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WO2025194074A1 - Modulateurs de kinase et leurs procédés d'utilisation - Google Patents

Modulateurs de kinase et leurs procédés d'utilisation

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Publication number
WO2025194074A1
WO2025194074A1 PCT/US2025/019990 US2025019990W WO2025194074A1 WO 2025194074 A1 WO2025194074 A1 WO 2025194074A1 US 2025019990 W US2025019990 W US 2025019990W WO 2025194074 A1 WO2025194074 A1 WO 2025194074A1
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WO
WIPO (PCT)
Prior art keywords
compound
methyl
alkyl
mmol
methoxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/US2025/019990
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English (en)
Inventor
Anh Pham TRUONG
Hui Li
Gyanendra Kumar
Kejia Derek WU
Claudio Aquino
Pankaj DAGA
Zhonghua Pei
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Neuron23 Inc
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Neuron23 Inc
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Publication of WO2025194074A1 publication Critical patent/WO2025194074A1/fr
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Anticipated expiration legal-status Critical

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains three hetero rings
    • C07D513/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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

Definitions

  • the invention provides compounds that modulate the activity of kinases, such as Tyrosine Kinase 2 (TYK2).
  • TYK2 Tyrosine Kinase 2
  • a variety of medical conditions that affect millions of people are caused or exacerbated by unregulated activity of protein kinases.
  • aberrant kinase activity is associated with autoimmune diseases, inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies, asthma, Alzheimer's disease, Parkinson's disease, multiple sclerosis, skin disorders, eye diseases, infectious diseases and hormone- related diseases.
  • autoimmune diseases inflammatory diseases, bone diseases, metabolic diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies, asthma, Alzheimer's disease, Parkinson's disease, multiple sclerosis, skin disorders, eye diseases, infectious diseases and hormone- related diseases.
  • no effective inhibitor or activator exists for the particular kinase that causes the disorder or its sy mptoms. Consequently, patients continue to suffer from an array of disorders due to the lack of suitable medicaments for their conditions.
  • the invention provides compounds that modulate the activity of protein kinases that are associated with human diseases, disorders, and conditions.
  • compounds of the invention inhibit TYK2, a member of the Janus Kinase (JAK) family of non-receptor protein kinases. Altered or unregulated activity of TYK2 promotes inflammation and is implicated in autoimmune diseases, such as psoriasis, lupus, multiple sclerosis, and inflammatory bowel disease.
  • autoimmune diseases such as psoriasis, lupus, multiple sclerosis, and inflammatory bowel disease.
  • embodiments of the invention are useful as phannaceutical compositions for treatment of such autoimmune conditions.
  • the invention also provides methods of using the compounds to modulate kinase activity in cells and to treat conditions, such as autoimmune conditions, for which modulation of kinase activity provides a therapeutic benefit.
  • the invention provides compounds of Formula (I), or pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein:
  • X is CR 3 or N
  • Y is NR 4 , S, O. SO 2 , or CH 2 ;
  • Z is absent, O, S. or NR 5 ;
  • W is NR 6 , O, or S;
  • R 1 is selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted C 1 -C 6 alkyd, substituted or unsubstituted C 3 -C 6 , cycloalkyl, wherein one or more substitutions are selected from the group consisting of deuterium, halo, or C 3 -C 6 cycloalkyl;
  • R 2 is selected from the group consisting of hydrogen, deuterium, and optionally substituted C 1 - C 6 alkyl;
  • R 3 is selected from the group consisting of hydrogen, deuterium, halogen, and substituted or unsubstituted C 1 -C 6 alkyl;
  • R 4 is selected from the group consisting of hydrogen, deuterium, and substituted or unsubstituted C 1 -C 6 alkyl;
  • R is selected from the group consisting of hydrogen, deuterium, and substituted or unsubstituted C 1 -C 6 alkyl;
  • R 6 is selected from the group consisting of hydrogen, deuterium, and substituted or unsubstituted C 1 -C 6 alkyl;
  • L is absent or a linker comprising 2-12 atom links, wherein each atom link in L is selected from the group consisting of -CR L1 R L2 , NR L1 . O, and S; wherein:
  • R L1 and R L2 are independently selected from the group consisting of: hydrogen, deuterium, halogen, hydroxy, optionally substituted alkoxy, substituted or unsubstituted C 1 -C 6 alky l, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted aryl, or heteroaryl, wherein R L1 and R L2 on the same or different atoms can be optionally combined to form a 3-12 membered cycloalkyl or heterocycloalkyl, wherein the one or more heteroatoms are N, O, or S;
  • A is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein one or more heteroatoms in the heterocycloalkyl or heteroary l is nitrogen, sulfur, or oxygen, and the hctcrocycloalkyl or hctcroaryl may optionally be fused;
  • R A1 and R A2 are independently selected from the group consisting of: hydrogen, deuterium, halogen, hydroxy, optionally substituted alkoxy, optionally substituted heterocycloalkylalkoxy, alkoxy, cyano.
  • each R a is independently C 1 -C 6 alkyl.
  • each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl is independently optionally substituted with one or more oxo.
  • C 1 -C 6 haloalkyl C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxy alky 1, C 1 -C 6 aminoalkyl, C 2 -C 6 alkenyl.
  • each R c and R d is independently hydrogen.
  • X is CR 3 in the compounds of Formula (I), X is CR 3 . In certain embodiments, when X is CR 3 , R 3 is unsubstituted C 1 -C 6 alkyl.
  • R 3 is hydrogen
  • X is N.
  • Y is NH
  • Y is S.
  • Y is -CH 2 -.
  • Z is O. In certain embodiments, in the compounds of Formula (I), Z is NR 5 . In certain embodiments, when Z is CR 5 , R 5 is unsubstituted C 1 -C 6 alkyl. In certain embodiments, R 5 is hydrogen or methyl. In certain embodiments, R 5 is hydrogen.
  • Z is absent.
  • W is NR 6 in the compounds of Formula (I). In certain embodiments, wherein W is W is NR 6 . In certain embodiments, R 6 is substituted or substituted C 1 -C 6 alkyl. In certain embodiments, R 6 is H.
  • W is NH
  • W is O.
  • ring A and R A A l 1 and R A2 do not form a fused bicyclic heteroaryl ring. In certain embodiments, in the compounds of Formula (I), ring A and R A1 and R A2 do not form a fused bicyclic cycloalkyl or heterocycloalkyl ring.
  • L comprises the linker -(CR L1 R L2 )-(CR L1 R L2 )-O-(CR L1 R L2 )-. In certain embodiments. L comprises the linker In certain embodiments, L comprises the linker
  • linker L does not comprise a cyclopentyl or cyclohexyl ring.
  • X is CR 3 .
  • R 3 is hydrogen or deuterium.
  • R 3 is substituted or substituted C 1 -C 6 alkyl.
  • R 3 is hydrogen.
  • R 3 is deuterium.
  • R 2 is selected from the group consisting of hydrogen, deuterium, or C 1-6 alkyl. In certain embodiments, R 2 is methyl. In certain embodiments, R 2 is hydrogen. In certain embodiments. R 2 is deuterium.
  • R 1 is selected from the group consisting of optionally substituted C 1-6 alkyl, optionally substituted C 3 -C 6 cycloalky I. and C 1-6 deuteroalkyl.
  • R 1 is hydrogen
  • R 1 is methyl
  • R 1 is -CD 3 .
  • R 1 is cyclopropyl
  • R 1 is -CH 2 -cyclopropyl. In certain embodiments, in the compounds of Fonnula (I), R 1 is ethyl.
  • Ring A is 5-12 membered aryl or heteroaryl. In certain embodiments, when the Ring A is heteroaryl ring, one or more heteroatoms in Ring A are selected from the group consisting of nitrogen, sulfur, or oxygen.
  • Ring A is 5-12 membered aryl.
  • Ring A is phenyl
  • Ring A is 5-12 membered heteroaryl ring, wherein the one or more heteroatom in the heteroaryl ring is nitrogen, sulfur or oxygen.
  • Ring A is a 5-12 membered heteroaryl ring having one or more nitrogen atoms.
  • Ring A is selected from the group consisting of pyridine, pyrimidine, pyridazine, pyridone. and pyridazinone.
  • Ring A, R A1 . and R A2 combine to form a 6,5 or 6,6 fused bicyclic ring.
  • the bicyclic ring formed by Ring A, R A1 . and R A2 include one or more substitutions.
  • the substitutions on said bicyclic rings are selected from the group consisting of hydrogen, deuterium, halogen, optionally substituted C 1 -C 6 alkyl, and C 1 -C 6 deuterated alkyl.
  • the substitutions on said bicyclic rings are selected from the group consisting of hydrogen, deuterium, -CH 3 , or -CD 3 .
  • one or more substitutions are selected from the group consisting of H, deuterium, C 1 -C 6 alkyl, C 1 -C 6 oxy alkyl, halogen, optionally deuterated C 1 -C 6 alkyl, and cyano.
  • R A1 and R A2 are independently selected from the group consisting of deuterium, halogen, -CN, -OR a .
  • -NR a R a , -C( O)R a , -CH 2 -R a , C 1-6 alky 1, C 1-6 haloalky 1, C 1-6 deuteroalkyl, cycloalky l, heterocy cloalkyl, aryl, or heteroaryl, wherein;
  • R a and R a are independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, Cj-Chydroxyalkyl.
  • R A1 and R A2 are independently spiro, monocyclic or bicyclic heterocycloalkyl or heteroaryl containing at least one nitrogen or oxygen.
  • R A1 and/or R A2 is substituted or unsubstituted monocyclic heterocycloalkyl, wherein the heterocycloalkyl comprises one or more heteroatoms selected from the group consisting of nitrogen or oxygen.
