl(2- methoxy-5-(trifluoromethoxy)phenyl)carbamate (Example 144); 1-(2-(1H-pyrazolo[3,4-b]pyridine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(4- (trifluoromethyl)pyridin-2-yl)urea (Example 145); 2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl(5- (trifluoromethyl)pyridin-3-yl)carbamate (Example 146); 2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl(3- (trifluoromethyl)phenyl)carbamate (Example 147); 1-(2-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3- (trifluoromethyl)phenyl)urea (Example 148); 1-(2-(imidazo[1,5-a]pyrazin-8-yl)-2-azaspiro[3.3]heptan-6-yl)-3-(3- (trifluoromethyl)phenyl)urea (Example 149); 1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(4-(2,2,2-trifluoroethyl)pyridin-2-yl)urea (Example 150); 1-methyl-3-(2-methyl-5-(trifluoromethoxy)phenyl)-1-(2-(pyrazolo[5,1-b]thiazole-7- carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 151); 1-(2-methoxy-5-(2,2,2-trifluoroethyl)phenyl)-3-(2-(1-methyl-1H-imidazo[1,2- b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 152); 1-(2-(1H-pyrazolo[3,4-b]pyridine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3- (2,2,2-trifluoroethyl)phenyl)urea (Example 153); 1-(2-(1H-pyrazolo[3,4-b]pyridine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(4- (trifluoromethoxy)pyridin-2-yl)urea (Example 154); 1-(4-cyclopropylpyridin-2-yl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7- carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 155); 3-(4-cyclopropylpyridin-2-yl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole- 7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 156); 3-(5-cyclopropylpyridin-3-yl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole- 7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 157); 1-(methyl-d3)-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 158); 1-(2-(1H-pyrazolo[3,4-b]pyridine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(5- (trifluoromethyl)pyridin-3-yl)urea (Example 159); 1-(2-(5-methyl-5H-pyrrolo[3,2-d]pyrimidine-4-carbonyl)-2-azaspiro[3.3]heptan-6- yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 160); 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)- 3-(3-((trifluoromethyl)sulfonyl)phenyl)urea (Example 161); 1-(2-(1H-pyrazolo[3,4-b]pyridine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3- ((trifluoromethyl)thio)phenyl)urea (Example 162); 1-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)-2-azaspiro[3.3]heptan-6-yl)-3-(5- (trifluoromethyl)pyridin-2-yl)urea (Example 163); 3-(4-(difluoromethyl)pyridin-2-yl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2- b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 164); 1-(2-methyl-5-(trifluoromethyl)pyridin-3-yl)-3-(2-(pyrazolo[5,1-b]thiazole-7- carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 165); 1-(2-(1-(oxetan-3-ylmethyl)-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 166); 1-(2-(1-(oxetan-3-yl)-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan- 6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 167); 1-(6-cyano-4-(trifluoromethyl)pyridin-2-yl)-3-(2-(1-methyl-1H-imidazo[1,2- b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 168); 1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea (Example 169); 1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(6-(trifluoromethyl)pyrimidin-4-yl)urea (Example 170); 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)- 3-(2-methyl-5-(trifluoromethyl)pyridin-3-yl)urea (Example 171); 1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(5-(trifluoromethoxy)pyridin-3-yl)urea (Example 172); 3-(5-(1,1-difluoroethyl)pyridin-3-yl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2- b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 173); 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)- 1-(2,2,2-trifluoroethyl)-3-(3-(trifluoromethyl)phenyl)urea (Example 174); 1-methyl-1-(2-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3- (5-(trifluoromethyl)pyridin-3-yl)urea (Example 175); 1-methyl-1-(2-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3- (5-(trifluoromethoxy)pyridin-3-yl)urea (Example 176); 3-(4-(difluoromethoxy)pyridin-2-yl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2- b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 177); 1-methyl-1-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3- (6-(trifluoromethyl)pyrimidin-4-yl)urea (Example 178); 1-methyl-1-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3- (5-(trifluoromethoxy)pyridin-3-yl)urea (Example 179); 1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)urea (Example 180); 