WO2013043964A1 - Acyclic cyanoethylpyrazoles as janus kinase inhibitors - Google Patents

Acyclic cyanoethylpyrazoles as janus kinase inhibitors Download PDF

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Publication number
WO2013043964A1
WO2013043964A1 PCT/US2012/056481 US2012056481W WO2013043964A1 WO 2013043964 A1 WO2013043964 A1 WO 2013043964A1 US 2012056481 W US2012056481 W US 2012056481W WO 2013043964 A1 WO2013043964 A1 WO 2013043964A1
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Prior art keywords
alkyl
amino
pyrazole
carboxamide
cyano
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PCT/US2012/056481
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French (fr)
Inventor
Jason Brubaker
Joshua T. CLOSE
Joon Jung
Michelle Martinez
Catherine White
Kevin Wilson
Jonathan R. Young
Hongjun Zhang
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Organon Pharma UK Ltd
Merck Sharp and Dohme LLC
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Merck Sharp and Dohme Ltd
Merck Sharp and Dohme LLC
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Priority to US14/345,977 priority Critical patent/US9493441B2/en
Priority to JP2014531994A priority patent/JP6014149B2/en
Priority to CA2849357A priority patent/CA2849357A1/en
Priority to AU2012312305A priority patent/AU2012312305B2/en
Priority to EP12834358.9A priority patent/EP2758050B1/en
Publication of WO2013043964A1 publication Critical patent/WO2013043964A1/en
Anticipated expiration legal-status Critical
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Definitions

  • Protein kinases are a group of enzymes that regulate the activity of their target proteins by the addition of phosphate groups to the protein substrate. Kinases play an essential role in many physiological processes including cell division, differentiation, cellular homeostasis and signal transduction. Kinases can be subdivided by their target into Serine/Threonine kinases and Tyrosine kinases. Tyrosine kinases are further subdivided into receptor tyrosine kinases and non-receptor tyrosine kinases. The mammalian Janus kinase (JAK) family members are nonreceptor tyrosine kinases.
  • JAK Janus kinase
  • JAK family has four members; JAKl, JAK2, JAK3 and TYK2. JAKl, JAK2 and TYK2 are universally expressed, whereas JAK3 expression is limited to hematopoetic cells.
  • the JAK family is involved in intracellular signal transduction from >70 different cytokines. Cytokines bind to their cell surface receptors resulting in receptor dimerization and subsequent activation/phosphorylation of JAK tyrosine kinases.
  • the JAKs are either constitutively associated with the receptor or are recruited upon cytokine binding. Specific tyrosine residues on the receptor are then phosphorylated by activated JAKs and serve as docking sites for STAT proteins. STATs are phosphorylated by JAKs, dimerize, then translocate to the nucleus where they bind specific DNA elements and activate gene transcription.
  • JAKl signals in conjunction with all JAK isoforms in a cytokine dependent manner.
  • JAKs are essential for multiple physiological functions. This has been demonstrated using genetically engineered mouse models that are deficient in specific JAKs. Jakl "A mice die perinatally, while Jak2 " _ mice have deficiencies in erythropoesis and die around day El 2. 3a 3 ⁇ ' ⁇ mice are viable, but have a SCID phenotype with deficiencies in T cells, B cells and NK cells. ⁇ 2 " ⁇ mice exhibit features of hyper IgE syndrome. These phenotypes demonstrate the essential and non-redundant roles of JAK activity in vivo (K. Ghoreschi, A. Laurence, J. J. O'Shea, Immunol. Rev. 228, 273 (2009)).
  • JAK3 or the cognate common gamma chain cytokine receptor
  • J. J. O'Shea M. Pesu, D. C. Borie, P. S. Changelian, Nat. Rev. Drug Discov. 3, 555 (2004)
  • Deletions of TYK2 result in hyper IgG syndrome and increased infection risk (Y. Minegishi et al, Immunity. 25, 745 (2006)).
  • No inactivating mutations have been reported for JAKl or JAK2, consistent with the data from mice that demonstrates that JAKl and JAK2 deficient mice are not viable.
  • JAK2 is the sole JAK family member involved in signal transduction of the critical hematopoetic cytokines IL-3, GMCSF, EPO and TPO.
  • the present invention provides novel compounds which are inhibitors of JAKs.
  • the invention also provides a method for the treatment and prevention of JAK-mediated diseases and disorders using the novel compounds, as well as pharmaceutical compositions containing the compounds.
  • the present invention provides compounds of formula I or pharmaceutically acceptable stereoisomer thereof:
  • R a and R 4 are each independently selected from hydrogen and C ⁇ alkyl;
  • R 5 is selected from aryl and heteroaryl, wherein R 5 is substituted with 0, 1, 2, 3, or 4, substituents, R 5a ;
  • R 1 , R 2 , and R 3 are each independently selected from
  • R 1 , R 2 , and R 3 are independently substituted with 0, 1, 2, 3, or 4, substituents
  • R 5a is selected from:
  • Ci-io heteroalkyl(oxy) 0-1 (carbonyl)0-lCo-10 alkyl Ci-io heteroalkyl(oxy) 0-1 (carbonyl)0-lCo-10 alkyl
  • Ci-io alkyl(carbonyl)0-loxyCo-10 alkyl Ci-io alkyl(carbonyl)0-loxyCo-10 alkyl
  • Ci-io heteroalkyl(carbonyl)o-loxyCo-10 alkyl Ci-io heteroalkyl(carbonyl)o-loxyCo-10 alkyl
  • Ci-io heteroalkyl(carbonyl)0-loxyCo-10 alkyl Ci-io heteroalkyl(carbonyl)0-loxyCo-10 alkyl
  • Ci-io alkylamino(oxy)o-icarbonylCo-10 alkyl Ci-io alkylamino(oxy)o-icarbonylCo-10 alkyl
  • Ci-io alkyl(oxy)o-icarbonylaminoCo-10 alkyl Ci-io alkyl(oxy)o-icarbonylaminoCo-10 alkyl
  • R 5a is each optionally substituted with 0, 1, 2, 3, or 4 R 6 substituents and R 6 independently selected from:
  • Ci-io heteroalkyl(oxy) 0-1 (carbonyl)0-lCo-10 alkyl Ci-io heteroalkyl(oxy) 0-1 (carbonyl)0-lCo-10 alkyl
  • Ci-io heteroalkyl(carbonyl)0-loxyCo-10 alkyl Ci-io heteroalkyl(carbonyl)0-loxyCo-10 alkyl
  • Ci-io alkylamino(oxy)o-icarbonylCo-10 alkyl Ci-io alkylamino(oxy)o-icarbonylCo-10 alkyl
  • Ci-io alkyl (oxy)o -1 carbonylaminoCo-10 alkyl Ci-io alkyl (oxy)o -1 carbonylaminoCo-10 alkyl
  • C3-8 cycloheteroalkylsulfonyl, heteroarylsulfonyl, arylsulfonyl, aminosulfonyl, -S02N(Ci-6alkyl) 1-2 , -S02Ci-6alkyl, -SO2CF3, -SO2CF2H, -C O alkylsulfinyl, -OSi(Ci_ioalkyl) 3 , -O(0-l)(Cl-10)haloalkyl, and NH2 ;
  • Representative compounds of the instant invention include, but are not limited to the following compounds and their pharmaceutically acceptable salts and stereoisomers thereof: 1 -(2-cyano- 1 -cyclopropylethyl)-3 -(phenylamino)- 1 H-pyrazole-4-carboxamide;
  • oxetan-3 -yl 4-[(lS)-l- ⁇ 4-carbamoyl-3 - [(4-fluorophenyl)amino] - 1 H-pyrazol- 1 -yl ⁇ -2- cyanoethyl]piperidine- 1 -carboxylate;
  • 2,2,2-trifIuoroethyl 4-[l- ⁇ 4-carbamoyl-3-[(4-fluorophenyl)amino]-lH-pyrazol-l-yl ⁇ -2- cyanoethyl]piperidine- 1 -carboxylate;
  • cyclopropylmethyl 4-[l - ⁇ 4-carbamoyl-3-[(4-fluorophenyl)amino]- 1 H-pyrazol- 1 -yl ⁇ -2- cyanoethyljpiperidine- 1 -carboxylate; cyclopropylmethyl 4-[( 1 S)- 1 - ⁇ 4-carbamoyl-3 - [(4-fluorophenyl)amino]- 1 H-pyrazol- 1 -yl ⁇ -2- cyanoethyl]piperidine- 1 -carboxylate;
  • representative compounds include, but are not limited to, the following compounds and their pharmaceutically acceptable salts and stereoisomers thereof: l-(2-cyano-l-cyclopentylethyl)-3-( ⁇ 4-[(l,l-dioxidothiom
  • cyclopropylmethyl 4-[ 1 - ⁇ 4-carbamoyl-3-[(4-fluorophenyl)amino]- 1 H-pyrazol- 1 -yl ⁇ -2- cyanoethyl]piperidine- 1 -carboxylate; 2,2,2-trifluoro- 1 -methylethyl 4-[l - ⁇ 4-carbamoyl-3-[(4-fluorophenyl)amino]- 1 H-pyrazol- 1 -yl ⁇ -2- cyanoethyl]piperidine- 1 -carboxylate;
  • the invention also encompasses pharmaceutical compositions containing a compound of formula I, and methods for treatment or prevention of JAK mediated diseases using compounds of formula I.
  • Acyl means a -C(0)R radical Where R is optionally substituted alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl heteroaryl, etc.
  • Acylamino means a -NRR' radical where R is ⁇ , ⁇ , or alkoxy and R' is acyl, as defined herein.
  • alkyl is intended to include both branched- and straight-chain saturated aliphatic hydrocarbon groups, including all isomers, having the specified number of carbon atoms. Commonly used abbreviations for alkyl groups are used throughout the specification, e.g. methyl may be represented by “Me” or CH 3 , ethyl may be represented by “Et” or CH 2 CH 3 , propyl may be represented by “Pr” or CH2CH2CH3, butyl may be represented by "Bu” or CH 2 CH 2 CH 2 CH 3 , etc.
  • Ci-6 alkyl (or “C1-C6 alkyl”) for example, means linear or branched chain alkyl groups, including all isomers, having the specified number of carbon atoms.
  • Ci-6 alkyl includes all of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- and t- butyl, n- and isopropyl, ethyl and methyl.
  • Ci-4 alkyl means n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl.
  • alkylene refers to both branched- and straight-chain saturated aliphatic hydrocarbon groups, including all isomers, having the specified number of carbons, and having two terminal end chain attachments. For illustration, the term
  • unsubstituted A-C4alkylene-B represents A-CH2-CH2-CH2-CH2-B.
  • alkoxy represents a linear or branched alkyl group of indicated number of carbon atoms attached through an oxygen bridge.
  • alkyl refers to an aliphatic hydrocarbon group which may be straight or branched and having the indicated number of carbon atoms.
  • alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s- and t-butyl, pentyl, hexyl, and the like.
  • heteroalkyl refers to an alkyl group where 1, 2, or 3 of the carbon atoms is substituted by a heteroatom independently selected from N, O, or S.
  • alkenyl refers to an aliphatic hydrocarbon group containing at least one carbon- carbon double bond and which may be straight or branched and having the indicated number of carbon atoms. Preferably alkenyl contains one carbon to carbon double bond, and up to four nonaromatic carbon-carbon double bonds may be present. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, 2-methyl-l-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.
  • Alkynyl refers to an aliphatic hydrocarbon group containing at least one carbon- carbon triple bond and which may be straight or branched and having the indicated number of carbon atoms.
  • suitable alkynyl groups include ethynyl, propynyl, 2- butynyl and 3-methylbutynyl.
  • Alkoxy refers to an alkyl-O- group in which the alkyl group is as described above.
  • Ci-6alkoxy for example, includes methoxy, ethoxy, propoxy, isopropoxy, and the like.
  • Alkoxyalkyl refers to an alkyl group as described above in which one or more
  • Aminoalkyl refers to an alkyl group as described above in which one hydrogen atom has been replaced by an amino, monoalkylamino or dialkylamino group. Examples include CH2NH2, CH2CH2NHCH3 and CH(N(CH3)2)CH3.
  • Co-6 alkyl means a direct covalent bond; or when the term appears at the terminus of a substituent, CO-6 alkyl means hydrogen or Cl-6alkyl.
  • an integer defining the presence of a certain number of atoms in a group is equal to connected directly by a bond. For example, in equal to zero, 1 or
  • C3-8 cycloalkyl (or “C3-C8 cycloalkyl”) means a cyclic ring of an alkane having three to eight total carbon atoms (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl).
  • C3-7 cycloalkyl "C3-6 cycloalkyl”
  • C5-7 cycloalkyl and the like have analogous meanings.
  • halogen refers to fluorine, chlorine, bromine and iodine (alternatively referred to as fluoro (F), chloro (CI), bromo (Br), and iodo (I)).
  • aryl refers to aromatic mono- and poly-carbocyclic ring systems, wherein the individual carbocyclic rings in the polyring systems are fused or attached to each other via a single bond.
  • Suitable aryl groups include phenyl, naphthyl, 2,3-dihydro-lH-indenyl, and biphenyl.
  • Carbocyclyl as used herein, unless otherwise indicated, refers to (i) a C3 to C8 monocyclic, saturated or unsaturated ring or (ii) a C7 to C 2 bicyclic saturated or unsaturated ring system. Each ring in (ii) is either independent of, or fused to, the other ring, and each ring is saturated or unsaturated.
  • the carbocycle may be attached to the rest of the molecule at any carbon atom which results in a stable compound.
  • fused bicyclic carbocycles are a subset of the carbocycles; i.e., the term "fused bicyclic carbocycle” generally refers to a C7 to Cio bicyclic ring system in which each ring is saturated or unsaturated and two adjacent carbon atoms are shared by each of the rings in the ring system.
  • a fused bicyclic carbocycle in which one ring is saturated and the other is saturated is a saturated bicyclic ring system.
  • a fused bicyclic carbocycle in which one ring is benzene and the other is saturated is an unsaturated bicyclic ring system.
  • a fused bicyclic carbocycle in which one ring is benzene and the other is unsaturated is an unsaturated ring system.
  • Saturated carbocyclic rings are also referred to as cycloalkyl rings, e.g., cyclopropyl, cyclobutyl, etc.
  • carbocycle is unsubstituted or substituted with Ci-6 alkyl, Ci-6 alkenyl, Ci-6 alkynyl, aryl, halogen, ⁇ 3 ⁇ 4 or ⁇ .
  • a subset of the fused bicyclic unsaturated carbocycles are those bicyclic carbocycles in which one ring is a benzene ring and the other ring is saturated or unsaturated, with attachment via any carbon atom that results in a stable compound. Representative examples of this subset include the following:
  • Cyanoalkyl refers to an alkyl group as described above in which one hydrogen atom has been replaced by a cyano group. Examples include CH2CN, CH2CH2CN and
  • Cycloalkyl means a carbocyclic ring system having 3 to 12 ring carbon atoms; said ring system may be (a) a monocyclic saturated carbocycle optionally fused to a benzene or a partially unsaturated carbocycle, or (b) a bicyclic saturated carbocycle.
  • the rings are fused across two adjacent ring carbon atoms (e.g., decalin), at one ring carbon atom (e.g., spiro[2.2]pentane), or are bridged groups (e.g., norbornane).
  • Haloalkyl refers to an alkyl group as described above wherein one or more (in particular 1 to 5) hydrogen atoms have been replaced by halogen atoms, with up to complete substitution of all hydrogen atoms with halo groups.
  • Ci_6haloalkyl for example, includes -CF3, -CF2CF3, CHFCH3, and the like.
  • Heterocycle represents a monocyclic or bicyclic 3-12 membered ring system in which at least one ring is non-aromatic (saturated or partially unsaturated) and containing at least one heteroatom selected from O, S and N.
  • the second ring may be a heteroaryl, heterocycle or a saturated, partially unsaturated or aromatic carbocycle, and the point(s) of attachment to the rest of the molecule may be on either ring.
  • Heterocyclyl therefore includes heteroaryls, as well as dihydro and tetrathydro analogs thereof. Attachment of a heterocyclyl substituent can occur via a carbon atom or via a heteroatom.
  • heterocycles include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, dihydroimidazolyl, dihydroindolyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine, 2,3- dihydrobenzofuranyl, benzo-1 ,4-dioxanyl, benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carboliny
  • tetrahydropyranyl tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, aziridinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl,
  • dihydroindolyl dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and
  • Saturated heterocyclics form a subset of the heterocycles; i.e., the terms “saturated heterocyclic and (C3-i2)heterocycloalkyl” generally refers to a heterocycle as defined above in which the entire ring system (whether mono- or poly-cyclic) is saturated.
  • saturated heterocyclic ring refers to a 4- to 8-membered saturated monocyclic ring or a stable 7- to 12- membered bicyclic ring system which consists of carbon atoms and one or more heteroatoms selected from N, O and S.
  • Representative examples include piperidinyl, piperazinyl, azepanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl (or tetrahydrofuranyl)
  • Heteroaromatics form another subset of the heterocycles; i.e., the term “heteroaromatic” (alternatively “heteroaryl”) generally refers to a heterocycle as defined above in which the entire ring system (whether mono- or poly-cyclic) is an aromatic ring system.
  • heteroaryl generally refers to a heterocycle as defined above in which the entire ring system (whether mono- or poly-cyclic) is an aromatic ring system.
  • heteroaryl refers a 5- or 6-membered monocyclic aromatic ring or a 7- to 12- membered bicyclic which consists of carbon atoms and one or more heteroatoms selected from N, O and S.
  • the second ring may be a heteroaromatic or an aromatic, saturated, or partially unsatuated carbocycle, and the point(s) of attachment to the rest of the molecule may be on either ring.
  • substituted heteroaryl rings containing at least one nitrogen atom e.g., pyridine
  • substitutions can be those resulting in N-oxide formation.
  • heteroaryl examples include, but are not limited to, furanyl, thienyl (or thiophenyl), pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, naphthyridinyl, benzothienyl, benzofuranyl, benzimidazole, benzpyrazolyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolizinyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzoxazo
  • bicyclic heterocycles include benzotriazolyl, indolyl, isoindolyl, indazolyl, indolinyl, isoindolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, chromanyl, isochromanyl, tetrahydroquinolinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl,
  • Hydroalkyl refers to an alkyl group as described above in which one or more
  • alkylene alkenylene
  • alkynylene alkynylene
  • cycloalkylene arylene
  • heteroarylene and “heterocyclylene” refer to a divalent radical obtained by the removal of one hydrogen atom from an alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl group, respectively, each of which is as defined above.
  • an “unsaturated” ring is a partially or fully unsaturated ring.
  • an “unsaturated monocyclic C6 carbocycle” refers to
  • heterocycle described as containing from “1 to 4 heteroatoms” means the heterocycle can contain 1 , 2, 3 or 4 heteroatoms.
  • substituted e.g., as in "aryl which is optionally substituted with one or more substituents "
  • substituents include mono- and poly-substitution by a named substituent to the extent such single and multiple substitution (including multiple substitution at the same site) is chemically allowed.
  • oxy means an oxygen (O) atom.
  • thio means a sulfur (S) atom.
  • Structural representations of compounds having substituents terminating with a methyl group may display the terminal methyl group either using the characters "CH3", e.g. "- n
  • CH3 or using a straight line representing the presence of the methyl group, e.g. , i.e., CH 3 and £ ,
  • Ri is a defined variable
  • Rj is a defined variable
  • the value of Ri may differ in each instance in which it occurs, and the value of Rj may differ in each instance in which it occurs.
  • Ri and Rj are independently selected from the group consisting of methyl, ethyl, propyl and butyl
  • (CRiRj)2 can be
  • R a is hydrogen, ethyl, propyl, butyl, pentyl, or methyl. In a variant of this embodiment, R a is hydrogen or methyl. In another variant, R a is hydrogen.
  • R 4 is hydrogen, ethyl, propyl, butyl, pentyl, or methyl. In a variant of this embodiment, R 4 is hydrogen. In another variant, R 4 is methyl, or propyl.
  • R 5 is aryl or heteroaryl, wherein R 5 is substituted with 0, 1, 2,
  • R 5 is selected from: furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, naphthyridinyl, benzothienyl, benzofuranyl, benzimidazole, benzpyrazolyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolizinyl, quinoxalinyl, quinazolinyl, benzoxazolyl, benzisoxazolyl, 5,6,7,8-t
  • R 5 is selected from: phenyl, l,3-dihydro-2H-isoindole, pyridinyl, quinolinyl, indoxplyl, isoquinolinyl, 2,3-dihydro-l-benzofuranyl, benzofuranyl, dihydro-lH- indenyl, indenyl, 2,3-dihydro-l,4-benzodioxinyl, 2,3,dihydro-lH-isoindolyl, isoindolyl, and benzo[b]thiophene, wherein R s is substituted with 0, 1, 2, 3, or 4 R 5a substituents.
  • R 5 is selected from: phenyl, l,3-dihydro-2H-isoindole, pyridinyl, isoquinolinyl, 2,3-dihydro-l-benzofuranyl, dihydro-lH-indenyl, 2,3-dihydro-l,4- benzodioxinyl, 2,3,dihydro-lH-isoindolyl, and benzo[b]thiophene, wherein R 5 is substituted with 0, 1, 2, 3, or 4 R a substituents
  • R , R , and R is selected from hydrogen, Ci-io alkyl, aryl CO-10 alkylCo-10 alkyl, (C3-8)heterocycloalkyl Co-10 alkyl> c 3-8 cycloalkylCO-10 alkyl, and heteroaryl CO-10 alkyl, wherein each of R 1 , R 2 , and R 3 are independently substituted with 0,
  • R , R , and R are selected from hydrogen, Ci-io alkyl, (C3-8)heterocycloalkyl Co-10 alkyl, and C3-8 cycloalkylCO-10 alkyl, wherein each of R 1 , R 2 , and R 3 are independently substituted with 0, 1, 2, 3, or 4 R 5a substituents.
  • R 1 , R 2 , and R 3 are independently selected from hydrogen, piperidinyl, cyclopropyl, pyrrolidinyl, cyclopentyl, methyl, ethyl, tetrahydro-2H-pyranyl, (tetrahydro-2H-pyranyl)methyl, propyl, tert-butyl, isopropyl,
  • R 1 , R 2 , and R 3 are independently substituted with 0, 1, 2, 3, or 4 R 5a substituents.
  • R 1 and R 2 are independently selected from hydrogen, piperidinyl, cyclopropyl, pyrrolidinyl, cyclopentyl, methyl, ethyl, tetrahydro-2H- pyranyl, (tetrahydro-2H-pyranyl)methyl, propyl, tert-butyl, isopropyl, dimethylpropyl,
  • R and R are independently substituted with 0, 1, 2, 3, or 4, R 5a substituents.
  • R 3 is hydrogen, methyl, ethyl, or butyl. In a variant of this embodiment, R is hydrogen or methyl.
  • R 1 is hydrogen, Ci_io heteroalkyl, or cyclopropyl.
  • R 2 is selected from hydrogen, Ci-io alkyl, Ci-io heteroalkyl, (C3-8)heterocycloalkyl Co-10 alkyl, and C3-8 cycloalkylCo-10 alkyl.
  • R 2 is hydrogen, C 1 - 10 heteroalkyl, or cyclopropyl.
  • R 2 and R 1 are each independently selected from Cl-10 alkyl, C2-10 alkenyl, and Ci-io heteroalkyl, and R 2 and R 1 and the atom to which they are attached together form a 4-, 5-, or 6-membered saturated ring system and each of R 1 , R 2 , and R 3 are independently substituted with 0, 1, 2, 3, or 4 R 5a substituents.
  • the saturated ring is selected from piperidinyl, piperidino, and aziretidinyl.
  • R 3 is selected from hydrogen, Cl-10 alkyl, Ci-io
  • heteroalkyl C3.8 cycloalkylCo-10 alkyl, and (C3_8)heterocycloalkyl Co-10 alkyl.
  • R ⁇ d R 3 are each independently selected from Ci-io alkyl, C2-10 alkenyl, and Ci-io heteroalkyl, and R*and R 3 and the atom to which they are attached together form a 4-, 5-, or 6-membered saturated ring system and each of R 1 , R 2 , and R 3 are independently substituted with 0, 1, 2, 3, or 4 R 5a substituents.
  • the saturated ring is selected from cyclohexyl, piperidinyl and piperidino.
  • R 5a is selected from: halogen
  • Ci-io alkylamino(oxy) 0-1 carbonylCo- 10 alkyl Ci-io alkylamino(oxy) 0-1 carbonylCo- 10 alkyl
  • R 5a is each optionally substituted with 0, 1, 2, 3, or 4 R 6 substituents.
  • R 5a is selected from: halogen, Ci-io alkyl(oxy) 0- ⁇ carbony ⁇ O-lCo-lO alkyl, Ci-io heteroalkyl(oxy) 0- i(carbonyl)0-lCo-10 alkyl, aryl Co-10 alkyl(oxy) 0- i(carbonyl)0-lCo-10 alkyl, C3-8 cycloalkyl Co-10 alkyl(oxy) 0-1 (carbonyl)0-lCo-10 alkyl, (C3_8)heteroaryl Co-10 alkyl(oxy) 0-1 (carbonyl)o-lCo-10 alkyl,
  • Ci-io alkyl(carbonyl)0-loxyCo-10 alkyl Ci_io heteroalkyl(carbonyl)0-loxyC0-10 alkyl, Ci-io heteroalkyl(carbonyl)o-loxyCo-10 alkyl, aryl Co-10 alkyl (carbonyl)o-loxyCo-lO alkyl,
  • R 5a is selected from: halogen
  • R 5a is selected from: tert-butyl formate, tert-butylcarbonyloxy; halogen, thiomorpholinylcarbonyl, triazolylmethyl, tert-butyloxycarbonyl, methylsulfonyl, oxo, trifluoromethyl, cyanoethyl, cyanomethyl, hydroxymethyl, methoxy, methylcarbamoyl, cyano, morpholinyl, 2,3-dihydrobenzofuranyl, acetylamino,
  • 1,3-oxazolyl imidazolyl, trifluoromethylsulfonyl, difluromethylsulfonyl, methyl, trifluoroethyl, methylsulfinyl, tert-butyloxycarbonylmethyl, oxadiazolyl, l-ethoxy-2,2-dimethylpropanyl, sulfamoyl, dimethylsulfamoyl, aceticacid, methylsulfonyl, ethyloxycarbonyl, methyloxycarbonyl, oxetan-3yloxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl, methyloxycarbonyl, tetrahydro-2H-pyran-4-yloxycarbonyl, methylethyloxycarbonyl, cyclopropylmethyloxycarbonyl, tetrahydrofuran-3 -ylmethyloxycarbonyl, 2-morpholin
  • R 6 is independently selected from:
  • alkyl(oxy)o-i(carbonyl)o-lCo-10 alkyl heteroaryl Co-10 alkyl(oxy) 0- i(carbonyl)0-lCo-10 alkyl, (C3-8)heterocycloalkyl Co-10 alkyl(oxy) 0 .i(carbonyl)0-lCo-10 alkyl, Ci-io alkyl (oxy) 0- icarbonylaminoCo-10 alkyl, C3.8 cycloalkyl Co-10 alkyl (oxy) 0-1 carbonylaminoCo-10 alkyl, aryl Co-10 alkyl(oxy)o -1 carbonylaminoCO-10 alkyl, heteroaryl Co-10 alkyl(oxy) 0- icarbonylaminoCO-10 alkyl, (C3-8)heterocycloalkyl Co-10 alkyl(oxy)o.icarbonylaminoCo-10 alkyl, -CO2(C0-10 alkyl), Oxo, Cl-10 alkylsulfon
  • C3-8 cycloalkylsulfonyl (C3-8) cycloheteroalkylsulfonyl, heteroarylsulfonyl, arylsulfonyl, aminosulfonyl, -S02Ci_6alkyl, amino, (CO-10 alkyl) 1-2 amino, hydroxy, Ci-io alkoxy, cyano, and Ci_6haloalkyl; wherein R 6 is optionally substituted.
  • R 6 is independently selected from: halogen, Ci-io alkyl(oxy)o-i(carbonyl)o-lCo-10 alkyl, Oxo, Ci-io alkylsulfonyl, (Co-10 alkyl) 1-2 amino, hydroxy, C i . i o alkoxy, and C i _6haloalkyl; wherein R 6 is optionally substituted.
  • R 6 is independently selected from: Oxo, methyl, 1 -hydroxy- 1-methylethyl, chloro, fluoro, trimethylfluoro, difluoromethyl, hydroxyl,
  • the compounds of the instant invention are selective JAK1 inhibitors relative to JAK2.
  • the determination of relative selectivity for a given compound of JAK1 inhibition is defined as the relative ratio of the (JAK2 ICso value/JAKl IC 50 value) is at least 2.
  • the relative ratios of the (JAK2 IC50 value/JAKl IC 50 value) is at least 5.
  • Patient includes both human and animals.
  • “Mammal” means humans and other mammalian animals.
  • “Therapeutically effective amount” means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, a system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • treatment or “treating” includes alleviating, ameliorating, relieving or otherwise reducing the signs and symptoms associated with a disease or disorder.
  • composition as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s)
  • compositions of the present invention encompass any composition made by admixing a compound of formula I, and pharmaceutically acceptable excipients.
  • optionally substituted means "unsubstituted or substituted," and therefore, the generic structural formulas described herein encompasses compounds containing the specified optional substituent as well as compounds that do not contain the optional substituent.
  • each variable is independently defined each time it occurs within the generic structural formula definitions. For example, when there is more than one substituent for aryl/heteroaryl, each substituent is independently selected at each occurrence, and each substituent can be the same or different from the other(s). As another example, for the group -(CR3R3)2-, each occurrence of the two R3 groups may be the same or different. As used herein, unless explicitly stated to the contrary, each reference to a specific compound of the present invention or a generic formula of compounds of the present invention is intended to include the compound(s) as well as pharmaceutically acceptable salts and stereoisomers thereof.
  • Compounds of formula I contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers.
  • the present invention is meant to comprehend all such isomeric forms of the compounds of formula I, either as single species or mixtures thereof.
  • tautomers Some of the compounds described herein may exist with different points of attachment of hydrogen, referred to as tautomers. Such an example may be a ketone and its enol form known as keto-enol tautomers. The individual tautomers as well as mixture thereof are encompassed with compounds of formula I. Specific embodiments of the present invention include a compound which is selected from the group consisting of the subject compounds of the Examples herein or a pharmaceutically acceptable salt thereof.
  • the compounds of the present invention may contain one or more asymmetric centers and can thus occur as "stereoisomers” including racemates and racemic mixtures, enantiomeric mixtures, single enantiomers, diastereomeric mixtures and individual
  • the compounds of Formula (I) may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of Formula (I) as well as mixtures thereof, including racemic mixtures, form part of the present invention.
  • the present invention embraces all geometric and positional isomers. For example, if a compound of Formula (I) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention.
  • Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
  • the compounds of Formula (I) may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of chiral HPLC column. It is also possible that the compounds of Formula (I) may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.
  • All stereoisomers for example, geometric isomers, optical isomers and the like
  • of the present compounds including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs
  • those which may exist due to asymmetric carbons on various substituents including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl).
  • stereomeric nomenclature includes “or”, for example, 1-(2S, 3S or 2R, 3R)-3-cyclobutan-2-yl]-3-(phenylamino)-lH-pyrazole-4-carboxamide, the "or” indicates that chiral resolution of racemate into individual enantiomers was accomplished but the actual optical activity of the specific enantiomer was not determined.
  • any enantiomer of a compound can be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.
  • salts refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, ⁇ , ⁇ '-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine,
  • salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p- toluenesulfonic acid, and the like.
  • Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
  • references to the compound of formula I subsets thereof, embodiments thereof, as well as specific compounds are meant to also include the pharmaceutically acceptable salts and stereoisomers thereof.
  • some of the crystalline forms for compounds of the present invention may exist as polymorphs and as such all forms are intended to be included in the present invention.
  • some of the compounds of the instant invention may form solvates with water (hydrates) or common organic solvents. Such solvates are encompassed within the scope of this invention.
  • the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
  • the present invention is meant to include all suitable isotopic variations of the compounds of generic Formula I.
  • different isotopic forms of hydrogen (H) include protium (lH) and deuterium ( ⁇ H).
  • Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
  • Isotopically-enriched compounds within generic Formula I can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.
  • Compound of formula I or its pharmaceutically acceptable salts and pharmaceutical compositions can be used to treat or prevent a variety of conditions or diseases mediated by Janus kinases, in particular diseases or conditions that can be ameliorated by the inhibition of a Janus kinase such as JAK1, JAK2 or JAK3, and TYK2.
  • Such conditions and diseases include, but are not limited to:
  • arthritis including rheumatoid arthritis, juvenile arthritis, and psoriatic arthritis
  • asthma and other obstructive airways diseases including chronic asthma, late asthma, airway hyper-responsiveness, bronchitis, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, recurrent airway obstruction, and chronic obstruction pulmonary disease including emphysema
  • autoimmune diseases or disorders including those designated as single organ or single cell-type autoimmune disorders, for example Hashimoto's thyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritis of pernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis, Goodpasture's disease, autoimmune thrombocytopenia, sympathetic ophthalmia, myasthenia gravis, Graves' disease, primary biliary cirrhosis, chronic aggressive hepatitis, ulcerative colitis and membranous glomerulopathy, those designated as involving systemic
  • neurodegenerative diseases including motor neuron disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, or
  • ischemic/reperfusion injury in stroke myocardial ischemica, renal ischemia, heart attacks, cardiac hypertrophy, atherosclerosis and arteriosclerosis, organ hypoxia, and platelet aggregation
  • skin diseases, conditions or disorders including atopic dermatitis, eczema, psoriasis, scleroderma, pruritus and other pruritic conditions
  • allergic reactions including anaphylaxis, allergic rhinitis, allergic dermatitis, allergic urticaria, angioedema, allergic asthma, or allergic reaction to insect bites, food, drugs, or pollen
  • transplant rejection including pancreas islet transplant rejection, bone marrow transplant rejection, graft- versus-host disease, organ and cell transplant rejection such as bone marrow, cartilage, cornea, heart, intervertebral disc, islet, kidney, limb, liver, lung, muscle, my
  • another aspect of the present invention provides a method for the treatment or prevention of a JAK-mediated disease or disorder comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of formula I.
  • diseases include asthma and rheumatoid arthritis.
  • Another aspect of the present invention provides for the use of a compound of formula I in the manufacture of a medicament for the treatment or prevention of a JAK-mediated diseases or disorder.
  • One aspect of the invention is the use of a compound of formula I or a
  • Another aspect of the invention is the use of a compound of Formula I or a pharmaceutically acceptable salt or a stereoisomer thereof and a second active agent in the manufacture of a medicament for the treatment of a desease or a disorder ameliorated by the selective inhibition of a Janus kinase JAK1 relative to JAK 2.
  • prophylactic or therapeutic dose of a compound of formula I will, of course, vary with the nature and the severity of the condition to be treated and with the particular compound of formula I and its route of administration. It will also vary according to a variety of factors including the age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination and response of the individual patient. In general, the daily dose from about 0.001 mg to about 100 mg per kg body weight of a mammal, preferably 0.01 mg to about 10 mg per kg. On the other hand, it may be necessary to use dosages outside these limits in some cases.
  • a formulation intended for the oral administration of humans may contain from 0.05 mg to 5 g of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 99.95 percent of the total composition.
  • Dosage unit forms will generally contain between from about 0.1 mg to about 0.4 g of an active ingredient, typically 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, or 400 mg.
  • compositions comprising a compound of formula I with a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier for the treatment of any of the prostanoid mediated diseases compounds of formula I may be
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
  • warmblooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, etc.
  • the compound of the invention is effective in the treatment of humans.
  • compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
  • compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the technique described in the U.S. Patent 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients is mixed with water-miscible solvents such as propylene glycol, PEGs and ethanol, or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • water-miscible solvents such as propylene glycol, PEGs and ethanol
  • an oil medium for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene- oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan mono
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
  • preservatives for example ethyl, or n-propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • flavoring agents such as sucrose, saccharin or aspartame.
  • sweetening agents such as sucrose, saccharin or aspartame.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerin, glycerin, glycerin, glycerin, glycerin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol, glycerol
  • the pharmaceutical compositions of the invention may also be in the form of an oil-in- water emulsion.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavoring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, and flavoring and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1 ,3 -butane diol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. Cosolvents such as ethanol, propylene glycol or polyethylene glycols may also be used.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • Dosage forms for inhaled administration may conveniently be formulated as aerosols or dry powders.
  • the active substance is in a particle-size-reduced form, and more preferably the size-reduced form is obtained or obtainable by micronization.
  • the medicinal preparation is adapted for use with a pressurized metered dose inhaler (pMDI) which releases a metered dose of medicine upon each actuation.
  • pMDI pressurized metered dose inhaler
  • the formulation for pMDIs can be in the form of solutions or suspensions in halogenated hydrocarbon propellants.
  • the type of propellant being used in pMDIs is being shifted to hydro fluoroalkanes (HFAs), also known as hydrofluorocarbons (HFCs).
  • HFAs hydro fluoroalkanes
  • HFCs hydrofluorocarbons
  • 1,1,1,2- tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA 227) are used in several currently marketed pharmaceutical inhalation products.
  • the composition may include other pharmaceutically acceptable excipients for inhalation use such as ethanol, oleic acid, polyvinylpyrrolidon
  • Pressurized MDIs typically have two components. Firstly, there is a canister component in which the drug particles are stored under pressure in a suspension or solution form. Secondly, there is a receptacle component used to hold and actuate the canister. Typically, a canister will contain multiple doses of the formulation, although it is possible to have single dose canisters as well.
  • the canister component typically includes a valve outlet from which the contents of the canister can be discharged.
  • Aerosol medication is dispensed from the pMDI by applying a force on the canister component to push it into the receptacle component thereby opening the valve outlet and causing the medication particles to be conveyed from the valve outlet through the receptacle component and discharged from an outlet of the receptacle.
  • the medication particles are "atomized", forming an aerosol. It is intended that the patient coordinate the discharge of aerosolized medication with his or her inhalation, so that the medication particles are entrained in the patient's aspiratory flow and conveyed to the lungs.
  • pMDIs use propellants to pressurize the contents of the canister and to propel the medication particles out of the outlet of the receptacle component.
  • the formulation is provided in a liquid or suspension form, and resides within the container along with the propellant.
  • the propellant can take a variety of forms.
  • the propellant can comprise a compressed gas or liquefied gas.