  • R A1 and/or R A2 is substituted or unsubstituted bicyclic heterocycloalkyl, wherein the heterocycloalkyl comprises one or more heleroatoms selected from the group consisting of nitrogen, sulfur or oxygen.
  • R A1 and/or R A2 is substituted or unsubstituted monocyclic heteroaryl, wherein the heterocyaryl comprises one or more heteroatoms selected from the group consisting of nitrogen, sulfur or oxygen.
  • R A1 and/or R A2 is substituted or unsubstituted bicyclic heteroaryl, wherein the heteroaryl comprises one or more heteroatoms selected from the group consisting of nitrogen, sulfur or oxygen.
  • R A1 and R A2 are independently substituted or unsubstituted morpholine, phenyl morpholine. 1.4-oxazepane, piperazine, piperidine, pyridine, triazole, tetrahyropyrane, pyrazole, oxazole, or pyridazine
  • R A1 and/or R A2 are independently substituted or unsubstituted morpholine.
  • R A1 and/or R A2 are independently substituted or unsubstituted pyridine.
  • R A1 and/or R A2 are independently substituted or unsubstituted pyridazine.
  • R A1 and/or R A2 are independently substituted or unsubstituted 1,4-oxazepane.
  • R A1 and/or R A2 are independently substituted or unsubstituted piperazine.
  • R A1 and/or R A2 are independently substituted or unsubstituted piperidine.
  • the linker L comprises 2-10 atom links, wherein each atom link in L is selected from the group consisting of -CR L1 R L2 , NR L1 , O, and S. In certain embodiments, L comprises between 2 and 8 atom links, wherein atom links are selected from the group consisting of -CR L1 R L2 , NR L1 , O, and S, and wherein between 0 and 2 atom links arc NR L1 , O, and S. In certain embodiments, in the compounds of Formula (I), L comprises betw een 1 and 7 atom links, wherein atom links are selected from the group consisting of are -CR L,1 R 1 2 .
  • L comprises between 1 and 6 atom links, wherein each atom links are selected from the group consisting of -CR L1 R L2 , NR L1 . O, and S, and wherein between 0 and 2 atom links are NR L1 , O, and S.
  • L comprises between 1 and 10 atom links, wherein the atom links are independently -CR L1 R L2 and/or R L1 and R L2 at different or same atom combine to fonn an optionally substituted cycloalkyl or heterocycloalkyl.
  • the one or more substitutions in said cycloalkyl or heterocycloalkyl are selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, alkoxy, or C1-C4 alkyl.
  • L is selected from the group consisting of: ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇
  • the invention provides pharmaceutical compositions containing one or more compounds of the invention, such as any of the compounds described above.
  • pharmaceutical composition comprises a pharmaceutically acceptable carrier or diluent.
  • the invention provides methods of modulating the activity of a kinase by contacting cells containing a kinase with one or more compounds of the invention, such as any of those described above.
  • the compound may inhibit activity of the kinase.
  • the compound may increase activity of the kinase.
  • the kinase may be a JAK family kinase.
  • the kinase may be TYK2.
  • the invention provides methods of treating a condition in a subject by administering to the subject a compound of the invention, such as any of those described above.
  • the condition may be characterized by elevated activity of a kinase.
  • the condition may be characterized by altered activity of a kinase.
  • the kinase may be a JAK family kinase.
  • the kinase may be TYK2.
  • the condition may be an autoimmune disease, inflammatory disease, bone disease, metabolic disease, neurological or neurodegenerative disease, cancer, cardiovascular disease, allergies, asthma, Alzheimer's disease, Parkinson's disease, multiple sclerosis, skin disorder, eye disease, infectious disease, or hormone-related disease.
  • the invention provides use of a compound of the invention, such as any of those described above, for making a medicament.
  • the medicament is useful for treating a condition in a subject.
  • the condition is characterized by elevated activity or altered activity of a kinase.
  • the kinase is a JAK family kinase.
  • the kinase isTYK2.
  • the condition is an autoiimnune disease, inflammatory' disease, bone disease, metabolic disease, neurological or neurodegenerative disease, cancer, cardiovascular disease, allergies, asthma, Alzheimer's disease, Parkinson's disease, multiple sclerosis, skin disorder, eye disease, infectious disease, or hormone -related disease.
  • the invention provides a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, and a pharmaceutically acceptable carrier or diluent.
  • the invention provides a method of inhibiting TYK2 activity' in a subject in need thereof with a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof or a pharmaceutical composition.
  • the invention provides a method of treating a TYK2 -mediated disease or disorder comprising administering to a subject in need thereof a compound of Fonnula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof or a phannaceutical composition.
  • the TYK.2 -mediated disease or disorder is an autoimmune disorder, an inflammatory disorder, a proliferative disorder, an endocrine disorder, a neurological disorder, or a disorder associated with transplantation.
  • the TYK2-mediated disease or disorder is multiple sclerosis.
  • alkyl refers to a radical of a straight-chain or branched saturated hydrocarbon group having from 1 to 20 carbon atoms (“C 1-20 alkyl”). In some embodiments, an alkyl group has 1 to 12 carbon atoms (“C 1-12 alky l”). In some embodiments, an alky l group has 1 to 10 carbon atoms (“C 1 - 1 0 alky l”). In some embodiments, an alkyl group has 1 to 9 carbon atoms (“C1-9 alkyl”). In some embodiments, an alkyl group has 1 to 8 carbon atoms (“C 1-8 alkyl”). In some embodiments, an alky l group has 1 to 7 carbon atoms (“C1-7 alky l”).
  • an alkyl group has 1 to 6 carbon atoms (“C 1-6 alky l”, also referred to herein as “lower alky l”). In some embodiments, an alkyl group has 1 to 5 carbon atoms (“C 1-5 alkyl”). In some embodiments, an alkyl group has 1 to 4 carbon atoms (“C 1 - 4 alkyl”). In some embodiments, an alkyl group has 1 to 3 carbon atoms (“C 1-3 alkyl”). In some embodiments, an alkyl group has 1 to 2 carbon atoms (“C1-2 alkyl”). In some embodiments, an alkyl group has 1 carbon atom (“ C 1 alky”l).
  • an alkyl group has 2 to 6 carbon atoms ("C 2-6 alkyl”).
  • C 1-6 alkyl groups include methyl (C 1 ), ethyl (C2). n-propyl (C 3 ). isopropyl (C 3 ), n-butyl (C 4 ). tert-butyl (C 4 ), sec-butyl (C 4 ). isobutyl (C 4 ), n-pentyl (C 5 ), 3-pentanyl (C 5 ). amyl (C 5 ), neopentyl (C 5 ).
  • alkyl groups include n-heptyl (C7), n-octyl (C 8 ) and the like.
  • each instance of an alkyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted alkyl”) or substituted (a “substituted alkyl”) with one or more substituents; e.g., from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • the alkyl group is unsubstituted C 1-10 alkyl (e.g., -CH 3 ). In certain embodiments, the alkyl group is substituted Ci.10 alkyl. Common alkyl abbreviations include Me (-CH 3 ). Et (-CH 2 CH 3 ), iPr (-CH(CH 3 ) 2 ), nPr (-CH 2 CH 2 CH 3 ), n-Bu (- CH 2 CH 2 CH 2 CH 3 ), or i-Bu (-CH 2 CH(CH 3 ) 2 ).
  • heteroalkyl refers to an alkyl group, as defined herein, which further comprises 1 or more (e.g., 1, 2. 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) within the parent chain, wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment.
  • a hctcroalkyl group refers to a saturated group having from 1 to 10 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC 1 - 10 alkyl").
  • a heteroalkyl group is a saturated group having 1 to 9 carbon atoms and 1, 2, 3, or 4 heteroatoms (“heteroC 1-9 alkyl”’). In some embodiments, a heteroalkyl group is a saturated group having 1 to 8 carbon atoms and 1. 2, 3, or 4 heteroatoms (“heteroC 1-8 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 7 carbon atoms and 1, 2. 3, or 4 heteroatoms (“heteroCi.? alkyl”). In some embodiments, a heteroalkyl group is a group having 1 to 6 carbon atoms and 1, 2, or 3 heteroatoms (“heteroC 1 -6 alkyl”).
  • a heteroalkyl group is a saturated group having 1 to 5 carbon atoms and 1 or 2 heteroatoms (“heteroC 1 -io alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 4 carbon atoms and lor 2 heteroatoms (“heteroC 1 -4 alky l”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 3 carbon atoms and 1 heteroatom (“heteroC 1 -3 alkyl”). In some embodiments, a heteroalkyl group is a saturated group having 1 to 2 carbon atoms and 1 heteroatom (“heteroC 1 -2 alkyl”).
  • a hctcroalkyl group is a saturated group having 1 carbon atom and 1 heteroatom (“heteroCi alkyl”). In some embodiments, a hctcroalkyl group is a saturated group having 2 to 6 carbon atoms and 1 or 2 heteroatoms ('"heteroCi alkyl”).
  • alkenyl refers to a radical of a straight-chain or branched hydrocarbon group having from 2 to 20 carbon atoms, one or more carbon-carbon double bonds (e.g., 1. 2, 3, or 4 carboncarbon double bonds) (“C2-20 alkenyl”).
  • an alkenyl group has 2 to 10 carbon atoms (“‘C2-10 alkenyl”).
  • an alkenyl group has 2 to 9 carbon atoms (“C2-9 alkenyl”).
  • an alkenyl group has 2 to 8 carbon atoms (“C2-8 alkenyl”).
  • an alkenyl group has 2 to 7 carbon atoms (“C2-7 alkenyl”).
