WO2024256827A1 - Composés (hétéro)aryl-sulfonamide en tant que modulateurs de gpr35 - Google Patents

Composés (hétéro)aryl-sulfonamide en tant que modulateurs de gpr35 Download PDF

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WO2024256827A1
WO2024256827A1 PCT/GB2024/051518 GB2024051518W WO2024256827A1 WO 2024256827 A1 WO2024256827 A1 WO 2024256827A1 GB 2024051518 W GB2024051518 W GB 2024051518W WO 2024256827 A1 WO2024256827 A1 WO 2024256827A1
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och
alkyl
alkylene
phenyl
heterocycloalkylene
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Inventor
Christoper Andrew LUCKHURST
Roger John Butlin
Ageo MICCOLI
Gianna TOSCHI
Mihiro Sunose
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Thirtyfivebio Ltd
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Thirtyfivebio Ltd
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Priority to EP24735684.3A priority Critical patent/EP4727652A1/fr
Priority to AU2024302413A priority patent/AU2024302413A1/en
Priority to CN202480050540.2A priority patent/CN121693492A/zh
Publication of WO2024256827A1 publication Critical patent/WO2024256827A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/20—Nitrogen atoms

Definitions

  • the present invention relates to compounds that are capable of modulating GPR35 function.
  • the compounds have potential therapeutic applications in the treatment of a variety of disorders, including proliferative, immune and inflammatory disorders.
  • GPR35 is a class A, G protein-coupled receptor. 1 2
  • the human gene can be expressed as three variants: Variant 1 encodes a 309 amino acid polypeptide designated GPR35a (short form), while variants 2 and 3 encode a long form, GPR35b, which has a 31 amino acid extension at the N-terminus.
  • Variant 1 encodes a 309 amino acid polypeptide designated GPR35a (short form)
  • variants 2 and 3 encode a long form, GPR35b, which has a 31 amino acid extension at the N-terminus.
  • the synthetic chemical zaprinast (5-(2-propoxyphenyl)- 1 H-[1 ,2,3]triazolo-[4,5-d]pyrimidin-7(4H)-one) is currently the standard GPR35 agonist used as a reference compound.
  • the only GPR35 activator that has advanced into clinical trials is sodium cromoglycate (also known as RVT-1601 or PA101) which was investigated in the treatment of chronic cough in idiopathic pulmonary fibrosis 1 37 .
  • GPR35 isoforms of GPR35 display similar pharmacology with respect to reported agonists 13 and any potential distinctive functions are unknown.
  • GPR35 is primarily expressed throughout the epithelium of the gastrointestinal (Gl) tract, including the stomach, gall bladder, duodenum, small intestine and colon 16 17 , although expression is also prominent in certain macrophages and dendritic cells.
  • Gl gastrointestinal
  • Increased GPR35 expression is also associated with certain cancers.
  • 25 High expression of GPR35 in gastric cancer is associated with poorer prognosis of patients. In vitro, GPR35 expression was associated with increased gastric cancer cell viability and proliferation, and reduced apoptosis.
  • GPR35 signalling therefore, represents an attractive pathway for therapeutic intervention for the treatment of a range of diseases. Accordingly, there is an ongoing need to develop new small molecule GPR35 modulators.
  • the present invention seeks to provide compounds that are capable of modulating GPR35. 5 As made clear from the above discussion, such compounds have potential therapeutic applications in the treatment of a variety of disorders, including proliferative disorders and immune disorders, as well as inflammatory disorders.
  • a first aspect of the invention relates to compounds of formula (I), or a pharmaceutically 10 acceptable salt or solvate thereof, wherein: X-Y is -CONR 6 - or -NR 6 CO-; 15 R 6 and R 7 are each independently selected from H and alkyl, more preferably H; R 8 is selected from alkyl, cycloalkyl, (CH 2 ) q -heterocycloalkyl and NR 34 R 35 ; ring C is a phenyl group or a 6-membered heteroaryl group containing at least one N, each of which is optionally further substituted by one or more substituents selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halo, CN, NR 9 SO 2 -R 10 , NR 9 COR 11 , NR 12 R 13 , OH, 20 SO 2 NR 14 R 15 , CONR 16 R 17 , cycloalkyl, O(CH 2
  • the presently claimed compounds are capable of modulating GPR35, thereby rendering the compounds of therapeutic interest in the treatment of various disorders, including oncology applications, inflammatory disorders, and gastrointestinal disorders.
  • a pharmaceutical composition comprising a compound as described above and a pharmaceutically acceptable diluent, excipient, or carrier.
  • Another aspect of the invention relates to a pharmaceutical composition as described above for use as a medicament.
  • Another aspect of the invention relates to a compound as described above for use in treating or preventing a disorder selected from a proliferative disorder, a gastrointestinal disorder, a fibrotic disorder, cardiovascular disease, and an inflammatory disorder.
  • Another aspect of the invention relates to a pharmaceutical composition as described above for use in treating or preventing a disorder selected from a proliferative disorder, a gastrointestinal disorder, a fibrotic disorder, a cardiovascular disease, and an inflammatory disorder.
  • Another aspect of the invention relates to a method of treating a disorder, comprising administering to a subject a compound or a pharmaceutical composition as described 5 above.
  • Another aspect of the invention relates to a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, for use in treating or preventing a GPR35-associated disease or disorder.
  • Another aspect of the invention relates to the use of a compound as defined herein, or a 10 pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicament for treating or preventing a GPR35-associated disease or disorder in a subject.
  • Another aspect of the invention relates to the use of a compound as defined herein, or a pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicament for treating or preventing a disorder selected from a proliferative disorder, a gastrointestinal 15 disorder, an inflammatory disorder, a fibrotic disorder and cardiovascular disease.
  • DETAILED DESCRIPTION The present invention relates to compounds that are capable of modulating GPR35.
  • Alkyl is defined herein as a straight-chain or branched alkyl radical, preferably C 1-20 alkyl, more preferably C 1-12 alkyl, even more preferably C 1-10 alkyl or C 1-6 alkyl, for example, 20 methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl. More preferably, the alkyl is a C 1-3 alkyl.
  • Cycloalkyl is defined herein as a cyclic alkyl ring, preferably, C 3-7 -cycloalkyl, more preferably C 3-6 -cycloalkyl.
  • Preferred examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, or a fused bicyclic ring system such as norbornane. 25
  • aryl or “aromatic” refers to a C 6-12 aromatic group, which may be benzocondensed, for example, phenyl or naphthyl.
  • Halogen or “halo” is defined herein as chloro, fluoro, bromo or iodo.
  • Haloalkyl is defined herein as a straight-chain or branched alkyl radical as defined above, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, that is substituted with one or more halogen atoms (that may be the same or different), such as fluorine, chlorine, bromine, and iodine.
  • the haloalkyl group is a C 1-20 haloalkyl, 5 more preferably C 1-12 haloalkyl, even more preferably C 1-10 haloalkyl or C 1-6 haloalkyl.
  • alkoxy is defined herein as an oxygen atom bonded to an alkyl group as defined above.
  • the alkoxy group is a C 1-20 alkoxy, more preferably C 1-12 alkoxy, even more preferably C 1-10 alkoxy or C 1-6 alkoxy, for example methoxy, ethoxy, propoxy, isopropoxy, 10 butoxy, isobutoxy, tert-butoxy, pentoxy and hexoxy.
  • a particularly preferred example is methoxy (–OCH 3 ).
  • Haloalkoxy is defined herein as an alkoxy group as described above substituted with one or more halogen atoms (that may be the same or different), such as fluorine, chlorine, bromine, and iodine.
  • the haloalkoxy group is a C 1-20 haloalkoxy, more 15 preferably C 1-12 haloalkoxy, even more preferably C 1-10 haloalkoxy or C 1-6 haloalkoxy.
  • a particularly preferred example is OCF 3 .
  • Heteroaryl is defined herein as a monocyclic aromatic ring comprising one or more heteroatoms (that may be the same or different), such as oxygen, nitrogen or sulphur.
  • heterocycloalkyl refers to a cyclic aliphatic group containing one or more heteroatoms selected from nitrogen, oxygen and sulphur, which is optionally interrupted by one or more 25 -(CO)- groups in the ring and/or which optionally contains one or more double bonds in the ring.
  • the heterocycloalkyl group is monocyclic or bicyclic.
  • the heterocycloalkyl group is a C 3-7 -heterocycloalkyl, more preferably a C 3-6 -heterocycloalkyl.
  • the heterocycloalkyl group is a C 4-7 -heterocycloalkyl, more preferably a C 4-6 -heterocycloalkyl.
  • Preferred heterocycloalkyl groups include, but are not limited to, 30 piperazinyl, piperidinyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, oxetanyl and azetidinyl.
  • the heterocycloalkyl group is monovalent.
  • the heterocycloalkyl group is monocyclic.
  • the heterocycloalkyl group can be bonded to an adjacent group via a carbon atom or via a heteroatom (e.g. a nitrogen). 5
  • the term “alkenyl” refers to both straight and branched carbon chains which have at least one carbon-carbon double bond.
  • alkenyl groups may include C 2 -C 12 alkenyl groups.
  • alkenyl includes C 2 -C 10 , C 2 -C 8 , C 2 -C 6 or C 2 -C 4 alkenyl groups.
  • alkenyl the number of double bonds is 1-3; in another embodiment of alkenyl, the number of double bonds is one.
  • Other 10 ranges of carbon-carbon double bonds and carbon numbers are also contemplated depending on the location of the alkenyl moiety on the molecule.
  • C 2 -C 10 -alkenyl” groups may include more than one double bond in the chain.
  • alkynyl refers to both straight and branched carbon chains which have at least one carbon-carbon triple bond.
  • alkynyl groups 15 may include C 2 -C 12 alkynyl groups.
  • alkynyl includes C 2 -C 10 , C 2 -C 8 , C 2 -C 6 or C 2 -C 4 alkynyl groups.
  • the number of triple bonds is 1-3; in another embodiment of alkenyl, the number of triple bonds is one.
  • a particularly preferred alkynyl group is –C ⁇ CH.
  • alkylene refers to a linear or branched saturated divalent 20 hydrocarbon radical.
  • the alkylene group is a linear saturated divalent hydrocarbon radical comprising one to six carbon atoms, or a branched saturated divalent hydrocarbon radical comprising three to six carbon atoms.
  • heteroalkylene refers to a divalent alkylene as defined above having one or more carbon atoms replaced with a heteroatom such as sulfur, oxygen, or 25 nitrogen (e.g. in the form of NR where R is H or alkyl).
  • the heteroalkylene group can be linked to an adjacent group via a carbon or via the heteroatom.
  • the heteroalkylene group is a divalent alkylene having one or two carbon atoms, more preferably one carbon, replaced with a group selected from sulfur, oxygen and nitrogen.
  • the heteroalkylene group is a divalent alkylene having one or more carbon atoms replaced with an oxygen, more preferably one or two carbon atoms replaced with an oxygen, more preferably, one carbon atom replaced with an oxygen.
  • the heteroalkylene group is a linear saturated divalent hydrocarbon radical 5 comprising two to six carbon atoms in which one carbon is replaced by a heteroatom, or a branched saturated divalent hydrocarbon radical comprising three to six carbon atoms in which one carbon is replaced by a heteroatom.
  • the term “cycloalkylene” refers to a divalent cyclic saturated hydrocarbon radical, preferably comprising three to ten carbon atoms.
  • the cycloalkylene10 group is 3-, 4-, 5- or 6-membered cycloalkylene group, more preferably, a 3-, 4-, or 5- membered cycloalkylene group.
  • heterocycloalkylene refers to a divalent cycloalkylene group as defined above, having one or more carbon atoms replaced with a heteroatom, for example, sulfur, oxygen, or nitrogen.
  • the nitrogen can be in the form of NR where R is H or alkyl, or the nitrogen can link the heterocycloalkylene group to an adjacent group, for example, as illustrated below:
  • the heterocycloalkylene group is a 3-, 4-, 5- or 6-membered heterocycloalkylene group, more preferably, a 3-, 4-, or 5-membered heterocycloalkylene 20 group.
  • alkyl is C 1- C 6 alkyl
  • haloalkyl is C 1- C 6 haloalkyl
  • haloalkoxy is C 1- C 6 haloalkoxy
  • alkoxy is C 1- C 6 alkoxy.