  • the medicinal preparation is adapted for use with a dry powder inhaler (DPI).
  • DPI dry powder inhaler
  • the inhalation composition suitable for use in DPIs typically comprises particles of the active ingredient and particles of a pharmaceutically acceptable carrier.
  • the particle size of the active material may vary from about 0.1 ⁇ to about 10 ⁇ ; however, for effective delivery to the distal lung, at least 95 percent of the active agent particles are 5 ⁇ or smaller.
  • Each of the active agent can be present in a concentration of 0.01 - 99%. Typically however, each of the active agents is present in a concentration of about 0.05 to 50%, more typically about 0.2 - 20% of the total weight of the composition.
  • the inhalable powder preferably includes pharmaceutically acceptable carrier, which may be composed of any pharmacologically inert material or combination of materials which is acceptable for inhalation.
  • the carrier particles are composed of one or more crystalline sugars; the carrier particles may be composed of one or more sugar alcohols or polyols.
  • the carrier particles are particles of dextrose or lactose, especially lactose.
  • the particle size of the carrier particles may range from about 10 microns to about 1000 microns.
  • the particle size of the carrier particles may range from about 20 microns to about 120 microns. In certain other embodiments, the size of at least 90% by weight of the carrier particles is less than 1000 microns and preferably lies between 60 microns and 1000 microns. The relatively large size of these carrier particles gives good flow and entrainment characteristics. Where present, the amount of carrier particles will generally be up to 95%, for example, up to 90%, advantageously up to 80% and preferably up to 50% by weight based on the total weight of the powder. The amount of any fine excipient material, if present, may be up to 50% and advantageously up to 30%, especially up to 20%, by weight, based on the total weight of the powder.
  • the powder may optionally contain a performance modifier such as L-leucine or another amino acid, and/or metals salts of stearic acid such as magnesium or calcium stearate.
  • compositions may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ambient temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at ambient temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at ambient temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • Topical formulations may generally be comprised of a pharmaceutical carrier, cosolvent, emulsifier, penetration enhancer, preservative system, and emollient.
  • compound of formula I may be co-administered with other therapeutic agents.
  • the present invention provides pharmaceutical compositions for treating JAK mediated diseases comprising a therapeutically effective amount of a compound of formula I and one or more other therapeutic agents.
  • a compound of formula I may be combined with agents such as: (1) TNF-a inhibitors such as Remicade® and Enbrel®); (2) non-selective COX-I/COX-2 inhibitors (such as piroxicam, diclofenac, propionic acids such as naproxen, fiubiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, apazone, pyrazolones such as phenylbutazone, salicylates such as aspirin); (3) COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxib and etoricoxib); (4) other agents for treatment of rheumato
  • TNF-a inhibitors such as Remicade® and Enbrel®
  • COX-I/COX-2 inhibitors such as piroxicam, diclofenac, prop
  • al- and ⁇ x2- adrenoceptor agonist vasoconstrictor sympathomimetic agent such as propylhexedrine, phenylephrine, phenylpropanolamine, pseudoephedrine, naphazoline hydrochloride,
  • anticholinergic agents such as ipratropium bromide, tiotropium bromide, oxitropium bromide, aclindinium bromide, glycopyrrolate, pirenzepine, and telenzepine;
  • ⁇ -adrenoceptor agonists such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, and pirbuterol, or methylxanthanines including theophylline and aminophylline, sodium
  • IGF-1 insulin-like growth factor type I mimetic
  • IGF-1 insulin-like growth factor type I mimetic
  • IGF-1 insulin-like growth factor type I mimetic
  • IGF-1 insulin-like growth factor type I
  • inhaled glucocorticoid with reduced systemic side effects such as prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide and mometasone furoate.
  • the compounds of the present invention can be prepared according to the following general schemes using appropriate materials, and are further exemplified by the subsequent specific examples.
  • the compounds illustrated in the examples are not to be construed as forming the only genus that is considered as the invention.
  • Ambient temperature is 15-25 °C.
  • Urea derivatives XXVIII are formed by reacting deprotected optionally substituted acrylonitriles with a doubly activated carbonyl equivalent, such as DSC, and optionally substituted alcohols in the presence of a suitable base, such as TEA.
  • N-arylated derivatives XXIX are formed by reacting deprotected optionally substituted acrylonitriles with optionally substituted aryl halides using a suitable palladium- ligand system, such as Pd 2 (dba)3 and X-Phos, an appropriate base, such as Cs 2 C0 3 , in a solvent, such as t-BuOH, at or around 90 °C.
  • This substituted cyclohexanone XXXIX is protected with ethylene glycol under acidic conditions, such as TsOH, in an appropriate solvent, such as benzene, at elevated temperatures, e.g. at or around 110 °C.
  • an appropriate solvent such as benzene
  • the acetal substituted acrylonitrile XL is obtained after elimination of the benzosulfone with an appropriate base, such as potassium tert-butoxide.
  • the intermediate nitriles XL VII and XL VIII are oxidized to the corresponding amides using an appropriate oxidant, such as hydrogen peroxide mixed with sodium hydroxide, and the SEM group is then removed by acid hydrolysis to yield pyrazole XLIII, an intermediate in the synthesis of examples of the instant invention.
  • an appropriate oxidant such as hydrogen peroxide mixed with sodium hydroxide
  • Methyl 5-amino-lH-pyrazole-4-carboxylate L is conjugatively added to substituted acrylonitriles including but not limited to those illustrated in Schemes # 12- 18 in the presence of a suitable base, such as catalytic sodium methoxide.
  • the resulting intermediates LI are cross coupled to (hetero)aryl halides XLII using an appropriate catalytic palladium-ligand system, such as Pd 2 (dba) 3 and X-Phos, and an appropriate base, such as K 3 P0 4 .
  • Saponification of LII using aqueous hydroxide, such as LiOH, followed by amide formation using standard conditions, such as EDC, HOBT, and optionally substituted primary and secondary amines yields examples LIV of the instant invention.
  • Alkylated 3-amino pyrazole carboxamides XLIX are cross coupled to (hetero)aryl halides XLII using an appropriate catalytic palladium-ligand system, such as Pd 2 (dba) 3 and X- Phos or Me 4 3 ⁇ 4u-X-Phos, and a suitable base, such as K 3 P0 4 or KOAc, in solvent, such as dioxane, to yield examples LV of the instant invention.
  • an appropriate catalytic palladium-ligand system such as Pd 2 (dba) 3 and X- Phos or Me 4 3 ⁇ 4u-X-Phos
  • a suitable base such as K 3 P0 4 or KOAc
  • N-(hetero)arylated pyrazole carboxamides XLIII can be alkylated with optionally substituted alkyl halides LXI using heat and an appropriate base, such as CS2CO3, to afford examples LXII of the instant invention.
  • Methyl 5-bromopicolinate 500 mg, 2.31 mmol was dissolved in THF (7.0 mL) and the flask was sealed with a septum and flushed with argon. The mixture was cooled to 0 °C and methylmagnesium bromide (3.1 mL, 9.3 mmol, 3M in THF) was added. The resulting mixture was allowed to stir at 0 °C for 1 hour before the reaction was quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The organic layer was then washed with brine, dried over anhydrous MgS0 4 , filtered, and concentrated in vacuo to afford the title compound, which was used without further purification.
  • 5-Bromopicolinaldehyde 500 mg, 2.70 mmol was dissolved in THF (9.0 mL) and the flask was then sealed with a septum, flushed with argon, and cooled to 0 °C.
  • 1,3-Dibromobenzene (0.38 mL, 3.2 mmol), l-methyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)- lH-pyrazole (595 mg, 2.86 mmol), Pd(dppf)Cl 2 (260 mg, 0.320 mmol), and potassium phosphate (2.0 g, 9.5 mmol) were combined in a flask and dissolved in dioxane (16 mL) and water (1.6 mL). The flask was then sealed and flushed with argon. The reaction mixture was allowed to stir at 90 °C for 90 minutes. The mixture was then cooled to ambient temperature and diluted with EtOAc. The organic layer was washed with water, brine, dried over anhydrous MgS0 4 , and concentrated in vacuo. The residue was purified by MPLC on silica gel (50% EtOAc/hexanes) to afford the title compound.
  • Step B 5-Bromo-2.3-dihvdro-l-benzothiophene-3-ol l.l-dioxide (Intermediate #13)
  • Methyl hydroxyacetate (0.80 g, 8.8 mmol) was dissolved in THF (10 mL) and allowed to stir at 0 °C under a nitrogen atmosphere. NaH (0.40 g, 9.6 mmol, 60% dispersion in oil) was added portionwise over approximately 5 minutes. The cooling bath was removed and the reaction mixture was allowed to warm to ambient temperature. l-Bromo-3- (bromomethyl)benzene (2.0 g, 8.0 mmol) was added in a single portion and the resulting mixture was heated to 40 °C. After 4 hours, the reaction mixture was allowed to cool to ambient temperature and partitioned between water and EtOAc.
  • Methyl [(3 -bromobenzyl)oxy] acetate (2.0 g, 7.7 mmol) was dissolved in THF (10 mL) and was allowed to stir under a nitrogen atmosphere. Methylmagnesium bromide (7.7 mL, 23 mmol, 3.0 M in THF) was added dropwise. The reaction mixture was allowed to stir at ambient temperature for 4 hours before the reaction was quenched with water and the mixture was extracted with EtOAc. The organic layer was washed with saturated aqueous NaHC0 3 , brine, dried over anhydrous Na 2 S0 4 , filtered, and concentrated in vacuo.
  • Step A-B 2-ri-(3-Bromobenzyl)-lfl r -1.2 -triazol-4-vIlpropan-2-oUIntermediate #18)
  • Step A-B H-(Ethylsulfonyl)azetidin-3-v idenelacetonitrilc (Intermediate # 23)
  • tgrt-Butyl 3-(cyanomethylidene)azetidine-l-carboxylate (5.0 g, 26 mmol) was dissolved in 4M HC1 in dioxane (25.7 mL) and allowed to stir at ambient temperature for 16 hours. The mixture was concentrated to dryness in vacuo, then dissolved in DCM (30.0 mL) and cooled to -10 °C. DIPEA (11.6 g, 90.0 mmol) was added followed by ethanesulfonyl chloride (5.0 g, 39 mmol). The resulting mixture was allowed to stir for 7 hours before the mixture was diluted with water and extracted with DCM.
  • Step A 4-(Cvanomethylidene)piperidinium trifluoroacetate (Step A).
  • 2,2,2-Trifluoroethanol (1.6 mL, 22 mmol) and TEA (6.2 mL, 45 mmol) were dissolved in acetonitrile (200 mL).
  • ⁇ , ⁇ -disuccinimidyl carbonate (8.6 g, 34 mmol) was added and the resulting mixture was stirred at ambient temperature for 90 minutes.
  • tert-Butyl 4-(cyanomethylidene)piperidine-l-carboxylate (20 g, 90 mmol) was dissolved in 4M HC1 in dioxane and allowed to stir at ambient temperature for 2 hours. The mixture was then concentrated in vacuo to afford the title compound.
  • Step A-C tert- utyl 3-cvanocvcIohex-3-ene-l-carboxylate (Intermediate # 26-1)
  • tert-Butyl 3-oxocyclohexanecarboxylate (1.35 g, 6.81 mmol) was taken up in water (11.4 mL) and stirred at ambient temperature. Sodium metabisulfite (0.75 g, 3.9 mmol) was added and the mixture was allowed to stir for 40 minutes. Diethyl ether (11.4 mL) was added, followed by potassium cyanide (0.70 g, 11 mmol). The resulting mixture was allowed to stir vigorously for 1 hour before it was partitioned between diethyl ether and water. The organic layer was washed with water, brine, dried over anhydrous MgS0 4 , filtered, and concentrated in vacuo.
  • Step A-B 4-Methylcyclohex-l-ene-l-carbonitrile (Intermediate # 27-1)
  • the organic layer was dried over anhydrous Na 2 S0 4 , filtered, and concentrated in vacuo (23 °C water bath) to afford 4-methyl -1-hydroxycyclohexanecarbonitrile as a crude residue, which was carried forward without further purification.
  • the crude residue (0.50 g, 3.6 mmol) was combined with pyridine (18.3 mL, 226 mmol), and POCl 3 (1.34 mL, 14.4 mmol) in a microwave vial and sealed.
  • the reaction mixture was heated to reflux for 16 hours.
  • the reaction mixture was then cooled to ambient temperature, diluted with diethyl ether, and washed with 2N aqueous HC1 saturated with sodium chloride (3x).
  • the organic layer was washed with brine, dried over anhydrous MgS0 , filtered, and concentrated in vacuo (23 °C water bath) to afford the title compound as an oil.
  • Step A-C (1R.2S and lS,2R)-4-Oxo-2-fphenylsulfonylkvclohexanecarbonitriIe
  • Benzenesulfinic acid sodium salt (9.4 g, 57 mmol) was dissolved in a mixture of water (18.3 mL) and acetic acid (9.1 mL). 2-Chloroprop-2-enenitrile (4.6 mL, 57 mmol) was added, followed by MeOH (18.3 mL). The resulting mixture was allowed to stir for 10 minutes before the solid product was collected by filtration and rinsed with minimal water. The majority of the solid filtered through with the rinse and so all material was rinsed through the filter.
  • reaction mixture was then concentrated in vacuo to afford an oily mixture of the intermediate adducts.
  • the residue was dissolved in aqueous acetic acid (80%) and allowed to stir. After 1 hour at ambient temperature, the mixture was diluted with water and extracted with DCM (2x). The combined organic extracts were concentrated in vacuo and the residue was dissolved in DCM. A solid precipitated from the solution and was collected by filtration to afford the title compound.
  • Step D-E 1 ,4-Dioxaspiro [4.51 dec-7-ene-8-car bonitrile (Intermediate #30)
  • the title compound, Intermediate #32 can also be prepared by dissolving 3-( ⁇ 4-[(trifluoromethyl)sulfanyl]phenyl ⁇ amino)-lH-pyrazole-4-carboxamide (0.50 g, 1.6 mmol) in acetic acid (5.0 mL) followed by the addition of hydrogen peroxide (0.87 mL, 9.9 mmol, 35 wt% in water). The resulting mixture was heated to 50 °C for 18 hours before additional hydrogen peroxide (0.87 mL, 9.9 mmol, 35 wt% in water) was added and the mixture was heated to 80 °C for 8 hours. The mixture was cooled to ambient temperature, concentrated in vacuo and diluted with EtOAc.
  • Step A 3-Amino-l-(f2-(trimethylsilyl)ethoxy1methyll-l J H-Pyrazole-4-carbonitrile
  • Step B 3-(Pyridin-4-ylamino - ⁇ [2-(trimethv
  • Step C 3-(Pyridin-4-ylamino)-li3 ⁇ 4 l -pyrazole-4-carboxaniide (Intermediate #34-1)

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Abstract

The instant invention provides compounds of formula I which are JAK inhibitors, and as such are useful for the treatment of JAK-mediated diseases such as rheumatoid arthritis, asthma, COPD and cancer.

Description

TITLE OF THE INVENTION
ACYCLIC CYANOETHYLPYRAZOLES AS JANUS KINASE INHIBITORS
BACKGROUND OF THE INVENTION
Protein kinases are a group of enzymes that regulate the activity of their target proteins by the addition of phosphate groups to the protein substrate. Kinases play an essential role in many physiological processes including cell division, differentiation, cellular homeostasis and signal transduction. Kinases can be subdivided by their target into Serine/Threonine kinases and Tyrosine kinases. Tyrosine kinases are further subdivided into receptor tyrosine kinases and non-receptor tyrosine kinases. The mammalian Janus kinase (JAK) family members are nonreceptor tyrosine kinases.
The JAK family has four members; JAKl, JAK2, JAK3 and TYK2. JAKl, JAK2 and TYK2 are universally expressed, whereas JAK3 expression is limited to hematopoetic cells. The JAK family is involved in intracellular signal transduction from >70 different cytokines. Cytokines bind to their cell surface receptors resulting in receptor dimerization and subsequent activation/phosphorylation of JAK tyrosine kinases. The JAKs are either constitutively associated with the receptor or are recruited upon cytokine binding. Specific tyrosine residues on the receptor are then phosphorylated by activated JAKs and serve as docking sites for STAT proteins. STATs are phosphorylated by JAKs, dimerize, then translocate to the nucleus where they bind specific DNA elements and activate gene transcription. JAKl signals in conjunction with all JAK isoforms in a cytokine dependent manner.
JAKs are essential for multiple physiological functions. This has been demonstrated using genetically engineered mouse models that are deficient in specific JAKs. Jakl"A mice die perinatally, while Jak2" _ mice have deficiencies in erythropoesis and die around day El 2. 3a 3~'~ mice are viable, but have a SCID phenotype with deficiencies in T cells, B cells and NK cells. ΤΥΚ2"Λ mice exhibit features of hyper IgE syndrome. These phenotypes demonstrate the essential and non-redundant roles of JAK activity in vivo (K. Ghoreschi, A. Laurence, J. J. O'Shea, Immunol. Rev. 228, 273 (2009)).
Furthermore, mutations in the JAK enzymes have been associated with diseases in humans. Inactivating mutations in JAK3 (or the cognate common gamma chain cytokine receptor) cause a severe SCID phenotype (J. J. O'Shea, M. Pesu, D. C. Borie, P. S. Changelian, Nat. Rev. Drug Discov. 3, 555 (2004)). Deletions of TYK2 result in hyper IgG syndrome and increased infection risk (Y. Minegishi et al, Immunity. 25, 745 (2006)). No inactivating mutations have been reported for JAKl or JAK2, consistent with the data from mice that demonstrates that JAKl and JAK2 deficient mice are not viable. However, several mutations that result in constitutively active JAK2 have been identified, resulting in myeloproliferative diseases and confirming the central role of JAK2 in hematopoesis (O. bdel-Wahab, Curr. Opin. Hematol. 18, 117 (2011)). JAK2 is the sole JAK family member involved in signal transduction of the critical hematopoetic cytokines IL-3, GMCSF, EPO and TPO.
The wealth of mouse and human genetic data demonstrating a central role for JAK kinase activity in autoimmune disease, hematopoesis and oncology has been supported by the use of pan- JAK inhibitors in clinical trials for autoimmune diseases and neoplasms (See K. Ghoreschi, et al, Immunol. Rev. 228, 273 (2009), and A. Quintas-Cardama, H. Kantarjian, J. Cortes, S. Verstovsek, Nat. Rev. DrugDiscov. 10, 127 (2011)). However, several adverse events have been reported that may be associated with inhibition of JAK2 signaling such as anemia, neutropenia and thrombocytopenia. Thus new or improved agents that selectively inhibit JAK1 activity but spare JAK2 activity are required for the treatment of several human diseases with an improved therapeutic index.
A considerable body of literature has accumulated that link the Jak/STAT pathway to various diseases and disorders including hyperproliferative disorders and cancer such as leukemia and lymphomas, immunological and inflammatory disorders such as transplant rejection, asthma, chronic obstructive pulmonary disease, allergies, rheumatoid arthritis, type I diabetes, amyotropic lateral sclerosis and multiple sclerosis.
SUMMARY OF THE INVENTION
The present invention provides novel compounds which are inhibitors of JAKs. The invention also provides a method for the treatment and prevention of JAK-mediated diseases and disorders using the novel compounds, as well as pharmaceutical compositions containing the compounds.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides compounds of formula I or pharmaceutically acceptable stereoisomer thereof:
Figure imgf000003_0001
Ra and R4 are each independently selected from hydrogen and C^alkyl; R5 is selected from aryl and heteroaryl, wherein R5 is substituted with 0, 1, 2, 3, or 4, substituents, R5a;
R1, R2, and R3 are each independently selected from
hydrogen,
halogen,
Ci-io alkyl,
C2-10 alkenyl,
Ci-io heteroalkyl,
aryl Co-10 alkylCo-10 alkyl,
C3-8 cycloalkylCo-10 alkyl,
heteroaryl Co-10 alkyl,
(C3_8)heterocycloalkyl Co-10 alkyl,
wherein each of R1, R2, and R3 are independently substituted with 0, 1, 2, 3, or 4, substituents
R5a;
R5a is selected from:
halogen,
Ci-io alkyl(oxy)o.1(carbonyl)0-lCO-10 alkyl,
Ci-io heteroalkyl(oxy)0-1(carbonyl)0-lCo-10 alkyl,
C2-10 alkenyl(oxy)o-1(carbonyl)0-lCo-10 alkyl,
aryl Co-10 alkyl(oxy)0-1(carbonyl)o-lCo-10 alkyl,
aryl C2-10 alkenyl(oxy)0-i(carbonyl)o-lCo-10 alkyl,
aryl C2-10 alkynyl(oxy)0-1(carbonyl)o-lCo-10 alkyl,
C3-8 cycloalkyl Co-10 alkyl(oxy)o-1(carbonyl)o-lCO-10 alkyl,
heteroaryl Co-10 alkyl(oxy)0-1(carbonyl)0-lC0-10 alkyl,
(C3-8)heterocycloalkyl Co-10 alkylCoxy iCcarbony o-lCO-lO alkyl,
Ci-io alkyl(carbonyl)0-loxyCo-10 alkyl,
Ci-io heteroalkyl(carbonyl)o-loxyCo-10 alkyl,
C2-10 alkenyl(carbonyl)0-loxyCo-10 alkyl,
Ci-io heteroalkyl(carbonyl)0-loxyCo-10 alkyl,
aryl Co-10 alkyl (carbonyl)o-loxyCo-lO alkyl,
(C3-8)cycloalkyl Co-10 alkyl(carbonyl)0-loxyCo-10 alkyl,
heteroarylCo-10 alkyl(carbonyl)0-loxyC0-10 alkyl,
(C3_8)heterocycloalkyl Co-10 alkyl(carbonyl)0-loxyCo-10 alkyl,
((CQ- 1 o)alkyl) !^aminocarbonyloxy, (CO- 10)heteroalkylaminocarbonyloxy,
aryl (Co-lO)alkylaminocarbonyloxy,
(C3-8)cycloalkyl(Co-10)alkylaminocarbonyloxy,
heteroaryl(Co- 1 O)alkylaminocarbonyloxy,
(C3 -8)heterocycloalkyl(Co- 1 o)alkylaminocarbonyloxy,
Ci-io alkylamino(oxy)o-icarbonylCo-10 alkyl,
(CO-10)heteroalkylamino(oxy)0-1carbonylC0-l 0 alkyl,
C3-8 cycloalkyl Co-10 alkylamino(oxy)0-icarbonylCo-10 alkyl, aryl Co.lOalkylamino(oxy)0-1carbonylCo-10 alkyl,
heteroarylCo-10al^lamino(oxy)0-1carbonylCO-10 alkyl,
(C3-8)heterocycloalkylCo-l Oalkylamino(oxy)o-1carbonylCo-l 0 alkyl,
Ci-io alkyl(oxy)o-icarbonylaminoCo-10 alkyl,
Cl-10 heteroalkyl (oxy)0-1carbonylaminoCo-10 alkyl,
C3-8 cycloalkyl Co-10 alkyl (oxy)0-1carbonylaminoCo-10 alkyl, aryl CO-10 alkyl(oxy)0-1carbonylaminoC0-10 alkyl,
heteroaryl CO-10 alkyl(oxy)o-1carbonylaminoCo-10 alkyl,
(C3-8)heterocycloalkyl Co-10 alkyl(oxy)o-1carbonylaminoCo-10 alkyl,
-CO2(C0-10 alkyl),
-(Co-10 alkyl)C02H,
Oxo (=0),
Ci-io alkylsulfonyl,
Ci-io heteroalkylsulfonyl,
(C3-8) cycloalkylsulfonyl,
(C3-8) cycloheteroalkylsulfonyl,
heteroarylsulfonyl,
arylsulfonyl,
aminosulfonyl,
-S02N(Ci-6alkyl)i-2,
-S02Ci-6alkyl,
-SO2CF3,
-SO2CF2H, Ci-io alkylsulfinyl,
amino,
(Co- 10 alkyl) 1-2 amino,
Ci-4acylamino Co-10 alkyl,
hydroxy,
Co-10 alkylalkoxy,
cyano,
Ci-6alkylcyano, and
Ci-6haloalkyl;
wherein R5a is each optionally substituted with 0, 1, 2, 3, or 4 R6 substituents and R6 independently selected from:
halogen,
Ci-io alkyl(oxy)0-i(carbonyl)0-lCo-10 alkyl,
Ci-io heteroalkyl(oxy)0-1(carbonyl)0-lCo-10 alkyl,
C2-10 alkenyl(oxy)0-i(carbonyl)o-lCo-10 alkyl,
aryl Co-10 alkyl(oxy)0-i(carbonyl)0-lC0-10 alkyl,
aryl C2-10 alkenyl(oxy)0-1(carbonyl)0-lC0-10 alkyl,
aryl C2-10 alkynyl(oxy)0-1(carbonyl)0-lCo-10 alkyl,
C3-8 cycloalkyl Co-10 alkyl(oxy)0-1(carbonyl)0-lC0-10 alkyl,
heteroaryl CO-10 alkyl(oxy)0-1(carbonyl)0-lC0-10 alkyl,
(C3-8)heterocycloalkyl Co-10 alkyl(oxy)0-i(carbonyl)0-lCo-10 alkyl,
Ci-10 alkyl(carbonyl)o-loxyCo-10 alkyl,
C2-10 alkenyl(carbonyl)0-loxyCo-10 alkyl,
Ci-io heteroalkyl(carbonyl)0-loxyCo-10 alkyl,
aryl Co-10 alkyl (carbonyl)O-loxyCo-lO alkyl,
(C3-8)cycloalkyl Co-10 alkyl(carbonyl)0-loxyCo-10 alkyl,
heteroarylCo-10 alkyl(carbonyl)o-loxyCo-10 alkyl,
(C3-8)heterocycloalkyl Co-10 alkyl(carbonyl)0-loxyCo-10 alkyl,
((CO- 10)alky i -2aminocarbonyloxy,
aryl (Co-lO)alkylaminocarbonyloxy,
(C3-8)cycloalkyl(Co-10)alkylaminocarbonyloxy, heteroaryl(Co- 1 o)alkylaminocarbonyloxy,
(C3_8)heterocycloalkyl(Co- 1 o)alkylaminocarbonyloxy,
Ci-io alkylamino(oxy)o-icarbonylCo-10 alkyl,
C3-8 cycloalkyl Co-10 alkylamino(oxy)o-icarbonylCo-10 alkyl, aryl Co-10 alkylamino(oxy)0-1carbonylCo-10 alkyl,
heteroaryl Co-10 alkylamino(oxy)0-icarbonylC0-10 alkyl,
(C3_8)heterocycloalkyl Co-10 alkylamino(oxy)0-1carbonylCo-10 alkyl,
Ci-io alkyl (oxy)o-1carbonylaminoCo-10 alkyl,
C3-8 cycloalkyl Co-10 alkyl
Figure imgf000007_0001
alkyl, aryl Co-10 alkyl(oxy)0-1carbonylaminoCo-10 alkyl,
heteroaryl Co-10 alkyl(oxy)o-1carbonylaminoCo-10 alkyl,
(C3_8)heterocycloalkyl Co-10 alkyl(oxy)o-1carbonylaminoCo-10 alkyl,
-C02(Co-10 alkyl),
-(Co-10 alkyl)C02H,
Oxo (=0),
Ci-io alkylsulfonyl,
C 1.10 heteroalkylsulfonyl,
(C3-8) cycloalkylsulfonyl,
(C3.8) cycloheteroalkylsulfonyl,
heteroarylsulfonyl,
arylsulfonyl,
aminosulfonyl,
-S02N(Ci-6alkyl)1.2,
-S02Ci-6alkyl,
-SO2CF3,
-SO2CF2H,
Ci-io alkylsulfinyl,
-OSi(Ci-i0alkyl)3,
amino,
(Co- 10 alkyl) 1-2 amino,
-(oxy)0-l(carbonyl)o-lN(Co-10 alkyl)l-2 Cl_4acylamino Co-10 alkyl,
hydroxy,
Ci-io lkoxy,
cyano, and
Ci-6haloalkyl; and
R6 is optionally substituted with 0, 1, 2, or 3 substituents independently selected from hydroxy, (Ci-6)alkox , halogen, CO2H, -(Co-6)alk lCN, -0(C=0)Ci-C6 alkyl, N02,trifluoromethoxy, trifluoroethoxy, -N-C(0)0(C()-6)alkyl, Ci-io alkylsulfonyl, Ci-io heteroalkylsulfonyl, oxo (0=), (C3-8) cycloalkylsulfonyl,
(C3-8) cycloheteroalkylsulfonyl, heteroarylsulfonyl, arylsulfonyl, aminosulfonyl, -S02N(Ci-6alkyl)1-2, -S02Ci-6alkyl, -SO2CF3, -SO2CF2H, -C O alkylsulfinyl, -OSi(Ci_ioalkyl)3, -O(0-l)(Cl-10)haloalkyl, and NH2;
with the proviso that the compound of formula I is other than:
2-(dimethylamino)ethy 1 4-( 1 - { 4-carbamoyl-3 - [(4-fluorophenyl)amino] - 1 H-pyrazol- 1 -yl } -2- cyanoethyl)piperidine- 1 -carboxylate; and
1-[(1 S or lR)-2-cyano-l-cyclopropylethyl]-3-(phenylamino)-lH-pyrazole-4-carboxamide.