  • an alkenyl group has 2 to 6 carbon atoms (“C2-6 alkeny l”). In some embodiments, an alkenyl group has 2 to 5 carbon atoms (“C2-5 alkenyl”). In some embodiments, an alkenyl group has 2 to 4 carbon atoms (“C2-4 alkenyl”). In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C2-3 alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C2 alkenyl”). The one or more carboncarbon double bonds can be internal (such as in 2 -butenyl) or terminal (such as in 1- butenyl).
  • Examples of C 2-4 alkenyl groups include ethenyl (C2), 1 -propenyl (C3), 2 -propenyl (C3), 1 -butenyl (C 4 ), 2 -butenyl (C 4 ), butadienyl (C 4 ), and the like.
  • Examples of C2-6 alkenyl groups include the aforementioned C2-4 alkenyl groups as well as pentenyl (C 5 ), pentadienyl (C 5 ), hexenyl (C 6 ), and the like. Additional examples of alkenyl include heptenyl (C?), octenyl (Cg), octatrienyl (Cg), and the like.
  • each instance of an alkenyl group is independently optionally substituted, i.e.. unsubstituted (an “unsubstituted alkenyl”) or substituted (a “substituted alkenyl”) with one or more substituents e.g., from 1 to 5 substituents, 1 to 3 substituents, or 1 substituent.
  • the alkenyl group is unsubstituted C2-10 alkenyl.
  • the alkenyl group is substituted C2-10 alkenyl.
  • heteroalkenyl refers to an alkenyl group, as defined herein, which further comprises one or more (e.g., 1, 2, 3, or 4) heteroatoms (e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus) wherein the one or more heteroatoms is inserted between adjacent carbon atoms within the parent carbon chain and/or one or more heteroatoms is inserted between a carbon atom and the parent molecule, i.e., between the point of attachment.
  • one or more heteroatoms e.g., oxygen, sulfur, nitrogen, boron, silicon, phosphorus
  • a heteroalkenyl group refers to a group having from 2 to 10 carbon atoms, at least one double bond, and 1, 2, 3, or 4 heteroatoms C'hctcroCXi,, alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms at least one double bond, and 1, 2, 3, or 4 heteroatoms C'hclcroCT.j alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 8 carbon atoms, at least one double bond, and 1. 2, 3, or 4 heteroatoms ("hctcroCXx alkenyl").
  • a heteroalkenyl group has 2 to 7 carbon atoms, at least one double bond, and 1, 2. 3, or 4 heteroatoms ("heteroC2-7 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1, 2, or 3 heteroatoms ("heteroC2-6 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC2-s alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 4 carbon atoms, at least one double bond, and 1 or 2 heteroatoms (“heteroC2-4 alkenyl”).
  • a heteroalkenyl group has 2 to 3 carbon atoms, at least one double bond, and 1 heteroatom (“heteroC2-3 alkenyl”). In some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at least one double bond, and 1 or 2 heteroatoms ('"hctcroCC: e alkenyl”).
  • cycloalkyl refers to a saturated or partially unsaturated (for example, a cycloalkenyl group) cyclic group that contains one or more rings, e.g., 2 or 3 rings, and contains from 3 to 14 ring carbon atoms, such as from 3 to 10 (e.g.. 3, 4, 5, 6 or 7) ring carbon atoms.
  • cycloalkyl groups arc a cyclopropyl, cyclobutyl, cyclopcntyl, spiro[4,5]decanyl, norbornyl, cyclohexyl, cyclopentenyl, cyclohexadienyl. decalinyl, bicyclo[4.3.0]nonyl, tetraline, cyclopentylcyclohexyl, fluorocyclohexyl or cyclohex-2-enyl group.
  • cycloheteroalkyl or heterocycloalkyl refers to a cycloalkyl group as defined above in which one or more (e.g., 1, 2, or 3) ring carbon atoms have been replaced by an oxygen, nitrogen, silicon, selenium, phosphorus or sulfur atom or a SO group or a SO2 group.
  • a cycloheteroalkyl or heterocycloalkyl group may have 1 or 2 rings containing from 3 to 10 (e.g., 3, 4, 5, 6 or 7) ring atoms (e.g., C, O. N or S).
  • Cycloheteroalkyl or heterocycloalkyl groups include cycloheteroalkenyl or heterocycloalkenyl groups.
  • Examples are a piperidinyl, prolinyl. imidazolidinyl, piperazinyl, morpholinyl, urotro pinyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrofuryl or 2-pyrazolinyl group and also lactams, lactones, cyclic imides and cyclic anhydrides.
  • alkylcycloalkyl refers to groups that contain both cycloalkyl and also alkyl. alkenyl or alkynyl groups in accordance with the above definitions, for example alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkcnyl. alkcnylcycloalkyl and alkynylcycloalky 1 groups.
  • An alkylcycloalkyl group preferably contains a cycloalkyl group that contains one or two rings having from 3 to 10 (e.g., 3, 4, 5, 6 or 7) ring carbon atoms, and one or two alkyl or alkynyl groups having 1 or 2 to 6 carbon atoms.
  • heteroalkylcycloalkyl refers to alkylcycloalky l groups as defined above in which one or more (e.g.. 1, 2 or 3) carbon atoms have been replaced by an oxygen, nitrogen, silicon, selenium, phosphorus or sulfur atom or a SO group or a SO2 group.
  • a heteroalky lcycloalky l group preferably contains 1 or 2 rings having from 3 to 10 (e.g.. 3, 4, 5, 6 or 7) ring atoms, and one or two alkyl, alkenyl, alkynyl or heteroalkyl groups having from 1 or 2 to 6 carbon atoms.
  • Examples of such groups aarree alkylheterocycloalkyl, alkylheterocycloalkenyl, alkenylheterocycloalkyl, alkynylheterocycloalkyl. heteroalkylcy cloalkyl, heteroalkylheterocycloalkyl and heteroalky lheterocycloalkenyl, the cyclic groups being saturated or mono-, di- or tri-unsaturated.
  • aryl refers to an aromatic group that contains one or more rings, e.g., 2 or 3 rings, containing from 6 to 14 ring carbon atoms, such as from 6 to 10 ring carbon atoms.
  • the expression aryl refers furthermore to groups that are substituted by fluorine, chlorine, bromine or iodine atoms or by CH 3 , OH. SH. NH 2 , N 3 or NO 2 groups. Examples are the phenyl, naphthyl, biphenyl, 2-fhiorophenyl, anilinyl, 3-nitrophenyl or 4-hydroxyphenyl group.
  • heteroaryl refers to an aromatic group that contains one or more rings, e.g., 2 or 3 rings, containing from 5 to 14 ring atoms, such as from 5 to 10 ring atoms, and contains one or more (e.g., 1, 2, 3 or 4) oxygen, nitrogen, phosphorus or sulfur ring atoms.
  • heteroaryl refers furthermore to groups that are substituted by fluorine, chlorine, bromine or iodine atoms or by CH 3 , OH, SH, N 3 , NH 2 or NO 2 groups. Examples are pyridyl (e.g. 4-pyridyl). imidazolyl (e.g.
  • aralkyl refers to groups containing both aiyl and also alkyl, alkenyl, alkynyl and/or cycloalkyl groups in accordance with the above definitions, such as, for example, aryl- alkyl, arylalkenyl, arylalkynyl, arylcycloalkyl. arylcycloalkenyl, alkylarylcycloalkyl and alkylarylcycloalkeny l groups.
  • Specific examples of aralkyls are toluene, xylene, mesitylene, styrene, benzyl chloride, o-fluorotoluene, IH-indene, tetraline.
  • An aralkyl group preferably contains one or two aromatic ring systems containing from 6 to 10 carbon atoms and one or two alkyl, alkenyl and/or alkynyl groups containing from 1 or 2 to 6 carbon atoms and/or a cycloalky l group containing 5 or 6 ring carbon atoms.
  • hctc roaralky I refers to an aralkyl group as defined above in which one or more (e.g., 1, 2, 3 or 4) carbon atoms have been replaced by an oxygen, nitrogen, silicon, selenium, phosphorus, boron or sulfur atom, that is to say to groups containing both aryl or heteroaryl, respectively, and also alkyl, alkenyl, alkynyl and/or heteroalkyl and/or cycloalky l and/or heterocycloalkyl groups in accordance with the above definitions.
  • a heteroaralkyl group preferably contains one or two aromatic ring systems containing from 5 or 6 to 10 ring carbon atoms and one or two alkyl, alkenyl and/or alkynyl groups containing 1 or 2 to 6 carbon atoms and/or a cycloalkyl group containing 5 or 6 ring carbon atoms, wherein 1, 2. 3 or 4 of these carbon atoms have been replaced by oxygen, sulfur or nitrogen atoms.
  • Examples are arylheteroalkyl, arylheterocycloalkyl, arylheterocycloalkenyl, arylalkyl heterocycloalkyl, , aarryyllaallkkeennyyllhheetteerrooccyyccllooaallkkyyll.. arylalkynylheterocycloalkyl, arylalkylhetero cycloalkenyl, heteroarylalkyl. heteroarylalkenyl, heteroarylalkynyl, heteroarylheteroalkyl. heteroarylcycloalkyl, heteroarylcycloalkenyl, heteroarylheterocycloalkyl.
  • hetero arylheteroalkylcycloalkyl, heteroarylheteroalkylcycloalkenyl and heteroarylheteroalkylhetero cycloalkyl groups the cyclic groups being saturated or mono-, di- or tri-unsaturated. Specific examples are a tetrahydroisoquinolinyl. benzoyl. 2- or 3-ethylindolyl, 4-methylpyridino, 2-. 3- or 4- methoxyphenyl, 4-ethoxyphenyl, 2-, 3- or 4-carboxj phenylalkyl group.