  • X-Y is -CONR 6 - or -NR 6 CO-; 5 R 6 and R 7 are each independently selected from H and alkyl, more preferably H; R 8 is selected from alkyl, cycloalkyl, (CH 2 ) q -heterocycloalkyl and NR 34 R 35 ; ring C is a phenyl group or a 6-membered heteroaryl group containing at least one N, each of which is optionally further substituted by one or more substituents selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halo, CN, NR 9 SO 2 -R 10 , NR 9 COR 11 , NR 12 R 13 , OH, 10 SO 2 NR 14 R 15 , CONR 16 R 17 , cycloalkyl, O(CH 2 ) q NR 18 R 19 , (CH 2 ) q -heterocycloalkyl and CO 2 R 20 ; each
  • X-Y is NH-CO
  • said compound is of formula (Ia'): 5 wherein X 1 , X 2 , X 3 , X 4 , X 5 , together with the carbon to which X 1 and X 5 are attached, form a phenyl group or a 6-membered heteroaryl group containing at least one N, and wherein said phenyl or heteroaryl group is optionally further substituted by one or more substituents selected from alkyl, CN, haloalkyl, alkoxy, haloalkoxy, halo, NR 9 SO 2 R 10 , NR 9 COR 11 , NR 12 R 13 , OH, SO 2 NR 14 R 15 , CONR 16 R 17 , cycloalkyl, O(CH 2 ) q NR 18 R 19 , (CH 2 ) q - 10 heterocycloalkyl and CO 2 R 20 ; and A, B, Z, L,
  • said compound is of formula (Ib'): wherein: X 1 is N or CR 1 ; X 3 is N or CR 3 ; X 4 is N or CR 4 ; 5 X 5 is N or CR 5 ; R 1 , R 3 , R 4 and R 5 are each independently selected from H, CN, alkyl, haloalkyl, alkoxy, haloalkoxy, halo, NR 12 R 13 , OH, NR 9 SO 2 -alkyl, CONR 16 R 17 , cycloalkyl, O(CH 2 ) q NR 18 R 19 and (CH 2 ) q -heterocycloalkyl; and wherein R a , R b , R 7 , R 8 , n, p, L, A, B, X, Y and Z are as defined above.
  • X 1 , X 2 , X 3 , X 4 and X 5 together with the carbon to which X 1 and X 5 are attached, form a 6-membered heteroaryl group comprising 1 or 2 nitrogens, preferably selected from pyridinyl, pyrimidinyl, pyradizinyl and pyrazinyl.
  • ring A is: 15 wherein ring A is a phenyl group or 6-membered heteroaryl group; and B, C, Z, L, X, Y, R a , R b , n and p are as defined above.
  • ring A is: wherein A is 5-membered heteroaryl group, and n is an integer from 0 to 3.
  • A is selected from pyrrolyl, thiazolyl, oxazolyl, furanyl, thienyl and pyrazolyl, each of which is optionally substituted by one to three R a groups as defined above.
  • the compound is of formula (I), or a pharmaceutically 5 acceptable salt or solvate thereof
  • X-Y is -CONR 6 - or -NR 6 CO-
  • R 6 and R 7 are each independently selected from H and alkyl, more preferably H
  • R 8 is selected from alkyl, cycloalkyl, (CH 2 ) q -heterocycloalkyl and NR 34 R 35
  • ring C is a phenyl group or a 6-membered heteroaryl group containing at least one N, each of which is optionally further substituted by one or more substituents selected from alkyl, haloalkyl, alkoxy, haloalkoxy, halo, CN, NR 9 SO 2 -R 10 , NR 9 COR 11 , NR 12 R 13 , OH, SO 2 NR 14 R 15 , CONR 16 R 17 , cycloalkyl, O(CH 2 ) q NR 18 R 19 , (CH
  • A is selected from phenyl, pyridinyl, pyrimidinyl and pyrazinyl, more preferably selected from phenyl and pyridinyl, each of which is optionally substituted by one to four R a groups, more preferably one to three R a groups.
  • each R a is independently selected from C 1-6 -alkyl, halo, C 1-6 - haloalkyl, C 1-6 -alkoxy, C 3-6 -cycloalkoxy, C 1-6 -haloalkoxy, cyano, NHCO-C 1-6 -alkyl, NHSO 2 - 15 C 1-6 -alkyl, S-C 1-6 -alkyl, SO-C 1-6 -alkyl, CH 2 SO 2 -C 1-6 -alkyl, SO 2 -C 1-6 -alkyl, SO 2 N(C 1-6 -alkyl) 2 , CH 2 OH, CH 2 O-C 1-6 -alkyl, N(C 1-6 -alkyl) 2 , CON(C 1-6 -alkyl) 2 , cycloalkyl, heterocycloalkyl and CH 2 -heterocycloalkyl.
  • each R a is independently selected from C 1-6 -alkyl, halo, C 1-6 - haloalkyl, C 1-6 -alkoxy, C 3-6 -cycloalkoxy and C 1-6 -haloalkoxy. 20 In one preferred embodiment, each R a is independently selected from halo, alkyl and alkoxy.
  • each R a is independently selected from Me, halo, CF 3 , OMe, OCF 3 , amino, cyano, NHCOMe, NHSO 2 Me, S-Me, CH 2 SO 2 Me, SO 2 Me, SO 2 NMe 2 , CH 2 OH, CH 2 OMe, cycloalkyl, CH 2 -(morpholin-4-yl) and morpholin-4-yl. 25
  • each R a is independently selected from F, Me and OMe.
  • n is 0.
  • said compound is of formula (Ic):
  • A is a phenyl or pyridinyl group, more preferably phenyl; and R a , R b , R 7 , R 8 , n, p, L, A, B, X, Y and Z are as defined above.
  • R 1 , R 3 , R 4 and R 5 are each independently selected from H, C 1-6 -alkyl, C 1-6 -haloalkyl, C 1-6 -alkoxy, C 1-6 -haloalkoxy, Cl, F, NH 2 , NH-C 1-6 -alkyl, NH-C 3-6 -15 cycloalkyl, N(C 1-6 -alkyl) 2, OH, NHSO 2 -C 1-6 -alkyl, CONR 17 R 18 , C 3-6 -cycloalkyl, NH-(hydroxy- C 1-6 -alkyl), NH-(C 1-6 -alkoxy), CH 2 -heterocycloalkyl and heterocycloalkyl.
  • R 1 , R 3 , R 4 and R 5 are each independently selected from H, Me, MeO, CF 3 , Cl, F, NH 2 , NH-Me, NH-cyclopropyl, NMe 2, OH, NHSO 2 Me, CONH 2 , cyclopropyl, NHCH 2 CH 2 OH, OCH 2 CH 2 NH 2 , NHCH 2 CH 2 OMe, CH 2 -( morpholin-4-yl) and 20 morpholin-4-yl.
  • X 1 is CR 1 ; X 3 is CR 3 ; X 4 is N; and X 5 is CR 5 .
  • X 1 is N; X 3 is CR 3 ; X 4 is CR 4 ; and X 5 is CR 5 .
  • X 1 is N; X 3 is CR 3 ; X 4 is N; and X 5 is CR 5 .
  • R 1 , R 4 and R 5 are H.
  • X 3 is CR 3
  • R 3 is selected from H, CN, C 1-6 -alkyl, C 3-6 - cycloalkyl, halo, C 1-6 -alkoxy, C 1-6 -haloalkyl, C 1-6 -haloalkoxy and O(CH 2 ) q NR 18 R 19 , more preferably, H, CN, C 1-6 -alkyl, C 1-6 -alkoxy, C 3-6 -cycloalkyl, halo and O(CH 2 ) q NR 18 R 19 .
  • X 3 is CR 3
  • R 3 is selected from H, Me, CN, MeO, CF 3 , Cl, F, NH 2 , NH-Me, NH-cyclopropyl, NMe 2, OH, NHSO 2 Me, CONH 2 , cyclopropyl, 15 NHCH 2 CH 2 OH, NHCH 2 CH 2 OMe, CH 2 -(morpholin-4-yl) and morpholin-4-yl, more preferably, H, Me, OMe, CN, cyclopropyl and OCH 2 CH 2 NH 2 .
  • X 3 is CR 3
  • R 3 is selected from H, CN, C 1-6 -alkyl, C 3-6 - cycloalkyl, halo, C 1-6 -alkoxy, C 1-6 -haloalkyl, C 1-6 -haloalkoxy and O(CH 2 ) q NR 18 R 19 , more preferably, H, CN, C 1-6 -alkyl, C 1-6 -alkoxy, C 3-6 -cycloalkyl, halo and O(CH 2 ) q NR 18 R 19 ; and R 1 , 20 R 4 and R 5 are H.
  • X 3 is CR 3
  • R 3 is selected from H, Me, CN, MeO, CF 3 , Cl, F, NH 2 , NH-Me, NH-cyclopropyl, NMe 2, OH, NHSO 2 Me, CONH 2 , cyclopropyl, NHCH 2 CH 2 OH, NHCH 2 CH 2 OMe, CH 2 -(morpholin-4-yl) and morpholin-4-yl, more 25 preferably, H, Me, OMe, CN, cyclopropyl and OCH 2 CH 2 NH 2 ; and R 1 , R 4 and R 5 are H.
  • said compound is of formula (Id):
  • A is a phenyl or pyridinyl group, more preferably phenyl; and R a , R b , R 7 , R 8 , n, p, L, A, B, X, Y and Z are as defined above.
  • X 1 is N; X 2 is CR 2 ; X 4 is N; and X 5 is CR 5 .
  • R 1 , R 4 and R 5 are H. 15
  • X 2 is CR 2
  • R 2 is selected from H, CN, C 1-6 -alkyl, C 3-6 - cycloalkyl, halo, C 1-6 -alkoxy, C 1-6 -haloalkyl, C 1-6 -haloalkoxy and O(CH 2 ) q NR 18 R 19 , more preferably, H, CN, C 1-6 -alkyl, C 1-6 -alkoxy, C 3-6 -cycloalkyl, halo and O(CH 2 ) q NR 18 R 19 .
  • X 2 is CR 2
  • R 2 is selected from H, CN, C 1-6 -alkyl, C 3-6 - cycloalkyl, halo, C 1-6 -alkoxy, C 1-6 -haloalkyl, C 1-6 -haloalkoxy and O(CH 2 ) q NR 18 R 19 , more 20 preferably, H, CN, C 1-6 -alkyl, C 1-6 -alkoxy, C 3-6 -cycloalkyl, halo and O(CH 2 ) q NR 18 R 19 ; and R 1 , R 4 and R 5 are H.
  • R 7 is H.
  • R 8 is selected from alkyl, cycloalkyl, heterocycloalkyl and dialkylamino, more preferably, Me, cyclopropyl, morpholin-4-yl and N(Me) 2 .
  • B is selected from phenyl, pyridinyl, pyradizinyl, pyrazinyl, pyrimidinyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrazolyl, and thiazolyl, each of which is 5 optionally substituted by one to four R b groups as defined above.
  • B is selected from phenyl and pyridinyl, more preferably phenyl, optionally substituted by one to four R b groups as above.
  • each R b is independently selected from C 1-6 -alkyl, halo, C 1-6 - haloalkyl, C 1-6 -alkoxy, C 3-6 -cycloalkoxy and C 1-6 -haloalkoxy.
  • each R b is independently selected from Me, halo, CF 3 , OMe, OCF 3 , amino, cyano, NHCOMe, NHSO 2 Me, S-Me, CH 2 SO 2 Me, SO 2 Me, SO 2 NMe 2 , CH 2 OH, CH 2 OMe, cycloalkyl, CH 2 -( morpholin-4-yl) and morpholin-4-yl.
  • B is preferably a phenyl or pyridinyl group, each of which is optionally substituted by one to four R b groups as defined above.
  • B is a phenyl group, optionally substituted by one or two groups selected from halo and alkoxy. In one preferred embodiment, B is a phenyl group, optionally substituted by one or two groups selected from F and MeO. In one preferred embodiment, B is a phenyl group, optionally substituted by one or two 20 halo groups. In one preferred embodiment, p is 0.
  • Z is a group selected from C 1-6 -alkyl, phenyl, heteroaryl, C 3- 6 -cycloalkyl and a 4-, 5- or 6-membered heterocycloalkyl group, each of which is optionally further substituted by one or more groups selected from alkyl, alkenyl, alkynyl, OH, halo, 25 haloalkyl, and alkoxy.