Representative compounds of the instant invention include, but are not limited to the following compounds and their pharmaceutically acceptable salts and stereoisomers thereof: 1 -(2-cyano- 1 -cyclopropylethyl)-3 -(phenylamino)- 1 H-pyrazole-4-carboxamide;
tert-butyl 4- { 1 - [4-carbamoyl-3 -(phenylamino)- 1 H-pyrazol- 1 -yl] -2-cyanoethyl jpiperidine- 1 - carboxylate;
tert-butyl 3 -( 1 - { 4-carbamoyl-3 - [(4-fluorophenyl)amino] - 1 H-pyrazol- 1 -yl } -2- cyanoethyl)pyrrolidine -1 -carboxylate;
l-(2-cyanoethyl)-3-(phenylamino)-lH-pyrazole-4-carboxamide;
1 -(2-cyano- 1 -cyclopentylethyl)-3 -({4- [(1,1 -dioxidothiomorpholin-4-yl)carbonyl]phenyl } amino)-
1 H-pyrazole-4-carboxamide;
1 -(2-cyano- 1 -methylethyl)-3-(phenylamino)- 1 H-pyrazole-4-carboxamide;
1 - [ 1 -(cyanomethyl)propyl] -3 -(phenylamino)- 1 H-pyrazole-4-carboxamide;
1 -(2-cyano- 1 -cyclopentylethyl)-3 - [(3 - { [4-( 1 -hydroxy- 1 -methylethyl)- 1 H- 1 ,2,3 -triazol- 1 - yljmethyl } phenyl)amino] - 1 H-pyrazole-4-carboxamide;
l-[2-cyano-l-(te1rahydro-2H-pyran-4-yl)ethyl]-3-( henylamino)-lH-pyrazole-4-carboxamide; 1 -[2-cyano- 1 -(tetrahydro-2H-pyran-4-ylmethyl)e11iyl]-3-( henylamino)-lH-pyrazole-4- carboxamide;
1 -[ 1 -(cyanomethyl)-2-methylpropyl]-3-(phenylamino)-lH-pyrazole-4-carboxamide;
1 -(2-cyano- 1 -cyclopropylethyl)-3-(phenylamino)- lH-pyrazole-4-carboxamide;
1 - [ 1 -(cyanomethyl)-3 , 3 -dimethylbutyl] -3 -(phenylamino)- 1 H-pyrazole-4-carboxamide;
1 - [2-cyano- 1 -(tetrahydrofuran-3 -yl)ethyl] -3 -(phenylamino)- 1 H-pyrazole-4-carboxamide;
1 - [2-cyano- 1 -(tetrahydro-2H-pyran-3 -yl)ethyl] -3 -(phenylamino)- 1 H-pyrazole-4-carboxamide;
1 -(2-cyano-l -methylethyl)-3-({4-[(l , 1 -dioxidothiomorpholin-4-yl)carbonyl]phenyl} amino)- 1H- pyrazole-4-carboxamide;
1 - [ 1 -(cyanomethyl)propyl] -3-({4-[(l,l -dioxidothiomorpholin-4-yl)carbonyl]phenyl } amino)- 1 H- pyrazole-4-carboxamide;
1 -(2-cyano- 1 -cyclopropyl- 1 -methylethyl)-3 -(phenylamino)- 1 H-pyrazole-4-carboxamide;
1 -(2-cyano- 1 -cyclobutylethyl)-3 -(phenylamino)- 1 H-pyrazole-4-carboxamide;
l-(2-cyano-l-cyclopentylethyl)-3-(phenylamino)-lH-pyrazole-4-carboxamide;
1 -(2-cyano- 1 , 1 -dimethylethyl)-3 -(phenylamino)- 1 H-pyrazole-4-carboxamide;
l-3-cyclobutan-2-yl]-3-(phenylamino)-lH-pyrazole-4-carboxamide;
1-(2S, 3S)-3-cyclobutan-2-yl]-3-(phenylamino)-lH-pyrazole-4-carboxamide;
1-(2R, 3R)-3-cyclobutan-2-yl]-3-(phenylamino)-lH-pyrazole-4-carboxamide;
1-(2S, 3R)-3-cyclobutan-2-yl]-3-(phenylamino)-lH-pyrazole-4-carboxamide;
1-(2R, 3S)-3-cyclobutan-2-yl]-3-(phenylamino)-lH-pyrazole-4-carboxamide;
1 -(3 -cyano- 1,1,1 -trifluoropropan-2-yl)-3 -(phenylamino)- 1 H-pyrazole-4-carboxamide;
tert-Butyl 4-(l - {4-carbamoyl-3-[(4-fluorophenyl)amino]- lH-pyrazol- 1 -yl} -2- cyanoethyl)piperidine- 1 -carboxylate;
tert-butyl 4-{ l-[4-carbamoyl-3-(phenylamino)-lH-pyrazol-l-yl]-2-cyanoethyl}-4- fluoropiperidine- 1 -carboxylate;
tert-butyl 4- (2-[4-carbamoyl-3-(phenylamino)- lH-pyrazol- 1 -yl]- 1 -cyanopropan-2-yl}piperidine-
1 -carboxylate;
l-(2-cyano-l-cyclopropylethyl)-3-{[4-(methylsulfonyl)phenyl]amino}-lH-pyrazole-4- carboxamide;
tert-butyl 5 - { [4-carbamoyl- 1 -(2-cyano- 1 -cyclopropylethyl)- 1 H-pyrazol-3 -yl] amino } - 1 -oxo- 1,3- dihydro-2H-isoindole-2-carboxylate;
1 -(2-cyano- 1 -cyclopropylethyl)-3- { [4-(trifluoromethyl)phenyl]amino} -lH-pyrazole-4- carboxamide; 1 -(2-cyano- 1 -cyclopropylethyl)-3- { [3-(trifluoromethyl)phenyl]amino} -lH-pyrazole-4- carboxamide;
l-(2-cyano-l-cyclopropyleliiyl)-3-[(2-fluorophenyl)amino]-lH-pyrazole-4-carboxamide;
l-(2-cyano-l-cyclopropylethyl)-3-(pyridin-3-ylamino)-lH-pyrazole-4-carboxamide;
1 -(2-cyano- 1 -cyclopropylethyl)-3- { [3-(2-cyanoethyl)phenyl]amino} - lH-pyrazole-4- carboxamide;
1 -(2-cyano- 1 -cyclopropylethyl)-3- { [4-(cyanomethyl)phenyl] amino} - lH-pyrazole-4-carboxamide; 1 -(2-cyano- 1 -cyclopropylethyl)-3 - { [3 -(cyanomethyl)phenyl] amino } - 1 H-pyrazole-4-carboxamide; l-(2-cyano-l-cyclopropylethyl)-3-{[3-(hydroxymethyl)phenyl]amino}-lH-pyrazole-4- carboxamide;
1 -(2-cyano- 1 -cyclopropylethyl)-3 - [(4-fluorophenyl)amino] - 1 H-pyrazole-4-carboxamide ;
1 -(2-cyano- 1 -cyclopropylethyl)-3 -[(2-methoxypyridin-4-yl)amino] - 1 H-pyrazole-4-carboxamide; 1 -(2-cyano- 1 -cyclopropylethyl)-3 - { [4-(methylcarbamoyl)phenyl] amino } - 1 H-pyrazole-4- carboxamide;
1 -(2-cyano- 1 -cyclopropylethyl)-3 - [(4-cyanophenyl)amino] - 1 H-pyrazole-4-carboxamide;
l-(2-cyano-l-cyclopropylethyl)-3-(isoquinolin-7-ylamino)-lH-pyrazole-4-carboxamide;
l-(2-cyano-l-cyclopropylethyl)-3-[(3-cyanophenyl)amino]-lH-pyrazole-4-carboxamide;
l-(2-cyano-l-cyclopropylethyl)-3-[(4-morpholin-4-ylphenyl)amino]-lH-pyrazole-4- carboxamide;
1 -(2-cyano- 1 -cyclopropylethyl)-3 - [(5 -cyanopyridin-3 -yl)amino] - 1 H-pyrazole-4-carboxamide; l-(2-cyano-l-cyclopropylethyl)-3-[(l-oxo-2 -dihydro-lH-inden-5-yl)amino]-lH-pyrazole-4- carboxamide;
1 -(2-cyano- 1 -cyclopropylethyl)-3 -(2,3-dihydro- 1 ,4-benzodioxin-6-ylamino)- 1 H-pyrazole-4- carboxamide;
- { [4-(acetylamino)phenyl] amino } - 1 -(2-cyano- 1 -cyclopropylethyl)- 1 H-pyrazole-4-carboxamide; 1 -(2-cyano- 1 -cyclopropylethyl)-3 - { [4-(dimethylcarbamoyl)phenyl] amino } - 1 H-pyrazole-4- carboxamide;
1 -(2-cyano- 1 -cyclopropylethyl)-3 - { [3 -(methylcarbamoyl)phenyl] amino } - 1 H-pyrazole-4- carboxamide;
1 -(2-cyano- 1 -cyclopropylethyl)-3 - { [4-( 1 ,3 -oxazol-5 -y l)phenyl] amino } - 1 H-pyrazole-4- carboxamide;
1 -(2-cyano- 1 -cyclopropylethyl)-3- { [4-(5-methyl- 1 ,3 ,4-oxadiazol-2-yl)phenyl]amino } - 1 H- pyrazole-4-carboxamide; 1 -(2-cyano- 1 -cyclopropylethyl)-3 - { [4-(5-methyl- 1 ,2,4-oxadiazol-3 -yl)phenyl] amino } - 1 H- pyrazole-4-carboxamide;
3 - [(2-chloropyridin-4-yl)amino]- 1 -(2-cyano- 1 -cyclopropylethyl)- 1 H-pyrazole-4-carboxamide; 1 -(2-cyano-l -cyclopropylethyl)-3-( {4- [(trifluoromethyl)sulfonyl]phenyl } amino)- lH-pyrazole-4- carboxamide;
l-(2-cyano-l-cyclopropylethyl)-3-({4-[(difluoromethyl)sulfonyl]phenyl}amino)-lH-pyrazole-4- carboxamide;
l-(2-cyano-l-cyclopropylethyl)-3-[(2,3,3-tri^
1 H-pyrazole-4-carboxamide;
1 -(2-cyano- 1 -cyclopropylethyl)-3 - { [ 1 -oxo-2-(2,2,2-trifluoroethyl)-2,3-dihydro- 1 H-isoindol-5- yl] amino } - 1 H-pyrazole-4-carboxamide;
l-(2-cyano-l-cyclopropylethyl)-3-{[4-(methylsulfinyl)phenyl]amino}-lH-pyrazole-4- carboxamide;
1 -(2-cyano- 1 -cyclopropylethyl)-3 - [(2 -methyl- 1 -oxo-2,3-dihydro- lH-isoindol-5 -yl)amino]- 1H- pyrazole-4-carboxamide;
/ert-butyl (5 - { [4-carbamoyl- 1 -(2-cyano- 1 -cyclopropylethyl)- 1 H-pyrazol-3 -yl] amino } - 1 -oxo- 1,3- dihydro-2H-isoindol-2-yl)acetate;
1 -(2-cyano- 1 -cyclopropylethyl)-3 -[(1,1 -dioxido- 1 -benzothiophen-5 -yl)amino] - 1 H-pyrazole-4- carboxamide;
1 -(2-cyano- 1 -cyclopropylethyl)-3 - { [4-(3-methyl- 1 ,2,4-oxadiazol-5-yl)phenyl]amino } - 1 H- pyrazole-4-carboxamide;
1 -(2-cyano- 1 -cyclopropylethyl)-3 - [(2-fluoropyridin-4-yl)amino]- 1 H-pyrazole-4-carboxamide; 1 -(2-cyano- 1 -cyclopropylethyl)-3 - [( 1 , 1 -dioxido-2,3 -dihydro- 1 -benzothiophen-5 -yl)amino] - 1 H- pyrazole-4-carboxamide;
1 -(2-cyano- 1 -cyclopropylethyl)-3 -( { 3 - [(2-hydroxy-2-methylpropoxy)methyl]phenyl } amino)- 1 H- pyrazole-4-carboxamide;
l-(2-cyano-l-cyclopropylethyl)-3-[(2-fluorophenyl)amino]-lH-pyrazole-4-carboxamide;
1 -(2-cyano- 1 -cyclopropylethyl] -3 - [(4-sulfamoylphenyl)amino] - 1 H-pyrazole-4-carboxamide; 1 -(2-cyano- 1 -cyclopropylethyl)-3 - { [4-(dimethylsulfamoyl)phenyl] amino } - 1 H-pyrazole-4- carboxamide;
1 -(2-cyano- 1 -cyclopropylethyl)-3 - [( 1 -oxo-2,3 -dihydro- 1 H-isoindol-5 -yl)amino] - 1 H-pyrazole-4- carboxamide;
(5-{ [4-carbamoyl-l -(2-cyano-l -cyclopropylethyl)- lH-pyrazol-3-yl]amino}-l -oxo-1 ,3-dihydro- 2H-isoindol-2-yl)acetic acid; 1- (2-cyanopropyl)-3-[(4-fluorophenyl)amino]-lH-pyrazole-4-carboxamide;
1 -(2-cyano- 1 -methylethyl)-3 - { [4-(methylsulfonyl)phenyl]amino} - 1 H-pyrazole-4-carboxamide;
2- (dimethylamino)ethyl 4-( 1 -{4-carbamoyl-3-[(4-fluorophenyl)amino]- lH-pyrazoI- 1 -yl} -2- cyanoethyl)piperidine- 1 -carboxylate;
methyl 4-( 1 - { 4-carbamoyl-3 - [(4-fluorophenyl)amino] - 1 H-pyrazol- 1 -yl } -2-cyanoethyl)piperidine-
1 - carboxylate;
2-(methylsulfonyl)ethyl 4-( 1 - {4-carbamoyl-3 - [(4-fluorophenyl)amino] - 1 H-pyrazol- 1 -yl } -2- cyanoethyl)piperidine- 1 -carboxylate;
oxetan-3 -yl 4- [ 1 - {4-carbamoyl-3 - [(4-fluorophenyl)amino] - 1 H-pyrazol- 1 -yl } -2- cyanoethyl]piperidine- 1 -carboxylate;
oxetan-3 -yl 4-[(lS)-l-{ 4-carbamoyl-3 - [(4-fluorophenyl)amino] - 1 H-pyrazol- 1 -yl } -2- cyanoethyl]piperidine- 1 -carboxylate;
cyclobutyl 4-[l -{4-carbamoyl-3-[(4-fluorophenyl)amino]-lH-pyrazol-l -yl}-2- cyanoethyl]piperidine- 1 -carboxylate;
cyclobutyl 4- [( 1 S)- 1 - {4-carbamoyl-3 - [(4-fluorophenyl)amino] - 1 H-pyrazol- 1 -yl } -2- cyanoethyl]piperidine- 1 -carboxylate;
cyclopentyl 4- [ 1 - {4-carbamoyl-3 - [(4-fluorophenyl)amino] - 1 H-pyrazol- 1 -yl } -2- cyanoethyljpiperidine- 1 -carboxylate;
cyclopentyl 4-[(lS)-l-{4-carbamoyl-3-[(4-fluorophenyl)amino]-lH-pyrazol-l-yl}-2- cyanoethyl]piperidine- 1 -carboxylate;
2,2,2-trifIuoroethyl 4-[l-{4-carbamoyl-3-[(4-fluorophenyl)amino]-lH-pyrazol-l-yl}-2- cyanoethyl]piperidine- 1 -carboxylate;
2,2,2-trifluoroethyl 4-[( 1 S)- 1 - {4-carbamoyl-3-[(4-fluorophenyl)amino]- 1 H-pyrazol-l -yl} -2- cyanoethyljpiperidine- 1 -carboxylate;
tetrahydro-2H-pyran-4-yl 4- [ 1 - {4-carbamoyl-3 - [(4-fluorophenyl)amino] - 1 H-pyrazol-l -yl } -2- cyanoethyljpiperidine- 1 -carboxylate;
tetrahydro-2H-pyran-4-yl 4-[( IS)- l-{4-carbamoyl-3-[(4-fluorophenyl)amino]-l H-pyrazol- 1-yl}-
2- cyanoethyl]piperidine- 1 -carboxylate;
2-methoxy- 1 -methylethyl 4- [ 1 - { 4-carbamoyl-3 - [(4-fluorophenyl)amino] - 1 H-pyrazol- 1 -yl } -2- cyanoethyl]piperidine- 1 -carboxylate;
2-methoxy-l -methylethyl 4-[(l S)-l -{4-carbamoyl-3-[(4-fluorophenyl)amino]-l H-pyrazol-l -yl}-
2-cyanoethyl]piperidine- 1 -carboxylate;
cyclopropylmethyl 4-[l -{4-carbamoyl-3-[(4-fluorophenyl)amino]- 1 H-pyrazol- 1 -yl} -2- cyanoethyljpiperidine- 1 -carboxylate; cyclopropylmethyl 4-[( 1 S)- 1 - {4-carbamoyl-3 - [(4-fluorophenyl)amino]- 1 H-pyrazol- 1 -yl} -2- cyanoethyl]piperidine- 1 -carboxylate;
2,2,2-trifluoro- 1 -methylethyl 4- [1 - {4-carbamoyl-3 - [(4-fluorophenyl)amino]- 1 H-pyrazol- 1 -yl} -2- cyanoethyl]piperidine- 1 -carboxylate;
2,2,2-trifluoro- 1 -methylethyl 4-[(l S)- 1 -{4-carbamoyl-3-[(4-fluorophenyl)amino]- 1 H-pyrazol- 1 - yl} -2-cyanoethyl]piperidine- 1 -carboxylate;
tetrahydrofuran-3 -ylmethyl 4- [ 1 - {4-carbamoyl-3 - [(4-fluorophenyl)amino] - 1 H-pyrazol- 1 -yl } -2- cyanoethyl]piperidine- 1 -carboxylate;
tetrahydrofuran-3 -ylmethyl 4- [( 1 S)- 1 - {4-carbamoyl-3 - [(4-fluorophenyl)amino] - 1 H-pyrazol- 1 - yl}-2-cyanoethyl]piperidine-l-carboxylate;
2-morpholin-4-ylethyl 4-[-l-{4-carbamoyl-3-[(4-fluorophenyl)amino]-lH-pyrazol-l-yl}-2- cyanoethyl]piperidine- 1 -carboxylate;
2-morpholin-4-ylethyl 4-[( 1 S)- 1 - {4-carbamoyl-3 -[(4-fluorophenyl)amino]- 1 H-pyrazol- 1 -yl } -2- cyanoethyl]piperidine- 1 -carboxylate;
2-methoxyethyl 4- [ 1 - {4-carbamoyl-3 - [(4-fluoropheny l)amino] - 1 H-pyrazol- 1 -yl } -2- cyanoethyl]piperidine- 1 -carboxylate;
2-methoxyethyl 4-[(lS)-l-{4-carbamoyl-3-[(4-fluorophenyl)amino]-lH-pyrazol-l-yl}-2- cyanoethyl]piperidine- 1 -carboxylate;
2,2-dimethylpropyl 4- [- 1 - {4-carbamoyl-3-[(4-fluorophenyl)amino] - 1 H-pyrazol- 1 -yl} -2- cyanoethyl]piperidine- 1 -carboxylate;
2,2-dimethylpropyl 4- [( 1 R)- 1 - {4-carbamoyl-3 - [(4-fluorophenyl)amino] - 1 H-pyrazol- 1 -yl } -2- cyanoethyljpiperidine- 1 -carboxylate;
2 ,2-dimethylpropyl 4- [( 1 S)- 1 - { 4-carbamoyl-3 - [(4-fluorophenyl)amino] - 1 H-pyrazol- 1 -yl } -2- cyanoethyljpiperidine- 1 -carboxylate;
2-methylpropyl 4-[l-{4-carbamoyl-3-[(4-fluorophenyl)amino]-l H-pyrazol- 1-yl} -2- cyanoethyl]piperidine- 1 -carboxylate;
2-methylpropyl 4-[(lS)-l-{4-carbamoyl-3-[(4-fluorophenyl)amino]-lH-pyrazol-l-yl}-2- cyanoethyl]piperidine- 1 -carboxylate;
2-methylpropyl 4- [( 1 R)- 1 - {4-carbamoyl-3- [(4-fluorophenyl)amino]- 1 H-pyrazol- 1 -yl} -2- cyanoethyl]piperidine- 1 -carboxylate;
ethyl 4-[l - {4-carbamoyl-3 -[(4-fluorophenyl)amino] -1 H-pyrazol- 1 -yl } -2-cyanoethyl]piperidine- 1 - carboxylate;
ethyl 4-[(lS)-l-{4-carbamoyl-3-[(4-fluorophenyl)amino]-lH-pyrazol-l-yl}-2- cyanoethyljpiperidine- 1 -carboxylate; ethyl 4-[( 1 R)- 1 - {4-carbamoyl-3-[(4-fluorophenyl)amino]- 1 H-pyrazol- 1 -yl} -2- cyanoethyljpiperidine- 1 -carboxylate;
cyclohexyl 4-[ 1 - {4-carbamoyl-3 - [(4-fluorophenyl)amino]- 1 H-pyrazol- 1 -yl } -2- cyanoethyl]piperidine- 1 -carboxylate;
cyclohexyl 4- [( 1 S)- 1 - { 4-carbamoyl-3 - [(4-fluorophenyl)amino] - 1 H-pyrazol- 1 -yl } -2- cyanoethyljpiperidine- 1 -carboxylate ;
cyclohexyl 4-[(l R)- 1 - {4-carbamoyl-3-[(4-fluorophenyl)amino]- 1 H-pyrazol- 1 -yl} -2- cyanoethyl]piperidine- 1 -carboxylate;
benzyl 4-[l-{4-carbamoyl-3-[(4-fluorophenyl)amino]-lH-pyrazol-l-yl}-2-cyanoethyl]piperidin
1 -carboxylate;
benzyl 4-[(lS)-l-{ 4-carbamoyl-3 - [(4-fluorophenyl)amino] - 1 H-pyrazol- 1 -yl } -2- cyanoethyljpiperidine- 1 -carboxylate;
benzyl 4-[(lR)-l-{ 4-carbamoyl-3 - [(4-fluorophenyl)amino] - 1 H-pyrazol- 1 -yl } -2- cyanoethyl]piperidine- 1 -carboxylate;
1 - { 1 - [ 1 -(6- Chloro-5 -methylpyrimidin-4-yl)piperidin-4-yl] -2-cyanoethyl } -3 - [(4- fluorophenyl)amino]-lH-pyrazole-4-carboxamide;
l-{(lS)-l-[l-(6- CWoro-5-methylpyrimidin-4-yl)piperidin-4-yl]-2-cyanoethyl}-3-[(4- fluorophenyl)amino] - 1 H-pyrazole-4-carboxamide;
l-[2-Cyano-l-cyclopropylethyl]-3-{[4-(methylsulfonyl)phenyl]arnino}-lH-pyrazole-4- carboxamide;
1 -[(1 R)-2-Cyano- 1 -cyclopropylethyl]-3- { [4-(methylsulfonyl)phenyl]amino} - 1 H-pyrazole-4- carboxamide;
1 - [( 1 S)-2-Cyano- 1 -cyclopropylethyl] -3 - { [4-(methylsulfonyl)phenyl] amino } - 1 H-pyrazole-4- carboxamide;
tert-butyl 4- [ 1 - { 4-carbamoyl-3 - [(4-fluorophenyl)amino] - 1 H-pyrazol- 1 -yl } -2- cyanoethyl)piperidine- 1 -carboxylate;
tert-butyl 4-[( 1 S)- 1 - {4-carbamoyl-3 -[(4-fluorophenyl)amino] - 1 H-pyrazol- 1 -yl} -2- cyanoethyl)piperidine- 1 -carboxylate;
tert-butyl 4-[( 1 R)- 1 - {4-carbamoyl-3 - [(4-fluorophenyl)amino] - lH-pyrazol- 1 -yl } -2- cyanoethyl)piperidine- 1 -carboxylate;
te^butyl 4-{l-[4-carbamoyl-3-(phenylamino)-lH-pyrazol-l-yl]-2-cyanoethyl}piperidine-l- carboxylate;
tert-butyl 4- { ( 1 S)- 1 - [4-carbamoyl-3 -(phenylamino)- 1 H-pyrazol- 1 -yl]-2-cyanoethyl } piperidine- carboxylate; fert-butyl 4- { ( 1 R)- 1 - [4-carbamoyl-3 -(phenylamino)- 1 H-pyrazol- 1 -yl] -2-cyanoethyl } iperidine- 1 - carboxylate;
1 - [ 1 -(cyanomethyl)propyl] -3 -(phenylamino)- 1 H-pyrazole-4-carboxamide;
1 - [( 1 R)- 1 -(cyanomethyl)propyl] -3 -(phenylamino)- 1 H-pyrazole-4-carboxamide;
1 - [( 1 S)- 1 -(cyanomethyl)propyl] -3 -(phenylamino)- 1 H-pyrazole-4-carboxamide;
1 - [2-cyano- 1 -cyclopentylethyl] -3 -(phenylamino)- 1 H-pyrazole-4-carboxamide;
l-[(lS)-2-cyano-l-cyclopentylemyl]-3-^henylamino)-lH-pyrazole-4-carboxamide;
1 - [( 1 R)-2-cyano- 1 -cyclopentylethyl] -3 -(phenylamino)- 1 H-pyrazole-4-carboxamide;
1 - [ 1 -cyanopropan-2-yl] -3 -(phenylamino)- 1 H-pyrazole-4-carboxamide ;
1 -[(2R)-1 -cyanopropan-2-yl]-3-(phenylamino)-lH-pyrazole-4-carboxamide;
l-[(2S)-l-cyanopropan-2-yl]-3-(phenylamino)-lH-pyrazole-4-carboxamide;
1 - [2-cyano- 1 -cyclopropylethyl] -3 -(phenylamino)- 1 H-pyrazole-4-carboxamide;
1 - [( 1 S)-2-cyano- 1 -cyclopropylethyl] -3 -(phenylamino)- 1 H-pyrazole-4-carboxamide;
1 - [( 1 R)-2-cyano- 1 -cyclopropylethyl] -3 -(phenylamino)- 1 H-pyrazole-4-carboxamide ;
1 -[2-cyano- 1 -cyclopropylethyl] -3 -[(2-fluoropyridin-4-yl)amino] - 1 H-pyrazole-4-carboxamide;
1 -[( 1 R)-2-cyano- 1 -cyclopropylethyl]-3-[(2-fluoropyridin-4-yl)amino]- lH-pyrazole-4- carboxamide;
1 - [( 1 S)-2-cyano- 1 -cyclopropylethyl] -3 - [(2-fluoropyridin-4-yl)amino]- 1 H-pyrazole-4- carboxamide;
l-[2-cyano-l-cyclopropylethyl]-3-{[4-(3-methyl-l,2,4-oxadiazol-5-yl)phenyl]amino}-lH- pyrazole-4-carboxamide;
l-[(lR)-2-cyano-l-cyclopropylethyl]-3-{[4-(3-methyl-l,2,4-oxadiazol-5-yl)phenyl]amino}-lH- pyrazole-4-carboxamide;
l-[(l S)-2-cyano-l-cyclopropylethyl]-3-{[4-(3-methyl-l,2,4-oxadiazol-5-yl)phenyl]amino}-lH- pyrazole-4-carboxamide;
1 - [2-cyano- 1 -cyclopropylethyl] -3 -[( 1 -oxo-2,3 -dihydro- 1 H-isoindol-5-yl)amino] - 1 H-pyrazole-4- carboxamide;
1 - [( 1 R)-2-cyano- 1 -cyclopropylethyl] -3 - [( 1 -oxo-2,3 -dihydro- 1 H-isoindol-5 -yl)amino] - 1 H- pyrazole-4-carboxamide; and
1 -[( 1 S)-2-cyano- 1 -cyclopropylethyl] -3 - [( 1 -oxo-2,3 -dihydro- 1 H-isoindol-5-yl)amino] - 1 H- pyrazole-4-carboxamide.
In one embodiment of the invention, representative compounds include, but are not limited to, the following compounds and their pharmaceutically acceptable salts and stereoisomers thereof: l-(2-cyano-l-cyclopentylethyl)-3-({4-[(l,l-dioxidothiom
1 H-pyrazole-4-carboxamide;
1 -(2-cyano- 1 , 1 -dimethylethyl)-3-(phenylamino)- 1 H-pyrazole-4-carboxamide;
tert-Butyl 4-( 1 - {4-carbamoyl-3 - [(4-fluorophenyl)amino]- 1 H-pyrazol- 1 -yl} -2- cyanoethyl)piperidine- 1 -carboxylate;
/ert-butyl 4- { 2-[4-carbamoyl-3 -(phenylamino)- 1 H-pyrazol- 1 -yl] - 1 -cyanopropan-2-yl } piperidine-
1 -carboxylate;
1 -(2-cyano- 1 -cyclopropylethyl)-3 - { [3-(2-cyanoethyl)phenyl]amino} - lH-pyrazole-4- carboxamide;
1 -(2-cyano- 1 -cyclopropylethyl)-3 - { [4-(methylcarbamoyl)phenyl] amino } - 1 H-pyrazole-4- carboxamide;
1 -(2-cyano- 1 -cyclopropylethyl)-3 - { [3 -(methylcarbamoyl)phenyl] amino } - 1 H-pyrazole-4- carboxamide;
1 -(2-cyano- 1 -cyclopropylethyl)-3 -({4-[(trifluoromethyl)sulfonyl]phenyl}amino)-lH-pyrazole-4- carboxamide;
1 -(2-cyano- 1 -cyclopropylethyl)-3 -( { 4- [(difluoromethyl)sulfonyl] phenyl } amino)- 1 H-pyrazole-4- carboxamide;
1 -(2-cyano- 1 -cyclopropylethyl)-3 - { [4-(methylsulfinyl)phenyl] amino} - 1 H-pyrazole-4- carboxamide;
1 -(2-cyano- 1 -cyclopropylethyl)-3 -[(2-methyl-l-oxo-2,3-dihydro-lH-isoindol-5-yl)amino]-lH- pyrazole-4-carboxamide;
1 -(2-cyano- 1 -cyclopropylethyl)-3 -[(1,1 -dioxido- 1 -benzothiophen-5 -yl)amino] - 1 H-pyrazole-4- carboxamide;
1 -(2-Cyano- 1 -cyclopropylethyl)-3-[(l , 1 -dioxido-2,3-dihydro- 1 -benzothiophen-5-yl)amino]- 1 H- pyrazole-4-carboxamide;
l-(2-cyano-l-cyclopropylethyl]-3-[(4-sulfamoylphenyl)amino]-lH-pyrazole-4-carboxamide; (5- { [4-Carbamoyl- 1 -(2-cyano- 1 -cyclopropylethyl)- lH-pyrazol-3-yl]amino}- 1 -oxo- 1 ,3-dihydro-
2H-isoindol-2-yl)acetic acid;
cyclobutyl 4- [ 1 - { 4-carbamoyl-3 - [(4-fluorophenyl)amino] - 1 H-pyrazol- 1 -yl } -2- cyanoethyl]piperidine- 1 -carboxylate;
2,2,2-trifluoroethyl 4-[ 1 - {4-carbamoyl-3-[(4-fluorophenyl)amino]- lH-pyrazol- 1 -yl} -2- cyanoethyljpiperidine- 1 -carboxylate;
cyclopropylmethyl 4-[ 1 - {4-carbamoyl-3-[(4-fluorophenyl)amino]- 1 H-pyrazol- 1 -yl} -2- cyanoethyl]piperidine- 1 -carboxylate; 2,2,2-trifluoro- 1 -methylethyl 4-[l - {4-carbamoyl-3-[(4-fluorophenyl)amino]- 1 H-pyrazol- 1 -yl} -2- cyanoethyl]piperidine- 1 -carboxylate;
ethyl 4-[l -{4-carbamoyl-3-[(4-fluorophenyl)amino]- 1 H-pyrazol- 1 -yl} -2-cyanoethyl]piperidine- 1 - carboxylate;
1 -[2-cyano- 1 -cyclopropylethyl]-3- { [4-(methylsulfonyl)phenyl]amino } - 1 H-pyrazole-4- carboxamide;
l-[2-Cyano-l-cyclopropylethyl]-3-{[4-(methylsulfonyl)phenyl]amino}-lH-pyrazole-4- carboxamide;
tert-Butyl 4- { 1 - [4-carbamoyl-3 -(phenylamino)- 1 H-pyrazol- 1 -yl] -2-cyanoethyl } piperidine- 1 - carboxylate;
l-[l-Cyanopropan-2-yl]-3-( henylamino)-lH-pyrazole-4-carboxamide;
l-[2-cyano-l-cyclopropylethyl]-3-[(2-fluoropyridin-4-yl)ammo]-lH-pyrazole-4-carboxam 1 -[2-Cyano- 1 -cyclopropylethyl]-3- { [4-(3 -methyl- 1 ,2,4-oxadiazol-5-yl)phenyl]amino} - 1H- pyrazole-4-carboxamide; and
1 - [2-Cyano- 1 -cyclopropylethyl] -3 - [( 1 -oxo-2,3 -dihydro- 1 H-isoindol-5 -yl)amino] - 1 H-pyrazole-4- carboxamide.
The invention also encompasses pharmaceutical compositions containing a compound of formula I, and methods for treatment or prevention of JAK mediated diseases using compounds of formula I.
The invention is described using the following definitions unless otherwise indicated.
" Acyl" means a -C(0)R radical Where R is optionally substituted alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl heteroaryl, etc.
"Acylamino" means a -NRR' radical where R is Η, ΟΗ, or alkoxy and R' is acyl, as defined herein.
As used herein except where noted, "alkyl" is intended to include both branched- and straight-chain saturated aliphatic hydrocarbon groups, including all isomers, having the specified number of carbon atoms. Commonly used abbreviations for alkyl groups are used throughout the specification, e.g. methyl may be represented by "Me" or CH3, ethyl may be represented by "Et" or CH2CH3, propyl may be represented by "Pr" or CH2CH2CH3, butyl may be represented by "Bu" or CH2CH2CH2CH3 , etc. "Ci-6 alkyl" (or "C1-C6 alkyl") for example, means linear or branched chain alkyl groups, including all isomers, having the specified number of carbon atoms. Ci-6 alkyl includes all of the hexyl alkyl and pentyl alkyl isomers as well as n-, iso-, sec- and t- butyl, n- and isopropyl, ethyl and methyl. "Ci-4 alkyl" means n-, iso-, sec- and t-butyl, n- and isopropyl, ethyl and methyl. The term "alkylene" refers to both branched- and straight-chain saturated aliphatic hydrocarbon groups, including all isomers, having the specified number of carbons, and having two terminal end chain attachments. For illustration, the term
"unsubstituted A-C4alkylene-B" represents A-CH2-CH2-CH2-CH2-B. The term "alkoxy" represents a linear or branched alkyl group of indicated number of carbon atoms attached through an oxygen bridge.
The term "alkyl" refers to an aliphatic hydrocarbon group which may be straight or branched and having the indicated number of carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, s- and t-butyl, pentyl, hexyl, and the like.
The term "heteroalkyl" refers to an alkyl group where 1, 2, or 3 of the carbon atoms is substituted by a heteroatom independently selected from N, O, or S.
"Alkenyl" refers to an aliphatic hydrocarbon group containing at least one carbon- carbon double bond and which may be straight or branched and having the indicated number of carbon atoms. Preferably alkenyl contains one carbon to carbon double bond, and up to four nonaromatic carbon-carbon double bonds may be present. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, 2-methyl-l-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.
"Alkynyl" refers to an aliphatic hydrocarbon group containing at least one carbon- carbon triple bond and which may be straight or branched and having the indicated number of carbon atoms. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2- butynyl and 3-methylbutynyl.
"Alkoxy" refers to an alkyl-O- group in which the alkyl group is as described above. Ci-6alkoxy, for example, includes methoxy, ethoxy, propoxy, isopropoxy, and the like.
"Alkoxyalkyl" refers to an alkyl group as described above in which one or more
(in particular 1 to 3) hydrogen atoms have been replaced by alkoxy groups. Examples include CH2OCH3, CH2CH2OCH3 and CH(OCH3)CH3.
"Aminoalkyl" refers to an alkyl group as described above in which one hydrogen atom has been replaced by an amino, monoalkylamino or dialkylamino group. Examples include CH2NH2, CH2CH2NHCH3 and CH(N(CH3)2)CH3.
The term "Co" as employed in expressions such as "Co-6 alkyl" means a direct covalent bond; or when the term appears at the terminus of a substituent, CO-6 alkyl means hydrogen or Cl-6alkyl. Similarly, when an integer defining the presence of a certain number of atoms in a group is equal to connected directly by a bond. For example, in
Figure imgf000019_0001
equal to zero, 1 or
2, the structure is when s is zero.
The term "C3-8 cycloalkyl" (or "C3-C8 cycloalkyl") means a cyclic ring of an alkane having three to eight total carbon atoms (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl). The terms "C3-7 cycloalkyl", "C3-6 cycloalkyl", "C5-7 cycloalkyl" and the like have analogous meanings.
The term "halogen" (or "halo") refers to fluorine, chlorine, bromine and iodine (alternatively referred to as fluoro (F), chloro (CI), bromo (Br), and iodo (I)).
The term "aryl" refers to aromatic mono- and poly-carbocyclic ring systems, wherein the individual carbocyclic rings in the polyring systems are fused or attached to each other via a single bond. Suitable aryl groups include phenyl, naphthyl, 2,3-dihydro-lH-indenyl, and biphenyl.
The term "carbocycle" (and variations thereof such as "carbocyclic" or
"carbocyclyl") as used herein, unless otherwise indicated, refers to (i) a C3 to C8 monocyclic, saturated or unsaturated ring or (ii) a C7 to C 2 bicyclic saturated or unsaturated ring system. Each ring in (ii) is either independent of, or fused to, the other ring, and each ring is saturated or unsaturated. The carbocycle may be attached to the rest of the molecule at any carbon atom which results in a stable compound. The fused bicyclic carbocycles are a subset of the carbocycles; i.e., the term "fused bicyclic carbocycle" generally refers to a C7 to Cio bicyclic ring system in which each ring is saturated or unsaturated and two adjacent carbon atoms are shared by each of the rings in the ring system. A fused bicyclic carbocycle in which one ring is saturated and the other is saturated is a saturated bicyclic ring system. A fused bicyclic carbocycle in which one ring is benzene and the other is saturated is an unsaturated bicyclic ring system. A fused bicyclic carbocycle in which one ring is benzene and the other is unsaturated is an unsaturated ring system. Saturated carbocyclic rings are also referred to as cycloalkyl rings, e.g., cyclopropyl, cyclobutyl, etc. Unless otherwise noted, carbocycle is unsubstituted or substituted with Ci-6 alkyl, Ci-6 alkenyl, Ci-6 alkynyl, aryl, halogen, Ν¾ or ΟΗ. A subset of the fused bicyclic unsaturated carbocycles are those bicyclic carbocycles in which one ring is a benzene ring and the other ring is saturated or unsaturated, with attachment via any carbon atom that results in a stable compound. Representative examples of this subset include the following:
Figure imgf000020_0001
"Cyanoalkyl" refers to an alkyl group as described above in which one hydrogen atom has been replaced by a cyano group. Examples include CH2CN, CH2CH2CN and
CH(CN)CH3.
"Cycloalkyl" means a carbocyclic ring system having 3 to 12 ring carbon atoms; said ring system may be (a) a monocyclic saturated carbocycle optionally fused to a benzene or a partially unsaturated carbocycle, or (b) a bicyclic saturated carbocycle. For a bicyclic system, within either (a) or (b), the rings are fused across two adjacent ring carbon atoms (e.g., decalin), at one ring carbon atom (e.g., spiro[2.2]pentane), or are bridged groups (e.g., norbornane).
Additional examples within the above meaning include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, perhydroindan, decalin, spiro[4.5]decane,
bicyclo[2.2.2]octane, and the like.
"Haloalkyl" refers to an alkyl group as described above wherein one or more (in particular 1 to 5) hydrogen atoms have been replaced by halogen atoms, with up to complete substitution of all hydrogen atoms with halo groups. Ci_6haloalkyl, for example, includes -CF3, -CF2CF3, CHFCH3, and the like.
"Heterocycle", "heterocyclic" or "heterocyclyl" represents a monocyclic or bicyclic 3-12 membered ring system in which at least one ring is non-aromatic (saturated or partially unsaturated) and containing at least one heteroatom selected from O, S and N. In a bicyclic ring system, the second ring may be a heteroaryl, heterocycle or a saturated, partially unsaturated or aromatic carbocycle, and the point(s) of attachment to the rest of the molecule may be on either ring. "Heterocyclyl" therefore includes heteroaryls, as well as dihydro and tetrathydro analogs thereof. Attachment of a heterocyclyl substituent can occur via a carbon atom or via a heteroatom.
Examples of heterocycles (heterocyclyl) include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, dihydroimidazolyl, dihydroindolyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6,7,8-tetrahydroimidazo[l,2-a]pyrazine, 2,3- dihydrobenzofuranyl, benzo-1 ,4-dioxanyl, benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridinyl, pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl,
tetrahydropyranyl, tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl, triazolyl, azetidinyl, aziridinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl, piperidinyl, pyrrolidinyl, morpholinyl, thiomorpholinyl, dihydrobenzoimidazolyl, dihydrobenzofuranyl,
dihydrobenzothiophenyl, dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl,
dihydroindolyl, dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl, dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl, dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl, dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and
tetrahydrothienyl, and N-oxides thereof.
Saturated heterocyclics form a subset of the heterocycles; i.e., the terms "saturated heterocyclic and (C3-i2)heterocycloalkyl" generally refers to a heterocycle as defined above in which the entire ring system (whether mono- or poly-cyclic) is saturated. The term "saturated heterocyclic ring" refers to a 4- to 8-membered saturated monocyclic ring or a stable 7- to 12- membered bicyclic ring system which consists of carbon atoms and one or more heteroatoms selected from N, O and S. Representative examples include piperidinyl, piperazinyl, azepanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, isothiazolidinyl, and tetrahydrofuryl (or tetrahydrofuranyl)
Heteroaromatics form another subset of the heterocycles; i.e., the term "heteroaromatic" (alternatively "heteroaryl") generally refers to a heterocycle as defined above in which the entire ring system (whether mono- or poly-cyclic) is an aromatic ring system. The term "heteroaromatic ring" refers a 5- or 6-membered monocyclic aromatic ring or a 7- to 12- membered bicyclic which consists of carbon atoms and one or more heteroatoms selected from N, O and S. For a bicyclic heteroaryl only one of the rings need to be heteroaromatic, the second ring may be a heteroaromatic or an aromatic, saturated, or partially unsatuated carbocycle, and the point(s) of attachment to the rest of the molecule may be on either ring. In the case of substituted heteroaryl rings containing at least one nitrogen atom (e.g., pyridine), such substitutions can be those resulting in N-oxide formation. Examples of heteroaryl include, but are not limited to, furanyl, thienyl (or thiophenyl), pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, naphthyridinyl, benzothienyl, benzofuranyl, benzimidazole, benzpyrazolyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolizinyl, phthalazinyl, quinoxalinyl, quinazolinyl, benzoxazolyl, benzisoxazolyl, 5,6,7,8-tetrahydroquinolinyl, imidazo[l,2-a]pyridinyl, imidazo[l,2-a]- pyrimidinyl, 5,6-dihydropyrrolo[l,2-&]pyrazolyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[2,3- >]pyridinyl, thieno[2,3-6]pyrrolyl, ruropyridine and thienopyridine.
Representative examples of bicyclic heterocycles include benzotriazolyl, indolyl, isoindolyl, indazolyl, indolinyl, isoindolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, chromanyl, isochromanyl, tetrahydroquinolinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl,
.0.
2,3-dihydrobenzofura -dihydrobenzo-l,4-dioxinyl (i.e., O ), imidazo(2,l-
b)(l,3)thiazole, (i.e.,
Figure imgf000022_0001
), and benzo-l,3-dioxolyl (i.e., ). In certain contexts herein, is alternatively referred to as phenyl having as a substituent methylenedioxy attached to two adjacent carbon atoms.
"Hydroxyalkyl" refers to an alkyl group as described above in which one or more
(in particular 1 to 3) hydrogen atoms have been replaced by hydroxy groups. Examples include
CH2OH, CH2CHOH and CHOHCH3.
"Alkylene," "alkenylene," "alkynylene," "cycloalkylene," "arylene,"
"heteroarylene," and "heterocyclylene" refer to a divalent radical obtained by the removal of one hydrogen atom from an alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, and heterocyclyl group, respectively, each of which is as defined above.
Unless expressly stated to the contrary, an "unsaturated" ring is a partially or fully unsaturated ring. For example, an "unsaturated monocyclic C6 carbocycle" refers to
cyclohexene, cyclohexadiene, and benzene.
Unless expressly stated to the contrary, all ranges cited herein are inclusive. For example, a heterocycle described as containing from "1 to 4 heteroatoms" means the heterocycle can contain 1 , 2, 3 or 4 heteroatoms.
When any variable occurs more than one time in any constituent or in any formula depicting and describing compounds of the invention, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
The term "substituted" (e.g., as in "aryl which is optionally substituted with one or more substituents ...") includes mono- and poly-substitution by a named substituent to the extent such single and multiple substitution (including multiple substitution at the same site) is chemically allowed.
The term "oxy" means an oxygen (O) atom. The term "thio" means a sulfur (S) atom. The term "oxo" means "=0". The term "carbonyl" means "C=0."
Structural representations of compounds having substituents terminating with a methyl group may display the terminal methyl group either using the characters "CH3", e.g. "- n
CH3" or using a straight line representing the presence of the methyl group, e.g. , i.e., CH3 and £ ,
^ have equivalent meanings.
For variable definitions containing terms having repeated terms, e.g., (CRiRj)r, where r is the integer 2, Ri is a defined variable, and Rj is a defined variable, the value of Ri may differ in each instance in which it occurs, and the value of Rj may differ in each instance in which it occurs. For example, if Ri and Rj are independently selected from the group consisting of methyl, ethyl, propyl and butyl, then (CRiRj)2 can be
I
H3CH2C C CH3
H3 CH2CH2CH2C C CH2CH2CH3 In one embodiment of the invention, Ra is hydrogen, ethyl, propyl, butyl, pentyl, or methyl. In a variant of this embodiment, Ra is hydrogen or methyl. In another variant, Ra is hydrogen.
In one embodiment of the invention R4 is hydrogen, ethyl, propyl, butyl, pentyl, or methyl. In a variant of this embodiment, R4 is hydrogen. In another variant, R4 is methyl, or propyl.
In one embodiment, R5 is aryl or heteroaryl, wherein R5 is substituted with 0, 1, 2,
3, or 4 R5a substituents.
In one embodiment R5 is selected from: furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl, quinolinyl, isoquinolinyl, naphthyridinyl, benzothienyl, benzofuranyl, benzimidazole, benzpyrazolyl, indolyl, isoindolyl, indolizinyl, indazolyl, purinyl, quinolizinyl, quinoxalinyl, quinazolinyl, benzoxazolyl, benzisoxazolyl, 5,6,7,8-tetrahydroquinolinyl, imidazo[l,2-tf]pyridinyl, imidazo[l,2-a]- pyrimidinyl, 5,6-dihydropyrrolo[l,2-0]pyrazolyl, pyrrolo[3,2-c]pyridinyl, pyrrolo[2,3-&]pyridinyl, thieno[2,3-6]pyrrolyl, furopyridinyl, thienopyridinyl, benzotriazolyl, indolyl, isoindolyl, indazolyl, indolinyl, isoindolinyl, quinoxalinyl, quinazolinyl, cinnolinyl, chromanyl, isochromanyl, tetrahydroquinolinyl, quinolinyl, tetrahydroisoquinolinyl, isoquinolinyl,
2,3-dihydrobenzofuranyl, 2,3-dihydrobenzo-l,4-dioxinyl, imidazo(2,l-b)(l,3)thiazole, and benzo-l,3-dioxolyl, phenyl, indenyl, and naphthyl.