  • carbocyclyl or carbocyclic refers to a radical of a non-aromatic cyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C3-10 carbocycly l”) and zero hctcroatoms in the nonaromatic ring system.
  • a carbocycly l group has 3 to 8 ring carbon atoms 10 (“C3-8 carbocyclyl”).
  • a carbocyclyl group has 3 to 7 ring carbon atoms (“C3-7 carbocyclyl”).
  • a carbocyclyl group has 3 to 6 ring carbon atoms (“C3-6 carbocyclyl”).
  • a carbocyclyl group has 5 to 10 ring carbon atoms (“C5-10 carbocyclyl”).
  • Exemplary C3-6 carbocyclyl groups include, without limitation, cyclopropyl (C 3 ), cyclopropenyl (C3). cyclobutyl (C 4 ), cyclobutenyl (C 4 ), cyclopentyl (Cs), cyclopentenyl (C 5 ), cyclohexyl (C 6 ). cyclohexenyl (C 6 ), cyclohexadienyl (C 6 ), and the like.
  • Exemplary C3-8 carbocyclyl groups include, without limitation, the aforementioned C3-6 carbocyclyl groups as well as cycloheptyl (C?), cycloheptenyl (C?), cycloheptadienyl (C?), cycloheptatrienyl (C?), cyclooctyl (G), cyclooctenyl (G), bicyclo[2.2.1]heptanyl (C?), bicyclo[2.2.2]octanyl (G), and the like.
  • Exemplary C3-10 carbocyclyl groups include, without 20 limitation, the aforementioned G-s carbocyclyl groups as well as cyclononyl (C9), cyclononenyl (C9), cyclodecyl (C10). cyclodecenyl (C10). octahydro- IH-indenvl (C9). decahydronaphthalenyl (C10), spiro[4.5]decanyl (C10), and the like. As the foregoing examples illustrate.
  • the carbocyclyl group is either monocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) and can be saturated or can be partially unsaturated.
  • “Carbocyclyl” also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaiyl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.
  • each instance of a carbocyclyl group is independently optionally substituted, i.e., unsubstituted (an “unsubstituted carbocyclyl”) or substituted (a “substituted carbocyclyl”) with one or more substituents.
  • the carbocyclyl group is unsubstituted C3-10 carbocyclyl.
  • the carbocyclyl group is a substituted C3-10 carbocyclyl.
  • “carbocyclyl” is a monocyclic, saturated carbocyclyl group having from 3 to 10 ring carbon atoms (“C3-10 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms (“C3-8 cycloalkyl”). In some embodiments, a cycloalkyl group has 3 to 6 ring carbon atoms (“C3-6 cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 6 ring carbon atoms (“C5- e cycloalkyl”). In some embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms (“C5-10 cycloalkyl”).
  • C5-6 cycloalkyl groups include cyclopentyl (Cs) and cyclohexyl (Cs).
  • C3-6 cycloalkyl groups include the aforementioned Cs-e cycloalkyl groups as well as cyclopropyl (C3) and cyclobutyl (C 4 ).
  • Examples of C3-8 cycloalkyl groups include the aforementioned C3-6 cycloalkyl groups as well as cycloheptyl (C?) and cyclooctyl (Cs).
  • each instance of a cycloalkyl group is independently unsubstituted (an “unsubstituted cycloalkyl”) or substituted (a “substituted cycloalkyl”) with one or more substituents.
  • the cycloalkyl group is unsubstituted C3-10 cycloalkyl.
  • the cycloalkyl group is substituted C3-10 cycloalkyl.
  • heterocyclyl or heterocyclic refers to a radical of a 3- to 14-mcmbcrcd nonaromatic ring sy stem having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-14 membered heterocyclyl”).
  • heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits.
  • a heterocyclyl group can either be monocyclic (“monocyclic heterocyclyl”) or a fused, bridged or spiro ring system such as a bicyclic system (“bicyclic heterocyclyl”).
  • Heterocyclyl bicyclic ring systems can include one or more heteroatoms in one or both rings.
  • “Heterocyclyl” also includes ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more carbocyclyl groups wherein the point of attachment is either on the carbocyclyl or heterocyclyl ring, or ring systems wherein the heterocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the heterocyclyl ring, and in such instances, the number of ring members continue to designate the number of ring members in the heterocyclyl ring system.
  • each instance of heterocyclyl is independently optionally substituted, i.e., unsubstituted (an “unsubstituted heterocyclyl”) or substituted (a “substituted heterocyclyl”) with one or more substituents.
  • the heterocyclyl group is unsubstituted 3-10 membered heterocyclyl. In certain embodiments, the heterocyclyl group is substituted 3-10 membered heterocyclyl.
  • a heterocyclyl group is a 5-10 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 membered heterocyclyl”).
  • a heterocyclyl group is a 5-8 membered non-aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”).
  • a heterocyclyl group is a 5- 6 membered non-aromatic ring system having ring carbon atoms and 1 ⁇ 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur (“5-6 membered heterocyclyl”).
  • the 5-6 membered heterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen. and sulfur.
  • the 5-6 membered heterocyclyl has 1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur.
  • the 5-6 membered heterocyclyl has one ring heteroatom selected from nitrogen, oxygen, and sulfur.
  • Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl.
  • Exemplar ⁇ ' 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl.
  • Exemplar ⁇ 5- membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuran ⁇ 1, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl- 2, 5-dione.
  • Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one.
  • Exemplar ⁇ ' 5-membered heterocyclyl groups containing three hctcroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl.
  • Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl.
  • Exemplary 6- membered heterocyclyl groups 5 containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, dithianyl, dioxanyl.
  • Exemplary 6-membered heterocyclyl groups containing two heleroatoms include, without limitation, triazinanyl.
  • Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl.
  • Exemplary 8- membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl.
  • Exemplary 5 -membered heterocyclyl groups fused to a C 6 aryl ring include, without limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl, benzoxazolinonyl, and the like.
  • Exemplary 6-membered heterocyclyl groups fused to an aryl ring include, without limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl. and the like.
  • optionally substituted means that at least one hydrogen present on a group (e.g.. a carbon or nitrogen atom) is replaced with a permissible substituent, e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • a permissible substituent e.g., a substituent which upon substitution results in a stable compound, e.g., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, or other reaction.
  • Heteroatoms, such as nitrogen may have substituents, such as any suitable substituent described herein which satisfies the valencies of the heteroatoms and results in the formation of a stable moiety.
  • optional substituents include fluorine, chlorine, bromine, and iodine atoms and CF,.
  • Optional substituents also include C 1 -Cw alkyl, C 2 -Cio alkenyl, C 1 -Cw heteroalkyl, C 3 -Cie cycloalkyl, C 2 -Ci? heterocycloalkyl, C4-C 2 o alkylcycloalkyl.
  • C 2 -Ci9 heteroalkylcycloalkyl C 6 -Cis aryl, C1-17 heteroaryl, C 7 -C 20 aralkyl or C 2 -Ci9 heteroaralkyl, C 1 -C 6 alkyl. C 2 -C 6 alkenyl. C 1 -C 6 heteroalkyl. C3-C10 cycloalkyl, C2-C9 heterocycloalkyl, C--Cj 2 alkylcycloalkyl, C2-C11 heteroalkylcycloalkyl, C 6 -Cio and. C1-C9 heteroaryl, C?-Ci 2 aralkyl, C 2 -Cn heteroaralkyl, and C1-C10 haloalkyl groups.
  • NMe 2 CONH 2 . CH 2 NMe 2 , NHSO 2 Me, C(CH 3 )2CN, COMe, OMe, SMe, COOMe. COOEt, CH 2 COOH, OCH 2 COOH, COOH, SOMe. SO 2 Me. cyclopropyl.
  • halogen preferably refers to F, Cl, Br or I.
  • all alkyl, alkenyl, alkynyl, heteroalkyd, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyd, aralky 1 and heteroaralkyl groups described herein may optionally be substituted.
  • aryl, hctcroaryd, cycloalkyd, alkydcycloalkyd, hctcroalkylcycloalkyl, hctcrocycloalkyd, aralkyl or heteroaralkyl group contains more than one ring, these rings may be bonded to each other via a single or double bond or these rings may be annulated.
  • substituents include, but are not limited to, halogen, -CN, -NO 2 , -N 3 , - SO 2 H, - - P(R CC ) 2 , -P(R CC ) 3 . -OP(R CC ) 2 . -OP(R CC ) 3 , -B(R aa ) 2 . -B(OR CC ) 2 , -BR aa (OR“), CMO alkyl, CMO haloalky l. C 2 .io alkenyl, C 3 .io carbocyclyl. 3-14 membered heterocyclyl. C 6 -i4 aryl, and 5-14 membered heteroary 1.
  • R dd groups each instance of R bb is, independently, selected from hydrogen, -OH. -OR aa , -N(R CC ) 2 . - CN. - P(O)(NR CC ) 2 .
  • heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1,2. 3, 4, or 5 R dd groups; each instance of R cc is, independently, selected from hydrogen, CMO alkyl, C 1 -io haloalkyl, C 2 .
  • each alkyl, alkenyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5 R dd groups; each instance of R dd is, independently, selected from halogen, -CN, -NO 2 , -N3, -SO 2 H, - SO3H, OP(O)(R“) 2 , -OP(O)(OR ee ) 2 , Cue alkyl.
  • Cue haloalkyl. CM alkenyl, C3- 10 carbocyclyl.