1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)- 3-(6-methyl-5-(trifluoromethyl)pyridin-3-yl)urea (Example 181); 1-(2-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 182); 1-(2-(5-(1,1-dioxidothiomorpholino)pyrazolo[1,5-a]pyridine-3-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 183); 1-(2-(5-aminopyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3- (trifluoromethyl)phenyl)urea (Example 184); 1-(2-(5-(3-hydroxypyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 185); 1-(2-(5-(4-methyl-2-oxopiperazin-1-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 186); 1-cyclopropyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 187); 1-(2-(1H-pyrazolo[3,4-b]pyridine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-1-methyl- 3-(2-methyl-5-(trifluoromethoxy)phenyl)urea (Example 188); 1-(2-(1H-pyrazolo[3,4-b]pyridine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-1-methyl- 3-(4-(trifluoromethoxy)pyridin-2-yl)urea (Example 189); 1-methyl-1-(2-(pyrazolo[1,5-a]pyrazine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3- (4-(trifluoromethoxy)pyridin-2-yl)urea (Example 190) 1-(6-methyl-2-(thieno[3,2-d]pyrimidine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3- (3-(trifluoromethyl)phenyl)urea (Example 191); 1-(2-(1-methyl-3-morpholino-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 192); 3-(2-fluoro-3-methyl-5-(trifluoromethyl)phenyl)-1-methyl-1-(2-(1-methyl-1H- imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 193); 1-(2-(1-(2-(methylthio)ethyl)-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 194); 1-(2-(1-(2-fluoroethyl)-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-1-methyl-3-(3-(trifluoromethyl)phenyl)urea (Example 195); 1-(2-(1-((methylthio)methyl)-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(3-(trifluoromethyl)phenyl)urea (Example 196); 3-(5-bromopyridin-3-yl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7- carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 197); 1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(3-(1-(trifluoromethyl)cyclopropyl)phenyl)urea (Example 198); 1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea (Example 199); 3-(4-bromopyridin-2-yl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7- carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 200); 1-(2-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-1- methyl-3-(2-methyl-5-(trifluoromethoxy)phenyl)urea (Example 201); 1-(2-(1-(2-methoxyethyl)-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-1-methyl-3-(4-(trifluoromethoxy)pyridin-2-yl)urea (Example 202); 1-(2-(1-(2-methoxyethyl)-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-1-methyl-3-(3-(trifluoromethyl)phenyl)urea (Example 203); 1-(2-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-1- methyl-3-(5-(trifluoromethoxy)pyridin-3-yl)urea (Example 204); 1-(2-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-1- methyl-3-(4-(trifluoromethoxy)pyridin-2-yl)urea (Example 205); 1-(2-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-1- methyl-3-(5-(trifluoromethyl)pyridin-3-yl)urea (Example 206); 1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(5-((trifluoromethyl)thio)pyridin-3-yl)urea (Example 207); 1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(5-(trifluoromethyl)pyridazin-3-yl)urea (Example 208); 1-(2-(1-(2-hydroxyethyl)-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-1-methyl-3-(4-(trifluoromethyl)pyridin-2-yl)urea (Example 209); 1-(2-(1-(2-hydroxyethyl)-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-1-methyl-3-(3-(pentafluoro-l6-sulfaneyl)phenyl)urea (Example 210); 1-(2-(1-(2-hydroxyethyl)-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-1-methyl-3-(4-(trifluoromethoxy)pyridin-2-yl)urea (Example 211); 1-(3-(hydroxymethyl)-2-methoxy-5-(trifluoromethoxy)phenyl)-3-(2-(pyrazolo[1,5- a]pyrazine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 212); 1-(2-(1-(2-methoxyethyl)-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-1-methyl-3-(5-(trifluoromethyl)pyridin-3-yl)urea (Example 213); 1-methyl-1-(2-(5-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea (Example 214); 3-(3-(tert-butyl)isoxazol-5-yl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole- 7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 215); 1-methyl-1-(2-(pyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3- (5-(trifluoromethyl)pyridin-3-yl)urea (Example 216); 1-methyl-1-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3- (4-(trifluoromethyl)pyridin-2-yl)urea (Example 217); 