In another embodiment, R5 is selected from: phenyl, l,3-dihydro-2H-isoindole, pyridinyl, quinolinyl, indoxplyl, isoquinolinyl, 2,3-dihydro-l-benzofuranyl, benzofuranyl, dihydro-lH- indenyl, indenyl, 2,3-dihydro-l,4-benzodioxinyl, 2,3,dihydro-lH-isoindolyl, isoindolyl, and benzo[b]thiophene, wherein Rs is substituted with 0, 1, 2, 3, or 4 R5a substituents.
In another embodiment, R5 is selected from: phenyl, l,3-dihydro-2H-isoindole, pyridinyl, isoquinolinyl, 2,3-dihydro-l-benzofuranyl, dihydro-lH-indenyl, 2,3-dihydro-l,4- benzodioxinyl, 2,3,dihydro-lH-isoindolyl, and benzo[b]thiophene, wherein R5 is substituted with 0, 1, 2, 3, or 4 R asubstituents
In one embodiment, R , R , and R is selected from hydrogen, Ci-io alkyl, aryl CO-10 alkylCo-10 alkyl, (C3-8)heterocycloalkyl Co-10 alkyl> c3-8 cycloalkylCO-10 alkyl, and heteroaryl CO-10 alkyl, wherein each of R1, R2, and R3 are independently substituted with 0,
1, 2, 3, or 4 RSa substituents
In another embodiment, R , R , and R are selected from hydrogen, Ci-io alkyl, (C3-8)heterocycloalkyl Co-10 alkyl, and C3-8 cycloalkylCO-10 alkyl, wherein each of R1, R2, and R3 are independently substituted with 0, 1, 2, 3, or 4 R5a substituents.
In another embodiment of the invention, R1, R2, and R3 are independently selected from hydrogen, piperidinyl, cyclopropyl, pyrrolidinyl, cyclopentyl, methyl, ethyl, tetrahydro-2H-pyranyl, (tetrahydro-2H-pyranyl)methyl, propyl, tert-butyl, isopropyl,
dimethylpropyl, dimethylbutyl, tetrahydrofuranyl, tertbutylmethyl, and cyclobutyl, ,wherein each of R1, R2, and R3 are independently substituted with 0, 1, 2, 3, or 4 R5a substituents.
In another embodiment of the invention, R1 and R2 are independently selected from hydrogen, piperidinyl, cyclopropyl, pyrrolidinyl, cyclopentyl, methyl, ethyl, tetrahydro-2H- pyranyl, (tetrahydro-2H-pyranyl)methyl, propyl, tert-butyl, isopropyl, dimethylpropyl,
dimethylbutyl, tetrahydrofuranyl, tertbutylmethyl, and cyclobutyl,wherein each of R and R are independently substituted with 0, 1, 2, 3, or 4, R5a substituents.
In one embodiment, R3 is hydrogen, methyl, ethyl, or butyl. In a variant of this embodiment, R is hydrogen or methyl.
In another embodiment, R1 is hydrogen, Ci_io heteroalkyl, or cyclopropyl.
In one embodiment, R2 is selected from hydrogen, Ci-io alkyl, Ci-io heteroalkyl, (C3-8)heterocycloalkyl Co-10 alkyl, and C3-8 cycloalkylCo-10 alkyl. In another embodiment, R2 is hydrogen, C 1 - 10 heteroalkyl, or cyclopropyl. In another embodiment, R2 and R1 are each independently selected from Cl-10 alkyl, C2-10 alkenyl, and Ci-io heteroalkyl, and R2 and R1 and the atom to which they are attached together form a 4-, 5-, or 6-membered saturated ring system and each of R1, R2, and R3 are independently substituted with 0, 1, 2, 3, or 4 R5a substituents. In a variant of this embodiment, the saturated ring is selected from piperidinyl, piperidino, and aziretidinyl.
In one embodiement, R3 is selected from hydrogen, Cl-10 alkyl, Ci-io
heteroalkyl, C3.8 cycloalkylCo-10 alkyl, and (C3_8)heterocycloalkyl Co-10 alkyl.
In another embodiment, R^d R3 are each independently selected from Ci-io alkyl, C2-10 alkenyl, and Ci-io heteroalkyl, and R*and R3 and the atom to which they are attached together form a 4-, 5-, or 6-membered saturated ring system and each of R1, R2, and R3 are independently substituted with 0, 1, 2, 3, or 4 R5a substituents. In a variant of this embodiment, the saturated ring is selected from cyclohexyl, piperidinyl and piperidino.
In one embodiment, wherein R5a is selected from: halogen,
Ci-io alkyl(oxy)0-i(carbonyl)o-lCO-10 alkyl,
Ci-io heteroalkyl(oxy)0-1 (carbonyl)o- 1 Co- 10 alkyl,
C2-10 alkenyl(oxy)0-i(carbonyl)0-lCo-10 alkyl,
aryl Co-10 alkyl(oxy)0-i(carbonyl)o-lCo-10 alkyl,
aryl C2-10 alkenyl(oxy)0-1(carbonyl)0-lCo-10 alkyl,
aryl C2-10 alkynyl(oxy)0-i(carbonyl)0-lCo-10 alkyl,
C3-8 cycloalkyl Co-10 alky oxy carbonyrjO-lCo-lO alkyl,
heteroaryl Co-10 alkyl(oxy)0-1(carbonyl)0-lCo-10 alkyl,
(C3-8)heterocycloalkyl Co-10 alkyl(oxy)0-i(carbonyl)o-lCo-10 alkyl,
Cl-10 alkyl(carbonyl)0-loxyCo-10 alkyl,
((CO- 10)alkyl)1-2aminocarbonyloxy,
Ci-io alkylamino(oxy)0-1carbonylCo- 10 alkyl,
Ci-io alkyl(oxy)0-1carbonylaminoCo-10 alkyl,
aryl Co-10 alkyl(oxy)o-icarbonylaminoCo-10 alkyl,
heteroaryl Co-10 alkyl(oxy)0-1carbonylaminoCo-10 alkyl,
-CO2(C0-10 alkyl),
-(Co-10 alkyl)C02H,
Oxo (=0), Ci-io alkylsulfonyl,
aminosulfonyl,
-S02N(Ci.6alkyl)1-2,
-S02Ci_6alkyl,
-SO2CF3,
-SO2CF2H,
Ci-io alkylsulfinyl,
amino,
(Co- 10 alkyl) x.2 amino,
hydroxy,
Co-10 alkylalkoxy,
cyano,
Ci-6alkylcyano,
and Ci-6haloalkyl; wherein R5a is each optionally substituted with 0, 1, 2, 3, or 4 R6 substituents.
In one embodiment, R5a is selected from: halogen, Ci-io alkyl(oxy)0- ^carbony^O-lCo-lO alkyl, Ci-io heteroalkyl(oxy)0-i(carbonyl)0-lCo-10 alkyl, aryl Co-10 alkyl(oxy)0-i(carbonyl)0-lCo-10 alkyl, C3-8 cycloalkyl Co-10 alkyl(oxy)0-1(carbonyl)0-lCo-10 alkyl, (C3_8)heteroaryl Co-10 alkyl(oxy)0-1(carbonyl)o-lCo-10 alkyl,
(C3-8)heterocycloalkyl Co-10 alkyl(oxy)0-1(carbonyl)0-lCo-10 alkyl,
Ci-io alkyl(carbonyl)0-loxyCo-10 alkyl, Ci_io heteroalkyl(carbonyl)0-loxyC0-10 alkyl, Ci-io heteroalkyl(carbonyl)o-loxyCo-10 alkyl, aryl Co-10 alkyl (carbonyl)o-loxyCo-lO alkyl,
(C3-8)cycloalkyl Co-10 alkyl(carbonyl)o-loxyCo-10 alkyl, (C3_8)heteroarylC0-10
alkyl(carbonyl)0-loxyCo-10 alkyl, (C3_8)heterocycloalkyl Co-10 alkyl(carbonyl)0-loxyC0-10 alkyl, -C02(Co-10 alkyl), Oxo (=0); -S02N(Ci-6alkyl)1-2, -S02Ci-6alkyl, -SO2CF3, - SO2CF2H, Cl-10 alkylsulfinyl, hydroxy, Co-10 alkylalkoxy, Ci-6alkylcyano, and
Cl-6haloalkyl.
In another embodiment of the invention, R5a is selected from: halogen,
((C0-10)alkyl)1-2aminocarbonyloxy, (Co-10)neteroalkylaminocarbonyloxy, aryl (Co- 1 o)alkylaminocarbonyloxy, (C3-8)cycloalkyl(Co-l o)alkylaminocarbonyloxy,
(C3-8)heteroaryl(Co- 1 o)alkylaminocarbonyloxy, (C3 -8)heterocycloalkyl(Co- 10)alkylaminocarbonyloxy, Ci-io alkylamino(oxy)0-1carbonylCo-10 alkyl, (CQ- 10)heteroalkylamino(oxy)0-1carbonylCo-10 alkyl, C3_8 cycloalkyl Co-10 alkylamino(oxy)0- jcarbonylCo-lO alkyl, aryl CO-10alkylamino(oxy)0-1carbonylCo-10 alkyl, (C3-8)heteroarylCo- 1 oalkylamino(oxy)0-1carbonylCo- 10 alkyl, (C3-8)heterocycloalkylC()- 1 Oalkylamino(oxy)0- icarbonylCo-10 alkyl, Ci-io alkyl(oxy)o-icarbonylaminoCo-10 alkyl, Ci-io heteroalkyl (oxy)0- icarbonylaminoCo-lO alkyl, C3.8 cycloalkyl Co-10 alkyl (oxy)0-1carbonylaminoCo-10 alkyl, aryl Co-10 alkyl(oxy)o-icarbonylaminoCo-10 alkyl, (C3-8)heteroaryl Co-10 alkyl(oxy)0.
icarbonylaminoCo-10 alkyl, (C3_8)heterocycloalkyl Co-10 alkyl(oxy)0.icarbonylaminoCo-10 alkyl, amino, (Co-10 lky!)^ amino, and Ci-4acylamino Co-10 alkyl.
In one embodiment of the invention, R5a is selected from: tert-butyl formate, tert-butylcarbonyloxy; halogen, thiomorpholinylcarbonyl, triazolylmethyl, tert-butyloxycarbonyl, methylsulfonyl, oxo, trifluoromethyl, cyanoethyl, cyanomethyl, hydroxymethyl, methoxy, methylcarbamoyl, cyano, morpholinyl, 2,3-dihydrobenzofuranyl, acetylamino,
dimethylcarbamoyl,
1,3-oxazolyl, imidazolyl, trifluoromethylsulfonyl, difluromethylsulfonyl, methyl, trifluoroethyl, methylsulfinyl, tert-butyloxycarbonylmethyl, oxadiazolyl, l-ethoxy-2,2-dimethylpropanyl, sulfamoyl, dimethylsulfamoyl, aceticacid, methylsulfonyl, ethyloxycarbonyl, methyloxycarbonyl, oxetan-3yloxycarbonyl, cyclobutyloxycarbonyl, cyclopentyloxycarbonyl, methyloxycarbonyl, tetrahydro-2H-pyran-4-yloxycarbonyl, methylethyloxycarbonyl, cyclopropylmethyloxycarbonyl, tetrahydrofuran-3 -ylmethyloxycarbonyl, 2-morpholin-4-ylethyloxycarbonyl, ethyloxycarbonyl, 2,2-dimethylpropyloxycarbonyl, 2-methylpropyloxycarbonyl, cyclohexyloxycarbonyl, benzyloxycarbonyl, pyrimidinyl, methylsulfonyl, tert-butyloxycarbonyl, and 1,2,4-oxadiazolyl; wherein R5a is independently substituted with 0, 1, 2, 3, or 4, R5 substituents.
In one embodiment of the invention, R6, is independently selected from:
halogen,Ci-io alkyl(oxy)0-i(carbonyl)0-lCo-10 alkyl, Cl-10 heteroalkyl(oxy)0.1(carbonyl)0- lCo-10 alkyl, aryl Co-10 alkyl(oxy)0-1(carbonyl)0-lCo-10 alkyl, C3-8 cycloalkyl Co-10
alkyl(oxy)o-i(carbonyl)o-lCo-10 alkyl, heteroaryl Co-10 alkyl(oxy)0-i(carbonyl)0-lCo-10 alkyl, (C3-8)heterocycloalkyl Co-10 alkyl(oxy)0.i(carbonyl)0-lCo-10 alkyl, Ci-io alkyl (oxy)0- icarbonylaminoCo-10 alkyl, C3.8 cycloalkyl Co-10 alkyl (oxy)0-1carbonylaminoCo-10 alkyl, aryl Co-10 alkyl(oxy)o-1carbonylaminoCO-10 alkyl, heteroaryl Co-10 alkyl(oxy)0- icarbonylaminoCO-10 alkyl, (C3-8)heterocycloalkyl Co-10 alkyl(oxy)o.icarbonylaminoCo-10 alkyl, -CO2(C0-10 alkyl), Oxo, Cl-10 alkylsulfonyl, Cl-10 heteroalkylsulfonyl,
(C3-8) cycloalkylsulfonyl, (C3-8) cycloheteroalkylsulfonyl, heteroarylsulfonyl, arylsulfonyl, aminosulfonyl, -S02Ci_6alkyl, amino, (CO-10 alkyl)1-2 amino, hydroxy, Ci-io alkoxy, cyano, and Ci_6haloalkyl; wherein R6 is optionally substituted.
In another embodiment , R6 is independently selected from: halogen, Ci-io alkyl(oxy)o-i(carbonyl)o-lCo-10 alkyl, Oxo, Ci-io alkylsulfonyl, (Co-10 alkyl)1-2 amino, hydroxy, C i . i o alkoxy, and C i _6haloalkyl; wherein R6 is optionally substituted. with 0, 1 , 2, or 3 substituents selected from hydrogen, hydroxy, (Ci-6)alkoxy, halogen, CO2H, -(Co-6)alkylCN, -0(C=0)Ci-C6 alkyl, NO2, trifluoromethoxy, trifluoroethoxy, -N-C(0)0(Co-6)alkyl,
Cl-10 alkylsulfonyl, Ci-io heteroalkylsulfonyl, oxo (0=), (C3-8) cycloalkylsulfonyl,
(C3-8) cycloheteroalkylsulfonyl, heteroarylsulfonyl, arylsulfonyl, aminosulfonyl,
-S02N(Ci-6alkyl)i-2, -S02Ci-6alkyl, -SO2CF3, -SO2CF2H, -Cl-10 alkylsulfinyl,
-OSi(C l .10alkyl)3, -O(0- 1 )(C 1.1 o)haloalkyl, and NH2.
In another embodiment, R6 is independently selected from: Oxo, methyl, 1 -hydroxy- 1-methylethyl, chloro, fluoro, trimethylfluoro, difluoromethyl, hydroxyl,
dimethylamino, methylsulfonyl and methoxy; wherein R6 is optionally substituted. with 1, 2, or 3 substituents selected from hydrogen, hydroxy, (Ci-6)alkoxy, halogen, CO2H, -(Co-6)alkylCN, -0(C=0)Ci-C6 alkyl, NO2, trifluoromethoxy, trifluoroethoxy, -N-C(0)0(C()-6)aIkyl,
Ci-io alkylsulfonyl, Ci_io heteroalkylsulfonyl, oxo (0=), (C3-8) cycloalkylsulfonyl,
(C3-8) cycloheteroalkylsulfonyl, heteroarylsulfonyl, arylsulfonyl, aminosulfonyl,
-S02N(Ci_6alkyl)1-2, -S02Ci_6alkyl, -SO2CF3, -SO2CF2H, -Cl-10 alkylsulfinyl,
-OSi(Ci-ioalkyl)3, -O(0-l )(Ci-io)haloalkyl, and NH2.
In one embodiment, the compounds of the instant invention are selective JAK1 inhibitors relative to JAK2. The determination of relative selectivity for a given compound of JAK1 inhibition is defined as the relative ratio of the (JAK2 ICso value/JAKl IC50 value) is at least 2. In yet another embodiment, for a given compound, the relative ratios of the (JAK2 IC50 value/JAKl IC50 value) is at least 5.
"Patient" includes both human and animals.
"Mammal" means humans and other mammalian animals.
"Therapeutically effective amount" means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, a system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. The term "treatment" or "treating" includes alleviating, ameliorating, relieving or otherwise reducing the signs and symptoms associated with a disease or disorder.
The term "composition", as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s)
(pharmaceutically acceptable excipients) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of formula I, and pharmaceutically acceptable excipients.
The term "optionally substituted" means "unsubstituted or substituted," and therefore, the generic structural formulas described herein encompasses compounds containing the specified optional substituent as well as compounds that do not contain the optional substituent.
Each variable is independently defined each time it occurs within the generic structural formula definitions. For example, when there is more than one substituent for aryl/heteroaryl, each substituent is independently selected at each occurrence, and each substituent can be the same or different from the other(s). As another example, for the group -(CR3R3)2-, each occurrence of the two R3 groups may be the same or different. As used herein, unless explicitly stated to the contrary, each reference to a specific compound of the present invention or a generic formula of compounds of the present invention is intended to include the compound(s) as well as pharmaceutically acceptable salts and stereoisomers thereof.
Optical Isomers - Diastereomers - Geometric Isomers - Tautomers
Compounds of formula I contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present invention is meant to comprehend all such isomeric forms of the compounds of formula I, either as single species or mixtures thereof.
Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.
Some of the compounds described herein may exist with different points of attachment of hydrogen, referred to as tautomers. Such an example may be a ketone and its enol form known as keto-enol tautomers. The individual tautomers as well as mixture thereof are encompassed with compounds of formula I. Specific embodiments of the present invention include a compound which is selected from the group consisting of the subject compounds of the Examples herein or a pharmaceutically acceptable salt thereof.
The compounds of the present invention may contain one or more asymmetric centers and can thus occur as "stereoisomers" including racemates and racemic mixtures, enantiomeric mixtures, single enantiomers, diastereomeric mixtures and individual
diastereomers. Additional asymmetric centers may be present depending upon the nature of the various substituents on the molecule. Each such asymmetric center will independently produce two optical isomers and it is intended that all of the possible optical isomers and diastereomers in mixtures and as pure or partially purified compounds are included within the scope of this invention. The present invention is meant to comprehend all such isomeric forms of these compounds. When bonds to the chiral carbon are depicted as straight lines in the Formulas of the invention, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the Formula. For example, Formula I shows the structure of the class of compounds without specific stereochemistry. When the compounds of the present invention contain one chiral center, the term "stereoisomer" includes both enantiomers and mixtures of enantiomers, such as the specific 50:50 mixture referred to as racemic mixtures.
The compounds of Formula (I) may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of Formula (I) as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention embraces all geometric and positional isomers. For example, if a compound of Formula (I) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention.
Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of Formula (I) may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of chiral HPLC column. It is also possible that the compounds of Formula (I) may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.
All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example, if a compound of Formula (I) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.) Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974
Recommendations. The use of the terms "salt", "solvate", "ester", "prodrug" and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.
In the present application when a particular stereomeric compound is named using an "and" in the stereomeric designation, for example, 1-(2S, 3S and 2R, 3R)-3-cyclobutan-2-yl]- 3-( henylamino)-lH-pyrazole-4-carboxarnide, the "and" indicates a racemic mixture of the enantiomers. That is, the individual enantiomers were not individually isolated.
When the stereomeric nomenclature includes "or", for example, 1-(2S, 3S or 2R, 3R)-3-cyclobutan-2-yl]-3-(phenylamino)-lH-pyrazole-4-carboxamide, the "or" indicates that chiral resolution of racemate into individual enantiomers was accomplished but the actual optical activity of the specific enantiomer was not determined.
The independent syntheses of these diastereomers or their chromatographic separations may be achieved as known in the art by appropriate modification of the methodology disclosed herein. Their absolute stereochemistry may be determined by the x-ray crystallography of crystalline products or crystalline intermediates which are derivatized, if necessary, with a reagent containing an asymmetric center of known absolute configuration. If desired, racemic mixtures of the compounds may be separated so that the individual enantiomers are isolated. The separation can be carried out by methods well known in the art, such as the coupling of a racemic mixture of compounds to an enantiomerically pure compound to form a diastereomeric mixture, followed by separation of the individual diastereomers by standard methods, such as fractional crystallization or chromatography. The coupling reaction is often the formation of salts using an enantiomerically pure acid or base. The diasteromeric derivatives may then be converted to the pure enantiomers by cleavage of the added chiral residue. The racemic mixture of the
compounds can also be separated directly by chromatographic methods utilizing chiral stationary phases, which methods are well known in the art. Alternatively, any enantiomer of a compound can be obtained by stereoselective synthesis using optically pure starting materials or reagents of known configuration by methods well known in the art.
Salts
The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like.
Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, Ν,Ν'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p- toluenesulfonic acid, and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
It will be understood that, unless otherwise specified, references to the compound of formula I subsets thereof, embodiments thereof, as well as specific compounds are meant to also include the pharmaceutically acceptable salts and stereoisomers thereof. Furthermore, some of the crystalline forms for compounds of the present invention may exist as polymorphs and as such all forms are intended to be included in the present invention. In addition, some of the compounds of the instant invention may form solvates with water (hydrates) or common organic solvents. Such solvates are encompassed within the scope of this invention.
Labelled Compounds
In the compounds of generic Formula I, the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature. The present invention is meant to include all suitable isotopic variations of the compounds of generic Formula I. For example, different isotopic forms of hydrogen (H) include protium (lH) and deuterium (^H). Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
Isotopically-enriched compounds within generic Formula I can be prepared without undue experimentation by conventional techniques well known to those skilled in the art or by processes analogous to those described in the Schemes and Examples herein using appropriate isotopically-enriched reagents and/or intermediates.
Utilities
Compound of formula I or its pharmaceutically acceptable salts and pharmaceutical compositions can be used to treat or prevent a variety of conditions or diseases mediated by Janus kinases, in particular diseases or conditions that can be ameliorated by the inhibition of a Janus kinase such as JAK1, JAK2 or JAK3, and TYK2. Such conditions and diseases include, but are not limited to:
(1) arthritis, including rheumatoid arthritis, juvenile arthritis, and psoriatic arthritis; (2) asthma and other obstructive airways diseases, including chronic asthma, late asthma, airway hyper-responsiveness, bronchitis, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, recurrent airway obstruction, and chronic obstruction pulmonary disease including emphysema; (3) autoimmune diseases or disorders, including those designated as single organ or single cell-type autoimmune disorders, for example Hashimoto's thyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritis of pernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis, Goodpasture's disease, autoimmune thrombocytopenia, sympathetic ophthalmia, myasthenia gravis, Graves' disease, primary biliary cirrhosis, chronic aggressive hepatitis, ulcerative colitis and membranous glomerulopathy, those designated as involving systemic autoimmune disorder, for example systemic lupus erythematosis, rheumatoid arthritis, Sjogren's syndrome, Reiter's syndrome, polymyositis-dermatomyositis, systemic sclerosis, polyarteritis nodosa, multiple sclerosis and bullous pemphigoid, and additional autoimmune diseases, which can be B-cell (humoral) based or T-cell based, including Cogan's syndrome, ankylosing spondylitis, Wegener's granulomatosis, autoimmune alopecia, Type I or juvenile onset diabetes, and thyroiditis; (4) cancers or tumors, including alimentary/gastro- intestinal tract cancer, colon cancer, liver cancer, skin cancer including mast cell tumor and squamous cell carcinoma, breast and mammary cancer, ovarian cancer, prostate cancer, lymphoma, leukemia, including acute myelogenous leukemia and chronic myelogenous leukemia, kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer, brain cancer, melanoma including oral and metastatic melanoma, Kaposi's sarcoma, myelomas including multiple myeloma, myeloproliferative disorders, proliferative diabetic retinopathy, and angiogenic-associated disorders including solid tumors; (5) diabetes, including Type I diabetes and complications from diabetes; (6) eye diseases, disorders or conditions including autoimmune diseases of the eye, keratoconjunctivitis, vernal conjunctivitis, uveitis including uveitis associated with Behcet's disease and lens-induced uveitis, keratitis, herpetic keratitis, conical keratitis, corneal epithelial dystrophy, keratoleukoma, ocular premphigus, Mooren's ulcer, scleritis, Grave's ophthalmopathy, Vogt-Koyanagi-Harada syndrome, keratoconjunctivitis sicca (dry eye), phlyctenule, iridocyclitis, sarcoidosis, endocrine ophthalmopathy, sympathetic ophthalmitis, allergic conjunctivitis, and ocular neovascularization; (7) intestinal inflammations, allergies or conditions including Crohn's disease and/or ulcerative colitis, inflammatory bowel disease, coeliac diseases, proctitis, eosinophilic gastroenteritis, and mastocytosis; (8)
neurodegenerative diseases including motor neuron disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, or
neurodegenerative disease caused by traumatic injury, strike, glutamate neurotoxicity or hypoxia; ischemic/reperfusion injury in stroke, myocardial ischemica, renal ischemia, heart attacks, cardiac hypertrophy, atherosclerosis and arteriosclerosis, organ hypoxia, and platelet aggregation; (9) skin diseases, conditions or disorders including atopic dermatitis, eczema, psoriasis, scleroderma, pruritus and other pruritic conditions; (10) allergic reactions including anaphylaxis, allergic rhinitis, allergic dermatitis, allergic urticaria, angioedema, allergic asthma, or allergic reaction to insect bites, food, drugs, or pollen; (11) transplant rejection, including pancreas islet transplant rejection, bone marrow transplant rejection, graft- versus-host disease, organ and cell transplant rejection such as bone marrow, cartilage, cornea, heart, intervertebral disc, islet, kidney, limb, liver, lung, muscle, myoblast, nerve, pancreas, skin, small intestine, or trachea, and xeno transplantation.
Accordingly, another aspect of the present invention provides a method for the treatment or prevention of a JAK-mediated disease or disorder comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of formula I. In one embodiment such diseases include asthma and rheumatoid arthritis.
Another aspect of the present invention provides for the use of a compound of formula I in the manufacture of a medicament for the treatment or prevention of a JAK-mediated diseases or disorder.
One aspect of the invention is the use of a compound of formula I or a
pharmaceutically acceptable salt or a stereoisomer thereof in the manufacture of a medicament for the treatment of a desease or a disorder ameliorated by the selective inhibition of a Janus kinase JAK1 relative to JAK 2.
Another aspect of the invention is the use of a compound of Formula I or a pharmaceutically acceptable salt or a stereoisomer thereof and a second active agent in the manufacture of a medicament for the treatment of a desease or a disorder ameliorated by the selective inhibition of a Janus kinase JAK1 relative to JAK 2.
Dose Ranges
The magnitude of prophylactic or therapeutic dose of a compound of formula I will, of course, vary with the nature and the severity of the condition to be treated and with the particular compound of formula I and its route of administration. It will also vary according to a variety of factors including the age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination and response of the individual patient. In general, the daily dose from about 0.001 mg to about 100 mg per kg body weight of a mammal, preferably 0.01 mg to about 10 mg per kg. On the other hand, it may be necessary to use dosages outside these limits in some cases.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration of humans may contain from 0.05 mg to 5 g of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 99.95 percent of the total composition. Dosage unit forms will generally contain between from about 0.1 mg to about 0.4 g of an active ingredient, typically 0.5 mg, 1 mg, 2 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 200 mg, or 400 mg. Pharmaceutical Compositions
Another aspect of the present invention provides pharmaceutical compositions comprising a compound of formula I with a pharmaceutically acceptable carrier. For the treatment of any of the prostanoid mediated diseases compounds of formula I may be
administered orally, by inhalation spray, topically, parenterally or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. In addition to the treatment of warmblooded animals such as mice, rats, horses, cattle, sheep, dogs, cats, etc., the compound of the invention is effective in the treatment of humans.
The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs.
Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example, magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the technique described in the U.S. Patent 4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients is mixed with water-miscible solvents such as propylene glycol, PEGs and ethanol, or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene- oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
The pharmaceutical compositions of the invention may also be in the form of an oil-in- water emulsion. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1 ,3 -butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. Cosolvents such as ethanol, propylene glycol or polyethylene glycols may also be used. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
Dosage forms for inhaled administration may conveniently be formulated as aerosols or dry powders. For compositions suitable and/or adapted for inhaled administration, it is preferred that the active substance is in a particle-size-reduced form, and more preferably the size-reduced form is obtained or obtainable by micronization.
In one embodiment the medicinal preparation is adapted for use with a pressurized metered dose inhaler (pMDI) which releases a metered dose of medicine upon each actuation. The formulation for pMDIs can be in the form of solutions or suspensions in halogenated hydrocarbon propellants. The type of propellant being used in pMDIs is being shifted to hydro fluoroalkanes (HFAs), also known as hydrofluorocarbons (HFCs). In particular, 1,1,1,2- tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA 227) are used in several currently marketed pharmaceutical inhalation products. The composition may include other pharmaceutically acceptable excipients for inhalation use such as ethanol, oleic acid, polyvinylpyrrolidone and the like.
Pressurized MDIs typically have two components. Firstly, there is a canister component in which the drug particles are stored under pressure in a suspension or solution form. Secondly, there is a receptacle component used to hold and actuate the canister. Typically, a canister will contain multiple doses of the formulation, although it is possible to have single dose canisters as well. The canister component typically includes a valve outlet from which the contents of the canister can be discharged. Aerosol medication is dispensed from the pMDI by applying a force on the canister component to push it into the receptacle component thereby opening the valve outlet and causing the medication particles to be conveyed from the valve outlet through the receptacle component and discharged from an outlet of the receptacle. Upon discharge from the canister, the medication particles are "atomized", forming an aerosol. It is intended that the patient coordinate the discharge of aerosolized medication with his or her inhalation, so that the medication particles are entrained in the patient's aspiratory flow and conveyed to the lungs. Typically, pMDIs use propellants to pressurize the contents of the canister and to propel the medication particles out of the outlet of the receptacle component. In pMDIs, the formulation is provided in a liquid or suspension form, and resides within the container along with the propellant. The propellant can take a variety of forms. For example, the propellant can comprise a compressed gas or liquefied gas.
In another embodiment the medicinal preparation is adapted for use with a dry powder inhaler (DPI). The inhalation composition suitable for use in DPIs typically comprises particles of the active ingredient and particles of a pharmaceutically acceptable carrier. The particle size of the active material may vary from about 0.1 μιη to about 10 μιη; however, for effective delivery to the distal lung, at least 95 percent of the active agent particles are 5 μηι or smaller. Each of the active agent can be present in a concentration of 0.01 - 99%. Typically however, each of the active agents is present in a concentration of about 0.05 to 50%, more typically about 0.2 - 20% of the total weight of the composition.
As noted above, in addition to the active ingredients, the inhalable powder preferably includes pharmaceutically acceptable carrier, which may be composed of any pharmacologically inert material or combination of materials which is acceptable for inhalation. Advantageously, the carrier particles are composed of one or more crystalline sugars; the carrier particles may be composed of one or more sugar alcohols or polyols. Preferably, the carrier particles are particles of dextrose or lactose, especially lactose. In embodiments of the present invention which utilize conventional dry powder inhalers, such as the Handihaler, Rotohaler, Diskhaler, Twisthaler and Turbohaler, the particle size of the carrier particles may range from about 10 microns to about 1000 microns. In certain of these embodiments, the particle size of the carrier particles may range from about 20 microns to about 120 microns. In certain other embodiments, the size of at least 90% by weight of the carrier particles is less than 1000 microns and preferably lies between 60 microns and 1000 microns. The relatively large size of these carrier particles gives good flow and entrainment characteristics. Where present, the amount of carrier particles will generally be up to 95%, for example, up to 90%, advantageously up to 80% and preferably up to 50% by weight based on the total weight of the powder. The amount of any fine excipient material, if present, may be up to 50% and advantageously up to 30%, especially up to 20%, by weight, based on the total weight of the powder. The powder may optionally contain a performance modifier such as L-leucine or another amino acid, and/or metals salts of stearic acid such as magnesium or calcium stearate.
Compounds of formula I may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ambient temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
For topical use, creams, ointments, gels, solutions or suspensions, etc., containing the compound of formula I are employed. (For purposes of this application, topical application shall include mouth washes and gargles.) Topical formulations may generally be comprised of a pharmaceutical carrier, cosolvent, emulsifier, penetration enhancer, preservative system, and emollient.
Combinations with Other Drugs
For the treatment and prevention of JAK mediated diseases, compound of formula I may be co-administered with other therapeutic agents. Thus in another aspect the present invention provides pharmaceutical compositions for treating JAK mediated diseases comprising a therapeutically effective amount of a compound of formula I and one or more other therapeutic agents. In particular, for the treatment of the inflammatory diseases rheumatoid arthritis, psoriasis, inflammatory bowel disease, COPD, asthma and allergic rhinitis a compound of formula I may be combined with agents such as: (1) TNF-a inhibitors such as Remicade® and Enbrel®); (2) non-selective COX-I/COX-2 inhibitors (such as piroxicam, diclofenac, propionic acids such as naproxen, fiubiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, apazone, pyrazolones such as phenylbutazone, salicylates such as aspirin); (3) COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxib and etoricoxib); (4) other agents for treatment of rheumatoid arthritis including low dose methotrexate, lefunomide, ciclesonide, hydroxychloroquine, d-penicillamine, auranofin or parenteral or oral gold; (5) leukotriene biosynthesis inhibitor, 5-lipoxygenase (5-LO) inhibitor or 5-lipoxygenase activating protein (FLAP) antagonist such as zileuton; (6) LTD4 receptor antagonist such as zafirlukast, montelukast and pranlukast; (7) PDE4 inhibitor such as roflumilast; (8) antihistaminic HI receptor antagonists such as cetirizine, loratadine,
desloratadine, fexofenadine, astemizole, azelastine, and chlorpheniramine; (9) al- and <x2- adrenoceptor agonist vasoconstrictor sympathomimetic agent, such as propylhexedrine, phenylephrine, phenylpropanolamine, pseudoephedrine, naphazoline hydrochloride,
oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, and ethylnorepinephrine hydrochloride; (10) anticholinergic agents such as ipratropium bromide, tiotropium bromide, oxitropium bromide, aclindinium bromide, glycopyrrolate, pirenzepine, and telenzepine; (11) β-adrenoceptor agonists such as metaproterenol, isoproterenol, isoprenaline, albuterol, salbutamol, formoterol, salmeterol, terbutaline, orciprenaline, bitolterol mesylate, and pirbuterol, or methylxanthanines including theophylline and aminophylline, sodium
cromoglycate; (12) insulin-like growth factor type I (IGF-1) mimetic; (13) inhaled glucocorticoid with reduced systemic side effects, such as prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, ciclesonide and mometasone furoate.
METHODS OF SYNTHESIS
SCHEMES AND EXAMPLES
The abbreviations used herein have the following tabulated meanings.
Abbreviations not tabulated below have their meanings as commonly used unless specifically stated otherwise.
ACN acetonitrile
MeCN acetonitrile
BAST bis(2-methoxyemyl)arninosulfur trifluoride
Chiral SFC chiral super critical fluid chromatography
C02 carbon dioxide
Cs2C03 cesium carbonate
DBU 1 , 8 -diazabicyclo [5.4.0]undec-7-ene
DCE 1 ,2-dichloroethane
DCM dichloromethane
DIPEA N,N-diisopropylethylamine
DMF N,N-dimethylformamide
DMSO dimethyl sulfoxide
DSC Ν,Ν-disuccinimidyl carbonate
EDC 3 -(ethyliminomethyleneamino)-N,N-dimethyl-propan- 1 - amine
EtOAc ethyl acetate
HATU 0-(7-aza-lH-benzotriazol-l-yl)-N,N,N',N*- tetramethyluronium hexafluorophosphate
HC1 hydrogen chloride HOBt 1 -hydroxybenzotriazole
HPLC high pressure liquid chromatography
IPA 2-propanol
LDA lithium diisopropylamide
w-CPBA meta-chloroperoxybenzoic acid
LRMS low resolution mass spectrometry
Mel iodomethane
Me-THF 2-methyltetrahydrofuran
MgS04 magnesium sulfate
MP-(OAc)3BH solid supported (macro porous) triacetoxyborohydride
MPLC medium pressure liquid chromatography
NaH sodium hydride
Na2S04 sodium sulfate
NaBH4 sodium borohydride
NaHC03 sodium bicarbonate
NaOMe sodium methoxide
Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0)
POCl3 phosphorus (V) oxychloride
PyBOP (7-azabenzotriazol- 1 -yloxy)tripyrrolidinophosphonium hexafluorophosphate
SEM-C1 2-(trimethylsilyl)ethoxymethyl chloride
SiliaCat® DPP-Pd silica bound diphenylphosphine palladium (II)
TBAF tetra-n-butylammonium fluoride
TBS-C1 tert-butyldimethylsilyl chloride
t-BuOH tert-butanol
TEA triethylamine
TFA trifluoroacetic acid
THF tetrahydrofuran
X-Phos 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl
Me^Bu-X-Phos di-rert-butyl[3,4,5,6-tetramethyl-2,,4',6'-tri(propan-2- yl)biphenyl-2-yl]phosphane
NMO 4-methylmorpholine N-oxide
TPAP tetra-n-propylammonium perruthenate (VII)
HCOOH formic acid
K'OBu potassium fert-butoxide
Na2S205 sodium metabisulfite
NMR nuclear magnetic resonance TLC thin layer chromatography
(EtO)2P(0)CH2CN diethyl (cyanomethyl)phosphonate
MsCl methanesulfonyl chloride
TsOH p-toluenesulfonic acid
KCN potassium cyanide
Si-DMT silica supported Dimercaptotriazine
TMS trimethylsilane
CF3TMS (trifluoromethyl)trimethylsilane
Alkyl Group Abbreviations
Figure imgf000043_0001
METHODS OF SYNTHESIS
The compounds of the present invention can be prepared according to the following general schemes using appropriate materials, and are further exemplified by the subsequent specific examples. The compounds illustrated in the examples are not to be construed as forming the only genus that is considered as the invention. The illustrative
Examples below, therefore, are not limited by the compounds listed or by any particular substituents employed for illustrative purposes. Substituent numbering as shown in the schemes does not necessarily correlate to that used in the claims and often, for clarity, a single substituent is shown attached to the compound where multiple substituents are allowed under the definitions of the instant invention herein above.
Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. The invention will now be illustrated in the following non-limiting Examples in which, unless otherwise stated: All reactions were stirred (mechanically, stir bar/stir plate, or shaken) and conducted under an inert atmosphere of nitrogen or argon unless specifically stated otherwise.
All temperatures are degrees Celsius (°C) unless otherwise noted.
Ambient temperature is 15-25 °C.
Most compounds were purified by reverse-phase preparative HPLC, MPLC on silica gel, recrystallization and/or swish (suspension in a solvent followed by filtration of the solid).
The course of the reactions was followed by thin layer chromatography (TLC) and/or LCMS and/or NMR and reaction times are given for illustration only.
All end products were analyzed by NMR and LCMS.
Intermediates were analyzed by NMR and/or TLC and/or LCMS.
Method 1
General procedures to prepare intermediates of the instant invention are described in Scheme 1. Alkyl Grignard reagents are reacted with appropriately subtituted (hetero)aryl carboxylates I at or around 0 °C in an appropriate solvent, such as THF, to afford intermediates II used in the synthesis of examples of the instant invention.
Figure imgf000044_0001
Method 2
General procedures to prepare intermediates of the instant invention are described in Scheme 2. A trifluoromethyl anion equivalent, such as CF3TMS, is reacted with TBAF and an appropriately substituted (hetero)aryl aldehyde III in an appropriate solvent, such as THF, to yield intermediates IV used in the synthesis of examples of the instant invention.
Figure imgf000044_0002
Method 3
General procedures to prepare intermediates of the instant invention are described in Scheme 3. Heteroaryl boronate esters or boronic acids VI are cross coupled to optionally substituted (hetero)aryl bromides V using a suitable palladium complex, such as Pd(dppf)Cl2, and an appropriate base, such as K3PO4, in a compatible solvent or solvent mixture, such as 10:1 v:v dioxane:water, at or around 90 °C to yield intermediates VII in the synthesis of examples of the instant invention. SCHEME 3
VII
Figure imgf000045_0001
Method 4
General procedures to prepare intermediates of the instant invention are described in Scheme 4. Appropriately substituted benzyl bromides VIII can be reacted with aza heterocycles using a suitable base, such as potassium acetate, or be reacted with sodium azide followed by optionally substituted acetylenes and standard 1,3-dipolar cycloaddition reagents to afford intermediates IX in the synthesis of examples of the instant invention.
Figure imgf000045_0002
-Ri
Method 5
General procedures to prepare intermediates of the instant invention are described in Scheme 5. Appropriately substituted benzyl bromides X can be reacted with methyl hydroxy acetate in the presence of a suitable base, such as sodium hydride, and then further reacted with alkyl Grignard reagents to afford intermediates XI in the synthesis of examples of the instant invention.
SCHEME 5
Figure imgf000045_0003
X
XI
Method 6
General procedures to prepare intermediates of the instant invention are described in Scheme 6. Appropriately substituted thiophenols XII are reacted with a suitable base, such as sodium hydride, and a trifluoromethylating agent, such as 5-
(trifluoromethyl)dibenzo[6,i ]thiophenium trifluoromethanesulfonate at ambient temperature in an appropropiate solvent, such as DMF. The resulting intermediate is oxidized to the corresponding sulfone XIII with a suitable oxidant, such as m-CPBA, to afford an intermediate used in the synthesis of examples of the instant invention.
SCHEME 6
Figure imgf000046_0001
XIII
Method 7
General procedures to prepare intermediates of the instant invention are described in Scheme 7. Appropriately substituted thiophenols XII are reacted with a suitable base, such as potassium hydroxide, and a difluoromethylating agent, such as diethyl
[bromo(difluoro)methyl]phosphonate, in an appropriate solvent or solvent mixture, such as 1 : 1 v:v MeCN:water. The resulting intermediate is oxidized to the corresponding sulfone XIV with a suitable oxidant, such as m-CPBA, to afford an intermediate used in the synthesis of examples of the instant invention.
SCHEME 7
Figure imgf000046_0002
XIV
Method 8
General procedures to prepare intermediates of the instant invention are described in Scheme 8. Appropriately substituted aryl sulfoxides XV are reacted with a lewis acid, such as zinc iodide, and a suitable nucleophilic fluorine source, such as BAST, in a solvent, such as 1,2- DCE, at or around 40 °C. The resulting intermediate is oxidized to the corresponding sulfone XVI with a suitable oxidant, such as m-CPBA, to afford an intermediate used in the synthesis of examples of the instant invention. SCHEME 8
Figure imgf000047_0001
XV XVI
Method 9
General procedures to prepare intermediates of the instant invention are described in Scheme 9. Appropriately substituted benzothiophenes XVII are oxidized to the
cooresponding sulfones with a suitable oxidant, such as m-CPBA, and then hydroxylated upon stirring in aqueous sodium hydroxide at at or around 100 °C to afford intermediates XVIII in the synthesis of examples of the instant invention.
Figure imgf000047_0002
XVII XVIII
Method 10
General procedures to prepare intermediates of the instant invention are described in Scheme 10. Appropriately substituted 2,3-dihydro-lH-isoindol-ones XIX can be poly- methylated using a suitable base, such as sodium hydride, and methyl iodide to afford intermediates XX used in the synthesis of examples of the instant invention.
Figure imgf000047_0003
xix xx
Method II
General procedures to prepare intermediates of the instant invention are described in Scheme 11. Appropriately substituted 2,3-dihydro-lH-isoindol-ones XIX can be mono- alkylated using a suitable base, such as sodium hydride, and optionally substituted alkylating agents to afford intermediates XXI in the synthesis of examples of the instant invention.
Figure imgf000048_0001
XIX
XXI
Method 12
General procedures to prepare intermediates of the instant invention are described in Scheme 12. Optionally substituted alkyl aldehydes XXII are condensed with diethyl
(cyanomethyl)phosphonate in the presence of a suitable base, such as potassium tert-butoxide to yield substituted acrylonitriles XXIII used as intermediates in the synthesis of examples of the instant invention.
SCHEME 12
Figure imgf000048_0002
XXIII XXII
Method 13
General procedures to prepare intermediates of the instant invention are described in Scheme 13. Optionally substituted carbamate protected heterocyclic ketones XXIV are condensed with diethyl (cyanomethyl)phosphonate in the presence of a suitable base, such as potassium ter/-butoxide, to yield optionally substituted acrylonitriles XXV used as intermediates in the synthesis of examples of the instant invention.
Figure imgf000048_0003
XXIV
XXV Method 14
General procedures to prepare intermediates of the instant invention are described in Scheme 14. Carbamate protected optionally substituted acrylonitriles XXV are deprotected in the presence of a suitable acid, such as TFA or HCl, to form amino intermediates XXVI that are further derivatized to form sulfonamide XXVII, urethane XXVIII, and N-arylated intermediates XXIX. Sulfonamide derivatives XXVII are formed by reacting deprotected optionally substituted acrylonitriles with optionally substituted sulfoyl chlorides in a suitable solvent, such as DCM, using an appropriate base, such as DDPEA. Urea derivatives XXVIII are formed by reacting deprotected optionally substituted acrylonitriles with a doubly activated carbonyl equivalent, such as DSC, and optionally substituted alcohols in the presence of a suitable base, such as TEA. N-arylated derivatives XXIX are formed by reacting deprotected optionally substituted acrylonitriles with optionally substituted aryl halides using a suitable palladium- ligand system, such as Pd2(dba)3 and X-Phos, an appropriate base, such as Cs2C03, in a solvent, such as t-BuOH, at or around 90 °C.
Figure imgf000049_0001
Method 15
General procedures to prepare intermediates of the instant invention are described in Scheme 15. Cyanohydrins XXXI of optionally substituted (hetero)cyclic ketones XXX are prepared using aqueous sodium metabisulfite, followed by the addition of a suitable cyanide source, such as potassium cyanide. Hydroxyl group activation with a suitable agent, such as mesyl chloride or POCl3, followed by elimination under apropriate conditions, such as refluxing pyridine, yields substituted acrylonitriles XXXII used as intermediates in the synthesis of examples of the instant invention.
SCHEME 15
Figure imgf000050_0001
95 °C XXXII
XXX XXXI
Method 16
General procedures to prepare intermediates of the instant invention are described in Scheme 16. Optionally substituted (hetero)cyclic ketones XXXIII are enolized with an appropriate base, such as LDA, and reacted with a suitable triflating agent, such as N-(5- chloropyridin-2-yl)- 1 ,1,1 -trifluoro-N-(trifluoromethylsulfonyl)methanesulfonamide. The resulting vinyl trifiate XXXIV is reacted with a suitable palladium complex, such as
tetrakis(triphenylphosphine) palladium (0), and an appropriate cyanide source, such as zinc cyanide, to afford substituted acrylonitriles XXXV used as intermediates in the synthesis of examples of the instant invention.
SCHEME 16
Figure imgf000050_0002
XXXIII
Method 17
General procedures to prepare intermediates of the instant invention are described in Scheme 17. Acrylonitrile is made to under go a Diels- Alder cyclization with an appropriately substituted butadiene using standard conditions, such as refluxing benzene. The cycloaddition product is deprotected with aqueous acid, such as IN HCl, to provide substituted cyclohexenone XXXVI, which is then reacted with a suitable reductant, such as cerium (III) chloride and sodium borohydride, to afford intermediates XXXVII used in the synthesis of examples of the instant invention.
SCHEME 17
Figure imgf000050_0003
XXXVI XXXVII
Method 18
General procedures to prepare intermediates of the instant invention are described in Scheme 18. 2-Chloroprop-2-enenitrile is reacted with benzene sulfuric acid sodium salt in aqueous acetic acid. The resulting olefin is regenerated by eliminating the chloro substituent with an appropriate base, such as TEA. The obtained acrylonitrile XXXVIII is made to undergo a Diels-Alder cyclization with an appropriately substituted butadiene using standard conditions, such as refluxing benzene, to yield a cyano benzosulfone substituted cyclohexanone XXXIX. This substituted cyclohexanone XXXIX is protected with ethylene glycol under acidic conditions, such as TsOH, in an appropriate solvent, such as benzene, at elevated temperatures, e.g. at or around 110 °C. The acetal substituted acrylonitrile XL is obtained after elimination of the benzosulfone with an appropriate base, such as potassium tert-butoxide. This synthetic sequence affords intermediates used in the synthesis of examples of the instant invention.
Figure imgf000051_0001
XXXVIII
XXXIX
Figure imgf000051_0002
XL
Method 19
General procedures to prepare intermediates of the instant invention are described in Scheme 19. 3 -Amino pyrazole carboxamide XLI is cross coupled to (hetero)aryl halides XLII using a catalytic palladium-ligand system, such as Pd2(dba)3, and Me^Bu-X-Phos, with a suitable base, such as K3P04 or KOAc, in an appropriate solvent, such as 2-propanol, to yield pyrazole intermediates XLIU.
Figure imgf000052_0001
Method 20
General procedures to prepare intermediates of the instant invention are described in Scheme 20. 3-Amino-lH-pyrazole-4-carbonitrile XLIV is reacted with a suitable base, such as sodium hydride, and SEM-Cl to yield a mixture of 3 -amino pyrazoles XL V and XL VI, which are arylated with an appropriately substituted halogenated (hetero)aromatic XLII using a suitable catalytic palladium-ligand system, such as Pd2(dba)3 and X-Phos, an appropriate base, such as K3P04, in a suitable solvent, such as dioxane. The intermediate nitriles XL VII and XL VIII are oxidized to the corresponding amides using an appropriate oxidant, such as hydrogen peroxide mixed with sodium hydroxide, and the SEM group is then removed by acid hydrolysis to yield pyrazole XLIII, an intermediate in the synthesis of examples of the instant invention.
Figure imgf000052_0002
XL VII XLVIII XLIII
Method 21
General procedures to prepare intermediates of the instant invention are described in Scheme 21. Using an appropriate base, such as DBU, in a suitable solvent, such as MeCN, EtOH, or tert-BuOH, 3 -amino pyrazole carboxamide XLI is conjugatively added to optionally substituted acrylonitriles, including but not limited to those illustrated in Schemes #12-18 to yield alkylated pyrazole carboxamide XLIX, an intermediate in the synthesis of examples of the instant invention.
Figure imgf000053_0001
Method 22
General procedures to prepare examples of the instant invention are described in Scheme 22. Methyl 5-amino-lH-pyrazole-4-carboxylate L is conjugatively added to substituted acrylonitriles including but not limited to those illustrated in Schemes # 12- 18 in the presence of a suitable base, such as catalytic sodium methoxide. The resulting intermediates LI are cross coupled to (hetero)aryl halides XLII using an appropriate catalytic palladium-ligand system, such as Pd2(dba)3 and X-Phos, and an appropriate base, such as K3P04. Saponification of LII using aqueous hydroxide, such as LiOH, followed by amide formation using standard conditions, such as EDC, HOBT, and optionally substituted primary and secondary amines yields examples LIV of the instant invention.
Figure imgf000054_0001
Method 23
General procedures to prepare examples of the instant invention are described in Scheme 23. Using an appropriate base, such as DBU, in a suitable solvent, such as MeCN, EtOH, or tert-BuOH, N-(hetero)arylated pyrazole carboxamides XLIII are conjugatively added to optionally substituted acrylonitriles, including but not limited to those illustrated in Schemes #12-18 to yield examples LV of the instant invention. SCHEME 23
Figure imgf000055_0001
XLIII LV
Method 24
General procedures to prepare examples of the instant invention are described in Scheme 24. Alkylated 3-amino pyrazole carboxamides XLIX are cross coupled to (hetero)aryl halides XLII using an appropriate catalytic palladium-ligand system, such as Pd2(dba)3 and X- Phos or Me4 ¾u-X-Phos, and a suitable base, such as K3P04 or KOAc, in solvent, such as dioxane, to yield examples LV of the instant invention.
SCHEME 24
Figure imgf000055_0002
LV
XLII
Method 25
General procedures to prepare examples of the instant invention are described in Scheme 25. Using a solid supported palladium system, such as SiliaCat® DPP-Pd and a suitable base, such as, K2C0 , optionally substituted boronic acids LVII are cross coupled to
bromophenyl substituted pyrazoles LVI to yield examples LVIII of the instant invention.
Figure imgf000056_0001
Method 26
General procedures to prepare examples of the instant invention are described in Scheme 26. Hydroxy substituted amino pyrazole carboxamides LIX can be fluorinated using a nucleophilic fluorine source, such as BAST, to afford examples LX of the instant invention.
SCHEME 26
Figure imgf000056_0002
Method 27
General procedures to prepare examples of the instant invention are described in Scheme 27. N-(hetero)arylated pyrazole carboxamides XLIII can be alkylated with optionally substituted alkyl halides LXI using heat and an appropriate base, such as CS2CO3, to afford examples LXII of the instant invention.
Figure imgf000056_0003
XLIII LXn Method 28
General procedures to prepare examples of the instant invention are described in Scheme 28. Carbamate protected substituted amino pyrazole carboxamides LXIII are deprotected in the presence of acid, such as TFA or HCl, to provide amino intermediates LXIV which are further derivatized using standard conditions known by those skilled in the art to yield examples of the instant invention. Examples include but are not limited to alkylated LXV, reuctively aminated LXVI, and arylated LXVII derivatives, as well as carbamates LXVIII, ureas LXIX, amides LXX, and sulfonamides LXXI.
SCHEME 28
LXV
LXVI
Figure imgf000057_0001
LXXI LXX
Method 29
General procedures to prepare examples of the instant invention are described in Scheme 29. Hydroxylated cyclohexyl pyrazole carboxamides LIX can be oxidized with an appropriate oxidant, such as TPAP and NMO, and then reductively aminated using standard conditions, such as AcOH, NaCNBH3, and optionally substituted primary and secondary amines, to afford examples LXXII of the instant invention.
Figure imgf000058_0001
Method 30
General procedures to prepare examples of the instant invention are described in Scheme 30. Hydroxylated cyclohexyl pyrazole carboxamides LIX can be reacted with optionally substituted isocyanates and DMAP to afford carbamate derivatives LXXIII of the instant invention.
Figure imgf000058_0002
Method 31
General procedures to prepare examples of the instant invention are described Scheme 31. Optionally substituted, carbamate protected pyrazole carboxamides LXXIV are deprotected in the presence of acid, such as TFA or HCl, and then reacted with optionally substituted alcohols in the presence of a doubly activated carbonyl group, such as DSC or phosgene, to afford carbamate derivatives LXXVI of the instant invention.
Figure imgf000059_0001
COMMERCIALLY AVAILABLE / PREVIOUSLY DESCRIBED MATERIALS
The following table lists commercial sources, and previously disclosed synthetic routes for chemical materials employed in the synthesis of intermediates, and Examples of the instant invention. The list is not intended to be exhaustive, exclusive, or limiting in any way.
Figure imgf000059_0002
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
methyl (4-bromophenyl)acetate Toyobo Co., Ltd.
Figure imgf000063_0001
INTERMEDIATES
The following experimental procedures detail the preparation of chemical materials used in the synthesis of Examples of the instant invention. The exemplified procedures are for illustrative purposes only, and are not intended to limit the scope of the instant invention in any way. Intermediate #1
Figure imgf000064_0001
l-{[fe^-Butyl(dimethyl)silyl1oxy)propan-2-oI
To a solution of propylene glycol (1.0 g, 13 mmol) in DCM (60 mL) was added tert-butyldimethylchlorosilane (2.0 g, 13 mmol) followed by DIPEA (3.2 mL, 18 mmol). The reaction mixture was stirred at ambient temperature for 18 hours. The solution was diluted with ether, washed with saturated aqueous NaHC03, brine, dried over anhydrous MgS04, filtered, and concentrated in vacuo to afford the title compound.
LRMS (ESI) calc'd for C9H2202Si [M+H]+: 191, Found: 191.
Intermediate #2
Figure imgf000064_0002
fert-Butyl 3-oxocvclohexanecarboxylate
Anhydrous MgS04 (3.4 g, 28 mmol) was suspended in DCM (28 mL) and to this vigorously stirred mixture was added concentrated sulfuric acid (0.7 g, 7 mmol). The resulting mixture was allowed to stir at ambient temperature for 30 minutes. 3-Oxocyclohexanecarboxylic acid (1.0 g, 7.0 mmol) was added followed by t-BuOH (2.6 g, 35 mmol). The resulting mixture was allowed to stir for 24 hours before it was filtered and flushed with DCM. The filtrate was washed with water, and the organic layer was again washed with water, brine, dried over anhydrous MgS04, filtered, and concentrated in vacuo to afford the title compound. The residue was used without further purification.
1H NMR (500 MHz, CDC13): δ 2.72-2.64 (m, 1H), 2.47 (d, J= 8.1 Hz, 2H), 2.36-2.24 (m, 2H), 2.08-1.98 (m, 2H), 1.84-1.66 (m, 2H), 1.44 (s, 9H).
Intermediate #3
Figure imgf000064_0003
Methyl 3-oxocyclohexanecarboxylate
To a solution of 3-oxocyclohexanecarboxylic acid (1.0 g, 7.0 mmol) in diethyl ether (28 mL) was added dropwise TMS-diazomethane (3.5 mL, 7.0 mmol, 2.0 mL in diethyl ether). MeOH (30 mL) was added and the mixture was maintained at ambient temperature for 30 minutes. The mixture was concentrated in vacuo, and the residue was purified by MPLC on silica gel (using a gradient elution of 0-45% EtOAc/hexanes). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound.
Ή NMR (500 MHz, CDC13): δ 3.66 (s, 3H), 2.82-2.72 (m, 1H), 2.54-2.46 (m, 2H), 2.38-2.24 (m, 2H), 2.12-1.98 (m, 2H), 1.86-1.75 (m, 1H), 1.75-1.64 (m, 1H).
Intermediate #4
Figure imgf000065_0001
5- { f f g -ButvKdimethv Dsilyll oxy) cyclohex- 1-ene-l carbonitrile
5-Hydroxycyclohex-l-ene-l-carbonitrile (500 mg, 4.06 mmol) was dissolved in anhydrous DMF (5.08 mL) and then cooled to 0 °C. Imidazole (276 mg, 4.06 mmol) and TBS- CI (612 mg, 4.06 mmol) were added and the reaction mixture was allowed to stir at 0 °C for 2 hours. The reaction mixture was partitioned between water and DCM. The organic layer was collected and the aqueous layer was again extracted with DCM. The combined organic extracts were washed with brine, dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-100%, EtOAc/hexanes) to afford the title compound.
LRMS (ESI) calc'd for C13H23NOSi [M+H]+: 238, Found: 238.
Scheme #1
Intermediate #5
Figure imgf000065_0002
2-(5-Bromopyridin-2-yl)propan-2-ol
Methyl 5-bromopicolinate (500 mg, 2.31 mmol) was dissolved in THF (7.0 mL) and the flask was sealed with a septum and flushed with argon. The mixture was cooled to 0 °C and methylmagnesium bromide (3.1 mL, 9.3 mmol, 3M in THF) was added. The resulting mixture was allowed to stir at 0 °C for 1 hour before the reaction was quenched with saturated aqueous ammonium chloride and extracted with EtOAc. The organic layer was then washed with brine, dried over anhydrous MgS04, filtered, and concentrated in vacuo to afford the title compound, which was used without further purification.
LRMS (ESI) calc'd for C8H10BrNO [M+H]+: 216, Found: 216. Scheme #2
Intermediate #6
Figure imgf000066_0001
l-(5-Bromopyridin-2-yl)-2,2,2-trifluoroethanol
5-Bromopicolinaldehyde (500 mg, 2.70 mmol) was dissolved in THF (9.0 mL) and the flask was then sealed with a septum, flushed with argon, and cooled to 0 °C.
(Trifluoromethyl)trimethylsilane (0.44 mL, 3.0 mmol) was then added followed by TBAF (2.7 mL, 2.7 mmol, 1M in THF). The resulting mixture was allowed to warm to ambient temperature and was stirred for 2 hours. The reaction was then quenched with water and extracted with DCM (2x). The combined organic extracts were washed with brine, dried over anhydrous MgS04, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 10-20% EtOAc/hexanes) to afford the title compound.
LRMS (ESI) calc'd for C8H6BrF30 [M+H]+: 256, Found: 256. Scheme #3
Intermediate #7-1
Figure imgf000066_0002
4-f3-Bromophenyl)-l-methyl-lH-pyrazole
1,3-Dibromobenzene (0.38 mL, 3.2 mmol), l-methyl-4-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)- lH-pyrazole (595 mg, 2.86 mmol), Pd(dppf)Cl2 (260 mg, 0.320 mmol), and potassium phosphate (2.0 g, 9.5 mmol) were combined in a flask and dissolved in dioxane (16 mL) and water (1.6 mL). The flask was then sealed and flushed with argon. The reaction mixture was allowed to stir at 90 °C for 90 minutes. The mixture was then cooled to ambient temperature and diluted with EtOAc. The organic layer was washed with water, brine, dried over anhydrous MgS04, and concentrated in vacuo. The residue was purified by MPLC on silica gel (50% EtOAc/hexanes) to afford the title compound.
LRMS (ESI) calc'd for Ci0H9BrN2 [M+H]+: 237, Found: 237.
The following intermediates found in TABLE 1 were prepared according to Scheme #3 following similar procedures described for Intermediate #7-1, which can be achieved by those of ordinary skill in the art of organic synthesis. TABLE 1:
Figure imgf000067_0002
Scheme #4
Intermediate #8-1
Figure imgf000067_0001
l-(3-BromobenzylM/y-benzotriazole
To a solution of lH-benzotriazole (0.52 g, 4.4 mmol) in THF (25 mL) was added potassium tert-butoxide (4.6 mL, 4.6 mmol, 1M in THF) followed by the addition of l-bromo-3- (bromomethyl)benzene (1.0 g, 4.0 mmol). The solution was allowed to stir for 4 hours before the reaction was quenched with saturated aqueous NaHC03 and diluted with EtOAc. The organic layer was separated and washed with brine, dried over anhydrous MgS04, filtered, and concentrated to dryness in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-80% EtOAc/hexanes) to afford the title compound as a white solid.
LRMS (ESI) calc'd for C13HnBrN3 [M+H]+: 288, Found 288.
The following intermediates disclosed in TABLE 2 were prepared according to Scheme #4 following similar procedures described for Intermediate #8-1, which can be achieved by those of ordinary skill in the art of organic synthesis.
Figure imgf000067_0003
Scheme #6
Intermediate #9
Figure imgf000068_0001
{5-Bromo-2-[(trifluoromethyl)sulfanyl]phenvUmethanol
NaH (120 mg, 3.01 mmol, 60% dispersion in oil) and 5- (trifluoromethyl)dibenzo[b,fi ]thiophenium trifluoromethanesulfonate (808 mg, 2.01 mmol) were added sequentially to a solution of (5-bromo-2-sulfanylphenyl)methanol (440 mg, 2.01 mmol) in DMF (10 mL) at 23 °C. The reaction mixture was stirred at 23 °C for 45 minutes, and was then partitioned between EtOAc and water. The organic layer was washed with brine, dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-20%, EtOAc/hexanes) to afford the title compound. 1H NMR (500 MHz, CDC13): 6 7.82 (d, J= 1.8 Hz, 1H), 7.53-7.48 (m, 2H), 4.92 (s, 2H), 2.02 (s, 1H).
Scheme #7
Intermediate #10
Figure imgf000068_0002
(5-Bromo-2-f(diflttoromethvDsuIfanyllphenyl)methanol
(5-Bromo-2-sulfanylphenyl)methanol (0.50 g, 2.8 mmol) was dissolved in acetonitrile (11.4 mL) followed by the addition of water (11.4 mL) and solid potassium hydroxide (2.56 g, 45.6 mmol). The mixture was plunged into a -78 °C bath and when the mixture began to freeze diethyl [bromo(difluoro)methyl]phosphonate (1.22 g, 4.56 mmol) was added all at once and the cold bath was removed. The mixture was allowed to warm to ambient temperature and was stirred for 20 minutes. The mixture was then partitioned between EtOAc and water. The organic layer was washed with brine, dried over anhydrous MgS04 and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-25% EtOAc/hexanes). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound.
Ή NMR (500 MHz, CDC13): δ 7.76 (s, 1H), 7.47 (m, 2H), 6.80 (t, J= 56.5 Hz, 1H), 4.87 (s, 2H), 1.96 (br s, 1H). Scheme #8
Intermediate #11
Figure imgf000069_0001
l-Bromo-4-[(fluoromethyl)sulf anvil benzene
l-Bromo-4-(methylsulfinyl)benzene (1.50 g, 6.85 mmol) was dissolved in 1,2-
DCE (13.7 HiL) and stirred at ambient temperature. BAST (3.79 g, 17.1 mmol) was added dropwise followed by zinc iodide (0.07 g, 0.2 mmol). The reaction vessel was sealed and the mixture was heated to 40 °C, allowed to stir for 24 hours, and then allowed to cool to ambient temperature. The mixture was partitioned between EtOAc and water, the layers were separated and the organic layer was dried over anhydrous MgS04, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-20% EtOAc/hexanes). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound.
1H NMR (500 MHz, CDC13): δ 7.49-7.44 (m, 2H), 7.38-7.33 (m, 2H), 5.69 (d, J= 52.8 Hz, 2H).
Scheme #6
Intermediate #12-1
Figure imgf000069_0002
(5-Bromo-2-[(trifluoromethyl)sulfonyllphenyl>methanol
A mixture of m-CPBA (452 mg, 2.62 mmol) and {5-bromo-2- [(trifluoromethyl)thio]phenyl}methanol (188 mg, 0.655 mmol) in DCM (6.6 mL) was heated to
40 °C and stirred in a microwave reaction vial for 30 hours. After cooling to 23 °C, the reaction mixture was partitioned between EtOAc and aqueous potassium bisulfate solution (40% w/w).
The organic layer was washed sequentially with saturated aqueous NaHC03, brine, dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-30%, EtOAc/hexanes) to afford the title compound.
XH NMR (500 MHz, CDC13): δ 8.06 (d, J= 1.7 Hz, 1H), 7.91 (d, J= 8.6 Hz, 1H), 7.73 (dd, J=
8.6, 2.0 Hz, 1H), 5.01 (s, 2H), 2.56 (s, 1H).
TABLE 3 discloses intermediates 12-2 and 12-3 that were prepared according to
Schemes #6-8 following similar procedures described for Intermediate #12-1, which can be achieved by those of ordinary skill in the art of organic synthesis.
Figure imgf000070_0002
Scheme #9
Intermediate #13
5-Bromo-2,3 -ol 1,1-dioxide
Figure imgf000070_0001
Step A. 5-Bromo-l-benzothiophene 1,1-dioxide (Step A Intermediate)
5-Bromo-l-benzothiophene (1.50 g, 7.04 mmol) was dissolved in chloroform (47 mL) and allowed to stir vigorously at ambient temperature. m-CPBA (4.34 g, 17.6 mmol) was added in three portions and the resulting mixture was maintained at ambient temperature for 16 hours. The mixture was then diluted with 1M aqueous sodium thiosulfate and extracted with EtOAc. The organic layer was again washed with 1M aqueous sodium thiosulfate, saturated aqueous NaHC03, brine, dried over anhydrous MgS04, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-30% EtOAc/hexanes). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound. 1H NMR (600 MHz, CDC13): δ 7.65 (dd, J= 7.9, 1.8 Hz, 1H), 7.55 (d, J= 7.9 Hz, 1H), 7.50 (d, J = 1.8 Hz, 1H), 7.15 (d, J= 6.9 Hz, 1H), 6.74 (d, J= 6.9 Hz, 1H).
Step B. 5-Bromo-2.3-dihvdro-l-benzothiophene-3-ol l.l-dioxide (Intermediate #13)
5-Bromo-l-benzothiophene 1,1 -dioxide (100 mg, 0.41 mmol) was suspended in IN aqueous sodium hydroxide (2.0 mL), heated to 100 °C in a microwave, and allowed to stir for 15 minutes. The mixture was then allowed to cool to ambient temperature before the mixture was diluted with saturated aqueous ammonium chloride and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgS04, filtered, and concentrated in vacuo. The residue was used without further purification. LRMS (ESI) calc'd for C8H7Br03S
[M+Na]+: 285, Found: 285.
Scheme #10
Intermediate #14
Figure imgf000071_0001
S-Bromo-l.S^-trimethyl-l.S-dihvdro-lH-isoindoI-l-one (Intermediate #14)
5-Bromo-2,3-dihydro-lH-isoindol-l-one (150 mg, 0.71 mmol) was dissolved in
DMF (3.5 mL) and stirred at ambient temperature. NaH (85 mg, 2.1 mmol, 60% dispersion in oil) was carefully added in two portions, and the resulting mixture was allowed to stir for 15 minutes before Mel (151 mg, 1.06 mmol) was added. The mixture was allowed to stir at ambient temperature for 30 minutes before water (10 mL) was carefully added. The mixture was extracted with EtOAc, and the organic layer was washed with water, brine, dried over anhydrous MgS04, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-20% EtOAc/hexanes). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound.
LRMS (ESI) calc'd for CnH12BrNO [M+H]+: 254, Found: 254.
Scheme #11
Intermediate #15
Figure imgf000071_0002
5-Bromo-2- .2.2-trifluoroethvn-2.3-dihvdro-lg-isoindol-l-one (Intermediate #15)
5-Bromo-2,3-dihydro-lH-isoindol-l-one (100 mg, 0.47 mmol) was dissolved in DMF (4.7 mL) and stirred at 0 °C. NaH (38 mg, 0.94 mmol, 60% dispersion in oil) was carefully added in two portions, and the resulting mixture was allowed to stir at 0 °C for 15 minutes before 2,2,2-trifluoroethyl tnfluoromethanesulfonate (110 mg, 0.47 mmol) was added. The mixture was allowed to stir at 0 °C for 30 minutes before saturated aqueous NaHC03 (10 mL) was carefully added, and the mixture was extracted with EtOAc. The organic layer was washed with water, brine, dried over anhydrous MgS04, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-20% EtOAc/hexanes). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound. LRMS (ESI) calc'd for C10H7BrF3NO [M+H]+: 294, Found: 294.
Scheme #11
Intermediate #16
Figure imgf000072_0001
fe -Butyl (5-bromo-l-oxo-1 -dihydro-2H-isoindol-2-yl)acetate (Intermediate #16)
5-Bromo-2,3-dihydro-lH-isoindol-l-one (100 mg, 0.47 mmol) was dissolved in DMF (4.7 mL) and stirred at 0 °C. NaH (38 mg, 0.94 mmol, 60% dispersion in oil) was carefully added in two portions, and the resulting mixture was allowed to stir at 0 °C for 15 minutes before tert-butyl bromoacetate (92 mg, 0.47 mmol) was added. The mixture was allowed to stir at 0 °C for 30 minutes before saturated aqueous NaHC03 (10 mL) was carefully added. The mixture was extracted with EtOAc, and the organic layer was washed with water, brine, dried over anhydrous MgS0 , filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-20% EtOAc/hexanes). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound. LRMS (ESI) calc'd for C14H16BrN03 [M+Na]+: 348, Found: 348.
Scheme #5
Intermediate #17
Figure imgf000072_0002
l-[(3-Bromobenzyl)oxy]-2-methylpropan-2-ol (Intermediate #17)
Figure imgf000073_0001
Step A Intermediate
Step A. Methyl f(3-bromobenzvDoxyl acetate (Step A Intermediate)
Methyl hydroxyacetate (0.80 g, 8.8 mmol) was dissolved in THF (10 mL) and allowed to stir at 0 °C under a nitrogen atmosphere. NaH (0.40 g, 9.6 mmol, 60% dispersion in oil) was added portionwise over approximately 5 minutes. The cooling bath was removed and the reaction mixture was allowed to warm to ambient temperature. l-Bromo-3- (bromomethyl)benzene (2.0 g, 8.0 mmol) was added in a single portion and the resulting mixture was heated to 40 °C. After 4 hours, the reaction mixture was allowed to cool to ambient temperature and partitioned between water and EtOAc. The layers were separated, and the organic layer was washed with saturated aqueous NaHC03 , brine, dried over anhydrous Na2S04, filtered, and concentrated in vacuo to afford the title compound, which was carried forward without further purification.
1H NMR (600 MHz, CDC13): δ 7.53-7.50 (m, 1H), 7.42-7.38 (m, 1H), 7.30-7.17 (m, 2H), 4.57 (s, 2H), 4.09 (s, 2H), 3.74 (s, 3H).
Ste B. l-K3-Bromobenzyl)oxyl-2-methylpropan-2-ol (#17 Intermediate)
Methyl [(3 -bromobenzyl)oxy] acetate (2.0 g, 7.7 mmol) was dissolved in THF (10 mL) and was allowed to stir under a nitrogen atmosphere. Methylmagnesium bromide (7.7 mL, 23 mmol, 3.0 M in THF) was added dropwise. The reaction mixture was allowed to stir at ambient temperature for 4 hours before the reaction was quenched with water and the mixture was extracted with EtOAc. The organic layer was washed with saturated aqueous NaHC03, brine, dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 2-70% EtOAc/hexanes). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound. JH NMR (600 MHz, CDC13): δ 7.46 (s, 1H), 7.40 (d, J- 7.9 Hz, 1H), 7.25-7.18 (m, 2H), 4.52 (s, 2H), 3.29 (s, 2H), 1.21 (s, 6H).
Scheme #4
Intermediate #18
Figure imgf000073_0002
Step A-B. 2-ri-(3-Bromobenzyl)-lflr-1.2 -triazol-4-vIlpropan-2-oUIntermediate #18)
To a solution of 1 -bromo-3-(bromomethyl)benzene (5.0 g, 20 mmol) in DMSO
(40 mL) was added sodium azide (1.3 g, 20 mmol). The resulting mixture was allowed to stir at ambient temperature for 18 hours before it was diluted with water and extracted with diethyl ether (2x). The combined organic extracts were washed with brine, dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The crude residue was dissolved in lBuOH (65 mL and water (39 mL) and to this mixture was added 2-methylbut-3-yn-2-ol (2.3 g, 27 mmol), and then a solution of copper (II) sulfate pentahydrate (0.26 g, 1.0 mmol) in water (10 mL) followed by a solution of sodium ascorbate (0.83 g, 4.2 mmol) in water (8 mL). The resulting mixture was allowed to stir at ambient temperature for 2 hours before it was diluted with water and extracted with EtOAc (2x). The combined organic extracts were washed with brine, dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The residue was used without further purification. LRMS (ESI) calc'd for C12H14BrN30 [M+H]+: 296, Found: 296.
Scheme #13
Intermediate #19-1
Figure imgf000074_0001
fert-Butyl 4-(cyanomethylidene)piperidine-l-carboxylate (Intermediate # 19-1)
To a three necked round bottom flask equipped with a mechanical stirring bar was added potassium tert-butoxide (263 mL, 263 mmol, 1.0 M in THF) and THF (200 mL). The mixture was cooled to 0 °C, followed by the addition of diethyl (cyanomethyl)phosphonate (43.7 mL, 276 mmol) slowly by syringe. The reaction mixture was maintained at 0 °C for 10 minutes, then warmed to ambient temperature and maintained for 1 hour. The mixture was cooled to 0 °C and treated with the dropwise addition of rt-butyl 4-oxopiperidine-l-carboxylate (50.0 g, 251 mmol) in THF (150 mL) over 30 minutes. After addition, the mixture was maintained at 0 °C for 20 minutes, then warmed to ambient temperature and maintained for 18 hours. The reaction mixture was then diluted with water (800 mL) and extracted with EtOAc (700 mL x2). The combined organic extracts were washed with water, brine, dried over anhydrous Na2S04, filtered, and concentrated in vacuo to afford the title compound as a light pink solid.
1H-NMR (600 MHz, CDC13) δ 5.19 (S, 1H), 3.48-3.53 (m, 4H), 2.56 (t, J=5.4Hz, 2H), 2.33 (t, J=5.4Hz, 2H), 1.47 (s, 9H).