  • heterocyclyl C 6 -io aryl, 5-10 membered heteroaryl, wherein each alkyl. alkenyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is independently substituted with 0, 1,2, 3, 4, or
  • each instance of R ff is, independently, selected from hydrogen, CM alkyl, CM haloalkyl, C 2 -e alkenyl, C3-10 carbocyclyl, 3-10 membered heterocyclyl, C 6 -io ary l, 5-10 membered heteroaryl, or two R ff groups are joined to form a 3-14 membered heterocyclyl or 5-14 membered heteroaiyl ring, wherein each alkyl, alkenyl, carbocyclyl, heterocyclyl. aryl, and heteroary l is independently substituted with 0, 1.2.
  • R 88 groups 3, 4, or 5 R 88 groups; and each instance of R 88 is, independently, halogen, -CN, -NO 2 , -N 3 , -SO2H, -SO3H. -OH, - OC1.6 alkyl. -0N(CM alkyl) 2 , -N(CM alkyl) 2 , -N(CM alkyl) 3 + X; -NH(CM alkyl) 2 + X", -NH 2 (CM alkyl) + X"-MR + X", -N(0CM alkyl)(Ci. 6 alkyl), -N(0H)(CM alkyl). - NH(OH), -SH. -SCM alkyl. -SS(Ci.
  • -NHC(0)N(CM alkyl) 2 -NHC(0)NH(CM alkyl), -NHC(O)NH 2 , -C(NH)0(CM alkyl), -0C(NH)(CM alkyl), -0C(NH)0CM alkyl, -C(NH)N(CM alkyl) 2 , -C(NH)NH(CM alkyl), - C(NH)NH 2 , -OC(NH)N(CI- 6 alkyl) 2 .
  • Janus tyrosine kinase (JAK) family members are regulators of multiple signal transduction pathways initiated by membrane Type I and Type II cytokine receptors.
  • JAK family members including JAK1, JAK2, JAK3, and TYK2 (Schwartz ct al, 2017).
  • STAT signal transducer and activator of transcription
  • the JAK-STAT signaling pathway is a chain of interactions between proteins in a cell, and is involved in processes such as immunity, cell division, cell death, and tumor fonnation (Aaronson et al Science 2002).
  • Type I and Type II cytokine receptor ligands such as interferons and interleukins
  • cell-surface receptors causes the receptors to dimerize, which brings the receptor-associated JAKs into close proximity (Jalini et al, Genes and Cancer 2011), and sets off a sequence of downstream changes.
  • JAK-dependent cytokines to immunopathology, and clinical benefit can be provided by blocking these cytokines with biologies and small-molecule inhibitors.
  • Some examples of this are the blockade of IL-6 in rheumatoid arthritis or IL- 12/IL-23 in inflammatory bowel disease (IBD) (Schwartz et al 2017).
  • TYK2 The tyrosine kinase 2 (TYK2) member of the JAK family specifically plays a role in the downstream signaling of Interleukin (IL)- 12, IL-23, and type I interferons (Baker and Isaacs, Ann Rheum Dis., 2018; Burke et al, Sci Trans Med, 2019).
  • IL Interleukin
  • IL-23 IL-23
  • type I interferons Boker and Isaacs, Ann Rheum Dis., 2018; Burke et al, Sci Trans Med, 2019.
  • TYK2 heterodimerizes with other JAK family members to provide ligand specificity and regulate downstream signal transduction pathways (Fig 1). Many of these pathways are altered in diseases and drive chronic inflammation in IBD, Psoriasis, and systemic lupus erythematosus (SEE) (Schwartz et al, Nat Rev Drug Dis, 2017).
  • TYK2 In addition to the role of TYK2 signaling cascades in disease there has been a strong body of genetic evidence of pointing to a role for TYK2. Genetic association studies have linked the TYK2 locus to an impact of the susceptibility in SEE, psoriasis, and multiple sclerosis (MS). This identification has been replicated and expanded in a number of recent analyses, and TYK2 is now recognized as a susceptibility gene in a variety of inflammatory and autoimmune diseases, including type I diabetes (T1D). The common characteristic of these diseases are changes in immunological function and activation, and downstream damage to target organs (Li et al, PEGS One. 2020).
  • TYK2 inhibition has also proven efficacious in preclinical models of disease for psoriasis and ulcerative colitis (Burke et al. Sci Trans Med. 2020).
  • the preclinical effects in rodents have since translated to humans with deucravacitinib demonstrating efficacy in Psoriasis patients (Armstrong et al, Ann of Rheu Dis, 2020).
  • TYK2 knockout (KO) or transgenic (TG)animals The genetic contribution of TYK2 has also been confirmed preclinically with the use of TYK2 knockout (KO) or transgenic (TG)animals.
  • Type I interferon signaling is reduced in in TYK2 KO animals as compared to WT mice (Karaghiosoff, Immunity, 2000) and TG animals with the Pl 104 protective variant of TYK2 are almost completely protected in the experimental autoimmune encephalitis (EAE) mouse model of MS (Gorman et al. Fmt in Immunology 7 , 2019). Together, this large body 7 of evidence provides supportive data for the role of cytokine signaling, and the support for the development of safe TYK2 inhibitors for a variety of inflammatory disorders.
  • EAE experimental autoimmune encephalitis
  • the invention provides compounds that modulate tire activity of protein kinases that are associated with human diseases, disorders, and conditions.
  • compounds of the invention inhibit TYK2, a member of the Janus Kinase (JAK) family of non-receptor protein kinases. Altered or unregulated activity of TYK2 promotes inflammation and is implicated in autoimmune diseases, such as psoriasis, lupus, multiple sclerosis, and inflammatory bowel disease.
  • autoimmune diseases such as psoriasis, lupus, multiple sclerosis, and inflammatory bowel disease.
  • embodiments of the invention are useful as pharmaceutical compositions for treatinent of such autoimmune conditions.
  • the invention also provides methods of using the compounds to modulate kinase activity in cells and to treat conditions, such as autoimmune conditions, for which modulation of kinase activity provides a therapeutic benefit.
  • the invention provides compounds of Formula (I), or pharmaceutically acceptable salt, stereoisomer, or solvate thereof,
  • X is CR 3 or N
  • V is NR 4 , S, O, or CH 2 ;
  • Z is absent, O, S. or NR 5 ;
  • W is NR 6 , O, or S
  • R 1 is selected from the group consisting of hydrogen, deuterium, substituted or unsubstituted C 1 -C 6 alkyl, wherein one or more substitutions are selected from the group consisting of deuterium, halo, or Ca-C 6 cycloalkyl;
  • R 2 is selected from the group consisting of hydrogen, deuterium, and optionally substituted C 1 - C 6 alkyl;
  • R 3 is selected from the group consisting of hydrogen, deuterium, and substituted or unsubstituted C 1 -C 6 alkyl;
  • R 4 is selected from the group consisting of hydrogen, deuterium, and substituted or unsubstituted C 1 -C 6 alkyl;
  • R 5 is selected from the group consisting of hydrogen, deuterium, and substituted or unsubstituted C 1 -C 6 alkyl;
  • R 6 is selected from the group consisting of hydrogen, deuterium, and substituted or unsubstituted C 1 -C 6 alkyl;
  • L is absent or a linker comprising 2-12 atom links, wherein each atom link in L is selected from the group consisting of -CR L1 R L2 , NR L1 . O, and S; wherein:
  • R L1 and R L2 are independently selected from the group consisting of: hydrogen, deuterium, halogen, hy droxy . optionally substituted alkoxy, substituted or unsubstituted C 1 -C 6 alky l, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted aryl, or heteroary l. wherein R L1 and R L2 on the same or different atoms can be optionally combined to form a 3-12 membered cycloalkyl or heterocycloalkyl, wherein the one or more heteroatoms are N, O, or S;
  • R A is selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, wherein one or more heteroatoms in the heterocycloalkyl or heteroary l is nitrogen, sulfur, or oxygen, and the heterocy cloalky l or heteroary l may optionally be fused;
  • R A1 and R A2 are independently selected from the group consisting of: hydrogen, deuterium, halogen, hydroxy, optionally substituted alkoxy, optionally substituted heterocycloalkylalkoxy, alkoxy, cyano.
  • C 1 -C 6 alkyl substituted or unsubstituted C 1 -C 6 alkyl, C 1 -G, hydroxy alkyl, C 1 -C 6 alkoxy alkyl, C 1 - C 6 aminoalkyl.
  • substituted or unsubstituted 3-12 membered monocyclic, bicyclic, bridged bicyclic, or spirocyclic cycloalkyl, oxycycloalkyl, monocyclic, bicyclic, bridged bicyclic, or spirocyclic heterocycloalkyl, ary l, or heteroaryl, wherein one or more heteroatoms in heterocycloalkyl or heteroaryl rings are N, S, Se, or O and wherein one or more substitutions are selected from the group consisting of hydrogen, deuterium, halogen, hydroxy, optionally substituted alkoxy, cyano. 0, substituted or unsubstituted C 1 -C 6 alkyl, Ch -C, hydroxy alkyl.
  • Ch-G alkoxyalkyl. 3- 12 membered cycloalkyl, or heterocycloalky l, aryl, or heteroaryl, wherein optionally R A1 and R A2 together form a substituted or unsubstituted 3-12 membered monocy arbor or bicyclic cycloalky l, hctcrocycloalkyl, ary l, or hctcroary 1 fused with Ring A; each R a is independently C 1 -C 6 alkyl, G -Ghaloalkyl. G -Gdcutcroalkyl.
  • each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is independently optionally substituted with one or more oxo, deuterium, halogen, -CN.
  • each R b is independently hydrogen, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 aminoalky l, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein each alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, and heteroary l is independently optionally substituted with one or more oxo.