1-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)-2-azaspiro[3.3]heptan-6-yl)-3-(3- (hydroxymethyl)-2-methoxy-5-(trifluoromethoxy)phenyl)-1-methylurea (Example 218); 1-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)-2-azaspiro[3.3]heptan-6-yl)-1-methyl-3-(4- (trifluoromethoxy)pyridin-2-yl)urea (Example 219); 1-(2-(1H-pyrrolo[2,3-b]pyridin-5-yl)-2-azaspiro[3.3]heptan-6-yl)-1-methyl-3-(5- (trifluoromethyl)pyridin-3-yl)urea (Example 220); 1-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)-2-azaspiro[3.3]heptan-6-yl)-1-methyl-3-(5- (trifluoromethoxy)pyridin-3-yl)urea (Example 221); 3-(5-(tert-butyl)isoxazol-3-yl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole- 7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 222); 1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(3-methyl-5-(trifluoromethyl)phenyl)urea (Example 223); 3-(3-chloro-5-(trifluoromethyl)phenyl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2- b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 224); 1-(2-(2-(2-methoxyethyl)-1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-1-methyl-3-(5-(trifluoromethyl)pyridin-3-yl)urea (Example 225); 3-(4-bromopyridin-2-yl)-1-methyl-1-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)urea (Example 226); 1-(2-(6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-1-methyl-3-(5-(trifluoromethyl)pyridin-3-yl)urea (Example 227); 1-methyl-1-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3- (5-(trifluoromethyl)pyridazin-3-yl)urea (Example 228); 1-methyl-1-(2-(6-(2-methyloxazol-5-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea (Example 229); 1-methyl-1-(2-(6-(pyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea (Example 230); 1-methyl-1-(2-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea (Example 231); 1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(2-methyl-5-(trifluoromethyl)phenyl)urea (Example 232); 1-(2-(6-(3,4-dimethoxyphenyl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-1-methyl-3-(5-(trifluoromethyl)pyridin-3-yl)urea (Example 233); 1-methyl-1-(2-(6-(2-methylthiazol-5-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea (Example 234); 1-methyl-1-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3- (5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea (Example 235); 1-(2-(6-(2-methoxypyridin-4-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-1-methyl-3-(5-(trifluoromethyl)pyridin-3-yl)urea (Example 236); 1-methyl-1-(2-(6-(3-methylisoxazol-5-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea (Example 237); 1-methyl-1-(2-(pyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3- (4-(trifluoromethyl)pyridin-2-yl)urea (Example 238); 1-methyl-1-(2-(pyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3- (4-(trifluoromethoxy)pyridin-2-yl)urea (Example 239); 1-methyl-1-(2-(6-(pyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea (Example 240); 1-methyl-1-(2-(6-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(4-(trifluoromethyl)pyridin-2-yl)urea (Example 241); 1-(2-(6-(1,2-dimethyl-1H-2l4-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-1-methyl-3-(4-(trifluoromethoxy)pyridin-2-yl)urea (Example 242); 1-methyl-1-(2-(5-(1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea (Example 243); 1-(2-(5-aminopyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-1- methyl-3-(5-(trifluoromethyl)pyridin-3-yl)urea (Example 244); 1-methyl-1-(2-(6-(pyrimidin-5-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea (Example 245); 1-methyl-1-(2-(6-(2-methylpyrimidin-5-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea (Example 246); 1-(2-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-1- methyl-3-(3-(trifluoromethyl)phenyl)urea (Example 247); 1-(2-(1H-pyrrolo[2,3-b]pyridine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-1-methyl- 3-(3-(trifluoromethyl)phenyl)urea (Example 248); 1-methyl-1-(2-(6-(pyridin-4-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(5-(trifluoromethyl)pyridin-3-yl)urea (Example 249); 1-(2-(6-methoxypyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-1- methyl-3-(5-(trifluoromethyl)pyridin-3-yl)urea (Example 250); 1-(2-(5-methoxypyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-1- methyl-3-(5-(trifluoromethyl)pyridin-3-yl)urea (Example 251); 1-(2-(5-(3,3-difluoropyrrolidin-1-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-1-methyl-3-(5-(trifluoromethyl)pyridin-3-yl)urea (Example 252); 1-(2-(6-(6-methoxypyridin-3-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-1-methyl-3-(5-(trifluoromethyl)pyridin-3-yl)urea (Example 253); 