TABLE 4 discloses Intermediates 19-2 through 19-18 that were prepared according to Scheme #12 and 13 following similar procedures described for Intermediate #19- 1, which can be achieved by those of ordinary skill in the art of organic synthesis. TABLE 4•
Figure imgf000075_0001
Figure imgf000076_0001
Figure imgf000077_0001
Scheme #13
Intermediate #20
Figure imgf000077_0002
fe -Butyl (4E and 4Z)-4-(cvanomethylidene)-3-fluoropiperidine-l-carboxylate (Intermediate # 201
To a solution of NaH (0.27 g, 6.6 mmol, 60% in mineral oil) in DMF (10 mL) was added diethyl (cyanomethyl)phosphonate (1.5 g, 6.6 mmol). The mixture was stirred at ambient temperature for 30 minutes before tert-butyl 3-fluoro-4-oxopiperidine-l-carboxylate (0.70 g, 3.3 mmol) was added. The resulting mixture was stirred for 1 hour before the reaction was quenched with water and the mixture was concentrated in vacuo. The crude residue was purified by MPLC on silica gel to afford the title compound.
LRMS (ESI) calc'd for (C12H18FN202) [M+H]+: 241, Found 241. Scheme #13
Intermediate #21
Figure imgf000078_0001
fert-Butyl 4-(l-cyanoethylidene)piperidine-l-carboxylate (Intermediate # 21)
To a solution of Mel (1.42 g, 10 mmol) in DMF was added NaH (0.40 g, 10 mmol, 60% in mineral oil), followed by diethyl (cyanomethyl)phosphonate (2.35g, 10 mmol). The mixture was stirred at ambient temperature. After 30 minutes another batch of NaH (0.40 g, 10 mmol, 60% in mineral oil) was added, followed by tert-butyl 4-oxopiperidine-l-carboxylate (1.99 g, 10 mmol). The resulting mixture was stirred for 30 minutes before the reaction was quenched with water and the mixture was concentrated in vacuo. The crude residue was purified by MPLC on silica gel to afford the title compound.
LRMS (ESI) calc'd for C13H21N202 [M+H]+237, Found 237.
Scheme #13
Intermediate #22
Figure imgf000078_0002
ferf-Butyl 4-[cvano(cvclopropyDmethylidenelpiperidme-l-carboxylate (Intermediate # 22)
tert-Butyl 4-oxopiperidine-l-carboxylate (2.0 g, 10 mmol) and
cyclopropylacetonitrile (0.97 g, 12 mmol) were dissolved in THF (20 mL), heated to reflux, and allowed to stir for 3 hours. The mixture was then cooled to ambient temperature and
concentrated in vacuo. The residue was purified by MPLC on silica gel to afford the title compound as a white solid.
LRMS (ESI) calc'd for C15H23N202 [M+H]+ 263, Found 263. Scheme #14
Intermediate #23
Figure imgf000079_0001
Step A-B. H-(Ethylsulfonyl)azetidin-3-v idenelacetonitrilc (Intermediate # 23)
tgrt-Butyl 3-(cyanomethylidene)azetidine-l-carboxylate (5.0 g, 26 mmol) was dissolved in 4M HC1 in dioxane (25.7 mL) and allowed to stir at ambient temperature for 16 hours. The mixture was concentrated to dryness in vacuo, then dissolved in DCM (30.0 mL) and cooled to -10 °C. DIPEA (11.6 g, 90.0 mmol) was added followed by ethanesulfonyl chloride (5.0 g, 39 mmol). The resulting mixture was allowed to stir for 7 hours before the mixture was diluted with water and extracted with DCM. The organic layer was dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 5-70% EtO Ac/heptane). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound.
LRMS (ESI) calc'd for C7H10N2O2S [M+H]+: 187, Found: 187.
Scheme #14
Intermediate #24
Figure imgf000079_0002
2,2,2-Trifluoroethyl 4-(cyanomethylene)piperidine-l-carboxylate
Figure imgf000079_0003
Step A. 4-(Cvanomethylidene)piperidinium trifluoroacetate (Step A
Intermediate)
tert-Butyl 4-(cyanomethylene)piperidine-l-carboxylate (5.0 g, 22.5 mmol) was dissolved in DCM (75.0 mL). TFA (8.7 mL, 110 mmol) was added, and the resulting mixture was allowed to stir at ambient temperature for 2 hours. The mixture was concentrated in vacuo to afford the title compound.
LRMS (ESI) calc'd for C7H10N2 [M+H]+: 123, Found: 123.
Step B. 2,2,2-Trifluoroethyl 4-(cvanomethylene)piperidine-l-carboxylate
(Intermediate # 24)
2,2,2-Trifluoroethanol (1.6 mL, 22 mmol) and TEA (6.2 mL, 45 mmol) were dissolved in acetonitrile (200 mL). Ν,Ν-disuccinimidyl carbonate (8.6 g, 34 mmol) was added and the resulting mixture was stirred at ambient temperature for 90 minutes. 4- (Cyanomethylidene)piperidinium trifluoroacetate (5.3 g, 23 mmol) in DMSO (10 mL ) was then added, followed by TEA (6.2 mL, 45 mmol). The resulting mixture was stirred at 50 °C for 16 hours. The reaction mixture was cooled to ambient temperature, diluted with EtOAc and washed sequentially with saturated NaHC03 (aq) and water. The organic layer was dried over anhydrous MgS04, filtered, and concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-5% MeOH in DCM) to afford the title compound. LRMS (ESI) calc'd for Ci0HnF3N2O2 [M+H]+: 249, Found: 249.
Scheme #14
Intermediate #25-1
Figure imgf000080_0001
[l-(3,4-Dimethoxyphenyl)piperidin-4-ylidene]acetonitrile
Figure imgf000080_0002
Step A. 4-(Cyanomethylidene)piperidinium chloride (Step A Intermediate)
tert-Butyl 4-(cyanomethylidene)piperidine-l-carboxylate (20 g, 90 mmol) was dissolved in 4M HC1 in dioxane and allowed to stir at ambient temperature for 2 hours. The mixture was then concentrated in vacuo to afford the title compound.
LRMS (ESI) calc'd for C7H]0N2 [M+H]+: 123, Found: 123.
Step B. [l-(3,4-Dimethoxyphenyl)piperidin-4-ylidenelacetonitriIe
(Intermediate #25-1)
In a sealed tube, 4-(cyanomethylidene)piperidinium chloride (16 mg, 0.10 mmol),
Pd2(dba)3 (14 mg, 0.015 mmol), X-Phos (20 mg, 0.020 mmol), 4-bromo-l,2-dimethoxybenzene (33 mg, 0.15 mmol), and Cs2C03 (98 mg, 0.30 mmol) were suspended in t-BuOH (0.5 mL). The reaction mixture was purged with argon for 5 minutes, the reaction flask was capped, and heated to 90 °C for 12 hours. The reaction was then cooled to ambient temperature and diluted with DMF:MeCN (1.0 mL, 50:50). To this mixture, Silica Supported-DMT (0.50 mmol, 0.57 mmol/g) followed by Silica Supported-Isocyanate (0.15 mmol, 1.33 mmol/g) was added. The resulting mixture was then shaken at 50 °C for 4 hours. The mixture was then passed through a nylon syringe filter (0.45 μηι), and the filtrate was concentrated in vacuo to afford the title compound. The crude residue was used without further purification.
LRMS (ESI) calc'd for C15H18N202 [M+H]+: 259, Found: 259.
TABLE 5 depicts intermediates 25-2 through 25-3 that were prepared according to Scheme #14 following similar procedures described for Intermediates #25-1, which can be achieved by those of ordinary skill in the art of organic synthesis. TABLE 5:
Figure imgf000081_0002
Scheme #15
Intermediate #26-1
Figure imgf000081_0001
Step A-C. tert- utyl 3-cvanocvcIohex-3-ene-l-carboxylate (Intermediate # 26-1)
tert-Butyl 3-oxocyclohexanecarboxylate (1.35 g, 6.81 mmol) was taken up in water (11.4 mL) and stirred at ambient temperature. Sodium metabisulfite (0.75 g, 3.9 mmol) was added and the mixture was allowed to stir for 40 minutes. Diethyl ether (11.4 mL) was added, followed by potassium cyanide (0.70 g, 11 mmol). The resulting mixture was allowed to stir vigorously for 1 hour before it was partitioned between diethyl ether and water. The organic layer was washed with water, brine, dried over anhydrous MgS04, filtered, and concentrated in vacuo. The residue, used without further purification, was dissolved in DCM (22.0 mL). DIPEA (1.07 g, 8.26 mmol) was added and the resulting mixture was cooled to 0 °C. Methanesulfonyl chloride (0.69 g, 6.1 mmol) was added dropwise and the resulting mixture was maintained at 0 °C for 20 minutes then allowed to warm to ambient temperature. The mixture was partitioned between DCM and water. The organic layer was dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The residue, used without further purification, was dissolved in pyridine (13.6 mL) and heated to 95 °C for 20 hours. The mixture was then allowed to cool to ambient temperature and was concentrated in vacuo. The residue was purified by MPLC on silica gel (using a gradient elution of 0-45% EtOAc/hexanes). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound.
1H NMR (500 MHz, CDC13): δ 6.63-6.58 (m, 1H), 2.54-2.48 (m, 1H), 2.44-2.40 (m, 2H), 2.36- 2.16 (m, 2H), 2.02-1.94 (m, 1H), 1.71-1.63 (m, 1H), 1.44 (s, 9H).
TABLE 6 depicts intermediates 26-2 through 26-4 that were prepared according to
Scheme #15 following similar procedures described for Intermediate #26-1, which can be achieved by those of ordinary skill in the art of organic synthesis.
TABLE 6:
Figure imgf000082_0001
Scheme #15
Intermediate #27-1
Figure imgf000082_0002
Step A-B. 4-Methylcyclohex-l-ene-l-carbonitrile (Intermediate # 27-1)
4-Methylcyclohexanone (1.0 g, 8.9 mmol) was added to a stirred solution of water (8.9 mL) containing sodium metabisulfite (0.98 g, 5.2 mmol). The resulting mixture was allowed to stir at ambient temperature for 15-30 minutes before diethyl ether (8.9 mL) was added followed by potassium cyanide (0.91g, 14 mmol). The biphasic mixture was stirred vigorously for at least 30 minutes before the layers were partitioned and the organic layer was washed with water, followed by brine. The organic layer was dried over anhydrous Na2S04, filtered, and concentrated in vacuo (23 °C water bath) to afford 4-methyl -1-hydroxycyclohexanecarbonitrile as a crude residue, which was carried forward without further purification. The crude residue (0.50 g, 3.6 mmol) was combined with pyridine (18.3 mL, 226 mmol), and POCl3 (1.34 mL, 14.4 mmol) in a microwave vial and sealed. The reaction mixture was heated to reflux for 16 hours. The reaction mixture was then cooled to ambient temperature, diluted with diethyl ether, and washed with 2N aqueous HC1 saturated with sodium chloride (3x). The organic layer was washed with brine, dried over anhydrous MgS0 , filtered, and concentrated in vacuo (23 °C water bath) to afford the title compound as an oil.
1H NMR (600 MHz, CDC13): δ 6.59-6.56 (m, 1H), 2.28-2.20 (m, 3H), 1.80-1.71 (m, 2H), 1.71— 1.59 (m, 1H), 1.28-1.21 (m, 1H), 0.96 (d, J= 6.6, 3H). TABLE 7 depicts intermediates 27-2 and 27-3 were prepared according to
Scheme #15 following similar procedures described for Intermediate #27-1, which can be achieved by those of ordinary skill in the art of organic synthesis.
TABLE 7:
Figure imgf000083_0002
Scheme #16
Intermediate #28
Figure imgf000083_0001
Steps A-B. fert-Butyl 5-cvano-3,6-dihvdropyridine-l(2fn-carboxylate (Intermediate 28)
A solution of n-butyllithium (2.8 mL, 7.0 mmol, 2.5 M in hexanes) was added to a solution of diisopropylamine (1.0 mL, 7.0 mmol) in THF (10.0 mL) at -78 °C. The cooling bath was removed for 15 minutes, and then the reaction mixture was cooled back to -78 °C. A solution of tert-butyl 3-oxopiperidine-l-carboxylate (1.0 g, 5.0 mmol) in THF (6 mL) was added to the cooled solution of LDA dropwise over 5 minutes, maintained for 15 minutes, and then N- (5-chloropyridin-2-yl)- 1,1,1 -trifluoro-N-[(trifluoromethyl)sulfonyl]methanesulfonamide (2.4 g, 6.0 mmol) was added in one portion. The reaction mixture was stirred at -78 °C for 15 minutes, and then the cooling bath was removed. The reaction mixture was stirred for 45 minutes after removal of the cooling bath, and was then partitioned between EtOAc and water. The organic layer was washed with brine, dried over anhydrous Na2S04 and filtered. The filtrate was concentrated in vacuo and the residue was purified by MPLC on silica gel (using a gradient elution of 0-20%, diethyl ether/hexanes) to afford ter/-butyl 5-{[(trifluoromethyl)sulfonyl]oxy}- 3,6-dihydropyridine-l(2H)-carboxylate as the second regioisomer to elute. A portion of the product (123 mg, 0.371 mmol) was combined with zinc cyanide (52 mg, 0.45 mmol), Pd(PPh3)4 (64 mg, 0.056 mmol) and DMF (1.9 mL) in a microwave tube. The reaction mixture was heated in the microwave at 100 °C for 20 minutes. After cooling to 23 °C, the reaction mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried over anhydrous Na2S04 and filtered. The filtrate was concentrated in vacuo and the residue was purified by MPLC on silica gel (using a gradient elution of 0-100%, EtOAc/hexanes) to afford the title compound.
Ή NMR (500 MHz, CDC13): δ 6.73 (br s, 1H), 4.02 (br s, 2H), 3.49 (t, J = 5.6 Hz, 2H), 2.29 (br s, 2H), 1.47 (s, 9H).
Scheme #17
Figure imgf000084_0001
4-Hydroxycyclohex-l-ene-l-carbonitriIe
Figure imgf000084_0002
Step A. 4-Oxocyclohex-l-ene-l-carbonitrile
In a sealed tube, {[(3E )-4-methoxybuta-l,3-dien-2-yl]oxy}(trimethyl)silane (5.65 mL, 29.0 mmol) and acrylonitrile (1.91 mL, 29.0 mmol) were combined in benzene (9.67 mL), heated to reflux, and allowed to stir for 16 hours. The reaction mixture was then cooled to ambient temperature and the volatiles were removed in vacuo (23 °C water bath). The residue was stirred into a mixture of IN aqueous HCl (29.0 mL, 29.0 mmol) and THF (9.67 mL). After being stirred at ambient temperature for 3 hours, the reaction mixture was extracted with diethyl ether. The organic layer was washed with de-ionized water (2x), brine, dried over anhydrous Na2S04, filtered and concentrated in vacuo (23 °C water bath). The residue was purified by
MPLC on silica gel (using a gradient elution of 0-50% hexanes/acetone). Desired fractions were identified, combined and concentrated in vacuo (23 °C water bath) to afford the title compound. 1H NMR (600 MHz, CDC13): 6 6.68 (tt, J= 4.0, 1.5, 1H), 3.05 (dt, J= 4.3, 2.2, 2H), 2.71 (tq, J= 6.9, 1.9, 2H), 2.61-2.53 (t, J= 6.9 2H).
Step B. 4-Hvdroxycvclohex-l-ene-l-carbonitrile (Intermediate #29)
To a stirred solution of 4-oxocyclohex-l-ene-l-carbonitrile (170 mg, 1.40 mmol) in MeOH (2.3 mL) at -78 °C was added cerium (III) chloride (484 mg, 1.96 mmol) in MeOH (4.7 mL). The resulting mixture was allowed to stir for 5 minutes at -78 °C before NaBEL; (48 mg, 1.26 mmol) was added in one portion. The mixture was stirred for 20 minutes and then allowed to warm to ambient temperature. After being stirred for 30 minutes, the reaction mixture was diluted with water and extracted with diethyl ether (3x). The combined organic extracts were washed with brine, dried over anhydrous Na2S04, filtered, and concentrated in vacuo (23 °C water bath) to afford the title compound.
1H NMR (600 MHz, CDC13): δ 6.50 (tt, J= 3.9, 1.8, 1H), 4.03-3.98 (m, 1H), 3.50 - 3.42 (qd, J= 11.4, 4.5, 1H), 2.50 (br d, J= 19.2, 1H), 2.46-2.38 (m, lH), 2.33-2.23 (m, 1H), 2.21-2.13 (m, 1H), 1.90-1.84 (m, 1H), 1.76-1.67 (m, 1H). Scheme #18
Intermediate #30
1 ,4-Dioxas rbonitrile
Figure imgf000085_0001
Step A-C. (1R.2S and lS,2R)-4-Oxo-2-fphenylsulfonylkvclohexanecarbonitriIe
Benzenesulfinic acid sodium salt (9.4 g, 57 mmol) was dissolved in a mixture of water (18.3 mL) and acetic acid (9.1 mL). 2-Chloroprop-2-enenitrile (4.6 mL, 57 mmol) was added, followed by MeOH (18.3 mL). The resulting mixture was allowed to stir for 10 minutes before the solid product was collected by filtration and rinsed with minimal water. The majority of the solid filtered through with the rinse and so all material was rinsed through the filter. The filtrate was extracted with DCM (2x) and the combined organic layers were washed with saturated aqueous NaHC03, brine, dried over anhydrous Na2S04, filtered, and concentrated in vacuo to afford 2-chloro-3-(phenylsulfonyl)propanenitrile as a crude residue. Crude 2-chloro-3- (phenylsulfonyl)propanenitrile (6.1 g, 27 mmol) was dissolved in chloroform (41 mL) cooled in an ice-salt bath and stirred before adding TEA (3.7 mL, 27 mmol) dropwise. The mixture was allowed to stir at 0 °C for 20 minutes. The reaction mixture was then washed sequentially with dilute IN aqueous HC1, followed by saturate aqueous NaHC03. The organic layer was dried over anhydrous Na2S04, filtered, and concentrated in vacuo (23 °C water bath) to afford (2E and 2Z)-3-(phenylsulfonyl)prop-2-enenitrile as a crude residue. The crude residue (4.9 g, 25.5 mmol) and (buta-l,3-dien-2-yloxy)(trimethyl)silane (4.2 g, 29.3 mmol) were refluxed together in benzene (63.8 mL) under nitrogen for 16 hours. The reaction mixture was then concentrated in vacuo to afford an oily mixture of the intermediate adducts. The residue was dissolved in aqueous acetic acid (80%) and allowed to stir. After 1 hour at ambient temperature, the mixture was diluted with water and extracted with DCM (2x). The combined organic extracts were concentrated in vacuo and the residue was dissolved in DCM. A solid precipitated from the solution and was collected by filtration to afford the title compound.
1H NMR (600 MHz, CDC13): δ 7.91 (d, J= 7.7, 2H), 7.74 (t, J= 7.4, 1H), 7.63 (t, J= 7.8, 2H), 3.81 (q, J= 4.4, 1H), 3.68 (q, J= 4.8, 1H), 2.76 (dd, J= 16.5, 6.3, 1H), 2.74 - 2.66 (m, 1H), 2.62 (dd, J= 11.4, 4.5, 1H), 2.61-2.56 (m, 2H), 2.25 (dq, J= 14.3, 4.9, 1H).
Step D-E. 1 ,4-Dioxaspiro [4.51 dec-7-ene-8-car bonitrile (Intermediate #30)
To a pressure vessel was added (1R,2S and 1 S,2R)-4-oxo-2-(phenylsulfonyl) cyclohexanecarbonitrile (100 mg, 0.380 mmol), benzene (19.0 mL), ethylene glycol (0.90 mL, 16 mmol), and p-toluenesulfonic acid monohydrate (14 mg, 0.076 mmol). The vessel was capped and the reaction mixture was heated to reflux and allowed to stir for 16 hours. The reaction mixture was allowed to cool to ambient temperature before it was diluted with EtOAc. The organic layer was washed with water (3x), brine, dried over anhydrous Na2S04, filtered, and concentrated in vacuo (23 °C water bath) to afford (7S,8R and 7R,8S)-7-(phenylsulfonyl)-l,4- dioxaspiro[4.5]decane-8-carbonitrile as a crude residue. To the crude residue (110 mg, 0.358 mmol) was added THF (7.1 mL) and potassium tert-butoxide (137 mg, 1.22 mmol). The reaction mixture was allowed to stir at ambient temperature for 15 minutes before it was diluted with diethyl ether. The organic layer was washed with water, brine, dried over anhydrous MgS04, filtered, and concentrated in vacuo (23 °C water bath) to afford the title compound. Ή NMR (600 MHz, CDC13): δ 6.48 (tt, J= 4.0, 1.8, 1H), 3.96 (s, 4H), 2.45 (tq, J= 6.6, 2.2, 2H), 2.39 (q, J= 3.1, 2H), 1.78 (t, J= 6.6, 2H).
Scheme #19
Intermediate #31-1
Figure imgf000086_0001
3-(Phenylamino)-LH-Pyrazole-4-carboxamide (Intermediate #31-1)
3-Amino-iH-pyrazole-4-carboxamide (19.8 g, 157 mmol), K3P04 (66.7 g, 314 mmol), bromobenzene (23.2 mL, 220 mmol) and 2-propanol (785 mL) were combined in a round bottom flask and purged with a stream of N2 gas for 40 minutes. Pd2(dba)3 (1.80 g, 1.96 mmol) and 2-di- butylphosp]lino-3,4,5,6-tetramemyl-2^4^6'-tri-z-propylbiphenyl (3.77 g, 7.85 mmol) were added and the reaction was purged for an additional 5 minutes. The reaction mixture was then heated to 80 °C and allowed to stir under a N2 atmosphere for 12 hours. The mixture was then allowed to cool to ambient temperature for an additional 16 hours. The reaction mixture was diluted with EtOAc (300 mL) and filtered through celite (slowly). The celite was washed with EtOAc (300 mL) and the combined filtrates were concentrated in vacuo to afford an oil which was purified by MPLC on silica gel (using a gradient elution of 0-10% MeOH/DCM). The major, low rf product, was isolated to afford a reddish-brown oily solid. The brown solid was suspended in 40 mL of warm MeOH, cooled to ambient temperature, and water (40 mL) was added. The mixture was stirred for 30 minutes and filtered. The solid was suction dried for 16 hours to afford the title compound as a peach-colored solid.
LRMS (ESI) calc'd for C10H10N4O [M+H]+: 203, Found: 203.
The following intermediates shown in TABLE 8 were prepared according to
Scheme #19 following similar procedures described for Intermediate #31-1, which can be achieved by those of ordinary skill in the art of organic synthesis.
Figure imgf000087_0001
Figure imgf000088_0001
Intermediate #32
Figure imgf000088_0002
3-(i4-[(Trifluoromethyl)sulfonyllphenyl}amino)-l -r-pyrazole-4-carboxamide (Intermediate #32)
The title compound, Intermediate #32, can be prepared according to the general procedure described for Intermediate #31-1 using 3-amino-iH-pyrazole-4-carboxamide (0.48 g, 3.8 mmol) and l-bromo-4-[(trifluoromethyl)sulfonyl]benzene (1.0 g, 3.5 mmol) as starting materials.
LRMS (ESI) calc'd for Ci7H18FN502 [M+H]+: 335, Found: 335.
Alternatively, the title compound, Intermediate #32, can also be prepared by dissolving 3-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)-lH-pyrazole-4-carboxamide (0.50 g, 1.6 mmol) in acetic acid (5.0 mL) followed by the addition of hydrogen peroxide (0.87 mL, 9.9 mmol, 35 wt% in water). The resulting mixture was heated to 50 °C for 18 hours before additional hydrogen peroxide (0.87 mL, 9.9 mmol, 35 wt% in water) was added and the mixture was heated to 80 °C for 8 hours. The mixture was cooled to ambient temperature, concentrated in vacuo and diluted with EtOAc. The mixture was washed three times with aqueous sodium thiosulfate adjusted to pH>8 with saturated aqueous bicarbonate. The organic layer was collected, dried over anhydrous Na2S04, filtered and concentrated in vacuo. The residue was purified by MPLC on silica gel (15% MeOH/DCM). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound.
LRMS (ESI) calc'd for Cu LFsN^S [M+H]+: 335, Found: 335.
Scheme #19
Intermediate #33
Figure imgf000088_0003
Propan-2-yl 4-[(4-carbamoyl-l/y-pyrazol-3-yl)amino]benzoate
A round-bottomed flask was charged with 2-propanol (595 mL), and nitrogen was bubbled through the 2-propanol for 2 hours. Pd2(dba)3 (1.63 g, 1.78 mmol) and di-fert- butyl(2,,4',6'-triisopropyl-3,4,5,6-tetramethylbiphenyl-2-yl)phosphine (3.43 g, 7.14 mmol) were added, and the mixture was stirred for 20 minutes. Potassium acetate (17.5 g, 178 mmol), 3- amino-lH-pyrazole-4-carboxamide (15.0 g, 119 mmol), and isopropyl 4-bromobenzoate (34.7 g, 143 mmol) were then added, and the reaction mixture was heated to 75 °C for 6.5 hours. The reaction mixture was then cooled to 23 °C, diluted with EtOAc (500 mL), and filtered through celite. The filtrate was adsorbed onto silica gel in vacuo and purified by MPLC on silica gel (using a gradient elution of 30-90%, EtOAc/hexanes) to afford the title compound.
LRMS (ESI) calc'd for C,4H,7N403 [M+H]+: 289, Found: 289.
Scheme #20
Intermediate #34-1
Figure imgf000089_0001
3-(Pyridin-4-yIamino)-liT-pyrazole-4-carboxamide
Step A. 3-Amino-l-(f2-(trimethylsilyl)ethoxy1methyll-lJH-Pyrazole-4-carbonitrile and
5-Amino-l-([2-(trimethylsilyl)ethoxylmethvn-lH-pyrazole-4-carbonitrile
3-Amino-lH-pyrazole-4-carbonitrile (10 g, 93 mmol) and NaH (4.0 g, 100 mmol, 60% dispersion in oil) were suspended in DMF (60 mL) at 0 °C. SEMC1 (19.7 mL, 111 mmol) was added dropwise and the resulting mixture was maintained at ambient temperature for 16 hours. Water was added and the mixture was extracted with EtOAc. The combined organic extracts were washed with brine, dried over anhydrous MgS04, filtered and concentrated in vacuo. Purification of the residue by MPLC on silica gel gave a mixture of two regioisomers as a yellow oily solid. 3-ammo-l-{[2-(trimethylsilyl)emoxy]memyl}-lH-pyrazole-4-carbonitrile and 5-amino- 1 - { [2-(trimethylsilyl)ethoxy]methyl} -lH-pyrazole-4-carbonitrile
1H NMR (600 MHz, DMSO-d6): 67.54 (s, 1H), 6.77 (s, 2H), 5.21 (s, 2H), 3.49 (m, 2H), 0.78 (m, 2H), 0.08 (s, 9H). 1H NMR (600 MHz, DMSO-d6): 8 8.24 (s, 1H), 5.60 (s, 2H), 5.11 (s, 2H), 3.47 (m, 2H), 0.79 (m, 2H), 0.07 (s, 9H).
Step B. 3-(Pyridin-4-ylamino -{[2-(trimethv
Figure imgf000089_0002
liZ-pyrazole-4-carboiiitrile
To a microwave vessel was added a mixture of 3-amino-l-{[2-(trimethylsilyl) ethoxyjmethyl } - 1 H-pyrazole-4-carbonitrile and 5-amino- 1 - { [2-(trimethylsilyl)ethoxy]methyl } - lH-pyrazole-4-carbonitrile (500 mg, 2.1 mmol), 4-iodopyridine (0.52 g, 2.5 mmol), dioxane (10.5 mL) and K3PO4 (0.89 g, 4.2 mmol). The mixture was degassed by bubbling nitrogen gas for 5 minutes. Pd2(dba)3 (0.19 mg, 0.21 mmol), and X-Phos (0.30 g, 0.63 mmol) were then added, and the mixture was heated to 100 °C and allowed to stir for 14 hours. The mixture was then allowed to cool to ambient temperature and was filtered through celite. The filtrate was adsorbed on silica gel in vacuo and the mixture was purified by MPLC on silica gel (using a gradient elution of 20- 100% EtO Ac/DCM) to afford the title compounds. LRMS (ESI) calc'd for C15H22N5OSi [M+H]+: 316, Found: 316.
Step C. 3-(Pyridin-4-ylamino)-li¾l-pyrazole-4-carboxaniide (Intermediate #34-1)
To a solution containing a mixture of 3-(pyridin-4-ylamino)-l-{[2- (trimethylsilyl)ethoxy]methyl}-7H-pyrazole-4-carbonitrile and 5-(pyridin-4-ylamino)-l-{[2- (trimethylsilyl)ethoxy]methyl}-7H-pyrazole-4-carbonitrile (150 mg, 0.50 mmol) in DMSO (1.2 mL) and EtOH (1.2 mL) was added 5M aqueous NaOH (0.70 mL, 3.3 mmol). The mixture was heated to 55 °C, followed by the dropwise addition of 30% H202 (0.7 mL, 7.1 mmol). After 10 minutes, additional 30% H202 (0.30 mL, 3.4 mmol) was added dropwise. The mixture was maintained for 30 minutes before it was allowed to cool to ambient temperature. To the crude reaction mixture was added MeOH (1 mL) and 6N aqueous HC1 (2 mL). The resulting mixture was heated at 55 °C for 1.5 hours. Additional 6N aqueous HC1 (1 mL) was added and the mixture continued stirring for another 1 hour. The mixture was cooled to ambient temperature and carefully neutralized with 5N aqueous NaOH until pH -6-7. The mixture was then concentrated in vacuo to remove most of the solvent. To the slurry-like residue was added MeOH (20 mL), and the resulting mixture was sonicated for 5 minutes. The mixture was filtered to remove insoluble precipitate and the filtrate was concentrated in vacuo to afford crude residue containing the title compound, Intermediate #34-1, which was used without further purification. LRMS (ESI) calc'd for C9H9N5O [M+H]+: 204, Found: 204.
The following intermediates shown in Table 9 were prepared according to
Scheme #20 following similar procedures described for Intermediate #34-1, which can be achieved by those of ordinary skill in the art of organic synthesis.
Figure imgf000090_0001
Figure imgf000091_0001
Scheme #21
Intermediate #35-1
Figure imgf000091_0002
fe -Butyl 4-(3-amino-4-carbamoyl-lH-pyrazol-l-vn-4-(cvanomethyl)piperidine-l- carboxylate
3-Amino-lH-pyrazole-4-carboxamide (0.80 g, 6.3 mmol) and fert-butyl 4- (cyanomethylene)piperidine-l-carboxylate (2.1 g, 9.5 mmol) were combined with acetonitrile (31 mL) in a pressure vessel. DBU (1.05 mL, 6.98 mmol) was then added at ambient temperature. The reaction vessel was sealed and the mixture was heated to 80 °C for 16 hours. The reaction mixture was then allowed to cool to ambient temperature before water (150 mL) was added. The aqueous mixture was extracted with EtOAc (2x). The organic layers were then combined and washed with brine, dried over anhydrous MgS04, filtered, and concentrated in vacuo. The crude residue was adsorbed on silica gel in vacuo and purified by MPLC on silica gel (using a gradient elution of 75- 100% EtOAc/hexanes) to afford the title compound, Intermediate #35-1.
LRMS (ESI) calc'd for Ci6H24N603 [M+H]+: 349, Found: 349
The following intermediates shown in TABLE 10 were prepared according to Scheme #21 following similar procedures described for Intermediate #35-1, which can be achieved by those of ordinary skill in the art of organic synthesis.
Figure imgf000091_0003
Figure imgf000092_0001
Scheme #21
Intermediate #36
Figure imgf000092_0002
3-Amino-l-[(lS,2S and lR,2R)-2-cvano-4-hvdroxycvclohexyll-IH-pyrazole-4-carboxamide
DBU (1.20 mL, 7.93 mmol) was added to a mixture of 3-amino-lH-pyrazole-4- carboxamide (500 mg, 3.96 mmol) and 5-hydroxycyclohex-l-ene-l-carbonitrile (976 mg, 7.93 mmol) in ethanol (7.2 mL) at 23 °C. The reaction mixture was then heated to 70 °C for 16 hours. The mixture was then cooled to ambient temperature, silica gel was added, and the mixture was concentrated in vacuo. The resulting powder was then purified by MPLC on silica gel (using a gradient elution of 0-15%, MeOH/EtOAc) to afford the title compound. The stereochemistry of the major isomer was 1,2-trans, 1,4- cis, and the minor isomer was 1,2-trans, 1,4-trans, with these two isomers constituting ~90% of the product mixture. LRMS (ESI) calc'd for C7Hi6N502 [M+H]+: 250, Found: 250.
Scheme #21
Intermediates # 37-1 & # 37-2
Figure imgf000092_0003
3-Amino-l-[(lS,2S and lR,2R)-2-cvanocvclohexyI1-lH-pyrazoIe-4-carboxamide and 3>- amino-l-KlS,2R and lR,2S)-2-cvanocvclohexyll-lJH-pyrazole-4-carboxamide
The title compounds were prepared according to the general procedure in Intermediate 36 using 3-amino-lH-pyrazole-4-carboxamide (10 g, 79 mmol) and cyclohex-l-ene-l-carbonitrile (17 g, 160 mmol) as starting materials.
Intermediate #37-1:
Figure imgf000092_0004
carboxamide
LRMS (ESI) calc'd for CnH16N50 [M+H]+: 234, Found: 234.
Intermediate #37-2: 3-Amino-l-[(15,2ii and l^S^-cyanocyclohexyll-Lff-pyrazole^- carboxamide LRMS (ESI) calc'd for CnH16N50 [M+H]+: 234, Found: 234.
Scheme #28
Intermediate #38
Figure imgf000093_0001
4-[4-CarbamoyI-3-(phenylaminoVl.fir-pyrazol-l-yll-4-(cvanomethyl)piperidinium
trifluoroacetate (Intermediate #38)
To a suspension of Example 14-4 (chiral), tert-butyl 4-[4-carbamoyl-3-
(phenylamino)-lH-pyrazol-l-yl]-4-(cyanomethyl)piperidine-l-carboxylate (1.1 g, 2.4 mmol), in DCM (2.5 mL) was added TFA (1.5 mL) dropwise. The resultant clear solution was maintained at ambient temperature for 3 hours. The mixture was then concentrated in vacuo, and the residue was dissolved in a mixture of MeCN/water (35 mL:15 mL) and lyophilized to afford the title compound, Intermediate #38.
LRMS (ESI) calc'd for C17H20N6O [M+H]+: 357, Found: 357 EXAMPLES OF THE INSTANT INVENTION
The following experimental procedures detail the preparation of specific examples of the instant invention. The examples are for illustrative purposes only and are not intended to limit the scope of the instant invention in any way.
Scheme #23
Example #1-1
Figure imgf000093_0002
l-(2-Cvano-l-cvclopropylethvn-3-(phenylamino)-lH-pyrazole-4-carboxamide
DBU (26.8 μΐν, 0.178 mmol) was added to a mixture of intermediate 31-1 (3- (phenylamino)-lH-pyrazole-4-carboxamide) (30 mg, 0.148 mmol) and intermediate 19-5 ((2Z)- 3-cyclopropylprop-2-enenitrile (17mg, 0.18 mmol)) in acetonitrile (742 μΐ,) and the vial was capped and allowed to stir at ambient temperature for 15 hours. The reaction mixture was partitioned between ethyl acetate and saturated aqueous ammonium chloride. The organic layer was washed with water, brine, dried over anhydrous NaS04, filtered, and concentrated in vacuo. The residue was purified by reverse-phase preparative HPLC (MeCN/water, with 0.1% v/v TFA modifier). Desired fractions were combined, basified with saturated aqueous NaHC03, and extracted with EtOAc. The organic layer was dried over anhydrous NaS04, filtered, and concentrated in vacuo to afford the title compound Example #1-1. 1H NMR (600 MHz, DMSO- D6) δ 9.10 (s, 1H), 8.28 (s, 1H), 7.62 (br. s, 1H), 7.49 (d, J= 7.7, 2H), 7.20 (t, J= 8.4, 7.5, 2H), 7.09 (br. s, 1H), 6.79 (t, J= 7.3, 1H), 3.79 (dt, J= 9.6, 6.1, 1H), 3.26 - 3.13 (m, 2H), 1.37 - 1.28 (m, 1H), 0.73 - 0.63 (m, 1H), 0.59 - 0.53 (m, 1H), 0.50 (td, J= 9.7, 4.6, 1H), 0.37 (td, J= 9.6, 4.6, 1H). LRMS (ESI) calc'd for C16H17N50 [M+H]+: 296, Found: 296.
The following examples shown in TABLE 11 were prepared according to Scheme #23 following similar procedures described for Example #1-1, utilizing intermediates from tables 4, 8, and 9, which can be achieved by those of ordinary skill in the art of organic synthesis.
Figure imgf000094_0001
Figure imgf000095_0001
Figure imgf000096_0001
Figure imgf000097_0001
Figure imgf000098_0001
Figure imgf000099_0001
Scheme #23
Example #2
Figure imgf000099_0002
l-(3-Cvaao-l,l,l-trifluoropropan-2-yl)-3-(phenylamino)-lH-pyrazole-4-carboxamide (2-l)
3-(Phenylamino)-lH-pyrazole-4-carboxamide (intermediate 31-1) (60 mg, 0.30 mmol) was combined with 4,4,4-trifluorobut-2-enenitrile (180 mg, 1.4 mmol) and DBU (90 mg, 0.59 mmol) in DMF (1.4 mL) and was stirred at ambient temeprature for 15 minutes. The reaction mixture was partitioned between EtOAc and water. The organic layer was washed with brine, dried over anhydrous NaS04, filtered, and concentrated in vacuo. The residue was purified by reverse phase preparative HPLC (using a gradient elution of 45-80% MeCN/water, with 0.1% v/v TFA modifier). Desired fractions were combined, basified with saturated aqueous NaHC03, and extracted with EtOAc. The organic layer was dried over anhydrous NaS04, filtered, and concentrated in vacuo to afford the title compound, Example # 2 (2-1).
1H NMR (600 MHz, DMSO-d6): δ 9.16 (s, 1 H); 8.33 (s, 1 H); 7.83 (s, 1 H); 7.48 (d, J = 8.1 Hz, 2 H); 7.21-7.22 (m, 3 H); 6.82 (t, J = 7.3 Hz, 1 H); 5.93 (d, J = 8.4 Hz, 1 H); 3.58 (dd, J = 17.2, 9.3 Hz, 1 H); 3.51 (dd, J = 17.2, 4.9 Hz, 1 H).