  • each R c and R d is independently hydrogen, C 1 -C 6 alkyl.
  • X is CR 3 in the compounds of Formula (I), X is CR 3 . In certain embodiments, when X is CR 3 , R 3 is unsubstituted C 1 -C 6 alkyl.
  • R 3 is hydrogen
  • X is N.
  • Y is NH
  • Y is S.
  • Y is -CH 2 -.
  • Z is O
  • Z is NR 3 in the compounds of Formula (I), Z is NR 3 . In certain embodiments, when Z is CR 3 . R 5 is unsubstituted C 1 -C 6 alkyl. In certain embodiments, R 3 is hydrogen or methyl. In certain embodiments. R 5 is hydrogen.
  • Z is absent.
  • W is NR 6 .
  • W is NR 6 .
  • R 6 is substituted or substituted C 1 -C 6 alkyl.
  • R 6 is H.
  • W is NH
  • W is O.
  • ring A and R' and R A2 do not form a fused bicyclic hctcroaryl ring. In certain embodiments, in the compounds of Formula (I), ring A and R A1 and R A2 do not form a fused bicyclic cycloalkyd or heterocycloalky l ring.
  • L comprises the linker -(CR L1 R L2 )-(CR L1 R L2 )-O-(CR L1 R L2 )-. In certain embodiments, L comprises the linker . In certain embodiments, L comprises the linker
  • linker L does not comprise a cyclopentyl or cyclohexyl ring.
  • X is CR 3 .
  • R 3 is hydrogen or deuterium.
  • R 3 is substituted or substituted C 1 -C 6 alkyl.
  • R 3 is hydrogen.
  • R 3 is deuterium.
  • R 2 is selected from the group consisting of hydrogen, deuterimn, or C 1-6 alkyl. In certain embodiments, R 2 is methyl. In certain embodiments, R 2 is hydrogen. In certain embodiments, R 2 is deuterium.
  • R 1 is selected from the group consisting of optionally substituted C 1-6 alkyl, optionally substituted C 3 -C cycloalkyl. and C 1 -6 deuteroalkyl.
  • R 1 is hydrogen
  • R 1 is methyl
  • R 1 is -CD 3 .
  • R 1 is cyclopropyl
  • R 1 is -CH 2 -cyclopropyl.
  • R 1 is ethyl
  • Ring A is 5-12 membered aryl or heteroaryl. In certain embodiments, when the Ring A is hctcroaryl ring, one or more heteroatoms in Ring A are selected from the group consisting of nitrogen, sulfur, or oxygen.
  • Ring A is 5-12 membered aryl.
  • Ring A is phenyl
  • Ring A is 5-12 membered heteroaryl ring, wherein the one or more heteroatom in the heteroaryl ring is nitrogen, sulfur or oxygen.
  • Ring A is a 5-12 membered heteroaryl ring having one or more nitrogen atoms.
  • Ring A is selected from the group consisting of pyridine, pyrimidine, pyridazine, pyridone, and pyridazinone.
  • Ring A, R A1 , and R A2 combine to fonn a 6,5 or 6,6 fused bicyclic ring.
  • the bicyclic ring fonned by Ring A, R A1 , and R A2 include one or more substitutions.
  • the substitutions on said bicyclic rings are selected from the group consisting of hydrogen, deuterium, halogen, optionally substituted Cj-C, alkyl. and C 1 -C 6 deuterated alkyl.
  • the substitutions on said bicyclic rings are selected from the group consisting of hydrogen, deuterimn, -CH,, or -CD 3 .
  • substitutions are selected from the group consisting of H, deuterium, C 1 -C 6 alkyl, C 1 -C 6 oxy alkyl, halogen, optionally deuterated C i -C, alky 1. and cyano.
  • R A1 and R A2 are independently selected from the group consisting of deuterium, halogen, -CN, -OR a .
  • -NR a R a , -C( O)R a , -CH 2 -R a , C 1-6 alkyl, C 1-6 haloalky 1, Cue deuteroalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein;
  • R a and R a are independently C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 deuteroalkyl, C 1 -C 6 hydroxyalkyl.
  • R A1 and R A2 are independently spiro, monocyclic or bicyclic heterocycloalkyl or heteroaryl containing at least one nitrogen or oxygen.
  • R A1 and/or R A2 is substituted or unsubstituted monocyclic heterocycloalkyl, wherein the heterocycloalkyl comprises one or more heteroatoms selected from the group consisting of nitrogen or oxygen.
  • R A1 and/or R A2 is substituted or unsubstituted bicyclic heterocycloalkyl, wherein the heterocycloalkyl comprises one or more heteroatoms selected from the group consisting of nitrogen, sulfur or oxygen.
  • R A1 and/or R A2 is substituted or unsubstituted monocyclic heteroary l. wherein the heterocyaryl comprises one or more heteroatoms selected from the group consisting of nitrogen, sulfur or oxygen.
  • R A1 and/or R A2 is substituted or unsubstituted bicyclic heteroaryl, wherein the heteroaryl comprises one or more heteroatoms selected from the group consisting of nitrogen, sulfur or oxygen.
  • R A1 and R A2 are independently substituted or unsubstituted morpholine, phenyl morpholine, 1 ,4-oxazepane, piperazine, piperidine, pyridine, triazole, tetrahyropyrane, pyrazole, oxazole, or pyridazine
  • R A1 and/or R A2 are independently substituted or unsubstituted morpholine.
  • R A1 and/or R A2 are independently substituted or unsubstituted pyridine.
  • R A1 and/or R A2 are independently substituted or unsubstituted pyridazine.
  • R A1 and/or R A2 are independently substituted or unsubstituted 1,4-oxazepane.
  • R A1 and/or R A2 are independently substituted or unsubstituted piperazine. In certain embodiments, in the compounds of Formula (I), R A1 and/or R A2 are independently substituted or unsubstituted piperidine.
  • the linker L comprises 2-10 atom links, wherein each atom link in L is selected from the group consisting of -CR L1 R L2 . NR L1 , O, and S. In certain embodiments, L comprises between 2 and 8 atom links, wherein atom links are selected from the group consisting of -CR L1 R L2 , NR L1 , O, and S, and wherein between 0 and 2 atom links are NR L1 , O, and S. In certain embodiments, in the compounds of Formula (I), L comprises between 1 and 7 atom links, wherein atom links are selected from the group consisting of are -CR L1 R L2 , NR L1 .
  • L comprises between 1 and 6 atom links, wherein each atom links are selected from the group consisting of -CR L1 R L2 , NR L1 , O, and S, and wherein between 0 and 2 atom links are NR L1 , O, and S.
  • L comprises betw een 1 and 10 atom links, wherein the atom links are independently -CR L1 R L2 and/or R L1 and R L2 at different or same atom combine to form an optionally substituted cycloalkyl or heterocycloalkyl.
  • the one or more substitutions in said cycloalkyl or heterocycloalkyl are selected from the group consisting of hydrogen, deuterium, halogen, hydroxyl, alkoxy, or C1-C4 alkyl.
  • L is selected from the group consisting of: F
  • the compotmd of the invention is a compound selected from the compounds listed below, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein the compound is selected from the group consisting of compounds provided in Table A:
  • the compotmd of the invention is a compound selected from the compounds listed below, or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, wherein the compound is selected from the group consisting of compounds provided in Tabic B:
  • the invention provides pharmaceutically acceptable isotopically labeled compounds described herein.
  • the isotopically labeled compounds are compounds where one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes suitable for inclusion in the compounds of the disclosure include isotopes of hydrogen, such as 2 H and 3 H, carbon, such as n C, 13 C and 14 C, chlorine, such as 36 C1, fluorine, such as 18 F, iodine, such as 123 I and 125 I. nitrogen, such as 13 N and 15 N, oxygen, such as 15 O, 17 O and 18 O, phosphorus, such as 32 P, and sulfur, such as 35 S.
  • the isotopically -labeled compounds of the disclosure are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e. 3 H. and carbon-14, i.e. 14 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • substitution with heavier 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.
  • positron emitting isotopes such as n C, 18 F, 15 O and 13 N
  • PET Positron Emission Topography
  • Isotopically-labeled compounds of the disclosure can generally be prepared by conventional techniques known to those skilled in the art.
  • the invention provides pharmaceutical compositions containing one or more compounds of the invention, such as any of the compounds described above.
  • the invention provides methods of modulating the activity of a kinase by contacting cells containing a kinase with one or more compounds of the invention, such as any of those described above.
  • the compound may inhibit activity of the kinase.
  • the compound may increase activity of the kinase.
  • the kinase may be a JAK family kinase.
  • the kinase may be TYK2.
  • the invention provides methods of treating a condition in a subject by administering to the subject a compound of the invention, such as any of those described above.
  • the condition may be characterized by elevated activity of a kinase.
  • the condition may be characterized by altered activity of a kinase.
  • the kinase may be a JAK family kinase.
  • the kinase may be TYK2.
  • the condition may be an autoimmune disease, inflammatory disease, bone disease, metabolic disease, neurological or neurodegenerative disease, cancer, cardiovascular disease, allergies, asthma, Alzheimer's disease, Parkinson's disease, multiple sclerosis, skin disorder, eye disease, infectious disease, or hormone-related disease.
  • the invention provides use of a compound of the invention, such as any of those described above, for making a medicament.
  • the medicament is useful for treating a condition in a subject.
  • the condition is characterized by elevated activity or altered activity of a kinase.
  • the kinase is a JAK family kinase.
  • the kinase is TYK2.
  • the condition is an autoimmune disease, inflammatory disease, bone disease, metabolic disease, neurological or neurodegenerative disease, cancer, cardiovascular disease, allergies, asthma, Alzheimer's disease, Parkinson's disease, multiple sclerosis, skin disorder, eye disease, infectious disease, or hormone -related disease.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof, and a pharmaceutically acceptable carrier or diluent.