  • Z is a group selected from phenyl, pyridinyl, methoxyphenyl, alkyl, tolyl, morpholinyl, pyrazolyl, oxetanyl, cyclohexyl, cyclopenyl, cyclobutyl, cyclopropyl, and tetrahydropyranyl, more preferably phenyl.
  • Z is a group selected from phenyl, alkyl, tolyl, morpholinyl, 5 pyrazolyl, oxetanyl, cyclohexyl, cyclopenyl, cyclobutyl, cyclopropyl, and tetrahydropyranyl.
  • Z is a group selected from phenyl, cyclopropyl and tetrahydropyranyl, more preferably phenyl. More preferably, Z is phenyl.
  • L is a direct bond or is a group selected from, -O-CO-, -CO-O-, -O-CO-O-, -SO 2 -, -O-SO 2 -, -SO 2 -O-, -O-, -NR 36 -SO 2 -, -NR 36 -SO 2 -alkylene, 10 alkylene-SO 2 -NR 36 -, -SO 2 -NR 36 -, -SO 2 -NR 36 -alkylene, alkylene-NR 36 -SO 2 -, alkylene, heteroalkylene, cycloalkylene, heterocycloalkylene, alkylene-cycloalkylene, alkylene-cycloalkylene, alkylene-cycloalkylene, alkylene-SO 2
  • R 36 is H or Me, more preferably H.
  • L is absent and the Z group is attached directly to the B ring. In one preferred embodiment L is present. In one preferred embodiment, L is -O- 25 In one preferred embodiment, L is a heteroalkylene group as defined hereinabove. In one preferred embodiment, L is an alkylene group having one or two carbon atoms, more preferably one carbon, replaced with a group selected from sulfur, oxygen and nitrogen. In one preferred embodiment, L is an alkylene group having one or two carbon atoms, more preferably one carbon, replaced with an oxygen. In one preferred embodiment, the heteroalkylene is a group selected from -O-alkylene, alkylene-O- and alkylene-O-alkylene.
  • L is selected from -O-CO-, -CO-O-, -O-CO-O-, -O-, -NH- SO 2 -, -NH-SO 2 -(CH 2 ) a -, -SO 2 -NH-, -SO 2 -NH-(CH 2 ) a -, -O-SO 2 -, -SO 2 -O-, -(CH 2 ) a -, -(CH 2 ) a - O-, -O-(CH 2 ) a -, -(CH 2 ) a -O-(CH 2 ) b -, -(CH 2 ) a -S-(CH 2 ) b -, -(CH 2 ) a -SO 2 -, -SO 2 -(CH 2 ) b -, -(CH 2 ) a -SO 2 -(CH 2 ) b -, -(CH 2 )
  • L is selected from -O-, -O-CO-, -CO-O-, -O-CO-O-, -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 OCH 2 -, -CH 2 O-, -OCH 2 -, -CH 2 CH 2 O-, -OCH 2 CH 2 -, -CH 2 CH 2 S-, -SCH 2 CH 2 -, -CH 2 CH 2 CH 2 O-, -OCH 2 CH 2 CH 2 -, -OCH 2 CH 2 CH 2 O-, - CH 2 SO 2 CH 2 -, -CH 2 SOCH 2 -, -CH 2 SCH 2 -, -NH-SO 2 -, -NH-SO 2 -CH 2 -, -O-SO 2 -, -SO 2 -O-, 5 -SO 2 -NH-, -SO 2 -NH-CH 2 -NH-CH 2
  • L is preferably selected from from -O-, -NH-SO 2 -, -NH- SO 2 -(CH 2 ) a -, -SO 2 -NH-, -SO 2 -NH-(CH 2 ) a -, -O-SO 2 -, -SO 2 -O-, -(CH 2 ) a -, -(CH 2 ) a -O-, O- 5 (CH 2 ) a -, -(CH 2 ) a -O-(CH 2 ) b -, -(CH 2 ) a -S-(CH 2 ) b -, -(CH 2 ) a -SO-(CH 2 ) b -, -(CH 2 ) a -SO 2 - (CH 2 ) b -, -(CH 2 ) a -SO 2 - (CH 2 ) b -, -(CH 2 ) a -SO
  • L is selected from -O-, -O-SO 2 -, -SO 2 -O-, -(CH 2 ) a -, -(CH 2 ) a -O-, O-(CH 2 ) a -, -(CH 2 ) a -O-(CH 2 ) b -, -(CH 2 ) a -S-(CH 2 ) b -, -(CH 2 ) a -S-(CH 2 ) b -O-, -O-(CH 2 ) a -S-(CH 2 ) b -, -(CH 2 ) a -O-(CH 2 ) b -, -S-(CH 2 ) a -O-(CH 2 ) b -, heterocycloalkylene-(CH 2 ) a -O- and -(CH 2 ) a -O-heterocycloalkylene
  • L is selected from -CH 2 -, -CH 2 CH 2 CH 2 -, -CH 2 CH 2 O-, -NH- SO 2 -, -NH-SO 2 -CH 2 -, -SO 2 -NH-, -SO 2 -NH-CH 2 -, -OCH 2 CH 2 -, -CH 2 CH 2 CH 2 O-, -OCH 2 CH 2 CH 2 -, -CH 2 SO 2 CH 2 -, -CH 2 SO 2 -, -SO 2 CH 2 -, -CH 2 SO-, -SOCH 2 -, -CH 2 SOCH 2 -, -CH 2 SOCH 2 -, -CH 2 SOCH 2 -, -CH 2 SCH 2 -, -CH 2 CH 2 CH 2 CH 2 O-, -OCH 2 CH 2 CH 2 CH 2 -, -CH 2 OCH 2 and -CH 2 SCH 2 O-.
  • L-Z is -OCH 2 CH 2 Ph, -OCH 2 Ph, -OCH 2 CH 2 CH(Me) 2 , -OCH 2 CH(Me) 2 , -OSO 2 -(4-methylphenyl), -CH 2 SO 2 CH 2 -Ph, -OCH 2 -cyclopropyl, -OCH 2 CH 2 CH 2 CH 3 , -CH 2 OCH 2 Ph, -OCH 2 SCH 2 Ph, -CH 2 OCH 2 Ph, 10
  • L-Z is -OCH 2 CH 2 CH 2 CH 2 Ph, -OCH 2 CH 2 CH 2 Ph, -OCH 2 CH 2 Ph, -OCH 2 Ph, -CH 2 CH 2 CH 2 Ph, -CH 2 CH 2 CH 2 Ph, -OCH 2 CH 2 -pyrazole, -CH 2 CH 2 Ph, -CH 2 Ph, -OCH 2 CH 2 CH(Me) 2 , -OCH 2
  • L-Z is -OCH 2 CH 2 Ph, -OCH 2 CH 2 CH 2 CH 2 Ph or -CH 2 OCH 2 Ph, more preferably -OCH 2 CH 2 Ph.
  • the compound is selected from the following:
  • the compound of formula (I) is selected from the following compounds as shown herein: 1-4, 6-10, 13, 14, 16-30, 33, 34, 36, 37 and 39-46, and pharmaceutically acceptable salts and solvates thereof. 5 In another preferred embodiment, the compound of formula (I) is selected from the following:
  • a further aspect of the invention relates to processes for preparing a compound as defined herein. Further details of the synthetic processes are set forth in the accompanying examples section. 5 THERAPEUTIC APPLICATIONS A further aspect of the invention relates to compounds as described herein for use in medicine. The compounds have particular use in the field of oncology, gastrointestinal disorders, and inflammatory disorders as described in more detail below.
  • the compound of the invention modulates GPR35 function. More preferably, 5 the compound is a GPR35 antagonist or inverse agonist.
  • One aspect of the invention therefore relates to compounds as described herein for use as a medicament.
  • the compound of the invention is for use in treating or preventing a disorder selected from a proliferative disorder, a fibrotic disorder, a gastrointestinal disorder, a 10 cardiovascular disease, and an inflammatory disorder.
  • the compounds have applications in the field of oncology.
  • the compounds are for use in treating a proliferative disorder, preferably a cancer or leukemia.
  • GPR35 expression is known to be associated with cancer. More specifically, GPR35 expression is commonly upregulated in 15 cancers of the GI tract, relative to normal tissue. 24 GPR35 expression is capable of transforming NIH3T3 murine fibroblast cells and is expressed in gastric cancer cells.
  • GPR35b is expressed by colon cancer cell lines and primary colon tumours, while involved patient lymph nodes can express high levels of GPR35b.
  • High expression of GPR35b in lymph nodes of colon cancer patients is a marker for poor prognosis.
  • high 20 expression of GPR35 in primary gastric tumours is associated with poor prognosis.
  • 40 Similarly, above median expression of GPR35 in primary tumours was seen as a poor prognostic marker in males with colorectal cancer, though the opposite effect was reported in females.
  • siRNA knockdown of GPR35 reduces viability and proliferation of human gastric cancer cells, while also reversing pro-tumour M2 macrophage phenotype.
  • Murine 25 Gpr35 was shown to promote glycolysis, proliferation and oncogenic signalling by engaging with the sodium potassium pump (Na/K-ATPase). 21 Deletion of Gpr35 promoted Na/K-ATPase-mediated ion transport and reduced Src kinase activation and overall metabolic activity in both macrophages and intestinal epithelial cells. Gpr35 deletion or inhibition, with a specific anti-Gpr35 peptide (pepducin), 28 prevented inflammation- 30 associated and spontaneous intestinal tumorigenesis in mice.
  • pepducin anti-Gpr35 peptide
  • the cancer is selected from cancers of the gastrointestinal tract (e.g. colon, rectum, stomach and oesophagus) and associated tissues (e.g.
  • the compounds have applications in the field of immune- oncology and the treatment of immune disorders.
  • the compound of the invention is for use in treating an immune disorder.
  • the compound of the invention is for use in immunotherapy for the treatment of cancer.
  • the disorder is fibrosis or a fibrotic disorder.
  • Fibrosis is defined by the excessive accumulation of fibrous connective tissue (components of the extracellular matrix (ECM) such as collagen and fibronectin) in and around inflamed or damaged tissue, which can lead to permanent scarring and organ malfunction.
  • the compounds have applications in treating or preventing 20 inflammatory disorders/diseases and/or inflammation.
  • the disorder is a gastrointestinal disorder, preferably selected from inflammatory bowel disease, ulcerative colitis, primary sclerosing cholangitis and Crohn’s disease.
  • Single nucleotide polymorphisms (SNPs) of human GPR35 have been investigated in genome wide association studies. 18 Six of these SNPs have been 25 associated with inflammatory diseases of the GI tract.
  • Types of inflammatory bowel disease include ulcerative colitis, Crohn’s disease and primary sclerosing cholangitis.
  • 19,20 SNP rs3749171 is synonymous with a coding variant T108M (GPR35a amino acid sequence numbering) and has been associated with IBD. Research has shown that this variant is hypermorphic, leading to activation of GPR35 and increased 30 proliferation and metabolism in bone marrow-derived macrophages. 21
  • expression of T108M GPR35 leads to increased production of VEGF and CXCL8 by macrophages compared to the reference allele, with reduced production in GPR35- deficient cells.
  • the disorder is a cardiovascular disease, preferably selected from hypertension, heart failure, atherosclerosis, peripheral vascular disease and stroke.
  • a number of recent publications have suggested a role for GPR35 in hypertension and the pathology of both heart failure and atherosclerosis. For example, a S294R SNP within 10 GPR35 was shown to have significant association with coronary artery calcification in a patient cohort 29 .
  • Another aspect of the invention relates to a method of treating a GPR35-associated disease or disorder in a subject.
  • the method according to this aspect of the present invention is effected by administering to a subject in need thereof a therapeutically effective amount of a compound of the present invention, as described hereinabove, either 25 per se, or, more preferably, as a part of a pharmaceutical composition, mixed with, for example, a pharmaceutically acceptable carrier, as is detailed hereinafter.
  • Yet another aspect of the invention relates to a method of treating a subject having a disease state alleviated by modulation of GPR35 wherein the method comprises administering to the subject a therapeutically effective amount of a compound according to 30 the invention.
  • Another aspect relates to a method of treating a disease state alleviated by modulation of GPR35, wherein the method comprises administering to a subject a therapeutically effective amount of a compound according to the invention.
  • the compound inhibits GPR35 activity, for example, as 5 demonstrated in the functional GPR35 assay described in the accompanying examples section.