3-(4-iodopyridin-2-yl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7- carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 254); 3-(4-(difluoromethyl)pyridin-2-yl)-1-methyl-1-(2-(pyrazolo[5,1-b]thiazole-7- carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 255); 3-(6-methoxy-4-(trifluoromethyl)pyridin-2-yl)-1-methyl-1-(2-(1-methyl-1H- imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 256); 3-(3,5-bis(trifluoromethyl)phenyl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2- b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 257); 1-(2-(6-(1,3-dimethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-1-methyl-3-(5-(trifluoromethyl)pyridin-3-yl)urea (Example 258); 1-methyl-1-(2-(pyrazolo[1,5-a]pyridine-3-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3- (5-(trifluoromethyl)pyridazin-3-yl)urea (Example 259); 1-(2-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(2- methoxy-5-(trifluoromethyl)phenyl)-1-methylurea (Example 260); 1-(2-(6-(1,5-dimethyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyridine-3-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-1-methyl-3-(5-(trifluoromethyl)pyridin-3-yl)urea (Example 261); 1-(2-methoxy-5-(trifluoromethyl)pyridin-3-yl)-3-(2-(pyrazolo[5,1-b]thiazole-7- carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 262); 1-methyl-1-(2-(thieno[3,2-d]pyrimidine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3- (4-(trifluoromethyl)pyridin-2-yl)urea (Example 263); 3-(2-ethyl-5-(trifluoromethyl)phenyl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2- b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 264); 3-(3-fluoro-4-methyl-5-(trifluoromethyl)phenyl)-1-methyl-1-(2-(1-methyl-1H- imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 265); 1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(5-(perfluoroethyl)pyridin-3-yl)urea (Example 266); 3-(6-chloro-4-(trifluoromethyl)pyridin-2-yl)-1-methyl-1-(2-(1-methyl-1H- imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 267); 1-(2-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-1- methyl-3-(3-methyl-5-(trifluoromethyl)phenyl)urea (Example 268); 1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-5-yl)urea (Example 269); 2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl(2- methyl-5-(trifluoromethyl)phenyl)carbamate (Example 270); 2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl(5- (1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)carbamate (Example 271); 2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl(4- (trifluoromethoxy)pyridin-2-yl)carbamate (Example 272); 2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl(5- (trifluoromethyl)pyridin-3-yl)carbamate (Example 273); 2-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)- N-(5-(trifluoromethyl)pyridin-3-yl)acetamide (Example 274); 2-(2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-N-(5- (trifluoromethoxy)pyridin-3-yl)acetamide (Example 275); N-(2-fluoro-5-(trifluoromethoxy)phenyl)-2-(2-(1-methyl-1H-imidazo[1,2- b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)acetamide (Example 276); 2-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)- N-(4-(trifluoromethoxy)pyridin-2-yl)acetamide (Example 277); 2-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)- N-(2-methyl-5-(trifluoromethoxy)phenyl)acetamide (Example 278); 2-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)- N-(4-(trifluoromethyl)pyridin-2-yl)acetamide (Example 279); 1-methyl-3-(2-methyl-5-(trifluoromethoxy)phenyl)-1-(2-(thieno[3,2-d]pyrimidine-4- carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 280); 1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(3-methyl-5-(trifluoromethoxy)phenyl)urea (Example 281); 1-(2-ethyl-5-(trifluoromethyl)phenyl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7- carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 282); 3-(3-fluoro-2-methyl-5-(trifluoromethyl)phenyl)-1-methyl-1-(2-(1-methyl-1H- imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 283); 1-(2-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3- cyano-5-(trifluoromethyl)phenyl)-1-methylurea (Example 284); 1-(2-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(2- chloro-5-(trifluoromethyl)phenyl)-1-methylurea (Example 285); 1-(2-(7H-pyrrolo[2,3-d]pyrimidine-4-carbonyl)-2-azaspiro[3.3]heptan-6-yl)-3-(3- chloro-5-(trifluoromethyl)phenyl)-1-methylurea (Example 286); 3-(3-methoxy-5-(trifluoromethyl)phenyl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2- b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 287); 3-(2-ethoxy-5-(trifluoromethyl)phenyl)-1-methyl-1-(2-(1-methyl-1H-imidazo[1,2- b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 