  • the invention provides a method of inhibiting TYK2 activity in a subject in need thereof with a compound of Fonnula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof or a pharmaceutical composition.
  • the invention provides a method of treating a TYK2 -mediated disease or disorder comprising administering to a subject in need thereof a compound of Formula (I), or a pharmaceutically acceptable salt, stereoisomer, or solvate thereof or a pharmaceutical composition.
  • the present invention provides pharmaceutical compositions containing one or more compounds described above, or a pharmaceutically acceptable ester, prodrug, hydrate, solvate or salt of such a compound, optionally in combination with a pharmaceutically acceptable carrier.
  • the invention further provides such compounds for the preparation of a medicament for the treatment of one or more diseases mentioned herein.
  • a pharmaceutical composition may contain one or more compounds of the invention in a therapeutically effective amount.
  • a therapeutically effective amount of a compound in accordance with this invention means an amount of compound that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is within the skill in the art.
  • the therapeutically effective amount or dosage of a compound according to this invention can vary within wide limits and may be determined in a manner known in the art. Such dosage may be adjusted to the individual requirements in each particular case including the specific compound being administered, the route of administration, the condition being treated, as well as the patient being treated.
  • compositions of the invention may include a vehicle for delivery of one or more compounds of the invention.
  • the composition may contain particles, such as nanoparticles, microparticles, liposomes, micelles, and virus particles.
  • Examples of pharmacologically acceptable salts of sufficiently basic compounds of the invention are salts of physiologically acceptable mineral acids like hydrochloric, hydrobromic, sulfuric and phosphoric acid; or salts of organic acids like methanesulfonic, p-toluenesulfonic, lactic, acetic, trifluoroacetic, citric, succinic, fumaric, maleic and salicylic acid.
  • a sufficiently acidic compound of the invention may form alkali or earth alkali metal salts, for example sodium, potassium, lithium, calcium or magnesium salts; ammonium salts; or organic base salts, for example methylamine, dimethylamine, trimethylamine, triethylamine, ethylenediamine, ethanolamine, choline hydroxide, meglumin, piperidine, morpholine, tris-(2- hydroxyethyljamine, lysine or arginine salts; all of which are also further examples of salts of the invention.
  • Compounds of the invention may be solvated, especially hydrated. The hydratization/hydration may occur during the process of production or as a consequence of the hygroscopic nature of the initially water free compounds of the invention.
  • the solvates and/or hydrates may e.g. be present in solid or liquid form.
  • certain compounds of the invention may have tautomeric forms from which only one might be specifically mentioned or depicted in the following description, different geometrical isomers (which are usually denoted as cis/trans isomers or more generally as (E) and (Z) isomers) or different optical isomers as a result of one or more chiral carbon atoms (which are usually nomenclatured under the Cahn-Ingold-Prelog or R/S system). All these tautomeric forms, geometrical or optical isomers (as well as racemates and diastereomers) and polymorphous forms are included in the invention.
  • the compounds of the invention may contain asymmetric C -atoms, they may be present either as achiral compounds, mixtures of diastereomers, mixtures of enantiomers or as optically pure compounds.
  • the present invention comprises both all pure enantiomers and all pure diastereomers, and also the mixtures thereof in any mixing ratio.
  • one or more hydrogen atoms of the compounds of the present invention may be replaced by deuterium.
  • Deuterium modification improves the metabolic properties of a drug with little or no change in its intrinsic pharmacology.
  • Deuterium substitution at specific molecular positions improves metabolic stability, reduces formation of toxic metabolites and/or increases the formation of desired active metabolites.
  • the present invention also encompasses the partially and fully deuterated compounds of the invention.
  • the term hydrogen also encompasses deuterium.
  • compositions according to the present invention may comprise at least one compound of the invention as an active ingredient and. optionally, carrier substances and/or adjuvants.
  • the present invention also relates to prodrugs which are composed of a compound of the invention and at least one pharmacologically acceptable protective group which will be cleaved off under physiological conditions, such as an alkoxy-, arylalkyloxy-, acyl-, acvloxymcthyl group (e.g. pivalovloxymcthyl). an 2-alkyl-, 2-ary I- or 2-ary lalkyl oxycarbonyl-2-alkylidene ethyl group or an acyloxy 7 group as defined herein, e.g.
  • compositions may contain pro-drugs of the hydroxy group of a compound of the invention.
  • ester especially refers to esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof.
  • Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms.
  • esters include, but are not limited to, formates, acetates, propionates, buty rates, acrylates and ethylsuccinates.
  • the present invention also relates to a prodrug, a biohydrolyzable ester, a biohydrolyzable amide, a polymorph, tautomer, stereoisomer, metabolite, N-oxide, biohydrolyzable carbamate, biohydrolyzable ether, physiologically functional derivative, atropisomer, or in vivo-hydrolysable precursor, diastereomer or mixture of diastereomers, chemically protected form, affinity reagent, complex, chelate and a stereoisomer of the compounds of the invention.
  • therapeutically useful agents that contain compounds of the invention. their solvates, salts or formulations are also comprised in the scope of the present invention.
  • compounds of the invention will be administered by using the known and acceptable modes known in the art, either alone or in combination with any other therapeutic agent.
  • such therapeutically useful agents can be administered by one of the following routes; oral, e.g. as tablets, dragees, coated tablets, pills, semisolids, soft or hard capsules, for example soft and hard gelatin capsules, aqueous or oily solutions, emulsions, suspensions or syrups, parenteral including intravenous, intramuscular and subcutaneous injection, e.g. as an injectable solution or suspension, rectal as suppositories, by inhalation or insufflation, e.g. as a powder formulation, as microcrystals or as a spray (e.g.
  • the therapeutically useful product may be mixed with pharmaceutically inert, inorganic or organic excipients as are e.g. lactose, sucrose, glucose, gelatine, malt, silica gel. starch or derivatives thereof, talc, stearinic acid or their salts, dried skim milk, and the like.
  • pharmaceutically inert, inorganic or organic excipients as are e.g. lactose, sucrose, glucose, gelatine, malt, silica gel. starch or derivatives thereof, talc, stearinic acid or their salts, dried skim milk, and the like.
  • excipients as are e.g.
  • excipients as are e.g. vegetable, petroleum, animal or synthetic oils, wax, fat and polyols.
  • compressed gases suitable for this purpose as are e.g. oxygen, nitrogen and carbon dioxide.
  • the pharmaceutically useful agents may also contain additives for conservation, stabilization, e.g. UV stabilizers, emulsifiers, sweetener, aromatizers, salts to change the osmotic pressure, buffers, coating additives and antioxidants.
  • the daily dosage can be administered as a single dose or in divided doses, or for parenteral administration, it may be given as continuous infusion or subcutaneous injection.
  • the invention also provides methods of making compounds of the invention, such as those described above. Synthesis schemes for making specific compounds of Fonnula (I) are provided in the Examples below.
  • the compounds and compositions of the invention modulate activity of one or more protein kinases.
  • the compounds and compositions may inhibit, activate, or otherwise alter kinase activity. Consequently, the compounds and compositions may be used to diagnose, treat, or prevent a condition, such as a disease, disorder, or other condition for which modulation of kinase activity provides therapeutic benefit.
  • the kinase may be a serine -threonine kinase or a tyrosine kinase, e.g., a receptor tyrosine kinase or non-receptor tyrosine kinase.
  • the kinase may be a member of the JAK family.
  • the kinase may be non-receptor tyrosine-protein kinase TYK2 (TYK2). including mutants of any of the aforementioned kinases.
  • the disease, disorder, or condition may be associated with aberrant TYK2 activity, such as autoimmune disorders, Crohn's disease, hyperimmunoglobulin E syndrome, inflammatory bowel disease, multiple sclerosis (MS), multiple sclerosis (MS), progressive supranuclear palsy (PSP), psoriasis, rheumatoid arthritis, systemic lupus erythematosus (SLE). type 1 diabetes (T1D). or ulcerative colitis.
  • TYK2 activity such as autoimmune disorders, Crohn's disease, hyperimmunoglobulin E syndrome, inflammatory bowel disease, multiple sclerosis (MS), multiple sclerosis (MS), progressive supranuclear palsy (PSP), psoriasis, rheumatoid arthritis, systemic lupus erythematosus (SLE). type 1 diabetes (T1D). or ulcerative colitis.
  • the disease, disorder, or condition may be or include a respiratory tract/obstructive airways disease or disorder, such as rhinorrhea, tracheal constriction, airway contraction, acute-, allergic, atrophic rhinitis or chronic rhinitis (such as rhinitis caseosa.
  • a respiratory tract/obstructive airways disease or disorder such as rhinorrhea, tracheal constriction, airway contraction, acute-, allergic, atrophic rhinitis or chronic rhinitis (such as rhinitis caseosa.
  • rhinitis hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca), rhinitis medicamentosa, membranous rhinitis (including croupous, fibrinous and pseudomembranous rhinitis), scrofulous rhinitis, perennial allergic rhinitis, seasonal rhinitis (including rhinitis nervosa (hay fever) and vasomotor rhinitis), pollinosis, asthma (such as bronchial, atopic, allergic, intrinsic, extrinsic, exercise-induced, cold air-induced, occupational, bacterial infection- induced, and dust asthma particularly chronic or inveterate asthma (e.g.