  • the compound is a GPR35 antagonist, which reverses the agonist-driven function of a receptor.
  • the compound is an inverse agonist of GPR35.
  • Inverse 10 agonists are compounds that interact with receptor-signal transduction systems that have a constitutive level of activity, and, through interaction with the receptor, reduce the activity in the direction opposite of that of a pure agonist.
  • the subject is a mammal, more preferably a human.
  • the term “method” refers to manners, means, techniques and procedures for 15 accomplishing a given task including, but not limited to, those manners, means, techniques and procedures either known to, or readily developed from known manners, means, techniques and procedures by practitioners of the chemical, pharmacological, biological, biochemical and medical arts.
  • the term “treating” includes abrogating, substantially inhibiting, slowing or reversing 20 the progression of a disease or disorder, substantially ameliorating clinical symptoms of a disease or disorder or substantially preventing the appearance of clinical symptoms of a disease or disorder.
  • the term “preventing” refers to a method for barring an organism from acquiring a disorder or disease in the first place.
  • a therapeutically effective amount refers to that amount of the compound being administered which will relieve to some extent one or more of the symptoms of the disease or disorder being treated.
  • a therapeutically effective amount also referred to herein as a therapeutically effective dose
  • a dose can be formulated in animal models to achieve a circulating concentration range that includes the IC 50 or the IC 90 as determined in cell culture. Such 5 information can be used to more accurately to determine useful doses in humans.
  • Initial dosages can also be estimated from in vivo data. Using these initial guidelines one of ordinary skill in the art could determine an effective dosage in humans.
  • toxicity and therapeutic efficacy of the compounds described herein can be determined by standard pharmaceutical procedures in cell cultures or experimental 10 animals, e.g., by determining the LD 50 and the ED 50 .
  • the dose ratio between toxic and therapeutic effect is the therapeutic index and can be expressed as the ratio between LD 50 and ED 50 .
  • Compounds which exhibit high therapeutic indices are preferred.
  • the data obtained from these cell cultures assays and animal studies can be used in formulating a dosage range that is not toxic for use in human.
  • the dosage of such compounds lies 15 preferably within a range of circulating concentrations that include the ED 50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.
  • Dosage amount and interval may be adjusted individually to provide plasma levels of the active compound which are sufficient to maintain therapeutic effect.
  • Usual patient dosages for oral administration range from about 50-2000 mg/day, commonly from about 100-1000 mg/day, preferably from about 150-700 mg/day and most preferably from 50-150 mg/day. 25
  • therapeutically effective serum levels will be achieved by administering multiple doses each day. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.
  • GPR35-related disease or disorder refers to a disease or disorder characterized by inappropriate GPR35 activity.
  • Inappropriate GPR35 activity refers to either an increase or decrease in GPR35 activity as measured by enzyme or cellular assays, for example, compared to the activity in a healthy subject. Inappropriate activity could also be due to overexpression of GPR35 in diseased tissue compared with healthy adjacent tissue where GPR35 expression is lower. 5 Preferred diseases or disorders that the compounds described herein may be useful in preventing include those described hereinbefore.
  • the present invention further provides use of compounds as defined herein in the preparation of a medicament for the treatment of a disease where it is desirable to modulate GPR35.
  • diseases include proliferative disorders, gastrointestinal 10 disorders, fibrotic disorders, cardiovasular diseases, and inflammatory disorders.
  • Proliferative disorders preferably include therapeutic applications in the field of oncology.
  • preparation of a medicament includes the use of the components of the invention directly as the medicament in addition to their use in any stage of the preparation of such a medicament.
  • the functional GPR35 assay as described in the accompanying examples measures the ability of GPR35 modulators to inhibit a GPR35 agonist-induced phospho-ERK signal.
  • the compound exhibits an IC 50 value in the aforementioned GPR35 assay of less than about 50 ⁇ M. More preferably, the compound exhibits an IC 50 value in the GPR35 assay of less than about 10 ⁇ M, more preferably, less than about 1 ⁇ M. In one preferred embodiment, the compound according to the invention exhibits an IC 50 of 25 ⁇ 10 ⁇ M in the aforementioned GPR35 assay.
  • the compound is selected from those denoted “A” or “B” in Table 1.
  • the compound according to the invention exhibits an IC 50 of > 1 ⁇ M and ⁇ 10 ⁇ M in the aforementioned GPR35 assay.
  • the compound is selected from those denoted “B” in Table 1.
  • the compound according to the invention exhibits an IC 50 of ⁇ 1 ⁇ M in the aforementioned assay.
  • the compound is selected from those denoted “A” in Table 1.
  • the compounds or physiologically acceptable salt, ester or other physiologically functional derivative thereof, described herein may be presented as a pharmaceutical formulation, comprising the compounds or physiologically acceptable salt, ester or other physiologically functional derivative thereof, together with one or more pharmaceutically acceptable carriers, excipients or diluents therefor and 10 optionally other therapeutic and/or prophylactic ingredients.
  • the carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the pharmaceutical compositions may be for human or animal usage in human and veterinary medicine.
  • suitable carriers include lactose, starch, glucose, methyl cellulose, magnesium stearate, mannitol, sorbitol and the like.
  • suitable diluents include ethanol, glycerol and water. 25
  • the choice of pharmaceutical carrier, excipient or diluent can be selected with regard to the intended route of administration and standard pharmaceutical practice.
  • compositions may comprise as, or in addition to, the carrier, excipient or diluent any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilising agent(s), buffer(s), flavouring agent(s), surface active agent(s), thickener(s), preservative(s) (including anti-oxidants) and the like, and substances included for the purpose of rendering the formulation isotonic with the blood of the intended recipient.
  • any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilising agent(s), buffer(s), flavouring agent(s), surface active agent(s), thickener(s), preservative(s) (including anti-oxidants) and the like and substances included for the purpose of rendering the formulation isotonic with the blood of the intended recipient.
  • binders examples include starch, gelatin, natural sugars such as glucose, anhydrous lactose, free-flow lactose, beta-lactose, corn sweeteners, natural and synthetic 5 gums, such as acacia, tragacanth or sodium alginate, carboxymethyl cellulose and polyethylene glycol.
  • suitable lubricants include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Preservatives, stabilizers, dyes and even flavoring agents may be provided in the 10 pharmaceutical composition.
  • preservatives examples include sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid.
  • Antioxidants and suspending agents may be also used.
  • Pharmaceutical formulations include those suitable for oral, topical (including dermal, buccal and sublingual), rectal or parenteral (including subcutaneous, intradermal, 15 intramuscular and intravenous), nasal and pulmonary administration e.g., by inhalation.
  • the formulation may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association an active compound with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product 20 into the desired formulation.
  • compositions suitable for oral administration wherein the carrier is a solid are most preferably presented as unit dose formulations such as boluses, capsules or tablets each containing a predetermined amount of active compound.
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
  • 25 Compressed tablets may be prepared by compressing in a suitable machine an active compound in a free-flowing form such as a powder or granules optionally mixed with a binder, lubricant, inert diluent, lubricating agent, surface-active agent or dispersing agent.
  • Moulded tablets may be made by moulding an active compound with an inert liquid diluent. Tablets may be optionally coated and, if uncoated, may optionally be scored.
  • Capsules 30 may be prepared by filling an active compound, either alone or in admixture with one or more accessory ingredients, into the capsule shells and then sealing them in the usual manner.
  • Cachets are analogous to capsules wherein an active compound together with any accessory ingredient(s) is sealed in a rice paper envelope.
  • An active compound may also be formulated as dispersible granules, which may for example be suspended in water 5 before administration, or sprinkled on food. The granules may be packaged, e.g., in a sachet.
  • Formulations suitable for oral administration wherein the carrier is a liquid may be presented as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil- in-water liquid emulsion.
  • Formulations for oral administration include controlled release dosage forms, e.g., tablets 10 wherein an active compound is formulated in an appropriate release - controlling matrix, or is coated with a suitable release - controlling film. Such formulations may be particularly convenient for prophylactic use.
  • Pharmaceutical formulations suitable for rectal administration wherein the carrier is a solid are most preferably presented as unit dose suppositories. Suitable carriers include cocoa 15 butter and other materials commonly used in the art. The suppositories may be conveniently formed by admixture of an active compound with the softened or melted carrier(s) followed by chilling and shaping in moulds.
  • Pharmaceutical formulations suitable for parenteral administration include sterile solutions or suspensions of an active compound in aqueous or oleaginous vehicles.
  • Injectable preparations may be adapted for bolus injection or continuous infusion. Such preparations are conveniently presented in unit dose or multi-dose containers which are sealed after introduction of the formulation until required for use.
  • an active compound may be in powder form which is constituted with a suitable vehicle, such as sterile, pyrogen-free water, before use.
  • An active compound may also be formulated as long-acting depot preparations, which may be administered by intramuscular injection or by implantation, e.g., subcutaneously or intramuscularly. Depot preparations may include, for example, suitable polymeric or hydrophobic materials, or ion-exchange resins. Such long-acting formulations are particularly convenient for prophylactic use.
  • Formulations suitable for pulmonary administration via the buccal cavity are presented such that particles containing an active compound and desirably having a diameter in the range of 0.5 to 7 microns are delivered in the bronchial tree of the recipient.
  • such formulations are in the form of finely comminuted powders which 5 may conveniently be presented either in a pierceable capsule, suitably of, for example, gelatin, for use in an inhalation device, or alternatively as a self-propelling formulation comprising an active compound, a suitable liquid or gaseous propellant and optionally other ingredients such as a surfactant and/or a solid diluent.
  • suitable liquid propellants include propane and the chlorofluorocarbons
  • suitable gaseous propellants include 10 carbon dioxide.
  • Self-propelling formulations may also be employed wherein an active compound is dispensed in the form of droplets of solution or suspension.
  • Such self-propelling formulations are analogous to those known in the art and may be prepared by established procedures.
  • they are presented in a container provided with either a manually-operable or automatically functioning valve having the desired spray 15 characteristics; advantageously the valve is of a metered type delivering a fixed volume, for example, 25 to 100 microlitres, upon each operation thereof.
  • an active compound may be in the form of a solution or suspension for use in an atomizer or nebuliser whereby an accelerated airstream or ultrasonic agitation is employed to produce a fine droplet mist for inhalation.
  • Formulations suitable for nasal administration include preparations generally similar to those described above for pulmonary administration. When dispensed such formulations should desirably have a particle diameter in the range 10 to 200 microns to enable retention in the nasal cavity; this may be achieved by, as appropriate, use of a powder of a suitable particle size or choice of an appropriate valve. Other suitable formulations include 25 coarse powders having a particle diameter in the range 20 to 500 microns, for administration by rapid inhalation through the nasal passage from a container held close up to the nose, and nasal drops comprising 0.2 to 5% w/v of an active compound in aqueous or oily solution or suspension.
  • Pharmaceutically acceptable carriers are well known to those skilled in the art and include, 30 but are not limited to, 0.1 M and preferably 0.05 M phosphate buffer or 0.8% saline. Additionally, such pharmaceutically acceptable carriers may be aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers include water, alcoholic/aqueous solutions, 5 emulsions or suspensions, including saline and buffered media.
  • Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's or fixed oils. Preservatives and other additives may also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases and the like.
  • Formulations suitable for topical formulation may be provided for example as gels, creams 10 or ointments. Such preparations may be applied e.g. to a wound or ulcer either directly spread upon the surface of the wound or ulcer or carried on a suitable support such as a bandage, gauze, mesh or the like which may be applied to and over the area to be treated.
  • Liquid or powder formulations may also be provided which can be sprayed or sprinkled directly onto the site to be treated, e.g. a wound or ulcer.
  • a carrier such as a 15 bandage, gauze, mesh or the like can be sprayed or sprinkle with the formulation and then applied to the site to be treated.
  • a process for the preparation of a pharmaceutical or veterinary composition as described above comprising bringing the active compound(s) into association with the carrier, for example 20 by admixture.
  • the formulations are prepared by uniformly and intimately bringing into association the active agent with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
  • the invention extends to methods for preparing a pharmaceutical composition
  • a pharmaceutical composition comprising bringing a compound as described herein into 25 conjunction or association with a pharmaceutically or veterinarily acceptable carrier or vehicle.
  • SALTS/ESTERS The compounds of the invention can be present as salts or esters, in particular pharmaceutically and veterinarily acceptable salts or esters.