288); 1-methyl-3-(2-methyl-6-(trifluoromethyl)pyrimidin-4-yl)-1-(2-(pyrazolo[5,1- b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 289); 1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(2-methyl-6-(trifluoromethyl)pyrimidin-4-yl)urea (Example 290); 1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(4-(trifluoromethyl)thiophen-2-yl)urea (Example 291); 2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl(6- (trifluoromethyl)pyrimidin-4-yl)carbamate (Example 292); 2-(pyrazolo[5,1-b]thiazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl (5-(1,1,1- trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)carbamate (Example 293); 2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl(4- (trifluoromethoxy)pyridin-2-yl)carbamate (Example 294); 2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl(2- methyl-5-(trifluoromethoxy)phenyl)carbamate (Example 295); 2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl(4- (trifluoromethyl)pyridin-2-yl)carbamate (Example 296); 2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl(6- (trifluoromethyl)pyrimidin-4-yl)carbamate (Example 297); 1-(2-ethoxy-5-(trifluoromethyl)phenyl)-3-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole- 7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 298); 2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl(5- (trifluoromethoxy)pyridin-3-yl)carbamate (Example 299); 1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(6-methyl-4-(trifluoromethyl)pyridin-2-yl)urea (Example 300); 2-(2-(1-(methyl-d3)-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan- 6-yl)-N-(4-(trifluoromethoxy)pyridin-2-yl)acetamide (Example 301); 2-(2-(1-(difluoromethyl)-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-N-(4-(trifluoromethoxy)pyridin-2-yl)acetamide (Example 302); 1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(5-methyl-4-(trifluoromethyl)pyridin-2-yl)urea (Example 303); 1-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)-2-azaspiro[3.3]heptan-6-yl)-3-(5- (trifluoromethyl)pyridin-3-yl)urea (Example 304); 1-methyl-1-(2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2- azaspiro[3.3]heptan-6-yl)-3-(4-(perfluoroethyl)pyridin-2-yl)urea (Example 305); 1-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)-2-azaspiro[3.3]heptan-6-yl)-3-(5- (trifluoromethyl)pyridazin-3-yl)urea (Example 306); 1-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)-2-azaspiro[3.3]heptan-6-yl)-3-(2-methyl-5- (trifluoromethoxy)phenyl)urea (Example 307); 3-(6-bromo-4-(trifluoromethyl)pyridin-2-yl)-1-methyl-1-(2-(1-methyl-1H- imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 308); 1-(2-ethyl-5-(trifluoromethyl)pyridin-3-yl)-3-(2-(1-methyl-1H-imidazo[1,2- b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 309); 3-(2-ethyl-5-(trifluoromethyl)pyridin-3-yl)-1-methyl-1-(2-(1-methyl-1H- imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl)urea (Example 310); 2-(1-methyl-1H-imidazo[1,2-b]pyrazole-7-carbonyl)-2-azaspiro[3.3]heptan-6-yl(5- (trifluoromethyl)pyridazin-3-yl)carbamate (Example 311); and 1-(2-(1H-pyrazolo[3,4-b]pyridin-5-yl)-2-azaspiro[3.3]heptan-6-yl)-3-(3- (hydroxymethyl)-2-methoxy-5-(trifluoromethyl)phenyl)urea (Example 312); or a stereoisomer, tautomer, solvate and pharmaceutically acceptable salt thereof.
11. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 10, in admixture with at least one or more pharmaceutically acceptable carrier and/or excipient.
12. The pharmaceutical composition according to claim 11 formulated for administration by inhalation.
13. The pharmaceutical composition according to claim 11 formulated for oral administration.
14. The compound of formula (I) according to any one of claims 1 to 10 or the pharmaceutical composition according to any one of claims 11 to 13 for use as a medicament.
15. The compound of formula (I)
Figure imgf000247_0001
wherein A is a ring selected from the group consisting of :
Figure imgf000247_0002