LRMS (ESI) calc'd for C14H12F3N50 [M+H]+: 324, Found: 324. Scheme #23
fert-Butyl 4-(l-(4-carbamoyl-3-f(4-fluorophenyl)aminol-lHr-pyrazol-l-yl>-2- cvanoethyl)piperidine-l-carboxylate (3-1)
DBU (443 uL, 2.94 mmol) was added to a mixture of intermediate 31-7 (30 mg, 0.148 mmol) and (2Z)-3-cyclopropylprop-2-enenitrile (Intermediate 19-13) (2.2 g, 10.0 mmol) in acetonitrile (30.3 mL) and the vial capped and allowed to stir at 80 °C for 15 hours. The reaction mixture was cooled to ambient temperature and diluted with diethyl ether. The organics were washed with brine, dried over anhydrous Na2S04, filtered, and concentrated in vacuo. The residue was purified by normal-phase chromatography (0-100% EtOAC/DCM using gradient elution). Desired fractions were combined and concentrated in vacuo to afford the title compound Example #3-1.
LRMS (ESI) calc'd for CuH16N50 [M+H]+: 457, Found: 457.
The following examples shown in TABLE 12 were prepared according to
Scheme #23 following similar procedures described for Example #3-1, which can be achieved by those of ordinary skill in the art of organic synthesis.
Figure imgf000101_0002
Scheme #24
Example #4-1
Figure imgf000101_0001
l-(2-Cvano-l-cvclopropylethyl)-3-(f4-(methylsulfonvnphenyll
amino)-l.g-pyrazole-4-carboxamide (4-1)
To a microwave vial was added Intermediate 35-2 (3-amino-l-(2-cyano-l- cyclopropylethyl)-lH-pyrazole-4-carboxamide) (0.20 g, 0.91 mmol), l-bromo-4-
(methylsulfonyl)benzene (0.21 g, 91 mmol), K3P04 (0.39 g, 1.8 mmol), and dioxane (9.1 mL). The mixture was degassed with bubbling argon for 5 minutes. Pd2(dba)3 (0.08 g, 0.09 mmol) and X-Phos (0.13 g, 0.27 mmol) were then added, and the vial was sealed and heated to 120 °C for 1.5 hours. The mixture was then cooled to ambient temperature, diluted with EtOAc, filtered through celite, and eluted with EtOAc. The filtrate was concentrated in vacuo, and the resulting yellow oil was purified by MPLC on silica gel (using a gradient elution of 50-100%
EtOAc/hexanes) to afford the title compound, Example #4-1.
Ή NMR (600 MHz, CDC13): δ 9.29 (s, 1 H); 7.88 (s, 1 H); 7.76 (d, J = 8.7 Hz, 2 H); 7.63 (d, J = 8.7 Hz, 2 H); 5.81 (br s, 2 H); 3.50-3.51 (m, 1 H); 3.13-3.14 (m, 2 H); 3.01 (s, 3 H); 1.44-1.45 (m, 1 H); 0.87 (td, J = 8.9, 4.7 Hz, 1 H); 0.74-0.75 (m, 1 H); 0.46-0.47 (m, 2 H).
LRMS (ESI) calc'd for C17H19N503S [M+H]+: 374, Found: 374.
The following examples, disclosed in TABLE 13 were prepared according to Scheme#24 following similar procedures described for Example #4-1, which can be achieved by those of ordinary skill in the art of organic synthesis.
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000106_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0001
Figure imgf000110_0001
Figure imgf000111_0001
Example #5
Figure imgf000111_0002
l-(2-Cvano-l-cvclopropylethyl)-3-r(lJ-dioxido-2 -dihvdro -benzothiophen-5-yl)aminol- lH-pyrazoIe-4-carboxamide (Example #5)
Example #4-35 ( 1 -(2-Cyano- 1 -cyclopropylethyl)-3 - { [4-(3 -methyl- 1 ,2,4- oxadiazol-5-yl)phenyl]amino}-lH-pyrazole-4-carboxamide) (0.07 g, 0.2 mmol) was dissolved in 1 :1 EtOAc:EtOH (35 mL) and added to a Parr shaker. 10 % Palladium on activated carbon (0.02 g, 0.02 mmol) was added and the resulting mixture was subjected to alternating vacuum and H2 gas (4x). The mixture was then allowed to shake under an atmosphere of ¾ (50 psi) for 1.5 hours. The mixture was then subjected to alternating vacuum and N2 gas (4x). The mixture was filtered through celite and rinsed with DCM. The filtrate was concentrated in vacuo, and the residue was purified by MPLC on silica gel (using a gradient elution of 0-60% EtOAc/hexanes followed by a gradient elution of 0-10% MeOH/DCM). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound, Example # 5-1.
Ή NMR (500 MHz, CD3OD): δ 8.27 (s, 1 H); 7.80 (s, 1 H); 7.55-7.56 (m, 2 H); 3.72-3.73 (m, 1 H); 3.49 (t, J= 6.9 Hz, 2 H); 3.36 (t, J= 6.9 Hz, 2 H); 3.24-3.25 (m, 2 H); 1.50-1.52 (m, 1 H); 0.84-0.86 (m, 1 H); 0.73-0.75 (m, 1 H); 0.56-0.57 (m, 1 H); 0.49-0.50 (m, 1 H).
LRMS (ESI) calc'd for C18H19 5O3S [M+H]+: 386, Found: 386.
Scheme #24
Example #6-1
Figure imgf000112_0001
1- (2-Cvano-l-cvclopropylethyl)-3-(i3-f(2-hvdroxy-2-methylpropoxy)methyllphenyl}amino)- l.H-PVrazole-4-carboxamide (Example # 6-1)
Intermediate#35-2 (3 - Amino- 1 -(2-cyano- 1 -cyclopropylethyl)- lH-pyrazole-4- carboxamide (50 mg, 0.23 mmol)), Intermediate #17 (l-[(3-bromobenzyl)oxy]-2-methylpropan-
2- ol) (67 mg, 0.27 mmol), K3P04 (97 mg, 0.46 mmol), Pd2(dba)3 (5 mg, 0.006 mmol), and di- tert-butyl[3,4,5,6-tetramethyl-2',4',6'-tri(propan-2-yl)biphenyl-2-yl]phosphane (11 mg, 0.020 mmol) were combined in a 5 mL microwave vial. Propan-2-ol (2.3 mL) was added, and then N2 gas was bubbled through the liquid for 5 minutes. The reaction vessel was sealed, heated to 80 °C, and the reaction mixture was allowed to stir for 6 hours. The reaction mixture was then
- I l l - cooled to ambient temperature and filtered through a pre-packed 2.5 g celite plug and flushed with MeOH (2 mL). The filtrate was purified by reverse-phase preparative HPLC (using a gradient elution of 35-70% MeCN/water, with 0.1% v/v TFA modifier). Desired fractions were identified, combined, and lyophilized to afford the title compound, Example # 6-1.
Ή NMR (600 MHz, CD3OD): δ 9.84 (s, IH), 9.08 (s, IH), 7.44-7.40 (m, IH), 7.20 (t, J= 7.4 Hz, IH), 6.83 (d, J= 7.4 Hz, IH), 5.42 (s, 2H), 3.70-3.65 (m, IH), 3.32-3.20 (m, 4H), 1.52-1.45 (m, IH), 1.42 (s, 6H), 0.85-0.78 (m, IH), 0.74-0.68 (m, IH), 0.58-0.51 (m, IH), 0.50-0.46 (m, IH). LRMS (ESI) calc'd for C21H27N503 [M+H]+: 398, Found: 398.
The following examples disclosed in TABLE 14 were prepared according to Scheme #24 following similar procedures described for Example #6-1, which can be achieved by those of ordinary skill in the art of organic synthesis.
Figure imgf000113_0001
Scheme #28
Example #7
Figure imgf000114_0001
1 -(2-Cvano-l -cyclopropylethyl)-3- id -oxo-2,3-dmydro-l/Msoindol-5-y Daminol - 1H- pyrazole-4-carboxamide (Example #7)
To a suspension of Example #4-2 tert-butyl 5-((4-carbamoyl-l-(2-cyano-l- cyclopropylethyl)-lH-pyrazol-3-yl)amino)-l-oxoisoindoline-2-carboxylate (30 mg, 0.067), in DCM (0.50 mL) was added TFA (0.10 mL) dropwise. The reaction mixture was stirred for 20 min at 23 °C, then was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to afford the title compound, Example #7.
LRMS (ESI) calc'd for CI8HI9N602 [M+H]+: 351, Found: 351.
Example #8
Figure imgf000114_0002
( 5- f 14-Carbamoyl-l -(2-cvano-l -cvclopropylethyl)-l//-pyrazol-3-yll amino|-l-oxo-l ,3- dihvdro-2H-isoindol-2-yl)acetic acid (Example #8)
The title compound was prepared according to the general procedure in Example #7 using Example #4-36 (tert-butyl (5-{[4-carbamoyl-l-(2-cyano-l-cyclopropylethyl)-lH- pyrazol-3-yl]amino}-l-oxo-l,3-dihydro-2H-isoindol-2-yl)acetate) (30 mg, 0.06 mmol) as a starting material.
'H NMR (500 MHz, DMSO-d6): δ 9.54 (s, 1 H); 8.35 (s, 1 H); 7.89 (s, 1 H); 7.73 (s, 1 H); 7.52 (s, 2 H); 7.21 (s, 1 H); 4.43 (s, 2 H); 4.21 (s, 2 H); 3.84 (t, J = 8.1 Hz, 1 H); 3.27 (d, J = 5.8 Hz, 2 H); 1.38 (s, 1 H); 0.71 (s, 1 H); 0.51-0.60 (m, 2 H); 0.41 (s, 1 H). LRMS (ESI) calc'd for
C20H20N6O4 [M+H]+: 409, Found: 409.
Scheme #27
Figure imgf000115_0001
l-(2-Cvanopropyl)-3-[(4-fluorophenyl)aminol-lg-pyrazole-4-carboxamide (Example #9)
In a microwave vial were combined Intermediate #31-7 (3-[(4- fluorophenyl)amino]-lH-pyrazole-4-carboxamide) (50 mg, 0.23 mmol), 3-chloro-2-methyl- propionitrile (36 mg, 0.34 mmol), Cs2C03 (89 mg, 0.27 mmol), and DMF (1.14 mL). The reaction vessel was capped and the reaction mixture was heated in a microwave to 150 °C and allowed to stir for 30 minutes. The resulting solution was filtered and purified directly by mass- triggered, reverse phase preparative HPLC (using a gradient elution of 10-100% MeCN/water, with 0.1% v/v TFA modifier). Desired fractions were identified, combined and lyophilized to afford the title compound, Example #9, as a white solid.
1H NMR (600 MHz, DMSO-d6): δ 9.08 (s, 1H), 8.14 (s, 1H), 7.65 (br s, 1H), 7.54-7.48 (m, 2H), 7.10 (br s, 1H), 7.05-6.98 (m, 2H), 4.30-4.20 (m, 2H), 3.45-3.35 (m, 1H), 1.23 (d, J=7.0 Hz, 3H).
LRMS (ESI) calc'd for Ci4H14FN50 [M+H]+: 288, Found: 288.
Scheme #27
Example #10
Figure imgf000115_0002
l-(2-Cvano-l-methylethylV3-(f4-fmethylsulfonvnphenyllaminol-lg-pyrazole-4- carboxamide (Example #10)
Cs2C03 (93 mg, 0.29 mmol) was added to a solution of Intermediate 34-2 (3- {[4-(methylsulfonyl)phenyl]amino}-lH-pyrazole-4-carboxamide) (40 mg, 0.14 mmol) and 3- bromobutanenitrile (32 mg, 0.22 mmol) in NMP (0.71 mL). The resulting mixture was heated to 120 °C in a microwave and allowed to stir for 15 minutes. The reaction mixture was cooled to 100 °C and allowed to continue stirring for 20 hours. The reaction mixture was then allowed to cool to ambient temperature, filtered through a 0.45 micron frit, and washed with DMSO. The filtrate was purified by reverse-phase preparative HPLC (MeCN/water, with 0.1% v/v TFA modifier) to afford the title compound, Example #10.
1H NMR (500 MHz, DMSO-d6): δ 9.58 (s, 1H), 8.29 (s, 1H), 7.74-7.71 (m, 4H), 7.69 (br s, 1H), 7.22 (br s, 1H), 4.70-4.64 (m, 1H), 3.12-3.10 (m, 2H), 3.09 (s, 3H), 1.51 (d, J= 5.5 Hz, 3H). LRMS (ESI) calc'd for C15Hi7N503S [M+H]+: 348, Found: 348.
Scheme #28
Example #11-1
Figure imgf000116_0001
2-(Dimethylamino)ethyl 4- i-(4-carbamoyl-3-f(4-flttorophenyl)aminol-lJH-pyrazol-l-y -2- cvanoethyl)piperidine-l-carboxylate (Example 11-1)
To a solution of N,N-dimethylaminoethanol (11 mg, 0.13 mmol) in acetonitrile
(0.47 mL) was added TEA (12 iL, 0.09 mmol) followed by Ν,Ν'-disuccinimidyl carbonate (33 mg, 0.13 mmol). The resulting mixture was allowed to stir at ambient temperature for 1.5 hours. A solution of Intermediate #38 (4-{4-carbamoyl-3-[(2-fluoropyridin-4-yl)amino]-lH-pyrazol-l- yl}-4-(cyanomethyl)piperidinium trifluoroacetate) (40 mg, 0.09 mmol) in DMSO (0.47 mL) was then added to the reaction mixture dropwise. The resulting mixture was heated to 50 °C and allowed to stir for 2 hours. The crude reaction mixture was cooled to ambient temperature and purified directly by reverse-phase preparative HPLC (MeCN/water, with 0.1% v/v TFA modifier). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound, Example #11-1.
LRMS (ESI) calc'd for C23H3oFN703 [M+H]+: 472, Found: 472. 1
The following compounds shown in TABLE 15 were prepared according to Scheme #28 following similar procedures described for Example #11-1, which can be achieved by those of ordinary skill in the art of organic synthesis.
Figure imgf000117_0001
56481
Figure imgf000118_0001
Figure imgf000119_0001
Figure imgf000120_0001
Scheme #28
Figure imgf000120_0002
2-Methoxyethyl 4-f(lS)-l-i4-carbamoyl-3-f(4-fluorophenyl)amino1-lH-
Pyrazol-l-vn-2-cvanoethyl1piperidiae-l-carboxylate (Example 12-1)
In a vial were combined Intermediate #38 (4-{4-carbamoyl-3-[(2-fluoropyridin- 4-yl)amino]-lH-pyrazol-l -yl}-4-(cyanomethyl)piperidine), 2-methoxyethylchloroformate (17.0 mg, 0.213 mmol), and DIEA (0.037 ml, 0.21 mmol) in DCM (2.2 mL). The vial was capped and the reaction was allowed to stir at ambient temperature overnight. The reaction mixture was filtered through a filter plate, diluted with DMSO (200 u L), dried in vacuo (Genevac), and diluted with DMSO (800 μ. L). The crude reaction mixture was purified by reverse-phase preparative HPLC (MeCN/water, with 0.1% v/v TFA modifier). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound, Example #12-1. LRMS (ESI) calc'd for C23H3oFN703 [M+H]+: 459, Found: 459. 56481
The following compounds shown in TABLE 16 were prepared according to Scheme #28 following similar procedures described for Example #12-1, which can be achieved by those of ordinary skill in the art of organic synthesis.
TABLE 16
Figure imgf000121_0001
1
Figure imgf000122_0002
Scheme #28
Example #13
Figure imgf000122_0001
l-((lS)-l-fl-(6- Chloro-5-methylpyrimidin-4-yl)DiDeridin-4-yll-2-cvanoethyl)-3-K4- fluorophenyl)amino1-l/7-pyrazole-4-earboxamide (Example #13)
In a vial were combined Intermediate #38 (4-{4-carbamoyl-3-[(2-fluoropyridin- 4-yl)arnino]-lH-pyrazol-l-yl}-4-(cyanomethyl)piperidine) (75 mg, 0.16 mmol), 4,6-dichloro-5- methylpyrimidine (29 mg, 0.18 mmol) and DIEA (44 μΐ, 0.25 mmol) in ethanol (530 μΐ). The vial was capped and the reaction mixture was heated to 80° C. The reaction was cooled to ambient temperature and the crude reaction mixture was purified by reverse-phase preparative HPLC (MeCN/water, with 0.1% v/v TFA modifier). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound, Example #13.
LRMS (ESI) calc'd for C23H3oFN703 [M+H]+: 483, Found: 483.
CHIRAL RESOLUTION
The following experimental procedures exemplify the chiral resolution and isolation of enantiopure Examples of the instant invention. The following Examples are for illustrative purposes only and are not intended to limit the scope of the instant invention in any way. 12 056481
Examples #14-1 and 14-2
Figure imgf000123_0001
1-[(1R or lSV2-Cvano-l-cvclopropylethyl1-3-ii4-(methylsulfonyl)phenyl1amino|-ljHr- pyrazole-4-carboxamide (Example #14-1 and #14-2
1-[(1S,2S and lR,2R)-2-Cyanocyclohexyl]-3-({4-
[(trifluoromethyl)sulfonyl] phenyl}amino)-lH-pyrazole-4-carboxamide (Example #4-1) was chirally resolved to the two constituent enantiomers by chiral SFC (Chiral Technology IC-H, 2.1x25 cm, 35% MeOH-C02, 100 mL/min, 35 °C, 100 bar). Desired fractions were identified, combined, and concentrated in vacuo to afford enantiomerically pure samples of the title compounds:
Example 14-1: First-eluting enantiomer, 1-[(1R or lS)-2-cyano-l-cycIopropyIethyI]-3-{[4- (methylsulfonyl)phenyl]amino}-lH-pyrazole-4-carboxamide.
Ή-NMR data is consistent with spectral data reported for the racemic mixture, Example# 4-1. Example 14-2: Second-eluting enantiomer, 1-[(1R or lS)-2-cyano-l-cyclopropylethyl]-3-{[4- (methylsulfonyl)phenyl] amino}-lH-pyrazole-4-carboxamide
1H-NMR data is consistent with spectral data reported for the racemic mixture, Example# 4-1.
The following compounds shown TABLE 17 were prepared following similar procedures described for Examples #14-1 and 14-2, which can be achieved by those of ordinary skill in the art of organic synthesis.
Figure imgf000123_0002
Figure imgf000124_0001
Example 15-1
Figure imgf000124_0002
fe -Biityl 4-K1S or lR)-l-[4-carbamoyl-3-(phenylainino)-lJH-pyrazol-l-yll-2- cvanoethyl)piperidine-l-carboxylate (Example # 15-1)
tert-Butyl 4-{(lS and lR)-l-[4-carbamoyl-3-(phenylamino)-lH-pyrazol-l-yl]-2- cyanoethyl}piperidine-l -carboxylate was chirally resolved to the constituent enantiomers by chiral SFC (Chiral Technology IB-H, 2.1x25 cm, 30% MeOH/C02, 70 mL/min). Desired fractions were identified, combined, and concentrated in vacuo to afford enantiomerically pure samples of the title compounds. The first enantiomer to elute from the column potently inhibits JAK1, the second enantionmer to elute from the column is not a potent inhibitor of JAK1.
Example 15-1 (first enantiomer to elute): tert-Butyl 4-{(lS or lR)-l-[4-carbamoyl-3- (phenylamino)-lH-pyrazol-l-yl]-2-cyanoethyl}piperidine-l-carboxylate, first enantiomer to elute from column.
'H NMR (600 MHz, DMSO-d6): δ 9.10 (s, 1H), 8.14 (s, 1H), 7.61 (br s, 1H), 7.47 (d, J= 7.9 Hz, 2H), 7.20 (t, J- 7.9 Hz, 2H), 7.11 (br s, 1H), 6.79 (t, J= 7.3 Hz, 1H), 4.32-4.25 (m, 1H), 4.00- 3.80 (m, 2H), 3.20-3.10 (m, 2H), 2.80-2.40 (m, 2H), 2.05-1.95 (m, 1H), 1.70 (d, J= 10.3 Hz, 1H), 1.32 (s, 9H), 1.12-0.98 (m, 3H). LRMS (ESI) calc'd for C23H30N6O3 [M+H]+: 439, Found: 439.
Figure imgf000125_0001
1-KlR or lS)-l-(Cvanomethyl)propyll-3-(phenylamino)-lJH-pyrazole-4-carboxamide
(Example # 16-1 and #16-2)
1-[(1R and lS)-l-(Cyanomethyl)propyl]-3-(phenylamino)-lH-pyrazole-4- carboxamide was chirally resolved to the constituent enantiomers by chiral SFC (Chiral
Technology OD-H, 2.1x25 cm, 25% MeOH/C02, 60 mL/min). Desired fractions were identified, combined, and concentrated in vacuo to afford enantiomerically pure samples of the title compounds:
Example 16-1: 1-[(1R or lS)-l-(cyanomethyl)propyl]-3-( henylarnino)-lH-pyrazole-4- carboxamide, first enantiomer to elute from column.
Ή NMR (600 MHz, CDC13): δ 8.73 (br. S, 1H), 7.59 (s, 1H), 7.53-7.50 (m, 2H), 7.29-7.25 (m, 2H), 6.89 (t, J= 7.3 Hz, 1H), 5.34 (br. S, 2H), 4.20-4.12 (m, 1H), 2.97 (ddd, J= 22.0, 16.9, 6.4 Hz, 2H), 2.31-1.84 (m, 2H), 0.89 (t, J= 7.3 Hz, 3H).
LRMS (ESI) calc'd for C15H17N50 [M+H]+: 284, Found: 284.
Example 16-2: 1-[(1R or lS)-l-(cyanomethyl)propyl]-3-(phenylamino)-lH"-pyrazole-4- carboxamide, second enantiomer to elute from column.
Ή NMR (600 MHz, CDC13): 5 8.73 (br. S, 1H), 7.59 (s, 1H), 7.52 (d, J= 7.7 Hz, 2H), 7.28-7.25 (m, 2H), 6.89 (t, J= 7.3 Hz, 1H), 5.39-5.29 (br. S, 2H), 4.19-4.13 (m. 1H), 2.97 (ddd, J= 22.0,
17.0, 6.4 Hz, 2H), 2.23-1.88 (m, 2H), 0.89 (t, J= 7.3 Hz, 3H).
LRMS (ESI) calc'd for C15H17N50 [M+H]+: 284, Found: 284.
The following compounds shown in TABLE 18 were prepared following similar procedures described for Examples #16-1 and 16-2, which can be achieved by those of ordinary skill in the art of organic synthesis.
Figure imgf000126_0002
amples 17-1 and 1
Figure imgf000126_0001
1-K2S or 2R)-l-Cvanopropan-2-yll-3-(phenylamino)-lg-pyrazole-4-carboxamide (Example
# 17-1 and #17-2)
1-[(2S and 2R)-l-cyanopropan-2-yl] -3 -(phenylamino)- lH-pyrazole-4- carboxamide was chirally resolved to the constituent enantiomers by chiral SFC (Chiral
Technology OD-H, 2.1x25 cm, 20%MeOH + 0.2% diethylamine /C02). Desired fractions were identified, combined, and concentrated in vacuo to afford enantiomerically pure samples of the title compounds:
Example 17-1: 1-[(2S or 2R)-l-cyanopropan-2-yl]-3-(phenylamino)-lH-pyrazole-4- carboxamide, first enantiomer to elute from column.
LRMS (ESI) calc'd for C14H15N50 [M+H]+: 270, Found: 270.
Example 17-2: 1-[(2S or 2R)-l-cyanopropan-2-yl]-3-(phenylamino)-lH-pyrazole-4- carboxamide, second enantiomer to elute from column.
LRMS (ESI) calc'd for C14H15N50 [M+H]+: 270, Found: 270. The following examples shown in TABLE 19 were prepared following similar procedures described for Examples #17-1 and 17-2, which can be achieved by those of ordinary skill in the art of organic synthesis.
Figure imgf000127_0002
Examples #18-1 and 18-2
Figure imgf000127_0001
l-f(lR or lSV2-Cvano-l-cvclopropylethyll-3-if4-(3-methvI-1.2,4-oxadiazol-5- yl)phenyllamino)-lH-pyrazole-4-carboxamide (Example #18-1 and #18-2)
l-[(lR and lS)-2-Cyano-l-cyclopropylethyl]-3-{[4-(3-methyl-l,2,4-oxadiazol-5- yl)phenyl]amino}-lH-pyrazole-4-carboxamide was chirally resolved to the constituent enantiomers by chiral SFC (Chiral Technology IA-H, 2.1x25 cm, 35% MeOH/C02, 70 mL/min). Desired fractions were identified, combined, and concentrated in vacuo to afford
enantiomerically pure samples of the title compounds:
Example 18-1: l-[(lR or lS)-2-cyano-l-cyclopropylethyl]-3-{[4-(3-methyl-l,2,4-oxadiazol-5- yl)phenyl]amino}-lH-pyrazole-4-carboxamide, first enantiomer to elute from column..
1H NMR (500 MHz, CD3OD): δ 8.28 (s, 1H), 8.00 (d, J= 8.8 Hz, 2H), 7.74 (d, J= 8.8 Hz, 2H), 3.80-3.70 (m, 1H), 3.38-3.24 (m, 2H), 2.40 (s, 3H), 1.58-1.48 (m, 1H), 0.90-0.80 (m, 1H), 0.78- 0.70 (m, 1H), 0.62-0.54 (m, 1H), 0.54-0.46 (m, 1H).
LRMS (ESI) calc'd for C19H19N702 [M+H]+: 378, Found: 378.
Example 18-2: 1-[(1R or lS)-2-cyano-l-cyclopropylethyl]-3-{[4-(3-methyl-l,2,4-oxadiazol-5- yl)phenyl] amino } - 1 H-pyrazole-4-carboxamide, second enantiomer to elute from column.
1H NMR (500 MHz, CD3OD): δ 8.28 (s, 1H), 8.00 (d, J= 8.8 Hz, 2H), 7.74 (d, J= 8.8 Hz, 2H),
3.80-3.70 (m, 1H), 3.38-3.24 (m, 2H), 2.40 (s, 3H), 1.58-1.48 (m, 1H), 0.90-0.80 (m, 1H), 0.78-
0.70 (m, 1H), 0.62-0.54 (m, 1H), 0.54-0.46 (m, 1H).
LRMS (ESI) calc'd for C19H19N702 [M+H]+: 378, Found: 378.
Examples 19-1 and 19-2
Figure imgf000128_0001
1-[(1R or lS)-2-Cvano-l-cvclopropylethyll-3-f(l-oxo-2.3-dihvdro-l -isoindol-5-vnamino]- l//-pyrazole-4-carboxamide (Example #19-1 and #19-2)
1-[(1R and 1 S)-2-cyano-l-cyclopropylethyl]-3-[(l-oxo-2,3-dihydro-lH-isoindol- 5-yl)amino]-lH-pyrazole-4-carboxamide was chirally resolved to the constituent enantiomers by chiral SFC (Chiral Technology ΙΑ-Η, 2.1x25 cm, 30% EtOH/C02, 70 mL/min). Desired fractions were identified, combined, and concentrated in vacuo to afford enantiomerically pure samples of the title compounds:
Example 19-1: l-[(lR or lS)-2-cyano-l-cyclopropylethyl]-3-[(l-oxo-2,3-dihydro-lH-isoindoI- 5-yl)amino]-lH-pyrazole-4-carboxamide, first enantiomer to elute from column..
LRMS (ESI) calc'd for ¾Η18Ν602 [M+H]+: 351, Found: 351. Example 19-2: l-[(lR or lS)-2-cyano-l-cyclopropylethyl]-3-[(l-oxo-2,3-dihydro-lH-isoindol- 5-yl)amino]-lH-pyrazole-4-carboxamide, second enantiomer to elute from column.
LRMS (ESI) calc'd for Ci8H18N602 [M+H]+: 351, Found: 351. BIOLOGICAL ASSAYS
Jak Biochemical HTRF Assay Protocol
The ability of compounds to inhibit the activity of JAK1, JAK2, JAK3, and Tyk2 was measured using a recombinant purified GST-tagged catalytic domain for each enzyme (Invitrogen JAK1 #M4290, JAK2 #M4290, JAK3 #M4290, Tyk2 #M4290) in an HTRF format biochemical assay. The reactions employed a common peptide substrate, LCB-
EQEDEPEGDYFEWLW-NH2 (in-house). The basic assay protocol is as follows: First, 250 nL of diluted compounds in DMSO were dispensed into the wells of a dry 384-well Black plate (Greiner #781076) using a Labcyte Echo 555 acoustic dispenser. Subsequent reagent additions employed an Agilent Bravo. Next, 18 μΐ, of 1.1 IX enzyme and 1.1 IX substrate in IX assay buffer (Invitrogen kinase buffer # PV3189, 2 mM DTT, 0.05% BSA) were added to the wells and shaken and then preincubated for 30 minutes at room temperature to allow compound binding to equilibrate. After equilibration, 2 μΐ, of 10X ATP in IX assay buffer was added to initiate the kinase reaction and the plates were shaken and then incubated at room temperature for 120 minutes. At the end of the incubation, 20 μΐ, of 2X stop buffer (streptavidin-Dylight 650 (Thermo #84547B/1 OOmL), Eu-tagged pY20 antibody (Perkin Elmer #AD0067), EDTA,
HEPES, and Triton) was added to quench the reaction. Plates were shaken and centrifuged and then incubated 60 minutes at room temperature and then read on a Perkin Elmer Envision KQX = 337 nm, λβη = 665 and 615 nm, TRF delay time = 20 μβ). HTRF signal = 10,000 * 665 nm reading / 615 nm reading. After normalization to untreated controls, the percent inhibition of the HTRF signal at each compound concentration was calculated. The plot of percent inhibition versus the log of compound concentration was fit with a 4-parameter dose response equation to calculate IC50 values.
Final reaction conditions were:
Figure imgf000129_0001
Compound concentrations tested were 1496, 499, 175, 49.9, 18.7, 6.2, 2.1, 0.75, 0.24, 0.075, and 0.0125 nM, with 1.25% residual DMSO.
BIOLOGICAL DATA
Examples of the instant invention were evaluated in JAKl and JAK2 in vitro binding assays as described above. The Table 20 tabulates the JAKl IC50 values and JAK2 IC50 values disclosed for the instant invention.
Table 20.
Figure imgf000130_0001
Example # JAK1 ICso (nM) JAK2 ICso (nM)
4-13 2 21
4-14 5 33
4-15 9 39
4-16 19 64
4-17 13 43
4-18 131 425
4-19 2 17
4-20 24 87
4-21 8 45
4-22 3 16
4-23 2 21
4-24 41 262
4-25 42 221
4-26 65 277
4-27 166 290
4-28 11 75
4-29 2 13
4-30 15 226
4-31 2 7
4-32 1 13
4-33 1 23
4-34 2 20
4-35 2 34
4-36 5 39
4-37 5 44
5 1 15
6-1 47 115
6-2 360 1481
6-3 1 10
6-4 1 3
7 2 38
8 1 34
9 59 524
10 7 45
11-1 959 1496
11-2 55 890
11-3 122 1496
11-4 52 861
11-5 33 1167
11-6 69 1202
11-7 7 425
11-8 220 1496
11-9 108 1032
11-10 44 1156
11-11 46 1038
11-12 181 1496
11-13 753 1496
12-1 181 1496
12-2 718 1496
12-3 245 1496
12-4 44 1055 Example # JAK1 ICso (nM) JAK2 ICso (nM)
12-5 628 1496
12-6 190 1496
13 823 1496
14-1 1 8
14-2 5 55
14-3 92 903
14-4 487 1496
15-1 13 601
16-1 43 578
16-2 136 800
16-3 47 742
16-4 141 567
17-1 224 1128
17-2 47 469
17-3 10 79
17-4 2 16
17-5 16 190
18-1 2 19
18-2 34 257
19-1 1 15
19-2 6 105

Claims

WHAT IS CLAIMED IS:
1. A compound of formula I or a pharmaceutically acceptable salt or stereoisomer thereof:
Figure imgf000133_0001
Ra and R4 are each independently selected from hydrogen and Ci-4alkyl;
R5 is selected from aryl and heteroaryl, wherein R5 is substituted with 0, 1, 2, 3, or 4, substituents, R5a;
R1, R2, and R3 are each independently selected from
hydrogen,
halogen,
Cl-i o alkyl,
C2-10 alkenyl,
Cl-io heteroalkyl,
aryl CO-10 alkylCO-10 alkyl*
C3-8 cycloalkylCo-10 alkyl,
heteroaryl CO-10 alkyl,
(C3-8)heterocycloalkyl Co-10 alkyl,
wherein each of R1, R2, and R3 are independently substituted with 0, 1, 2, 3, substituents R5a;
R5a is selected from:
halogen,
Ci-10 alkyl(oxy)0-1(carbonyl)0-lC0-10 alkyl,
Ci-io heteroalkyl(oxy)o-1(carbonyl)0-lCo-10 alkyl,
C2-IO alkenyl(oxy)0-i(carbonyl)o-lCO-10 alkyl,
aryl Co-10 alkylCoxy^Ccarbony o-lCO-lO alkyl,
aryl C2-10 alkenyl(oxy)0-1(carbonyl)0-lC0-10 alkyl,
aryl C2-10 alkynyl(oxy)0-1(carbonyl)0-lCo-10 alkyl, C3-8 cycloalkyl Co-10 alkyl(oxy)0-1(carbonyl)0-lC0-10 alkyl, heteroaryl CO-10 alkyl(oxy)o-i(carbonyl)o-l CO-10 alkyl,
(C3-8)heterocycloalkyl Co-10
Figure imgf000134_0001
alkyl,
Ci-io alkyl(carbonyl)o-loxyCo-10 alkyl,
Ci-io heteroalkyl(carbonyl)0-loxyCo-10 alkyl,
C2-10 alkenyl(carbonyl)0-loxyCo-10 alkyl,
Ci-io heteroalkyl(carbonyl)o-loxyCo-10 alkyl,
aryl CO-10 alkyl (carbonyl)o-loxyCo-lO alkyl,
(C3-8)cycloalkyl Co-10 alkyl(carbonyl)o-loxyCo-10 alkyl, heteroarylCO-10 alkyl(carbonyl)o-loxyCo-10 alkyl,
(C3-8)heterocycloalkyl Co-10 alkyl(carbonyl)0-loxyCo-10 alkyl,
((CO- 10)alkyl) 1 -2aminocarbonyloxy,
(CO- 10)neteroalkylaminocarbonyloxy,
aryl (Co-lO)alkylaminocarbonyloxy,
(C3 -8)cycloalkyl(Co- 1 o)alkylaminocarbonyloxy,
heteroaryl(Co- 10)alkylaminocarbonyloxy,
(C3 -8)heterocycloalkyl(Co- 10)alkylaminocarbonyloxy,
Ci-io alkylamino(oxy)o-icarbonylCo-10 alkyl,
(Co-10)heteroalkylamino(oxy)o-icarbonylCo-10 alkyl,
C3-8 cycloalkyl CO-10 alkylamino(oxy)0-1carbonylCo-10 alkyl, aryl Co-lOalkylaminoioxy^earbonylCo-lO alkyl,
heteroarylCo- 1 oalkylamino(oxy)o-1 carbonylCo- 10 alkyl,
(C3 -8)heterocycloalkylC0- 1 oalkylamino(oxy)0-1carbonylC()- 10 alkyl,
Ci-io alkyl (oxy)0-icarbonylaminoCo- 10 alkyl,
Ci-io heteroalkyl (oxy)0-1carbonylaminoCo-10 alkyl,
C3-8 cycloalkyl Co-10 alkyl (oxy)0-1carbonylaminoCo-10 alkyl, aryl Co-10 alkyl(oxy)0-icarbonylaminoCo-10 alkyl,
heteroaryl Co-10 alkyl(oxy)0-1carbonylaminoCo-10 alkyl,
(C3-8)heterocycloalkyl Co-10 alkyl(oxy)0.1carbonylaminoC0-10 alkyl,
-CO2(C0-10 alkyl),
-(Co-10 alkyl)C02H, Οχο (=0),
Cl-io alkylsulfonyl,
Ci-io heteroalkylsulfonyl,
(C3-8) cycloalkylsulfonyl,
(C3-8) cycloheteroalkylsulfonyl,
heteroarylsulfonyl,
arylsulfonyl,
aminosulfonyl,
-S02N(Ci-6alkyl)1-2,
-S02Ci-6alkyl,
-SO2CF3,
-SO2CF2H,
Ci-io alkylsulfinyl,
amino,
(Co-10 alkyl)1-2 amino,
Cl-4acylamino Co-10 alkyl,
hydroxy,
Co-10 alkylalkoxy,
cyano,
Ci-6alkylcyano, and
Ci-6haloalkyl;
wherein R5a is each optionally substituted with 0, 1, 2, 3, or 4 R6 substituents and R6 independently selected from:
halogen,
Cl-io alkyl(oxy)0-1(carbonyl)o-lCO-10 alkyl,
Ci-io heteroalkyl(oxy)o-i(carbonyl)0-lCO-10 alkyl,
C2-10 alkenyl(oxy)0-1(carbonyl)0-lC0-10 alkyl,
aryl Co-10 alkyl(oxy)0-1(carbonyl)0-lC0-10 alkyl,
aryl C2-10 alkenyl(oxy)0-1(carbonyl)0-lCo-10 alkyl,
aryl C2-10 alkynyl(oxy)0-i(carbonyl)0-lCo-10 alkyl,
C3-8 cycloalkyl Co-10 alkyl(oxy)0-1(carbonyl)0-lCo-10 alkyl,
heteroaryl Co-10 alkyl(oxy)o-i(carbonyl)0-lCo-10 alkyl, (C3-8)heterocycloalkyl Co-10 alkyl(oxy)0-1(carbonyl)o-lCo-10 alkyl,
Ci-io alkyl(carbonyl)o-loxyCO-10 alkyl,
C2-10 alkenyl(carbonyl)0-loxyCo-10 alkyl,
Ci-io heteroalkyl(carbonyl)0-loxyC0-10 alkyl,
aryl Co-10 alkyl (carbonyl)O-loxyCo-lO alkyl,
(C3-8)cycloalkyl Co-10 alkyl(carbonyl)0-loxyCo-10 alkyl, heteroarylCo-10 alkyl(carbonyl)o-loxyCo-10 alkyl,
(C3-8)heterocycloalkyl Co-10 alkyl(carbonyl)0-loxyCo-10 alkyl,
((CO- 10)alkyl) i ^aminocarbonyloxy,
aryl (Co-lO)alkylaminocarbonyloxy,
(C3-8)cycloalkyl(C0-10)alkylaminocarbonyloxy,
heteroaryl(Co- 1 o)alkylaminocarbonyloxy,
(C3-8)heterocycloalkyl(Co- 1 o)alkylaminocarbonyloxy,
Ci-io alkylamino(oxy)0-1carbonylCo-10 alkyl,
C3_8 cycloalkyl Co-10 alkylamino(oxy)0.1carbonylCo-10 alkyl, aryl Co-10 alkylamino(oxy)0-1carbonylCo-10 alkyl,
heteroaryl Co-10 alkylamino(oxy)0-1carbonylC0-10 alkyl,
(C3-8)heterocycloalkyl Co-10 alkylamino(oxy)0-1carbonylCo-10 alkyl,
Ci-io alkyl (oxy)0-1carbonylaminoCo-10 alkyl,
C3-8 cycloalkyl Co-10 alkyl (oxy)o-1carbonylaminoCo-10 alkyl, aryl Co-10 alkyl(oxy)0-1carbonylaminoCo-10 alkyl,
heteroaryl Co-10 alkyl(oxy)0-icarbonylaminoCo-10 alkyl,
(C3-8)heterocycloalkyl Co-10 alkyl(oxy)0-1carbonylaminoCo-10 alkyl,
-C02(Co-10 alkyl),
-(Co-10 alkyl)C02H,
Oxo (=0);
Ci-io alkylsulfonyl,
Ci-io heteroalkylsulfonyl,
(C3-8) cycloalkylsulfonyl,
(C3-8) cycloheteroalkylsulfonyl,
heteroarylsulfonyl, arylsulfonyl,
aminosulfonyl,
-S02N(Ci-6alkyl)i-2,
-S02Ci-6alkyl,
-SO2CF3,
-SO2CF2H,
Ci-io alkylsulfinyl,
-OSi(Ci.i0alkyl)3,
amino,
(Co- 10 alkyl) i-2 amino,
-(oxy)o- 1 (carbonyl)o- lN(Co- 10 alkyl) 1 -2
Ci-4acylamino Co-10 alkyl,
hydroxy,
Ci-io alkoxy,
cyano, and
Ci_6haloalkyl; and
wherein R6 is optionally substituted with 0, 1, 2, or 3 substituents independently selected from hydroxy, (Ci-6)alkoxy, halogen, CO2H, -(Co-6)alkylCN, -0(C=0)Ci-C6 alkyl, NO2, trifluoromethoxy, trifluoroethoxy, -N-C(0)0(Co-6)alkyl, Ci-io alkylsulfonyl,
Ci-io heteroalkylsulfonyl, oxo (0=), (C3-8) cycloalkylsulfonyl,
(C3-8) cycloheteroalkylsulfonyl, heteroarylsulfonyl, arylsulfonyl, aminosulfonyl,
-S02N(Ci_6alkyl)1-2, -S02Ci-6alk l, -SO2CF3, -SO2CF2H, -Ci-io alkylsulfinyl,
-OSi(Ci.i oalkyI)3, -0(0-l)(Ci_lo)haloalkyl, and NI¾
with the proviso that the compound of formula I is other than:
2-(dimethylamino)ethyl 4-(l - {4-carbamoyl-3-[(4-fluorophenyl)amino]- IH-pyrazol- 1 - yl} -2-cyanoethyl)piperidine- 1 -carboxylate; and
1 - [( 1 S or 1 R)-2-cyano- 1 -cyclopropylethyl] -3 -(phenylamino)- 1 H-pyrazole-4- carboxamide.