  • Pharmaceutically acceptable salts of the compounds of the invention include suitable acid addition or base salts thereof. A review of suitable pharmaceutical salts may be found in Berge et al, J Pharm Sci, 66, 1-19 (1977). Salts are formed, for example with strong inorganic acids such as mineral acids, e.g.
  • hydrohalic acids such as hydrochloride, 5 hydrobromide and hydroiodide, sulphuric acid, phosphoric acid sulphate, bisulphate, hemisulphate, thiocyanate, persulphate and sulphonic acids; with strong organic carboxylic acids, such as alkanecarboxylic acids of 1 to 4 carbon atoms which are unsubstituted or substituted (e.g., by halogen), such as acetic acid; with saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or 10 tetraphthalic; with hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid; with aminoacids, for example aspartic or glutamic acid; with benzoic acid; or with organic sulfonic acids, such as (C 1 -C 4 )-alkyl- or aryl-
  • Salts which are not pharmaceutically or veterinarily acceptable may still be 15 valuable as intermediates.
  • Preferred salts include, for example, acetate, trifluoroacetate, lactate, gluconate, citrate, tartrate, maleate, malate, pantothenate, adipate, alginate, aspartate, benzoate, butyrate, digluconate, cyclopentanate, glucoheptanate, glycerophosphate, oxalate, heptanoate, hexanoate, fumarate, nicotinate, palmoate, pectinate, 3-phenylpropionate, picrate, 20 pivalate, proprionate, tartrate, lactobionate, pivolate, camphorate, undecanoate and succinate, organic sulphonic acids such as methanesulphonate, ethanesulphonate, 2- hydroxyethane sulphonate, camphorsulphonate, 2-naphthalenes
  • Esters are formed either using organic acids or alcohols/hydroxides, depending on the functional group being esterified.
  • Organic acids include carboxylic acids, such as alkanecarboxylic acids of 1 to 12 carbon atoms which are unsubstituted or substituted (e.g., by halogen), such as acetic acid; with saturated or unsaturated dicarboxylic acid, for 30 example oxalic, malonic, succinic, maleic, fumaric, phthalic or tetraphthalic; with hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid; with aminoacids, for example aspartic or glutamic acid; with benzoic acid; or with organic sulfonic acids, such as (C 1 -C 4 )-alkyl- or aryl-sulfonic acids which are unsubstituted or substituted (for example, by a halogen) such as methane- or p-
  • Suitable hydroxides include inorganic hydroxides, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminium hydroxide.
  • Alcohols include alkanealcohols of 1- 5 12 carbon atoms which may be unsubstituted or substituted, e.g. by a halogen).
  • ENANTIOMERS/TAUTOMERS In all aspects of the present invention previously discussed, the invention includes, where appropriate all enantiomers, diastereoisomers and tautomers of the compounds of the invention. The person skilled in the art will recognise compounds that possess optical 10 properties (one or more chiral carbon atoms) or tautomeric characteristics. The corresponding enantiomers and/or tautomers may be isolated/prepared by methods known in the art.
  • Enantiomers are characterised by the absolute configuration of their chiral centres and described by the R- and S-sequencing rules of Cahn, Ingold and Prelog. Such 15 conventions are well known in the art (e.g. see ‘Advanced Organic Chemistry’, 3 rd edition, ed. March, J., John Wiley and Sons, New York, 1985). Compounds of the invention containing a chiral centre may be used as a racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well- known techniques and an individual enantiomer may be used alone.
  • Some of the compounds of the invention may exist as stereoisomers and/or geometric isomers – e.g. they may possess one or more asymmetric and/or geometric centres and so may exist in two or more stereoisomeric and/or geometric forms.
  • the present invention contemplates the use of all the individual stereoisomers and geometric isomers of those 25 compounds, and mixtures thereof.
  • the terms used in the claims encompass these forms, provided said forms retain the appropriate functional activity (though not necessarily to the same degree).
  • the present invention also includes all suitable isotopic variations of the compound or a pharmaceutically acceptable salt thereof.
  • An isotopic variation of a compound of the 30 present invention or a pharmaceutically acceptable salt thereof is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
  • isotopes that can be incorporated into the agent and pharmaceutically acceptable salts thereof include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine 5 such as 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F and 36 Cl, respectively.
  • isotopic variations of the agent and pharmaceutically acceptable salts thereof are useful in drug and/or substrate tissue distribution studies.
  • Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability.
  • 10 substitution with isotopes such as deuterium, i.e., 2 H may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half- life or reduced dosage requirements and hence may be preferred in some circumstances.
  • the invention includes compounds of general formula (I) where any hydrogen atom has been replaced by a deuterium atom.
  • Isotopic variations of the agent of the 15 present invention and pharmaceutically acceptable salts thereof of this invention can generally be prepared by conventional procedures using appropriate isotopic variations of suitable reagents.
  • ATROPISOMERS Some of the compounds of the invention may exist as atropisomers. Atropisomers are 20 stereoisomers arising because of hindered rotation about a single bond, where energy differences due to steric strain or other contributors create a barrier to rotation that is high enough to allow for isolation of individual conformers. The invention encompasses all such atropisomers.
  • PRODRUGS 25 The invention further includes the compounds of the present invention in prodrug form, i.e. covalently bonded compounds which release the active parent drug in vivo.
  • Such prodrugs are generally compounds of the invention wherein one or more appropriate groups have been modified such that the modification may be reversed upon administration to a human or mammalian subject.
  • Reversion is usually performed by an 30 enzyme naturally present in such subject, though it is possible for a second agent to be administered together with such a prodrug in order to perform the reversion in vivo.
  • Examples of such modifications include ester (for example, any of those described above), wherein the reversion may be carried out by an esterase etc.
  • Other such systems will be well known to those skilled in the art.
  • SOLVATES 5 The present invention also includes solvate forms of the compounds of the present invention. The terms used in the claims encompass these forms. Preferably, the solvate is a hydrate.
  • a further aspect of the invention relates to a combination comprising a compound as 10 described herein and one or more additional active agents.
  • the one or more compounds of the invention are administered in combination with one or more additional active agents, for example, existing drugs available on the market.
  • the compounds of the invention may be administered consecutively, simultaneously or sequentially with the one or more other active agents.
  • Drugs in general can be more effective when used in combination.
  • combination therapy is desirable in order to avoid an overlap of major toxicities, mechanism of action and resistance mechanism(s).
  • the major advantages of combining chemotherapeutic drugs are 20 that it may promote additive or possible synergistic effects through biochemical interactions and also may decrease the emergence of resistance. Beneficial combinations may be suggested by studying the activity of the test compounds with agents known or suspected of being valuable in the treatment of a particular disorder. This procedure can also be used to determine the order of administration of the agents, i.e. 25 before, simultaneously, or after delivery. Such scheduling may be a feature of all the active agents identified herein.
  • compounds of the invention can be used in combination with immunotherapies such as cancer vaccines and/or with other immune-modulators.
  • the additional active agent is an immunotherapy agent, more 30 preferably a cancer immunotherapy agent.
  • An “immunotherapy agent“ refers to a
  • the invention further relates to the compounds of the present invention in their various crystalline forms, polymorphic forms and (an)hydrous forms. It is well established within the pharmaceutical industry that chemical compounds may be isolated in any of such 10 forms by slightly varying the method of purification and or isolation form the solvents used in the synthetic preparation of such compounds.
  • compositions of the present invention may be adapted for rectal, nasal, intrabronchial, topical (including buccal and sublingual), vaginal or parenteral 15 (including subcutaneous, intramuscular, intravenous, intraarterial and intradermal), intraperitoneal or intrathecal administration.
  • the formulation is an orally administered formulation.
  • the formulations may conveniently be presented in unit dosage form, i.e., in the form of discrete portions containing a unit dose, or a multiple or sub-unit of a unit dose.
  • the formulations may be in the form of tablets and 20 sustained release capsules, and may be prepared by any method well known in the art of pharmacy.
  • Formulations for oral administration in the present invention may be presented as: discrete units such as capsules, gellules, drops, cachets, pills or tablets each containing a predetermined amount of the active agent; as a powder or granules; as a solution, 25 emulsion or a suspension of the active agent in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion; or as a bolus etc.
  • these compositions contain from 1 to 250 mg and more preferably from 10-100 mg, of active ingredient per dose.
  • the term “acceptable 30 carrier” includes vehicles such as common excipients e.g. binding agents, for example
  • Flavouring agents such as peppermint, oil of wintergreen, cherry flavouring and the like can also be used. It may be desirable to add a colouring agent to make the dosage form readily identifiable. Tablets may also be coated by methods well known in 10 the art.
  • a tablet may be made by compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active agent in a free flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface-active or dispersing agent.
  • Moulded 15 tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may be optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active agent.
  • Other formulations suitable for oral administration include lozenges comprising the active 20 agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active agent in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active agent in a suitable liquid carrier.
  • Other forms of administration comprise solutions or emulsions which may be injected intravenously, intraarterially, intrathecally, subcutaneously, intradermally, intraperitoneally 25 or intramuscularly, and which are prepared from sterile or sterilisable solutions.
  • Injectable forms typically contain between 10 - 1000 mg, preferably between 10 - 250 mg, of active ingredient per dose.
  • the pharmaceutical compositions of the present invention may also be in form of suppositories, pessaries, suspensions, emulsions, lotions, ointments, creams, gels, 30 sprays, solutions or dusting powders.
  • An alternative means of transdermal administration is by use of a skin patch.
  • the active ingredient can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin.
  • the active ingredient can also be incorporated, at a concentration of between 1 and 10% by weight, into an ointment consisting of a white 5 wax or white soft paraffin base together with such stabilisers and preservatives as may be required.
  • DOSAGE A person of ordinary skill in the art can easily determine an appropriate dose of one of the instant compositions to administer to a subject without undue experimentation. Typically, a 10 physician will determine the actual dosage which will be most suitable for an individual patient, and it will depend on a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the individual 15 undergoing therapy.
  • the dosages disclosed herein are exemplary of the average case. There can of course be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
  • the dosage amount will further be modified according to the mode of administration of the compound. For example, to achieve an “effective amount” for acute therapy, parenteral 20 administration of a compound is typically preferred.
  • An intravenous infusion of the compound in 5% dextrose in water or normal saline, or a similar formulation with suitable excipients, is most effective, although an intramuscular bolus injection is also useful.
  • the parenteral dose will be about 0.01 to about 100 mg; preferably between 0.1 and 20 mg, in a manner to maintain the concentration of drug in the plasma at a 25 concentration effective to modulate GPR35.
  • the compounds may be administered one to four times daily at a level to achieve a total daily dose of about 0.4 to about 400 mg.
  • the precise amount of an inventive compound which is therapeutically effective, and the route by which such compound is best administered, is readily determined by one of ordinary skill in the art by comparing the blood level of the agent to the concentration required to 30 have a therapeutic effect.
  • the compounds of this invention may also be administered orally to the patient, in a manner such that the concentration of drug is sufficient to achieve one or more of the therapeutic indications disclosed herein.
  • a pharmaceutical composition containing the compound is administered at an oral dose of between about 0.1 to about 5 500 mg or about 0.1 to about 50 mg in a manner consistent with the condition of the patient.
  • the oral dose would be about 0.5 to about 50 mg or about 0.5 to about 20 mg.
  • No unacceptable toxicological effects are expected when compounds of the present invention are administered in accordance with the present invention.
  • the compounds of 10 this invention which may have good bioavailability, may be tested in one of several biological assays to determine the concentration of a compound which is required to have a given pharmacological effect. The invention is further described by way of the following non-limiting examples.
  • Aqueous Ar Aryl B 2 Pin 2 Bis(pinacolato)diboron C18 Octadecyl carbon Celite ® Diatomaceous earth d Days d Doublet (context of NMR)
  • DCE 1,2-Dichloroethane
  • DCM Dichloromethane Dioxane 1,4-Dioxane
  • DIPEA N,N-Diisopropylethylamine
  • DMA N,N-Dimethylacetamide
  • DMAP 4-Dimethylaminopyridine
  • DME 1,2-Dimethoxyethane
  • DMF N,N-Dimethylformamide
  • DMSO Dimethyl sulfoxide Et 2 O Diethyl ether EtOAc Ethyl acetate EtOH Ethanol eq.