wherein indicates a direct bond to NH; W1, W2 and W3 are substituents of ring A independently selected from the group consisting of hydrogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)halohydroxyalkyl, (C1- C4)alkoxy, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)haloalkoxy, (C1-C4)hydroxyalkyl, halogen, cyano, SF5, NR1R2-(C1-C4)alkyl, CONR1R2, NHCOR1, NR1R2, heterocycloalkyl, (C3- C7)cycloalkyl, (C1-C4)alkyl-heterocycloalkyl, (C1-C4)alkyl-heterocycloalkyl-(C1-C4)alkyl, (C1-C4)haloalkyl-cycloalkyl, (C1-C4)alkyl-(C3-C7)cycloalkyl, heterocycloalkyl-(C1- C4)alkyl, heterocycloalkyl-NH-(C1-C4)alkyl, (C3-C7)cycloalkyl-(C1-C4)alkyl, heterocycloalkyl-(C1-C4)alkoxy, (C1-C4)alkyl-CO-heterocycloalkyl-oxy, (C3- C7)cycloalkyl-(C1-C4)alkoxy, heterocycloalkyl-oxy, (C3-C7)cycloalkyl-oxy, (C1-C4)alkyl- heterocycloalkyl-carbonyl, monocyclic (C1-C4)alkyl-heteroaryl, (C1-C4)alkyl-sulfonyl, (C1- C4)haloalkyl-sulfonyl, (C1-C4)haloalkyl-sulfonylamino, (C1-C4)haloalkyl-sulfinyl, (C1- C4)haloalkyl-thio, (C1-C4)alkyl-thio-(C1-C4)alkyl, (C1-C4)alkyl-sulfonyl-(C1-C4)alkyl and (C1-C4)alkyl-sulfinyl-(C1-C4)alkyl; or, wherein W1 and W2 are in adjacent positions on ring A, W1 and W2 form a (C5-C6)cycloalkyl or a 5- or 6-membered heterocycloalkyl, wherein the (C5-C6)cycloalkyl or the 5- or 6-membered heterocycloalkyl are optionally substituted with 1 to 3 halogen atoms; L is selected from CO and CH2 or is absent; L1 is selected from NR, CH2 and O, wherein R is selected from the group consisting of hydrogen, (C1-C4)alkyl, (C1-C4)hydroxyalkyl, (C1-C4)haloalkyl, (C3-C7)cycloalkyl, (C3- C7)cycloalkyl-(C1-C4)alkyl and deuterated (C1-C4)alkyl; RS is selected from hydrogen and methyl, when L1 is NR; RS is hydrogen, when L1 is CH2 or O; B is mono- or bi-cyclic heteroaryl ring or bi-cyclic semisaturated heteroaryl ring; Y1 and Y2 are substituents of ring B independently selected from the group consisting of hydrogen, (C1-C4)alkyl, deuterated (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, (C1- C4)haloalkoxy, (C1-C4)hydroxyalkyl, halogen, cyano, SF5, (C1-C4)cyanoalkyl, (C1-C4)alkyl- sulfonyl, (C1-C4)haloalkyl-sulfonyl, CONR1R2, NHCOR1, NR1R2, NR1R2-(C1-C4)alkyl, heterocycloalkyl optionally substituted with 1 to 3 halogens, heterocycloalkyl-NH-(C1- C4)alkyl, (C3-C7)cycloalkyl, (C1-C4)alkyl-heterocycloalkyl, (C1-C4)alkyl-(C3-C7)cycloalkyl, heterocycloalkyl-(C1-C4)alkyl, (C3-C7)cycloalkyl-(C1-C4)alkyl, heterocycloalkyl-(C1- C4)alkoxy, (C3-C7)cycloalkyl-(C1-C4)alkoxy, heterocycloalkyl-oxy, (C3-C7)cycloalkyl-oxy, phenyl, (C1-C4)alkoxy substituted phenyl, (C1-C4)alkyl-thio-(C1-C4)alkyl, (C1-C4)alkyl- sulfonyl-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)haloalkyl-cycloalkyl, (C1- C4)alkyl-heterocycloalkyl-carbonyl and monocyclic heteroaryl, optionally substituted with 1 to 3 groups selected from the group consisting of (C1-C4)alkyl, (C1-C4)alkoxy and (C1- C4)alkoxy-(C1-C4)alkyl; R1 and R2 are independently selected from the group consisting of hydrogen, (C1- C4)alkyl, (C1-C4)hydroxyalkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkylamino-(C1- C4)alkyl, di-(C1-C4)alkylamino-(C1-C4)alkyl, optionally substituted (C3-C7)cycloalkyl, optionally substituted heterocycloalkyl and optionally substituted heterocycloalkyl-(C1- C4)alkoxy, wherein optional substituents are from 1 to 3 and are selected from the group consisting of (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy and carbamoyl; R3 is selected from the group consisting of (C1-C4)alkyl, (C1-C4)haloalkyl, (C1- C4)alkyl-phenyl and monocyclic heteroaryl; or a stereoisomer, tautomer, solvate and pharmaceutically acceptable salt thereof, for use in the prevention and/or treatment of a disease, disorder or condition associated with dysregulation of DDR.
16. The compound of formula (I) for use according to claim 15, wherein, when A ring is phenyl and L1 is NH, W1, W2 and W3 are independently selected from the group consisting of hydrogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)halohydroxyalkyl, (C1-C4)alkoxy, (C1- C4)alkoxy-(C1-C4)alkyl, (C1-C4)haloalkoxy, (C1-C4)hydroxyalkyl, fluorine, bromine, iodine, cyano, SF5, NR1R2-(C1-C4)alkyl, CONR1R2, NHCOR1, NR1R2, heterocycloalkyl, (C3- C7)cycloalkyl, (C1-C4)alkyl-heterocycloalkyl, (C1-C4)alkyl-heterocycloalkyl-(C1-C4)alkyl, (C1-C4)haloalkyl-cycloalkyl, (C1-C4)alkyl-(C3-C7)cycloalkyl, heterocycloalkyl-(C1- C4)alkyl, heterocycloalkyl-NH-(C1-C4)alkyl, (C3-C7)cycloalkyl-(C1-C4)alkyl, heterocycloalkyl-(C1-C4)alkoxy, (C1-C4)alkyl-CO-heterocycloalkyl-oxy, (C3- C7)cycloalkyl-(C1-C4)alkoxy, heterocycloalkyl-oxy, (C3-C7)cycloalkyl-oxy, (C1-C4)alkyl- heterocycloalkyl-carbonyl, monocyclic (C1-C4)alkyl-heteroaryl, (C1-C4)alkyl-sulfonyl, (C1- C4)haloalkyl-sulfonyl, (C1-C4)haloalkyl-sulfonylamino, (C1-C4)haloalkyl-sulfinyl, (C1- C4)haloalkyl-thio, (C1-C4)alkyl-thio-(C1-C4)alkyl, (C1-C4)alkyl-sulfonyl-(C1-C4)alkyl and (C1-C4)alkyl-sulfinyl-(C1-C4)alkyl; or, wherein W1 and W2 are in adjacent positions on ring A, W1 and W2 form a (C5-C6)cycloalkyl or a 5- or 6-membered heterocycloalkyl, wherein the (C5-C6)cycloalkyl or the 5- or 6-membered heterocycloalkyl are optionally substituted with 1 to 3 halogen atoms.