2. A compound according to claim 1 , wherein Ra and R4 are hydrogen.
3. A compound according to claim 1, wherein R a is selected from: halogen,
C i . i o alkyl(oxy)0- : (carbonyl)O- 1 Co- 10 alkyl,
Ci-io heteroalkyl(oxy)0-1(carbonyl)0-lCo-10 alkyl,
C2-10 alkenyl(oxy)0-1(carbonyl)o-lCo-10 alkyl,
aryl Co-10 alkyl(oxy)0.1(carbonyl)o-lCO-10 alkyl,
aryl C2-10 alkenyl(oxy)0-1(carbonyl)0-lC0-10 alkyl.
aryl C2-10 alkynyl(oxy)0-1(carbonyl)o-lCo-10 alkyl,
C3.8 cycloalkyl Co-10 alkyl(oxy)0-1(carbonyl)0-lCo-10 alkyl, heteroaryl Co-10 alkyl(oxy)0-1(carbonyl)0-lCo-10 alkyl,
(C3-8)heterocycloalkyl Co-10 alkyl(oxy)o-i(carbonyl)0-lCO-10 alkyl, Ci-io alkyl(carbonyl)0-loxyCo-10 alkyl,
((CO- 10)alkyl) i ^aminocarbonyloxy,
Ci-io alkylamino(oxy)0-1carbonylCo-10 alkyl,
Ci-io alkyl(oxy)o-icarbonylaminoCo-10 alkyl,
aryl Co-10 alkyl(oxy)o-1carbonylaminoCo-10 alkyl,
heteroaryl Co-10 alkyl(oxy)0-icarbonylaminoCo-10 alkyl,
-C02(Co-10 alkyl),
-(Co-10 alkyl)C02H,
Oxo (=0),
Ci-io alkylsulfonyl,
aminosulfonyl,
-S02N(Ci.6alkyl)I-2,
-S02Ci-6alkyl,
-SO2CF3,
-SO2CF2H,
Ci-io alkylsulfinyl,
amino,
(Co-10 lkyl)1-2 amino,
hydroxy,
Co-10 alkylalkoxy,
cyano, Ci-6alkylcyano, and
Ci_6haloalkyl;
wherein R5a is each optionally substituted with 0, 1, 2, 3, or 4 R6.
4. A compound according to Claim 1 , wherein R is selected from: halogen,
Ci-io alkyl(oxy)0-i(carbonyl)o-lC()-10 alkyl, Ci-io heteroalkyl(oxy)0-1(carbonyl)0-lCo-10 alkyl, aryl Co-10 alkyl(oxy)0-i(carbonyl)0-lC0-10 alkyl,
C3-8 cycloalkyl Co-10 alkyl(oxy)0-i(carbonyl)o-lCO-10 alkyl,
heteroaryl Co-10 alkyl(oxy)0-1(carbonyl)0-lCo-10 alkyl,
(C3-8)heterocycloalkyl CO-10 alkylCoxy carbony^O-lCO-lO alkyl,
Ci-io alkyl (oxy)0-1carbonylaminoCo-10 alkyl,
C3-8 cycloalkyl Co-10 alkyl (oxy)o-icarbonylaminoCo-lO alkyl,
aryl CO-10 alkyl(oxy)o-icarbonylaminoCo-10 alkyl,
heteroaryl Co-10 alkyl(oxy)o-1carbonylaminoCo-10 alkyl,
(C3-8)heterocycloalkyl Co-10 alkyl(oxy)0-1carbonylaminoCo-10 alkyl, -CO2(C0-10 alkyl), Oxo,
Ci-io alkylsulfonyl, Cl-10 heteroalkylsulfonyl, (C3-8) cycloalkylsulfonyl,
(C3-8) cycloheteroalkylsulfonyl, heteroarylsulfonyl, arylsulfonyl,
aminosulfonyl, -S02Cl-6alkyl, amino, (Co-10 alkyl)1-2 amino, hydroxy, Ci-io alkoxy, cyano, and Cl- 6haloalkyl; wherein R6 is optionally substituted.with 0, 1, 2, or 3 substituents selected from hydrogen, hydroxy, (C 1 -6)alkoxy, halogen, CO2H, -(C0-6)alkylCN, -0(C=0)C 1 -C6 alkyl, Νθ2, trifluoromethoxy, trifluoroethoxy, -N-C(O)O(C0-6)alkyl, Cl-10 alkylsulfonyl, Cl-10
heteroalkylsulfonyl, oxo (0=), (C3-8) cycloalkylsulfonyl, (C3-8) cycloheteroalkylsulfonyl,
heteroarylsulfonyl, arylsulfonyl, aminosulfonyl, -S02N(Cl-6alkyl),-2, -S02Cl-6alkyl, -SO2CF3, - SO2CF2H, -Cl-10 alkylsulfinyl, -OSi(Ci-ioalkyl)3, -0(0-l)(Ci-io)haloalkyl, and NH2.
5. . A compound of Group A, or a pharmaceutically acceptable salt, or a stereoisomer thereof, where in the compound of Group A is selected from:
1 -(2-cyano- 1 -cyclopropylethyl)-3 -(phenylamino)- lH-pyrazole-4-carboxamide;
tert-butyl 4- { 1 -[4-carbamoyl-3-(phenylamino)- IH-pyrazol- 1 -yl]-2-cyanoethyl}piperidine-l - carboxylate;
tert-butyl 3 -( 1 - {4-carbamoyl-3 - [(4-fluorophenyl)amino] - 1 H-pyrazol- 1 -yl } -2- cyanoethyl)pyrrolidine - 1 -carboxylate;
1 -(2-cyanoethyl)-3-(phenylamino)- lH-pyrazole-4-carboxamide; 1 -(2-cyano-l -cyclopentylethyl)-3-({4-[(l , 1 -dioxidottøomoφholin-4-yl)carbonyl]phenyl}amino)- lH-pyrazole-4-carboxamide;
1 -(2-cyano- 1 -methylethyl)-3 -(phenylamino)- 1 H-pyrazole-4-carboxamide;
l-[l-(cyanomet yl)propyl]-3-(phenylamino)-lH-pyrazole-4-carboxamide;
1 -(2-cyano- 1 -cyclopentylethyl)-3 - [(3 - { [4-( 1 -hydroxy- 1 -methylethyl)- 1 H- 1 ,2,3 -triazol- 1 - yl] methyl } phenyl)amino] - 1 H-pyrazole-4-carboxamide;
l-[2-cyano-l-(tetrahydro-2H-pyran-4-yl)ethyl]-3-^henylamino)-lH-pyrazole-4-carboxamide; 1 - [2-cyano- 1 -(tetrahydro-2H-pyran-4-ylmethyl)ethyl] -3 -(phenylamino)- 1 H-pyrazole-4- carboxamide;
l-[l-(cyanomethyl)-2-methylpropyl]-3-(phenylamino)-lH-pyrazole-4-carboxamide;
l-(2-cyano-l-cyclopropylethyl)-3-(phenylamino)-lH-pyrazole-4-carboxamide;
1 -[ 1 -(cyanomethyl)-3 ,3 -dimethylbutyl] -3 -(phenylamino)- 1 H-pyrazole-4-carboxamide;
1 - [2-cyano- 1 -(tetrahydrofuran-3 -yl)ethyl] -3 -(phenylamino)- 1 H-pyrazole-4-carboxamide;
1 - [2-cyano- 1 -(tetrahydro-2H-pyran-3 -yl)ethyl] -3 -(phenylamino)- 1 H-pyrazole-4-carboxamide ;
1 -(2-cyano- 1 -methylethyl)-3 -( {4-[( 1 , 1 -dioxidothiomorpholin-4-yl)carbonyl]phenyl} amino)- 1 H- pyrazole-4-carboxamide ;
1 - [1 -(cyanomethyl)propyl] -3 -({4-[( 1 , 1 -dioxidothiomorpholin-4-yl)carbonyl]phenyl} amino)- 1 H- pyrazole-4-carboxamide;
1 -(2-cyano- 1 -cyclopropyl- 1 -methylethyl)-3-(phenylamino)-lH-pyrazole-4-carboxamide;
1 -(2-cyano- 1 -cyclobutylethyl)-3 -(phenylamino)- 1 H-pyrazole-4-carboxamide;
1 -(2-cyano- 1 -cyclopentylethyl)-3 -(phenylamino)- lH-pyrazole-4-carboxamide;
1 -(2-cyano- 1 , 1 -dimethylethyl)-3 -(phenylamino)- lH-pyrazole-4-carboxamide;
1 -3-cyclobutan-2-yl] -3 -(phenylamino)- 1 H-pyrazole-4-carboxamide;
1-(2S, 3S)-3-cyclobutan-2-yl]-3-(phenylamino)-lH-pyrazole-4-carboxamide;
1 -(2R, 3 R)-3 -cyclobutan-2-yl] -3 -(phenylamino)- 1 H-pyrazole-4-carboxamide ;
1 -(2S, 3R)-3-cyclobutan-2-yl]-3-(phenylamino)- lH-pyrazole-4-carboxamide;
1 -(2R, 3 S)-3 -cyclobutan-2-yl]-3 -(phenylamino)- 1 H-pyrazole-4-carboxamide;
1 -(3-cyano- 1,1,1 -trifluoropropan-2-yl)-3 -(phenylamino)- 1 H-pyrazole-4-carboxamide;
tert-Butyl 4-( 1 - {4-carbamoyl-3 - [(4-fluorophenyl)amino] - 1 H-pyrazol- 1 -yl } -2- cyanoethyl)piperidine- 1 -carboxylate;
tert-butyl 4- { 1 -[4-carbamoyl-3-(phenylamino)- lH-pyrazol- 1 -yl]-2-cyanoethyl} -4- fluoropiperidine- 1 -carboxylate;
4- {2-[4-carbamoyl-3-(phenylamino)- lH-pyrazol- 1 -yl]- 1 -cyanopropan-2-yl}piperidine-
1 -carboxylate; I -(2-cyano- 1 -cyclopropylethyl)-3 - { [4-(methylsulfonyl)phenyl] amino } - 1 H-pyrazole-4- carboxamide;
'err-butyl 5- { [4-carbamoyl- 1 -(2-cyano- 1 -cyclopropylethyl)- lH-pyrazol-3-yl]amino} - 1 -oxo- 1 ,3- dihydro-2H-isoindole-2-carboxylate;
1 -(2-cyano- 1 -cyclopropylethyl)-3 - { [4-(trifluoromethyl)phenyl] amino } - 1 H-pyrazole-4- carboxamide;
I -(2-cyano- 1 -cyclopropylethyl)-3- { [3-(trifluoromethyl)phenyl]amino} - lH-pyrazole-4- carboxamide;
l-(2-cyano-l-cyclopropylethyl)-3-[(2-fluorophenyl)amino]-lH-pyrazole-4-carboxamide;
I -(2-cyano- 1 -cyclopropylethyl)-3-(pyridin-3 -ylamino)- 1 H-pyrazole-4-carboxamide;
I -(2-cyano- 1 -cyclopropylethyl)-3 - { [3 -(2-cyanoethyl)phenyl] amino } - 1 H-pyrazole-4- carboxamide;
I -(2-cyano- 1 -cyclopropylethyl)-3 - { [4-(cyanomethyl)phenyl] amino } - 1 H-pyrazole-4-carboxamide; I -(2-cyano- 1 -cyclopropylethyl)-3 - { [3 -(cyanomethyl)phenyl] amino } - 1 H-pyrazole-4-carboxamide; [ -(2-cyano- 1 -cyclopropylethyl)-3 - { [3 -(hydroxymethyl)phenyl] amino } - 1 H-pyrazole-4- carboxamide;
I -(2-cyano- 1 -cyclopropylethyl)-3 - [(4-fluorophenyl)amino] - 1 H-pyrazole-4-carboxamide;
[-(2-cyano-l-cyclopropylethyl)-3-[(2-methoxypyridin-4-yl)amino]-lH-pyrazole-4-carboxamide; L -(2-cyano- 1 -cyclopropylethyl)-3 - { [4-(methylcarbamoyl)phenyl] amino } - 1 H-pyrazole-4- carboxamide;
ί -(2-cyano- 1 -cyclopropylethyl)-3 - [(4-cyanophenyl)amino] - 1 H-pyrazole-4-carboxamide;
I -(2-cyano- 1 -cyclopropylethyl)-3 -(isoquinolin-7-ylamino)- 1 H-pyrazole-4-carboxamide;
[-(2-cyano-l-cyclopropylethyl)-3-[(3-cyanophenyl)amino]-lH-pyrazole-4-carboxamide;
[ -(2-cyano- 1 -cyclopropylethyl)-3 - [(4-morpholin-4-ylphenyl)amino] - 1 H-pyrazole-4- carboxamide;
[ -(2-cyano- 1 -cyclopropylethyl)-3 - [(5 -cyanopyridin-3 -yl)amino] - 1 H-pyrazole-4-carboxamide; [ -(2-cyano- 1 -cyclopropylethyl)-3 -[( 1 -oxo-2,3-dihydro- 1 H-inden-5-yl)amino]- 1 H-pyrazole-4- carboxamide;
-(2-cyano- 1 -cyclopropylethyl)-3-(2,3-dihydro- 1 ,4-benzodioxin-6-ylamino)- lH-pyrazole-4- carboxamide;
! - { [4-(acetylamino)phenyl] amino } - 1 -(2-cyano- 1 -cyclopropylethyl)- 1 H-pyrazole-4-carboxamide ; . -(2-cyano- 1 -cyclopropylethyl)-3 - { [4-(dimethylcarbamoyl)phenyl] amino } - 1 H-pyrazole-4- carboxamide; 1 -(2-cyano- 1 -cyclopropylethyl)-3- { [3 -(methylcarbamoyl)phenyl]amino} - 1 H-pyrazole-4- carboxamide;
l-(2-cyano-l-cyclopropylethyl)-3-{[4-(l,3-oxazol-5-yl)phenyl]amino}-lH-pyrazole-4- carboxamide;
1 -(2-cyano- 1 -cyclopropylethyl)-3- { [4-(5 -methyl- 1 ,3,4-oxadiazol-2-yl)phenyl]amino}- 1H- pyrazole-4-carboxamide;
1 -(2-cyano- 1 -cyclopropylethyl)-3- { [4-(5-methyl- 1 ,2,4-oxadiazol-3-yl)phenyl]amino } - 1 H- pyrazole-4-carboxamide;
3 - [(2-chloropyridin-4-yl)amino] - 1 -(2-cyano- 1 -cyclopropylethyl)- 1 H-pyrazole-4-carboxamide; I -(2-cyano- 1 -cyclopropylethyl)-3-({4-[(trifluoromethyl)sulfonyl]phenyl}aniino)- lH-pyrazole-4- carboxamide;
1 -(2-cyano- 1 -cyclopropylethyl)-3 -( { 4- [(difluoromethy l)sulfonyl]phenyl } amino)- 1 H-pyrazole-4- carboxamide;
l-(2-cyano-l-cyclopropylemyl)-3-[(2,3,3-trimethyl-l-oxo-2,3-dihydro-lH-isoindol-5-yl)amino]-
1 H-pyrazole-4-carboxamide;
l-(2-cyano-l-cyclopropylethyl)-3-{[l-oxo-2-(2,2,2-trifluoroethyl)-2,3-dihydro-lH-isoindol-5- yl]amino}-lH-pyrazole-4-carboxamide;
I -(2-cyano- 1 -cyclopropylethyl)-3 - { [4-(methylsulfmyl)phenyl] amino } - 1 H-pyrazole-4- carboxamide;
1 -(2-cyano- 1 -cyclopropylethyl)-3-[(2-methyl- 1 -oxo-2,3 -dihydro- 1 H-isoindol-5-yl)amino] - 1 H- pyrazole-4-carboxamide;
fert-butyl (5- { [4-carbamoyl- 1 -(2-cyano- 1 -cyclopropylethyl)- 1 H-pyrazol-3 -yljamino } - 1 -oxo- 1,3- dihydro-2H-isoindol-2-yl)acetate;
I -(2-cyano- 1 -cyclopropylethyl)-3 -[( 1 , 1 -dioxido- 1 -benzothiophen-5 -yl)amino] - 1 H-pyrazole-4- carboxamide;
[ -(2-cyano- 1 -cyclopropylethyl)-3-{ [4-(3 -methyl- 1 ,2,4-oxadiazol-5-yl)phenyl]amino}-lH- pyrazole-4-carboxamide;
I -(2-cyano- 1 -cyclopropylethyl)-3-[(2-fluoropyridin-4-yl)amino]- 1 H-pyrazole-4-carboxamide; I -(2-cyano- 1 -cyclopropylethyl)-3 -[( 1 , 1 -dioxido-2,3 -dihydro- 1 -benzothiophen-5-yl)amino]- 1H- pyrazole-4-carboxamide;
L-(2-cyano-l-cyclopropylethyl)-3-({3-[(2-hydroxy-2-methylpropoxy)methyl]phenyl}amino)-lH- pyrazole-4-carboxamide;
l-(2-cyano-l-cyclopropylethyl)-3-[(2-fluorophenyl)amino]-lH-pyrazole-4-carboxamide;
[-(2-cyano-l-cyclopropylethyl]-3-[(4-sulfamoylphenyl)amino]-lH-pyrazole-4-carboxamide; 1 -(2-cyano-l -cyclopropylethyl)-3-{ [4-(dm^
carboxamide;
1 -(2-cyano- 1 -cyclopropylethyl)-3 - [( 1 -oxo-2,3 -dihydro- lH-isoindol-5 -yl)amino] - 1 H-pyrazole-4- carboxamide;
(5- { [4-carbamoyl- 1 -(2-cyano- 1 -cyclopropylethyl)- 1 H-pyrazol-3-yl]amino} - 1 -oxo- 1 ,3 -dihydro- 2H-isoindol-2-yl)acetic acid;
1- (2-cyanopropyl)-3-[(4-fluorophenyl)amino]-lH-pyrazole-4-carboxamide;
1 -(2-cyano- 1 -methylethyl)-3 - { [4-(methylsulfonyl)phenyl] amino } - 1 H-pyrazole-4-carboxamide ;
2- (dimethylamino)ethyl 4-( 1 - {4-carbamoyl-3 - [(4-fluorophenyl)amino] - 1 H-pyrazol- 1 -yl } -2- cyanoethyl)piperidine- 1 -carboxylate;
methyl 4-( 1 - { 4-carbamoyl-3 - [(4-fluorophenyl)amino] - 1 H-pyrazol- 1 -yl } -2-cyanoethyl)piperidine-
1 - carboxylate;
2-(methylsulfonyl)ethyl 4-( 1 - {4-carbamoyl-3 - [(4-fluorophenyl)amino]- 1 H-pyrazol- 1 -yl } -2- cyanoethyl)piperidine- 1 -carboxylate;
oxetan-3 -yl 4- [ 1 - {4-carbamoyl-3 - [(4-fluorophenyl)amino] - 1 H-pyrazol- 1 -yl } -2- cyanoethyljpiperidine- 1 -carboxylate;
oxetan-3 -yl 4- [( 1 S)- 1 - {4-carbamoyl-3 - [(4-fluorophenyl)amino] - 1 H-pyrazol- 1 -yl } -2- cyanoethyl]piperidine- 1 -carboxylate;
cyclobutyl 4-[ 1 - {4-carbamoyl-3-[(4-fluorophenyl)amino]- 1 H-pyrazol- 1 -yl} -2- cyanoethyl]piperidine- 1 -carboxylate;
cyclobutyl 4- [( 1 S)- 1 - {4-carbamoyl-3 - [(4-fluorophenyl)amino]- 1 H-pyrazol- 1 -yl } -2- cyanoethyl]piperidine- 1 -carboxylate;
cyclopentyl 4-[ 1 - {4-carbamoyl-3-[(4-fluorophenyl)amino]- 1 H-pyrazol- 1 -yl} -2- cyanoethyl]piperidine- 1 -carboxylate;
cyclopentyl 4-[(lS)-l-{4-carbamoyl-3-[(4-fluorophenyl)amino]-lH-pyrazol-l-yl}-2- cyanoethyl]piperidine- 1 -carboxylate;
2,2,2-trifluoroethyl 4-[l-{4-carbamoyl-3-[(4-fluorophenyl)amino]-lH-pyrazol-l-yl}-2- cyanoethyl]piperidine- 1 -carboxylate;
2,2,2-trifluoroethyl 4-[(l S)- 1 - {4-carbamoyl-3-[(4-fluorophenyl)amino]- 1 H-pyrazol- 1 -yl} -2- cyanoethyl]piperidine- 1 -carboxylate;
tetrahydro-2H-pyran-4-yl 4-[l-{4-carbamoyl-3-[(4-fluorophenyl)amino]-lH-pyrazol-l-yl}-2- cyanoethyl]piperidine- 1 -carboxylate;
tetrahydro-2H-pyran-4-yl 4- [( 1 S)- 1 - {4-carbamoyl-3 -[(4-fluorophenyl)amino] - 1 H-pyrazol- 1 -yl } -
2- cyanoethyl]piperidine- 1 -carboxylate; 2-methoxy-l -methylethyl 4-[l -{4-carbamoyl-3-[(4-fluorophenyl)amino]-l H-pyrazol- 1 -yl}-2- cyanoethyljpiperidine- 1 -carboxylate;
2-methoxy- 1 -methylethyl 4- [( 1 S)- 1 - {4-carbamoyl-3 - [(4-fluorophenyl)ainino] - 1 H-pyrazol- 1 -yl } -
2-cyanoethyl]piperidine- 1 -carboxylate;
cyclopropylmethyl 4-[ 1 -{4-carbamoyl-3-[(4-fluorophenyl)amino]-l H-pyrazol- 1 -yl} -2- cyanoethyljpiperidine- 1 -carboxylate;
cyclopropylmethyl 4-[(l S)- 1 - {4-carbamoyl-3-[(4-fluorophenyl)amino]- 1 H-pyrazol- 1 -yl}-2- cyanoethyljpiperidine- 1 -carboxylate;
2,2,2-trifluoro- 1 -methylethyl 4- [ 1 - {4-carbamoyl-3 - [(4-fluorophenyl)amino] - 1 H-pyrazol- 1 -yl } -2- cyanoethyl]piperidine- 1 -carboxylate;
2,2,2-trifluoro- 1 -methylethyl 4-[( 1 S)- 1 - {4-carbamoyl-3- [(4-fluorophenyl)amino]- 1 H-pyrazol- 1 - yl } -2-cyanoethyl]piperidine- 1 -carboxylate;
tetrahydrofuran-3-ylmethyl 4-[l -{4-carbamoyl-3-[(4-fluorophenyl)amino]-lH-pyrazol-l -yl}-2- cyanoethyl]piperidine- 1 -carboxylate;
tetrahydrofuran-3-ylmethyl 4-[(lS)-l-{4-carbamoyl-3-[(4-fluorophenyl)amino]-lH-pyrazol-l- yl } -2-cyanoethyl]piperidine- 1 -carboxylate;
2-morpholin-4-ylethyl 4- [- 1 - { 4-carbamoyl-3 - [(4-fluorophenyl)amino] - 1 H-pyrazol- 1 -yl } -2- cyanoethyl]piperidine- 1 -carboxylate;
2-morpholin-4-ylethyl 4- [( 1 S)- 1 - {4-carbamoyl-3 - [(4-fluoropheny l)amino] - 1 H-pyrazol- 1 -yl } -2- cyanoethyl]piperidine- 1 -carboxylate;
2-methoxyethyl 4-[l-{4-carbamoyl-3-[(4-fluorophenyl)amino]-lH-pyrazol-l-yl}-2- cyanoethyl]piperidine- 1 -carboxylate;
2-methoxyethyl 4-[( 1 S)- 1 - {4-carbamoyl-3 - [(4-fluorophenyl)amino] - 1 H-pyrazol- 1 -yl } -2- cyanoethyl]piperidine- 1 -carboxylate;
2,2-dimethylpropyl 4-[- 1 - {4-carbamoyl-3-[(4-fluorophenyl)amino]-l H-pyrazol- 1 -yl} -2- cyanoethyl]piperidine- 1 -carboxylate;
2,2-dimethylpropyl 4-[( 1 R)- 1 - {4-carbamoyl-3-[(4-fluorophenyl)amino]-l H-pyrazol- 1 -yl} -2- cyanoethyljpiperidine- 1 -carboxylate;
2,2-dimethylpropyl 4-[( 1 S)- 1 - {4-carbamoyl-3 -[(4-fluorophenyl)amino]- 1 H-pyrazol- 1 -yl } -2- cyanoethyl]piperidine-l-carboxylate;
2-methylpropyl 4-[l-{4-carbamoyl-3-[(4-fluorophenyl)amino]-lH-pyrazol-l-yl}-2- cyanoethyl]piperidine- 1 -carboxylate;
2-methylpropyl 4-[(l S)- 1 - {4-carbamoyl-3-[(4-fluorophenyl)amino]- 1 H-pyrazol- 1 -yl} -2- cyanoethyl]piperidine- 1 -carboxylate; 2-methylpropyl 4-[(lR)- 1 - {4-carbamoyl-3-[(4-fluorophenyl)arnino]- 1 H-pyrazol- 1 -yl} -2- cyanoethyl]piperidine- 1 -carboxylate;
ethyl 4- [ 1 - {4-carbamoyl-3 - [(4-fluorophenyl)amino]- 1 H-pyrazol- 1 -yl } -2-cyanoethyl]piperidine- 1 - carboxylate;
ethyl 4- [( 1 S)- 1 - {4-carbamoyl-3 -[(4-fluorophenyl)amino]- 1 H-pyrazol- 1 -yl } -2- cyanoethyljpiperidine- 1 -carboxylate;
ethyl 4- [( 1 R)- 1 - {4-carbamoyl-3 - [(4-fluorophenyl)ammo] - 1 H-pyrazol- 1 -yl } -2- cyanoethyl]piperidine- 1 -carboxylate ;
cyclohexyl 4- [ 1 - {4-carbamoyl-3 - [(4-fluorophenyl)amino] - 1 H-pyrazol- 1 -yl } -2- cyanoethyl]piperidine- 1 -carboxylate;
cyclohexyl 4-[(lS)-l-{4-carbamoyl-3-[(4-fluorophenyl)amino]-lH-pyrazol-l-yl}-2- cyanoethyl]piperidine- 1 -carboxylate;
cyclohexyl 4- [( 1 R)- 1 - {4-carbamoyl-3 - [(4-fluorophenyl)amino] - 1 H-pyrazol- 1 -yl } -2- cyanoethyljpiperidine- 1 -carboxylate;
benzyl 4-[l - {4-carbamoyl-3-[(4-fluorophenyl)amino]- 1 H-pyrazol- 1 -yl} -2-cyanoethyl]piperidine-
1 -carboxylate;
benzyl 4-[(l S)- 1 - {4-carbamoyl-3-[(4-fluorophenyl)amino]- 1 H-pyrazol- 1 -yl}-2- cyanoethyljpiperidine- 1 -carboxylate;
benzyl 4-[(lR)-l-{4-carbamoyl-3-[(4-fluorophenyl)amino]-lH-pyrazol-l-yl}-2- cyanoethyljpiperidine- 1 -carboxylate;
1 - { 1 -[ 1 -(6- CWoro-5-methylpyrirnidin-4-yl)piperidin-4-yl]-2-cyanoethyl} -3-[(4- fluorophenyl)amino]-lH-pyrazole-4-carboxamide;
l-{(lS)-l-[l-(6- Chloro-5-methylpyrimidin-4-yl)piperidin-4-yl]-2-cyanoethyl}-3-[(4- fluorophenyl)amino]-lH-pyrazole-4-carboxamide;
1 -[2-Cyano- 1 -cyclopropylethyl]-3- { [4-(methylsulfonyl)phenyl]amino} - lH-pyrazole-4- carboxamide;
1 - [( 1 R)-2-Cyano- 1 -cyclopropylethyl] -3 - { [4-(methylsulfonyl)phenyl] amino } - 1 H-pyrazole-4- carboxamide;
1 - [( 1 S)-2-Cyano- 1 -cyclopropylethyl]-3 - { [4-(methylsulfonyl)phenyl]amino} - 1 H-pyrazole-4- carboxamide;
tert-butyl 4-[l-{4-carbamoyl-3-[(4-fluorophenyl)amino]-lH-pyrazol-l-yl}-2- cyanoethyl)piperidine- 1 -carboxylate;
tert-butyl 4-[(lS)-l-{4-carbamoyl-3-[(4-fluorophenyl)amino]-lH-pyrazol-l-yl}-2- cyanoethyl)piperidine- 1 -carboxylate; ¾^butyl 4-[(lR)-l-{4-carbamoyl-3-[(4-fluorophenyl)amino]-lH-pyrazol-l-yl}-2- cyanoethyl)piperidine- 1 -carboxylate;
¾rt-butyl 4- { 1 - [4-carbamoyl-3 -(phenylamino)- 1 H-pyrazol- 1 -yl] -2-cyanoethyl }piperidine- 1 - carboxylate;
tert-butyl 4- {(lS)-l-[4-carbamoyl-3-(phenylamino)-lH-pyrazol-l-yl] -2-cyanoethyl }piperidine-l carboxylate;
¾rt-butyl 4- { ( 1 R)- 1 - [4-carbamoyl-3 -(phenylamino)- 1 H-pyrazol- 1 -yl] -2-cyanoethyl } piperidine- 1 carboxylate;
I -[ 1 -(cyanomethyl)propyl]-3-(phenylamino)- lH-pyrazole-4-carboxamide;
I - [( 1 R)- 1 -(cyanomethyl)propyl] -3 -(phenylamino)- 1 H-pyrazole-4-carboxamide;
I -[( 1 S)- 1 -(cyanomethyl)propyl]-3 -(phenylamino)- 1 H-pyrazol e-4-carboxamide;
I -[2-cyano- 1 -cyclopentylethyl] -3-(phenylamino)- 1 H-pyrazole-4-carboxamide;
I - [( 1 S)-2-cyano- 1 -cyclopentylethyl] -3 -(phenylamino)- 1 H-pyrazole-4-carboxamide;
I - [( 1 R)-2-cyano- 1 -cyclopentylethyl] -3 -(phenylamino)- 1 H-pyrazole-4-carboxamide;
I - [ 1 -cyanopropan-2-yl] -3 -(phenylamino)- 1 H-pyrazole-4-carboxamide;
1 - [(2R)- 1 -cyanopropan-2-yl] -3 -(phenylamino)- 1 H-pyrazole-4-carboxamide;
l-[(2S)-l-cyanopropan-2-yl]-3-(phenylamino)-lH-pyrazole-4-carboxamide;
l-[2-cyano-l-cyclopropylethyl]-3-(phenylamino)-lH-pyrazole-4-carboxamide;
I - [( 1 S)-2-cyano- 1 -cyclopropylethyl]-3 -(phenylamino)- 1 H-pyrazole-4-carboxamide;
l-[(lR)-2-cyano-l-cyclopropylethyl]-3-(phenylamino)-lH-pyrazole-4-carboxamide;
I - [2-cyano- 1 -cyclopropylethyl] -3-[(2-fluoropyridin-4-yl)amino] - 1 H-pyrazole-4-carboxarnide; [ -[( 1 R)-2-cyano- 1 -cyclopropylethyl]-3-[(2-fluoropyridin-4-yl)amino]- 1 H-pyrazole-4- carboxamide;
I -[( 1 S)-2-cyano- 1 -cyclopropylethyl] -3 -[(2-fluoropyridin-4-yl)amino]- lH-pyrazole-4- carboxamide;
I - [2-cyano- 1 -cyclopropylethyl] -3 - { [4-(3 -methyl- 1 ,2,4-oxadiazol-5-yl)phenyl] amino } - 1 H- pyrazole-4-carboxamide;
l-[(lR)-2-cyano-l-cyclopropylethyl]-3-{[4-(3-methyl-l,2,4-oxadiazol-5-yl)phenyl]amino}-lH- pyrazole-4-carboxamide;
l-[(lS)-2-cyano-l-cyclopropylethyl]-3-{[4-(3-methyl-l,2,4-oxadiazol-5-yl)phenyl]amino}-lH- pyrazole-4-carboxamide ;
I - [2-cyano- 1 -cyclopropylethyl]-3 - [( 1 -oxo-2,3-dihydro- 1 H-isoindol-5-yl)amino]- 1 H-pyrazole-4- carboxamide; 1 - [( 1 R)-2-cyano- 1 -cyclopropylethyl] -3 - [( 1 -oxo-2,3 -dihydro- 1 H-isoindol-5 -yl)amino] - 1 H- pyrazole-4-carboxamide; and
l-[(lS)-2-cyano-l-cyclopropylethyl]-3-[(l-oxo-2,3-dihydro-lH-isoindol-5-yl)amino]-l^
pyrazole-4-carboxamide.
6. A pharmaceutical composition comprising a compound of Claim 1 or a pharamceutically acceptable salt or a stereoisomer, thereof and a pharmaceutically acceptable carrier.
7. A method for the treatment of a JAK-mediated disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Claim 1 or a pharmaceutically acceptable thereof.
8. A method of treating a condition in a mammal that can be ameliorated by the selective inhibition of a Janus kinase JAKl relative to JAK 2 and JAK 3 which condition is selected from, arthritis, asthma and obstructive airways diseases, autoimmune diseases or disorders, and cancer comprising administering to the mammal in need of such treatment, a therapeutically effective amount of a compound according to Claim lor a pharmaceutically acceptable salt or a stereoisomer thereof.
9. A method according to Claim 8, wherein said condition is arthritis.
10. A method according to Claim 9, wherein said condition is selected from rheumatoid arthritis, juvenile arthritis, and psoriatic arthritis.
11. A method according to Claim 8, wherein said condition is asthma or obstructive airways diseases.
12. A method according to Claim 8, wherein said condition is selected from: chronic asthma, late asthma, airway hyper-responsiveness, bronchitis, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, recurrent airway obstruction, and chronic obstruction pulmonary disease (COPD), and emphysema.
13. A method according to Claim 8, wherein said condition is autoimmune diseases or disorders.
14. A method of treating asthma in a mammal in need thereof, comprising administering a therapeutically effective amount of a compound according to Claim 1 or a pharmaceutically acceptable salt, or stereoisomer thereof.
15. A method of treating arthritis in a mammal in need thereof, comprising administering a therapeutically effective amount of a compound according to Claim 1 or a pharmaceutically acceptable salt, or stereoisomer thereof.
16. Use of a compound of Claim 1 or a pharmaceutically acceptable salt or a stereoisomer thereof in the manufacture of a medicament for the treatment of a desease or a disorder ameliorated by the selective inhibition of a Janus kinase JAK1 relative to JAK 2.
17. Use of a compound of Claim 1 or a pharmaceutically acceptable salt or a stereoisomer thereof and a second active agent in the manufacture of a medicament for the treatment of a desease or a disorder ameliorated by the selective inhibition of a Janus kinase JAK1 relative to JAK 2.
PCT/US2012/056481 2011-09-22 2012-09-21 Acyclic cyanoethylpyrazoles as janus kinase inhibitors Ceased WO2013043964A1 (en)

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US10961247B2 (en) 2016-06-30 2021-03-30 Daewoong Pharmaceutical Co., Ltd. Pyrazolopyrimidine derivatives as kinase inhibitor

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