  • NMR spectra were recorded using a Bruker 500 MHz Avance III HD spectrometer equipped with a Bruker 5mm SmartProbe TM or a Bruker 400 MHz Avance Neo spectrometer fitted with a Bruker 5mm iProbe. Data were acquired using Bruker TopSpin software and processed using MestreNova software. 10 Where reaction is likely at two or more atoms (e.g. N-alkylation of heterocycles containing two or more N to provide N-protection) and a mixture of two or more isomers was obtained as determined by LCMS, that mixture was carried through without further purification unless stated otherwise.
  • reaction is likely at two or more atoms (e.g. N-alkylation of heterocycles containing two or more N to provide N-protection) and a mixture of two or more isomers was obtained as determined by LCMS, that mixture was carried through without further purification unless stated otherwise.
  • N-(5-Bromopyrazin-2-yl)morpholine-4-sulfonamide (I-10) Using morpholine-4-sulfonyl chloride (CAS 1828-66-6, BLD) in place of methanesulfonyl10 chloride, and 5-bromopyrazin-2-amine (CAS 59489-71-3, BLD) in place of 6-bromo-3- chloropyrazin-2-amine, and without purification, was obtained N-(5-bromopyrazin-2- yl)morpholine-4-sulfonamide in 41% yield.
  • LCMS Method A, 1.12 min, MS ES + 323.0/325.0.
  • N-(5-Bromo-3-methoxypyrazin-2-yl)methanesulfonamide (I-15) Using 5-bromo-3-methoxypyrazin-2-amine (CAS 5900-13-0, Apollo Scientific) in place of 6-10 bromo-3-chloropyrazin-2-amine, and without purification, was obtained N-(5-bromo-3- methoxypyrazin-2-yl)methanesulfonamide in 51% yield.
  • LCMS Method A, 1.07 min, MS ES + 282.0/284.0.
  • Step 2 4-phenethoxyaniline (I-18) To a solution of 1-nitro-4-phenethoxybenzene (4.50 g, 18.5 mmol) in EtOH (55 mL) and 10 THF (30 mL), was added 10% Pd/C (wet with 50% water, 0.98 g, 9.3 mmol) and the mixture was stirred at rt under hydrogen (3 bar) for 18 h. The reaction mixture was filtered through Celite ® and concentrated under reduced pressure to afford 4-phenethoxyaniline (3.50 g, 86%). LCMS: Method A, 0.99 min, MS: ES + 214.2.
  • Step 3 N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19)
  • 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid CAS 20 269409-73-6, BLD, 4.48 g, 18.1 mmol
  • DIPEA 8.6 mL, 49.2 mmol
  • HATU 7.49 g, 20.0 mmol
  • 4-phenethoxyaniline I-18, 3.50 g, 16.4 mmol
  • Step 3 N-(4-((benzyloxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (I-21) Following the procedure of Intermediate 19 Step 3, using 4-((benzyloxy)methyl)aniline (I- 20) in place of 4-phenethoxyaniline (I-18), was obtained N-(4-((benzyloxy)methyl)phenyl)- 15 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide in 51% yield.
  • LCMS Method A, 2.27 min, MS: ES + 444.2.
  • Step 2 4-((benzyloxy)methyl)-2-methoxyaniline To a stirred suspension of 4-((benzyloxy)methyl)-2-methoxy-1-nitrobenzene (1.30 g, 4.76 mmol) and CaCl 2 (2.38 g, 21.4 mmol) in EtOH (10 mL) and water (2 mL) was added iron 15 (2.39 g, 42.8 mmol). The mixture was stirred at 40 °C for 16 h. The mixture was diluted with sat. aq. NaHCO 3 (25 mL) and extracted with EtOAc (2 x 25 mL).
  • Step 3 N-(4-((benzyloxy)methyl)-2-methoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (I-22) Following the procedure of Intermediate 19 Step 3, using 4-((benzyloxy)methyl)-2- methoxyaniline in place of 4-phenethoxyaniline (I-18), and purification by flash chromatography (silica gel, 0-10% MeOH/DCM) was obtained N-(4-((benzyloxy)methyl)-2- methoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide in 30% yield.
  • Step 3 N-(3-fluoro-4-((pyridin-2-ylmethoxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (I-23)
  • Step 3 using 3-fluoro-4-((pyridin-2- ylmethoxy)methyl)aniline in place of 4-phenethoxyaniline (I-18) was obtained N-(3-fluoro-4-10 ((pyridin-2-ylmethoxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide in 72% yield.
  • Step 1 1-(bromomethyl)-2-fluoro-4-nitrobenzene
  • 2-fluoro-1-methyl-4-nitrobenzene CAS 455-88-9, Sigma Aldrich, 5 10.0 g, 64.46 mmol
  • anhydrous DCE 100 mL
  • NBS CAS 128-08-5, Apollo Scientific
  • AIBN CAS 78-67-1, Sigma Aldrich
  • the mixture was stirred at reflux for 18 h then additional NBS (2.87 g, 16.1 mmol) and AIBN (212 mg, 1.29 mmol) were added.
  • Step 2 2-fluoro-1-(((4-methoxybenzyl)oxy)methyl)-4-nitrobenzene Following the procedure of Intermediate 20 Step 1, using 4-methoxyphenyl)methanol (CAS 105-13-5, Apollo Scientific) in place of benzyl alcohol, 1-(bromomethyl)-2-fluoro-4- nitrobenzene in place of 1-(bromomethyl)-4-nitrobenzene, and purification by flash chromatography (silica gel, 0-100% EtOAc in isohexane) was obtained 2-fluoro-1-(((4- 5 methoxybenzyl)oxy)methyl)-4-nitrobenzene in 73% yield.
  • 4-methoxyphenyl)methanol CAS 105-13-5, Apollo Scientific
  • Step 4 N-(3-fluoro-4-(((4-methoxybenzyl)oxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2- 15 dioxaborolan-2-yl)benzamide (I-26) Following the procedure of Intermediate 19 Step 3, using 3-fluoro-4-(((4- methoxybenzyl)oxy)methyl)aniline in place of 4-phenethoxyaniline (I-18) was obtained N- (3-fluoro-4-(((4-methoxybenzyl)oxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2- 20 dioxaborolan-2-yl)benzamide in 49% yield.
  • Step 2 4-(cyclopropylmethoxy)aniline Following the procedure of Intermediate 20 Step 2, using 1-(cyclopropylmethoxy)-4- nitrobenzene in place of 1-((benzyloxy)methyl)-4-nitrobenzene and without purification of 15 crude product, was obtained 4-(cyclopropylmethoxy)aniline in 60% yield.
  • LCMS Method A, 0.22 min, MS ES + 164.2.
  • Step 3 N-(4-(cyclopropylmethoxy)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (I-27) Following the procedure of Intermediate 19 Step 3, using 4-(cyclopropylmethoxy)aniline in 5 place of 4-phenethoxyaniline (I-18) was obtained N-(4-(cyclopropylmethoxy)phenyl)-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide in 86% yield.
  • LCMS Method A, 2.09 min, MS ES + 394.2.
  • Step 3 N-(3-fluoro-4-(((3-methoxybenzyl)oxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (I-28) 15 Following the procedure of Intermediate 19 Step 3, using 3-fluoro-4-(((3- methoxybenzyl)oxy)methyl)aniline in place of 4-phenethoxyaniline (I-18) was obtained N- (3-fluoro-4-(((3-methoxybenzyl)oxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide in 56% yield.
  • Step 1 1-((benzyloxy)methyl)-2-fluoro-4-nitrobenzene Following the procedure of Intermediate 20 Step 1 using (2-fluoro-4-nitrophenyl)methanol 5 (CAS 127349-56-8, Apollo Scientific) in place of benzyl alcohol, benzyl bromide (CAS 100- 39-0, Sigma Aldrich) in place of 1-(bromomethyl)-4-nitrobenzene, at 45 °C for 48 h, and without purification was obtained 1-((benzyloxy)methyl)-2-fluoro-4-nitrobenzene in 43% yield.
  • (2-fluoro-4-nitrophenyl)methanol 5 CAS 127349-56-8, Apollo Scientific
  • benzyl bromide CAS 100- 39-0, Sigma Aldrich
  • Step 2 4-((benzyloxy)methyl)-3-fluoroaniline Following the procedure of Intermediate 22 Step 2, using 1-((benzyloxy)methyl)-2-fluoro-4- nitrobenzene in place of 4-((benzyloxy)methyl)-2-methoxy-1-nitrobenzene, stirring at 80 °C 15 for 16 h, and with purification by capturing the crude concentrate on SCX, washing with MeOH and eluting with 0.7M ammonia/MeOH, was obtained 4-((benzyloxy)methyl)-3- fluoroaniline in 55% yield.
  • LCMS Method A, 1.57 min, MS ES + 232.2.
  • Step 3 N-(4-((benzyloxy)methyl)-3-fluorophenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (I-29) Following the procedure of Intermediate 19 Step 3, using 2-fluoro-5-(4,4,5,5-tetramethyl- 5 1,3,2-dioxaborolan-2-yl)benzoic acid (CAS 882679-10-9, BLD) in place of 3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid, and 4-((benzyloxy)methyl)-3-fluoroaniline in place of 4-phenethoxyaniline (I-18) was obtained N-(4-((benzyloxy)methyl)-3- fluorophenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide in 44% yield
  • Step 2 4-((benzyloxy)methyl)-2-fluoroaniline Following the procedure of Intermediate 20 Step 2, using 4-((benzyloxy)methyl)-2-fluoro-1- nitrobenzene in place of 1-((benzyloxy)methyl)-4-nitrobenzene and with purification by flash chromatography (silica gel, 0 - 50% TBME in isohexane), was obtained 4- ((benzyloxy)methyl)-2-fluoroaniline in 75% yield. 5 LCMS: Method A, 1.64 min, MS ES + 232.1.
  • Step 3 N-(4-((benzyloxy)methyl)-2-fluorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (I-32) Following the procedure of Intermediate 19 Step 3, using 4-((benzyloxy)methyl)-2-10 fluoroaniline in place of 4-phenethoxyaniline (I-18), was obtained N-(4-((benzyloxy)methyl)- 2-fluorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide in 46% yield.
  • LCMS Method A, 2.26 min, MS ES + 462.2.
  • Step 3 N-(4-((1-phenylethoxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (I-37) Following the procedure of Intermediate 19 Step 3, using 4-((1- phenylethoxy)methyl)aniline in place of 4-phenethoxyaniline (I-18) was obtained N-(4-((1- 20 phenylethoxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide in 17% yield.
  • LCMS Method A, 2.30 min, MS ES + 458.2.
  • Step 1 6-chloro-3-methylpyrazin-2-amine
  • 3-bromo-6-chloropyrazin-2-amine CAS: 212779-21-0, BLD, 2.00 g, 9.60 5 mmol
  • 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane 2.96 mL, 50% Wt, 10.6 mmol
  • Pd-118 625 mg, 0.960 mmol
  • Cs 2 CO 3 (6.25 g, 19.2 mmol) in MeCN/water (4:1, 20 mL) was sparged with N 2 then stirred 80 °C for 40 h. After cooling to rt, the mixture was filtered through Celite, washing with EtOAc (50 mL).
  • Step 2 5-(6-amino-5-methylpyrazin-2-yl)-N-(4-((benzyloxy)methyl)phenyl)-2- 15 fluorobenzamide (I-39)
  • a mixture of 6-chloro-3-methylpyrazin-2-amine (150 mg, 1.02 mmol), N-(4- ((benzyloxy)methyl)phenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (577 mg, 1.13 mmol), Pd-118 (67 mg, 0.102 mmol) and Cs 2 CO 3 (667 mg, 2.05 mmol) in MeCN/water (4:1, 7 mL) was sparged with N 2 then stirred at 80 °C for 1.5 h.
  • Step 1 6-chloro-3-cyclopropylpyrazin-2-amine Following the procedure of Intermediate 39 Step 1, using cyclopropaneboronic acid (CAS: 411235-57-9, Fluorochem) in place of 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane, and with stirring for 40 h (adding additional cyclopropaneboronic acid (0.4 eq) and Pd-118 (0.05 eq) after 22 h) afforded 6-chloro-3-cyclopropylpyrazin-2-amine in 62% yield.
  • cyclopropaneboronic acid CAS: 411235-57-9, Fluorochem
  • Step 2 5-(6-amino-5-cyclopropylpyrazin-2-yl)-N-(4-((benzyloxy)methyl)phenyl)-2- 5 fluorobenzamide (I-40) Following the procedure of Intermediate 39 Step 2, using 6-chloro-3-cyclopropylpyrazin-2- amine in place of 6-chloro-3-methylpyrazin-2-amine afforded 5-(6-amino-5- cyclopropylpyrazin-2-yl)-N-(4-((benzyloxy)methyl)phenyl)-2-fluorobenzamide in 41% yield.