17. The compound of formula (I) for use according to claim 15 or 16 in the prevention and/or treatment of fibrosis and/or diseases, disorders or conditions that involve fibrosis.
18. The compound of formula (I) for use according to claim 17 in the prevention and/or treatment of fibrosis, including pulmonary fibrosis, idiopathic pulmonary fibrosis (IPF), hepatic fibrosis, progressive pulmonary fibrosis, sarcoidosis, familiar pulmonary fibrosis, chronic hypersensitivity pneumonitis (CHP), kidney fibrosis, renal fibrosis, ocular fibrosis, cardiac fibrosis, arterial fibrosis and systemic sclerosis.
19. The compound of formula (I) for use according to claim 18 in the prevention and/or treatment of idiopathic pulmonary fibrosis (IPF).
20. The compound of formula (I) for use according to claim 18 in the prevention and/or treatment of kidney fibrosis.
21. An intermediate compound of formula IV
Figure imgf000250_0001
wherein A is a ring selected from the group consisting of :
Figure imgf000250_0002
wherein indicates a direct bond to NH; W1, W2 and W3 are substituents of ring A independently selected from the group consisting of hydrogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)halohydroxyalkyl, (C1- C4)alkoxy, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)haloalkoxy, (C1-C4)hydroxyalkyl, halogen, cyano, SF5, NR1R2-(C1-C4)alkyl, CONR1R2, NHCOR1, NR1R2, heterocycloalkyl, (C3- C7)cycloalkyl, (C1-C4)alkyl-heterocycloalkyl, (C1-C4)alkyl-heterocycloalkyl-(C1-C4)alkyl, (C1-C4)haloalkyl-cycloalkyl, (C1-C4)alkyl-(C3-C7)cycloalkyl, heterocycloalkyl-(C1- C4)alkyl, heterocycloalkyl-NH-(C1-C4)alkyl, (C3-C7)cycloalkyl-(C1-C4)alkyl, heterocycloalkyl-(C1-C4)alkoxy, (C1-C4)alkyl-CO-heterocycloalkyl-oxy, (C3- C7)cycloalkyl-(C1-C4)alkoxy, heterocycloalkyl-oxy, (C3-C7)cycloalkyl-oxy, (C1-C4)alkyl- heterocycloalkyl-carbonyl, monocyclic (C1-C4)alkyl-heteroaryl, (C1-C4)alkyl-sulfonyl, (C1- C4)haloalkyl-sulfonyl, (C1-C4)haloalkyl-sulfonylamino, (C1-C4)haloalkyl-sulfinyl, (C1- C4)haloalkyl-thio, (C1-C4)alkyl-thio-(C1-C4)alkyl, (C1-C4)alkyl-sulfonyl-(C1-C4)alkyl and (C1-C4)alkyl-sulfinyl-(C1-C4)alkyl; or, wherein W1 and W2 are in adjacent positions on ring A, W1 and W2 form a (C5-C6)cycloalkyl or a 5- or 6-membered heterocycloalkyl, wherein the (C5-C6)cycloalkyl or the 5- or 6-membered heterocycloalkyl are optionally substituted with 1 to 3 halogen atoms; L1 is selected from NR, CH2 and O, wherein R is selected from the group consisting of hydrogen, (C1-C4)alkyl, (C1-C4)hydroxyalkyl, (C1-C4)haloalkyl, (C3-C7)cycloalkyl, (C3- C7)cycloalkyl-(C1-C4)alkyl and deuterated (C1-C4)alkyl, preferably selected from the group consisting of hydrogen, CD3, cyclopropylmethyl, cyclopropyl, CH2CF3, CH2CH3 or CH3; Rs is selected from hydrogen and methyl when L1 is NR; RS is hydrogen when L1 is CH2 or O; R1 and R2 are independently selected from the group consisting of hydrogen, (C1- C4)alkyl, (C1-C4)hydroxyalkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkylamino-(C1- C4)alkyl, di-(C1-C4)alkylamino-(C1-C4)alkyl, optionally substituted (C3-C7)cycloalkyl, optionally substituted heterocycloalkyl and optionally substituted heterocycloalkyl-(C1- C4)alkoxy, wherein optional substituents are from 1 to 3 and are selected from the group consisting of (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)haloalkyl, (C1-C4)haloalkoxy and carbamoyl; and R3 is selected from the group consisting of (C1-C4)alkyl, (C1-C4)haloalkyl, (C1- C4)alkyl-phenyl and monocyclic heteroaryl; or a stereoisomer, tautomer, solvate and pharmaceutically acceptable salt thereof; wherein the intermediate compound of formula IV is not 1-(3,5-dichlorophenyl)-3-(2- azaspiro[3.3]heptan-6-yl)urea; and wherein, when A ring is phenyl, L1 is NH and W1 and W2 are hydrogen, W3 is not para-OCF3.