  • Examples 2-9 The following Examples 2-9 were prepared analogously to Example 1, substituting N-(6- bromo-3-chloropyrazin-2-yl)methanesulfonamide (I-1) and N-(4-phenethoxyphenyl)-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19) with the appropriate starting 20 materials, using dioxane or acetonitrile at 80 °C for 1 h, and with any other minor modifications described. Examples 2, 3 and 4 were purified with basic modifier.
  • Example 3 3-(5-Chloro-6-(methylsulfonamido)pyrazin-2-yl)-N-(4- (cyclopropylmethoxy)phenyl)benzamide 15 Using N-(6-bromo-3-chloropyrazin-2-yl)methanesulfonamide (I-1) and N-(4- (cyclopropylmethoxy)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I- 27) and with trituration with CH 3 CN and Et 2 O, afforded 3-(5-chloro-6- (methylsulfonamido)pyrazin-2-yl)-N-(4-(cyclopropylmethoxy)phenyl)benzamide in 52% yield.
  • Example 8 N-(4-((Benzyloxy)methyl)-3-fluorophenyl)-5-(6-chloro-5-(methylsulfonamido)pyrazin-2-yl)- 2-fluorobenzamide 15 Using N-(5-bromo-3-chloropyrazin-2-yl)-N-(methylsulfonyl)methanesulfonamide (I-3) and N-(4-((benzyloxy)methyl)-3-fluorophenyl)-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzamide (I-29) afforded N-(4-((benzyloxy)methyl)-3-fluorophenyl)-5- (6-chloro-5-(methylsulfonamido)pyrazin-2-yl)-2-fluorobenzamide in 14% yield.
  • Examples 10-21 The following Examples 10-21 were prepared analogously to Example 1, substituting N-(6- bromo-3-chloropyrazin-2-yl)methanesulfonamide (I-1) and N-(4-phenethoxyphenyl)-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19) with the appropriate starting 20 materials, using Pd-118 in place of Pd(dppf)Cl 2 , and either dioxane or acetonitrile at 80 °C for 9-18 h. Any other minor modifications are described. Examples 10-12, 14-15 and 18-21 were purified with basic modifier.
  • Example 10 3-(6-Chloro-5-(methylsulfonamido)pyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide Using N-(5-bromo-3-chloropyrazin-2-yl)methanesulfonamide (I-3) and N-(4- 5 phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19) afforded 3-(6-chloro-5-(methylsulfonamido)pyrazin-2-yl)-N-(4- phenethoxyphenyl)benzamide in 7% yield.
  • Example 11 15 3-(5-Cyano-6-(methylsulfonamido)pyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide Using N-(6-chloro-3-cyanopyrazin-2-yl)methanesulfonamide (I-4) and N-(4- phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19) afforded 3-(5-cyano-6-(methylsulfonamido)pyrazin-2-yl)-N-(4- 20 phenethoxyphenyl)benzamide in 21% yield.
  • Example 12 5 3-(5-Methyl-4-(methylsulfonamido)pyrimidin-2-yl)-N-(4-phenethoxyphenyl)benzamide Using N-(2-chloro-5-methylpyrimidin-4-yl)-N-(methylsulfonyl)methanesulfonamide (I-11) and N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I- 19) afforded 3-(5-methyl-4-(methylsulfonamido)pyrimidin-2-yl)-N-(4- 10 phenethoxyphenyl)benzamide in 23% yield.
  • Example 13 3-(6-Methyl-5-(methylsulfonamido)pyridin-3-yl)-N-(4-phenethoxyphenyl)benzamide Using N-(5-bromo-2-methylpyridin-3-yl)-N-(methylsulfonyl)methanesulfonamide (I-12) and 20 N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19) afforded 3-(6-methyl-5-(methylsulfonamido)pyridin-3-yl)-N-(4- phenethoxyphenyl)benzamide in 52% yield.
  • Example 15 3-(4-(Methylsulfonamido)pyrimidin-2-yl)-N-(4-phenethoxyphenyl)benzamide 20 Using N-(2-chloropyrimidin-4-yl)-N-(methylsulfonyl)methanesulfonamide (I-6) and N-(4- phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19) afforded 3-(4-(methylsulfonamido)pyrimidin-2-yl)-N-(4-phenethoxyphenyl)benzamide in 23% yield.
  • Example 16 3-(6-(Methylsulfonamido)pyridin-2-yl)-N-(4-phenethoxyphenyl)benzamide 10 Using N-(6-bromopyridin-2-yl)-N-(methylsulfonyl)methanesulfonamide (I-7) and N-(4- phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19), with trituration with CH 3 CN and Et 2 O, afforded 3-(6-(methylsulfonamido)pyridin-2-yl)-N-(4- phenethoxyphenyl)benzamide in 19% yield.
  • Example 17 20 N-(4-((Benzyloxy)methyl)phenyl)-3-(6-(methylsulfonamido)pyrazin-2-yl)benzamide Using N-(6-bromopyrazin-2-yl)-N-(methylsulfonyl)methanesulfonamide (I-5) and N-(4- ((benzyloxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I- 21) afforded N-(4-((benzyloxy)methyl)phenyl)-3-(6-(methylsulfonamido)pyrazin-2- yl)benzamide in 14% yield.
  • Example 18 3-(6-(Cyclopropanesulfonamido)pyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide 10 Using N-(6-bromopyrazin-2-yl)cyclopropanesulfonamide (I-8) and N-(4-phenethoxyphenyl)- 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19) afforded 3-(6- (cyclopropanesulfonamido)pyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide in 33% yield.
  • LCMS Method A, 1.92 min, MS ES + 515.1.
  • the isolated compound contains up to 1 mol. eq. 10 of ammonia
  • Example 20 3-(5-(Methylsulfonamido)pyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide Using N-(5-bromopyrazin-2-yl)methanesulfonamide (I-9) and N-(4-phenethoxyphenyl)-3-15 (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19) afforded 3-(5- (methylsulfonamido)pyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide in 25% yield.
  • Example 21 3-(5-(Morpholine-4-sulfonamido)pyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide Using N-(5-bromopyrazin-2-yl)morpholine-4-sulfonamide (I-10) and N-(4- 5 phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19) afforded 3-(5-(morpholine-4-sulfonamido)pyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide in 17% yield.
  • Example 22 N-(4-((Benzyloxy)methyl)phenyl)-3-(5-cyclopropyl-6-(methylsulfonamido)pyrazin-2- yl)benzamide N-(4-((Benzyloxy)methyl)phenyl)-3-(5-cyclopropyl-6-(methylsulfonamido)pyrazin-2- yl)benzamide A mixture of 2-cyclopropyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (CAS 126689-01-8, BLD, 51 mg, 0.306 mmol), Cs 2 CO 3 (100 mg, 0.306 mmol), and N-(4- ((benzyloxy)methyl)phenyl)-3-(5-chloro-6-(methylsulfonamido)pyrazin-2-yl)benzamide 5 (Example 2, 40 mg, 0.077 mmol
  • Example 23 N-(4-((Benzyloxy)methyl)phenyl)-3-(5-cyclopropyl-6-(morpholine-4-sulfonamido)pyrazin-2- yl)benzamide
  • Step 1 N-(4-((benzyloxy)methyl)phenyl)-3-(5-chloro-6-(morpholine-4-sulfonamido)pyrazin- 2-yl)benzamide 5
  • N-(6-bromo-3-chloropyrazin-2-yl)morpholine- 4-sulfonamide (I-38) in place of N-(6-bromo-3-chloropyrazin-2-yl)methanesulfonamide (I- 1)
  • purification by flash chromatography silica gel, 0-10
  • Step 2 N-(4-((benzyloxy)methyl)phenyl)-3-(5-cyclopropyl-6-(morpholine-4- sulfonamido)pyrazin-2-yl)benzamide
  • Example 24 3-(5-Methyl-6-(methylsulfonamido)pyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide 3-(5-Methyl-6-(methylsulfonamido)pyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide 5
  • a mixture of 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (0.024 mL, 0.172 mmol), Cs 2 CO 3 (150 mg, 0.459 mmol), and 3-(5-chloro-6-(methylsulfonamido)pyrazin-2-yl)-N-(4- phenethoxyphenyl)benzamide Example 1, 60 mg, 0.115 mmol) in dioxane (4 mL) and water (1 mL) was purged with nitrogen for 5 min, after which Pd-118 (7 mg, 0.012 mmol) 10 was added and the mixture
  • Examples 25-30 The following Examples 25-30 were prepared analogously to Example 24, substituting 3- (5-chloro-6-(methylsulfonamido)pyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide (Example 1) with the appropriate starting material, using dioxane or acetonitrile at 80 °C 5 for 16-18 h, and with any other minor modifications described. Examples 25-27 and 30 were purified with basic modifier.
  • Example 25 N-(4-((Benzyloxy)methyl)phenyl)-3-(5-methyl-6-(methylsulfonamido)pyrazin-2- 10 yl)benzamide Using N-(4-((benzyloxy)methyl)phenyl)-3-(5-chloro-6-(methylsulfonamido)pyrazin-2- yl)benzamide (Example 2) afforded N-(4-((benzyloxy)methyl)phenyl)-3-(5-methyl-6- (methylsulfonamido)pyrazin-2-yl)benzamide in 34% yield. 15 LCMS: Method A, 1.80 min, MS ES + 503.2.
  • Example 26 N-(4-((Benzyloxy)methyl)phenyl)-3-(5-methyl-6-(morpholine-4-sulfonamido)pyrazin-2- yl)benzamide 5 Using N-(4-((benzyloxy)methyl)phenyl)-3-(5-chloro-6-(morpholine-4-sulfonamido)pyrazin-2- yl)benzamide (Example 57) afforded N-(4-((benzyloxy)methyl)phenyl)-3-(5-methyl-6- (morpholine-4-sulfonamido)pyrazin-2-yl)benzamide in 29% yield.
  • Example 27 N-(4-(Cyclopropylmethoxy)phenyl)-3-(5-methyl-6-(methylsulfonamido)pyrazin-2- yl)benzamide Using 3-(5-chloro-6-(methylsulfonamido)pyrazin-2-yl)-N-(4-(cyclopropylmethoxy)phenyl)- benzamide (Example 3) afforded N-(4-(cyclopropylmethoxy)phenyl)-3-(5-methyl-6- 20 (methylsulfonamido)pyrazin-2-yl)benzamide in 22% yield.
  • Example 28 N-(3-Fluoro-4-(((3-methoxybenzyl)oxy)methyl)phenyl)-3-(5-methyl-6-(methylsulfonamido)- pyrazin-2-yl)benzamide 10 Using 3-(5-chloro-6-(methylsulfonamido)pyrazin-2-yl)-N-(3-fluoro-4-(((3- methoxybenzyl)oxy)methyl)phenyl)benzamide (Example 7) afforded N-(3-fluoro-4-(((3- methoxybenzyl)oxy)methyl)phenyl)-3-(5-methyl-6-(methylsulfonamido)pyrazin-2- yl)benzamide in 22% yield.
  • Example 29 20 N-(3-Fluoro-4-(((4-methoxybenzyl)oxy)methyl)phenyl)-3-(5-methyl-6- (methylsulfonamido)pyrazin-2-yl)benzamide Using 3-(5-chloro-6-(methylsulfonamido)pyrazin-2-yl)-N-(3-fluoro-4-(((4- methoxybenzyl)oxy)methyl)phenyl)benzamide (Example 6) afforded N-(3-fluoro-4-(((4- methoxybenzyl)oxy)methyl)phenyl)-3-(5-methyl-6-(methylsulfonamido)pyrazin-2- yl)benzamide in 23% yield.
  • Step 2 N-(4-((benzyloxy)methyl)phenyl)-4-methoxy-3-(5-methyl-6-(methylsulfonamido)- pyrazin-2-yl)benzamide
  • N-(4-((benzyloxy)methyl)phenyl)-3-(5- 5 chloro-6-(methylsulfonamido)pyrazin-2-yl)-4-methoxybenzamide in place of 3-(5-chloro-6- (methylsulfonamido)pyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide (Example 1), at 80 °C for 16 h and with purification by RP chromatography (C18, 0-100% MeCN in 0.1% aq.
  • Step 1 N-(4-((benzyloxy)methyl)-2-fluorophenyl)-3-(5-chloro-6-(methylsulfonamido)- pyrazin-2-yl)benzamide 5
  • chromatography on RP chromatography C18, 0-100% MeCN in 0.1% aq.
  • Example 36 N-(4-((Benzyloxy)methyl)phenyl)-4-methyl-3-(5-methyl-6-(methylsulfonamido)pyrazin-2- yl)benzamide 5 Step 1: N-(4-((benzyloxy)methyl)phenyl)-3-(5-chloro-6-(methylsulfonamido)pyrazin-2-yl)-4- methylbenzamide Following the procedure of Example 1, using N-(4-((benzyloxy)methyl)phenyl)-4-methyl-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-25) in place of N-(4- 10 phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19), at 80 °C for 1 h and without purification afforded N-(4-((benzyloxy)methyl)pheny
  • Example 37 N-(4-((Benzyloxy)methyl)phenyl)-2,6-difluoro-3-(5-methyl-6-(methylsulfonamido)pyrazin-2- yl)benzamide 15 Step 1: N-(4-((benzyloxy)methyl)phenyl)-3-(5-chloro-6-(methylsulfonamido)pyrazin-2-yl)- 2,6-difluorobenzamide Following the procedure of Example 1, using (3-((4-((benzyloxy)methyl)phenyl)carbamoyl)- 5 2,4-difluorophenyl)boronic acid (I-24) in place of N-(4-phenethoxyphenyl)-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19), at 80 °C for 1 h and without purification afforded N-(4-((benzyloxy)methyl)
  • Step 2 N-(4-((benzyloxy)methyl)phenyl)-2,6-difluoro-3-(5-methyl-6- (methylsulfonamido)pyrazin-2-yl)benzamide
  • N-(4-((benzyloxy)methyl)phenyl)-3-(5- chloro-6-(methylsulfonamido)pyrazin-2-yl)-2,6-difluorobenzamide in place of 3-(5-chloro-6- 15 (methylsulfonamido)pyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide (Example 1), at 80 °C for 16 h and with purification by RP chromatography (C18, 0-100% MeCN in 0.1% aq.
  • Example 38 N-(3-Fluoro-4-((pyridin-2-ylmethoxy)methyl)phenyl)-3-(5-methyl-6-(methylsulfonamido)- pyrazin-2-yl)benzamide 5 Step 1: 3-(5-chloro-6-(methylsulfonamido)pyrazin-2-yl)-N-(3-fluoro-4-((pyridin-2- ylmethoxy)methyl)phenyl)benzamide Following the procedure of Example 1, using N-(3-fluoro-4-((pyridin-2- ylmethoxy)methyl)phenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-23)10 in place of N-(4-phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzamide (I-19), at 80 °
  • the isolated compound 15 contains up to 1 mol. eq. of ammonia.
  • Example 39 N-(4-((Benzyloxy)methyl)phenyl)-4-fluoro-3-(5-methyl-6-(methylsulfonamido)pyrazin-2- yl)benzamide
  • Step 1 N-(4-((benzyloxy)methyl)phenyl)-3-(5-chloro-6-(methylsulfonamido)pyrazin-2-yl)-4- fluorobenzamide 5
  • Example 1 using (5-((4-((benzyloxy)methyl)phenyl)carbamoyl)- 2-fluorophenyl)boronic acid (I-34) in place of N-(4-phenethoxyphenyl)-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19), at 80 °C for 1 h and purification by chromatography on RP chromatography (C18, 0-100% MeCN in 0.1% aq.
  • Step 2 N-(4-((benzyloxy)methyl)phenyl)-4-fluoro-3-(5-methyl-6-(methylsulfonamido)- pyrazin-2-yl)benzamide
  • N-(4-((benzyloxy)methyl)phenyl)-3-(5- chloro-6-(methylsulfonamido)pyrazin-2-yl)-4-fluorobenzamide in place of 3-(5-chloro-6- (methylsulfonamido)pyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide (Example 1), at 80 °C for 16 h and with purification by RP chromatography (C18, 0-100% MeCN in 0.1% aq.
  • Example 40 N-(4-((Benzyloxy)methyl)phenyl)-2-fluoro-5-(5-methyl-6-(methylsulfonamido)pyrazin-2- yl)benzamide 15 Step 1: N-(4-((benzyloxy)methyl)phenyl)-5-(5-chloro-6-(methylsulfonamido)pyrazin-2-yl)-2- fluorobenzamide Following the procedure of Example 1, using N-(4-((benzyloxy)methyl)phenyl)-2-fluoro-5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-33) in place of N-(4- phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19), at 80 5 °C for 1 h and purification by chromatography on RP chromatography (C18,
  • Step 2 N-(4-((benzyloxy)methyl)phenyl)-2-fluoro-5-(5-methyl-6-(methylsulfonamido)- 10 pyrazin-2-yl)benzamide
  • N-(4-((benzyloxy)methyl)phenyl)-5-(5- chloro-6-(methylsulfonamido)pyrazin-2-yl)-2-fluorobenzamide in place of 3-(5-chloro-6- (methylsulfonamido)pyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide (Example 1), at 80 15 °C for 16 h and with purification by RP chromatography (C18, 0-100% MeCN in 0.1% aq.
  • Example 41 3-(5-(2-Aminoethoxy)-6-(methylsulfonamido)pyrazin-2-yl)-N-(4-phenethoxyphenyl)- benzamide 5 3-(5-(2-Aminoethoxy)-6-(methylsulfonamido)pyrazin-2-yl)-N-(4-phenethoxyphenyl)- benzamide A mixture of 3-(5-chloro-6-(methylsulfonamido)pyrazin-2-yl)-N-(4-phenethoxyphenyl)- benzamide (Example 1, 25 mg, 0.048 mmol), 2-aminoethan-1-ol (0.019 mL, 0.239 mmol) 10 and NEt 3 (0.020 mL, 0.143 mmol) in THF (2 mL) was stirred at 40 °C for 72 h.
  • Examples 42-46 The following Examples 42-46 were prepared analogously to Example 1, substituting N-(6- bromo-3-chloropyrazin-2-yl)methanesulfonamide (I-1) and N-(4-phenethoxyphenyl)-3- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19) with the appropriate starting materials, using Pd-118 in place of Pd(dppf)Cl 2 , at 80-90 °C for 9-18 h. Any other minor modifications are described. All examples were purified with basic modifier.
  • Example 45 3-(6-Methoxy-5-(methylsulfonamido)pyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide 5 Using N-(5-bromo-3-methoxypyrazin-2-yl)methanesulfonamide (I-15) and N-(4- phenethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19) afforded 3-(6-methoxy-5-(methylsulfonamido)pyrazin-2-yl)-N-(4- phenethoxyphenyl)benzamide in 45% yield.
  • the isolated compound 15 contains up to 1 mol. eq. of ammonia.
  • Example 46 3-(6-((N,N-Dimethylsulfamoyl)amino)pyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide Using N′-(6-Bromo-2-pyrazinyl)-N,N-dimethylsulfamide (I-16) and N-(4-phenethoxyphenyl)-20 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (I-19) afforded 3-(6-((N,N- dimethylsulfamoyl)amino)pyrazin-2-yl)-N-(4-phenethoxyphenyl)benzamide in 20% yield.
  • Example 59 N-(4-((Benzyloxy)methyl)phenyl)-5-(5-cyclopropyl-6-(methylsulfonamido)pyrazin-2-yl)-2- fluorobenzamide 5
  • Example 58 using 5-(6-amino-5-cyclopropylpyrazin-2-yl)-N-(4- ((benzyloxy)methyl)phenyl)-2-fluorobenzamide (I-40) in place of 5-(6-amino-5- methylpyrazin-2-yl)-N-(4-((benzyloxy)methyl)phenyl)-2-fluorobenzamide (I-39) and methanesulfonyl chloride in place of cyclopropanesulfonyl chloride afforded N-(4- ((benzyloxy)methyl)phenyl)-5-(5-cyclopropyl-6-(
  • the isolated compound contains up to 1 mol. eq. of ammonia.
  • GPR35 assay The functional assay described measures the ability of GPR35 modulators to inhibit a GPR35 agonist-induced phospho-ERK signal. This is expressed as the concentration of 20 modulator required to reduce the phospho-ERK signal by 50 percent, i.e. the IC 50 ; the signal window being defined as the difference between agonist plus modulator vehicle (no modulator) and agonist vehicle (no agonist) controls.
  • This assay is a cellular GPR35 phospho-ERK homogeneous time resolved fluorescence (HTRF) assay using the GPR35-CHO-K1-mt aequorin-G ⁇ 16 cell line.
  • HTRF time resolved fluorescence
  • ERK 1/2 Upon activation of 25 GPR35 with the agonist lodoxamide at EC 80 concentration, ERK 1/2 is phosphorylated, and after lysis of the cell membrane, phospho-ERK1/2 (Thr202/Tyr204) is detected in a sandwich assay using two different specific antibodies, one labelled with Eu 3+ -cryptate (donor) and the second with d2 (acceptor).
  • donor Eu 3+ -cryptate
  • acceptor acceptor
  • the excitation of the donor with a light source (laser or flash lamp) triggers a Fluorescence Resonance Energy Transfer (FRET) towards the acceptor, resulting in specific acceptor fluorescence (at 665 nm).
  • FRET Fluorescence Resonance Energy Transfer
  • the specific signal is directly proportional to the amount of phospho-ERK1/2 5 (Thr202/Tyr204) in the sample.

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Abstract

Un aspect de l'invention concerne un composé de formule (I), ou un sel ou solvate pharmaceutiquement acceptable de celui-ci, X-Y est -CONR6- ou -NR6CO- ; R6 et R7 sont chacun indépendamment H ou alkyle ; R8 est alkyle, cycloalkyle, (CH2)q-hétérocycloalkyle ou NR34R35 ; le cycle C est phényle ou un groupe hétéroaryle à 6 chaînons contenant au moins un N, dont chacun est éventuellement substitué en outre par un ou plusieurs substituants choisis parmi alkyle, haloalkyle, alcoxy, haloalcoxy, halo, CN, NR9SO2-R10, NR9COR11, NR12R13, OH, SO2NR14R15, CONR16R17, cycloalkyle, O(CH2)qNR18R19, (CH2)q-hétérocycloalkyle et CO2R20 ; le cycle A est un phényle ou un groupe hétéroaryle à 6 chaînons ; le cycle B est un phényle ou un groupe hétéroaryle à 6 chaînons ; n et p sont chacun indépendamment de 0 à 4 ; chaque q est indépendamment de 0 à 4 ; Ra et Rb sont sélectionnés indépendamment parmi alkyl, halo, haloalkyl, alkoxy, cycloalkoxy, haloalkoxy, cyano, NR21COR22, NR21SO2R23, (CH2)qSR24, (CH2)qSOR25, (CH2)qSO2R26, SO2NR27R28, (CH2)qOH, (CH2)qOR29, NR30R31, CONR32R33, cycloalkyle et (CH2)q-hétérocycloalkyle ; L est une liaison directe ou est choisi parmi, -O-CO-, -CO-O-, -O-CO-O-, -SO2-, -O-SO2-, -SO2-O-, -O-, -NR36-SO2-, -NR36-SO2-alkylène, -SO2-NR36-, -SO2-NR36-alkylène, alkylène, hétéroalkylène, cycloalkylène, hétérocycloalkylène, alkylène-cycloalkylène, alkylène-SO2-, -SO2-alkylène, alkylène-SO-, -SO-alkylène, alkylène-SO2- alkylène, alkylène-SO-alkylène, cycloalkylène-alkylène, alkylène-hétérocycloalkylène, hétérocycloalkylène-alkylène, -CO-hétérocycloalkylène-alkylène, alkylène-hétérocycloalkylène-CO-, CO2-hétérocycloalkylène-alkylène,alkylène-hétérocycloalkylène-CO2-, hétéroalkylène-hétérocycloalkylène, hétérocycloalkylène-hétéroalkylène, hétéroalkylène-cycloalkylène, cycloalkylène-hétéroalkylène, la fraction alkylène étant éventuellement substituée. D'autres aspects de l'invention concernent des compositions pharmaceutiques, et l'utilisation desdits composés dans le traitement de divers troubles liés à GPR35.
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