22. The intermediate compound of claim 20, wherein, when A ring is phenyl and L1 is NH, W1, W2 and W3 are independently selected from the group consisting of hydrogen, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)halohydroxyalkyl, (C1-C4)alkoxy, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)haloalkoxy, (C1-C4)hydroxyalkyl, fluorine, bromine, iodine, cyano, SF5, NR1R2- (C1-C4)alkyl, CONR1R2, NHCOR1, NR1R2, heterocycloalkyl, (C3-C7)cycloalkyl, (C1- C4)alkyl-heterocycloalkyl, (C1-C4)alkyl-heterocycloalkyl-(C1-C4)alkyl, (C1-C4)haloalkyl- cycloalkyl, (C1-C4)alkyl-(C3-C7)cycloalkyl, heterocycloalkyl-(C1-C4)alkyl, heterocycloalkyl-NH-(C1-C4)alkyl, (C3-C7)cycloalkyl-(C1-C4)alkyl, heterocycloalkyl-(C1- C4)alkoxy, (C1-C4)alkyl-CO-heterocycloalkyl-oxy, (C3-C7)cycloalkyl-(C1-C4)alkoxy, heterocycloalkyl-oxy, (C3-C7)cycloalkyl-oxy, (C1-C4)alkyl-heterocycloalkyl-carbonyl, monocyclic (C1-C4)alkyl-heteroaryl, (C1-C4)alkyl-sulfonyl, (C1-C4)haloalkyl-sulfonyl, (C1- C4)haloalkyl-sulfonylamino, (C1-C4)haloalkyl-sulfinyl, (C1-C4)haloalkyl-thio, (C1-C4)alkyl- thio-(C1-C4)alkyl, (C1-C4)alkyl-sulfonyl-(C1-C4)alkyl and (C1-C4)alkyl-sulfinyl-(C1- C4)alkyl, preferably selected from the group consisting of hydrogen, CH3, OCH3, OCF3, CF3, CHF2, C(CH3)3, CH2CF3, CF2CH3, CF2CF3, C(CH3)2CF3, OCF2H, CH2OH, cyano, CF3SO2, SCF3, SF5, F, Br, I, cyclopropyl, morpholino-N-ethoxy, N-acetylpiperidinyl-oxy, N- acetylazetidinyl-oxy, 2,2,2-trifluoro-1-hydroxyethyl, oxetanyloxy, CH2N(CH3)2 and 4- methylpiperazin-1-yl; or, wherein W1 and W2 are in adjacent positions on ring A, W1 and W2 form a (C5-C6)cycloalkyl or a 5- or 6-membered heterocycloalkyl, wherein the (C5- C6)cycloalkyl or the 5- or 6-membered heterocycloalkyl are optionally substituted with 1 to 3 halogen atoms; or a stereoisomer, tautomer, solvate and pharmaceutically acceptable salt thereof.
23. Use of the intermediate compound IV, as defined in claim 21 or 22, in the preparation of a compound of formula (I), as defined in claim 1.
24. A process for the preparation of a compound of formula (I), as defined in claim 1, or a pharmaceutically acceptable salt thereof, comprising the step of: a) reacting an intermediate compound IV
Figure imgf000252_0001
with either a carboxylic acid XI
Figure imgf000252_0002
or an aldehyde XII
Figure imgf000252_0003
or an aryl halide XIII to obtain a compound of formula (I), wherein the compound of formula IV is as defined in claim 21 or 22, wherein B, Y1 and Y2 are as defined in claim 1 and X is halogen, preferably bromine.
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