  • bronchitis including chronic, acute, arachidic, catarrhal, croupus, phthinoid and eosinophilic bronchitis
  • cardiobronchitis pneumoconiosis, chronic inflammatory disease of the lung which result in interstitial fibrosis, such as interstitial lung disease (ILD) (e.g., idiopathic pulmonary fibrosis, or ILD associated with rheumatoid arthritis, or other autoimmune conditions), acute lung injury (ALI), adult respiratory distress syndrome (ARDS), chronic obstructive pulmonary, airways or lung disease (CORD, COAD, COLD or COPD, such as irreversible COPD), chronic sinusitis, conjunctivitis (e.g.
  • ILD interstitial lung disease
  • COAD idiopathic pulmonary fibrosis
  • ILD associated with rheumatoid arthritis, or other autoimmune conditions
  • ALI acute lung injury
  • ARDS adult respiratory distress syndrome
  • allergic conjunctivitis cystic fibrosis, extrinsic allergic alveolitis (like farmer's lung and related diseases), fibroid lung, hypersensitivity lung diseases, hypersensitivity pneumonitis, idiopathic interstitial pneumonia, nasal congestion, nasal polyposis, otitis media, and cough (chronic cough associated with inflammation or iatrogenic induced), pleurisy, pulmonary congestion, emphysema, bronchiectasis, sarcoidosis, lung fibrosis, including cryptogenic fibrosing alveolitis, fibrosis complicating anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections, vasculitic and thrombotic disorders of the lung vasculature, and pulmonary hypertension, acute viral infection including the common cold, and infection due to respiratory syncytial virus, influenza, coronavirus (including SARS) and adenovirus, allergic bronchopulmonary my
  • emphysema diffuse panbronchiolitis, systemic anaphylaxis or hypersensitivity responses, drug allergies (e.g., to penicillin, cephalosporins), insect sting allergies, and food related allergies which may have effects remote from the gut (such as migraine, rhinitis and eczema), anaphylactic shock, or vascular spasms.
  • drug allergies e.g., to penicillin, cephalosporins
  • insect sting allergies e.g., to insect sting allergies
  • food related allergies which may have effects remote from the gut (such as migraine, rhinitis and eczema), anaphylactic shock, or vascular spasms.
  • the disease, disorder, or condition may be or include a bone and joint related disease or disorder, such as osteoporosis, arthritis (including rheumatic, infectious, autoimmune, chronic, malignant), seronegative spondyloarthropathies (such as ankylosing spondylitis, rheumatoid spondylitis, psoriatic arthritis, enthesopathy, Bechet's disease, Marie-Strumpell arthritis, arthritis of inflammatory bowel disease, and Reiter's disease), systemic sclerosis, osteoarthritis, osteoarthrosis, both primary and secondary to e.g.
  • arthritis including rheumatic, infectious, autoimmune, chronic, malignant
  • seronegative spondyloarthropathies such as ankylosing spondylitis, rheumatoid spondylitis, psoriatic arthritis, enthesopathy, Bechet's disease, Marie-Strumpell arthritis, arthritis of inflammatory bowel disease, and Re
  • the disease, disorder, or condition may be or include a skin or eye related disease or disorder, such as glaucoma, ocular hypertension, cataract, retinal detachment, psoriasis (including psoriasis vulgaris, pustular psoriasis, arthritic psoriasis, erythroderma psoriatiemn), palmoplantar pustulosis, xerodoma, eczematous diseases (like atopic dermatitis, ultraviolet radiation dermatitis, contact dermatitis, and seborrheic dermatitis), phytodermatitis, photodermatitis, cutaneous eosinophilias, chronic skin ulcers, cutaneous lupus erythematosus, contact hypersensitivity /allergic contact dermatitis (including sensitivity to poison ivy, sumac, or oak), and eosinophilic folliculitis (Ofuji's disease), pruri
  • acne erythema, dermatitis herpetiformis, scleroderma, vitiligo, lichen planus, lichen sclerosus et atrophica, pyodenna gangrenosum, skin sarcoid, pemphigus, ocular pemphigus, pemphigoid, epidermolysis bullosa.
  • angioedema vasculitides, toxic erythemas, cutaneous eosinophilias, alopecia areata, male-pattern baldness, Sweet's syndrome, Stevens-Johnson syndrome, Weber-Christian syndrome, erythema multiforme, cellulitis, both, infective and non infective, panniculitis, cutaneous Lymphomas, non-' melanoma skin cancer and other dysplastic lesions, blepharitis, ulceris, anterior and posterior uveitis, choroiditis, autoimmune, degenerative or inflammatory disorders affecting the retina, ophthalmitis including sympathetic ophthalmitis, sarcoidosis, xerosis infections including viral, fungal, and bacterial, allergic conjunctivitis, increased fibrosis, keloids, keloplasty, post surgical scars, epidermolysis bullosa, dry eye.
  • ocular inflammation allergic conjunctivitis, vernal conjunctivitis, vernal keratoconjunctivitis, and giant papillary conjunctivitis, ocular angiogenesis, cornea damage and scar, all forms of macular degeneration, macular edema, macular dystrophy, abnormal wound healing, scleritis, episcleritis, pachydermia, peripheral ulcerative keratitis, fungal keratitis, herpetic keratitis, invasive aspergillosis; conical cornea, dystorphia epithelialis comeae, or severe intraocular inflammation.
  • the disease, disorder, or condition may be or include a gastrointestinal tract and abdominal related disease or disorder, such as celiac/coeliac disease (e.g. celiac sprue), cholecystitis, enteritis (including infectious, ischemic, radiation, drug-induced, and eosinophilic gastroenteritis), eosinophilic esophagitis, eosinophilic gastrointestinal inflammation, allergen induced diarrhea, enteropathy associated with seronegative arthropathies, gastritis, autoimmune atrophic gastritis, ischemic bowel disease, inflammatory bowel disease (Crohn's disease and ulcerative colitis), colitis, Mooren's ulcer, irritable bowel syndrome, necrotizing enterocolitis, gut ischemia, glossitis, gingivitis, periodontitis, oesophagitis, including reflex, proctitis, fibrosis and cirrhosis of the liver, pancreatitis, both acute and
  • the disease, disorder, or condition may be or include a hematological disease or disorder, such as anemias, coagulation, myeloproliferative disorders, hemorrhagic disorders, leukopenia, eosinophilic disorders, leukemias (e.g. myelogenous, lymphomas, plasma cell dyscrasias. disorders of the spleen, Band's disease, hemophilia, purpura (including idiopathic thrombocytopenic purpura), or Wiskott- Aldrich syndrome.
  • a hematological disease or disorder such as anemias, coagulation, myeloproliferative disorders, hemorrhagic disorders, leukopenia, eosinophilic disorders, leukemias (e.g. myelogenous, lymphomas, plasma cell dyscrasias. disorders of the spleen, Band's disease, hemophilia, purpura (including idiopathic thrombocytopenic pur
  • the disease, disorder, or condition may be or include a metabolic disease or disorder, such as obesity, amyloidosis, disturbances of the amino and acid metabolism like branched chain disease, hyperaminoacidemia, hyperaminoaciduria, disturbances of the metabolism of urea, hyperammonemia, mucopolysaccharidoses e.g.
  • Maroteaux-Lamy syndrome storage disease like glycogen storage diseases and lipid storage diseases, glycogenosis I diseases like Cori's disease, malabsorption diseases like intestinal carbohydrate malabsorption, oligosaccharidase deficiency like maltase-, lactase-, sucrase- insufficiency, disorders of the metabolism of fructose, disorders of the metabolism of galactose, galactosaemia, disturbances of carbohydrate utilization like diabetes, hypoglycemia, disturbances of pyruvate metabolism, hypolipidemia, hypolipoproteinemia, hyperlipidemia, hyperlipoproteinemia, carnitine or carnitine acyltransferase deficiency, disturbances of the porphyrin metabolism, porphyrins, disturbances of the purine metabolism, lysosomal diseases, metabolic diseases of nerves and nervous systems like gangliosidoses, sphingolipidoses, sulfatidoses, leucodystrophies, or
  • the disease, disorder, or condition may be or include a cerebellar dysfunction or disturbance of brain metabolism, such as dementia.
  • Alzheimer's disease Huntington's chores, Parkinson's disease, Pick's disease, toxic encepha-lopathy.
  • demyelinating neuropathies like inflammatory neuropathy, Guillain-Barre syndrome; Meniere's disease and radiculopathy, primary and secondary metabolic disorders associated with hormonal defects like any disorder stemming from either an hyperfunction or hypofunction of some hormone- secreting endocrine gland and any combination thereof.
  • Sipple's syndrome pituitary gland dysfunction and its effects on other endocrine glands, such as the thyroid, adrenals, ovaries, and testes, acromegaly, hyper- and hypothyroidism, euthyroid goiter, euthyroid sick syndrome, thyroiditis, and thyroid cancer, over or underproduction of the adrenal steroid hormones, adrenogenital syndrome.
  • Cushing's syndrome Addison's disease of the adrenal cortex, Addison's pernicious anemia, primary and secondary aldosteronism, diabetes insipidus, diabetes mellitus, carcinoid syndrome, disturbances caused by the dysfunction of the parathyroid glands, pancreatic islet cell dysfunction, diabetes, disturbances of the endocrine system of the female like estrogen deficiency, resistant ovary syndrome; muscle weakness, myotonia.
  • the disease, disorder, or condition may be or include a transplant rejection related condition, such as acute and chronic allograft rejection following solid organ transplant, for example, transplantation of kidney, heart, liver, lung, and cornea, chronic graft versus host disease, skin graft rejection, and bone marrow transplant rejection, or immunosuppression.
  • a transplant rejection related condition such as acute and chronic allograft rejection following solid organ transplant, for example, transplantation of kidney, heart, liver, lung, and cornea, chronic graft versus host disease, skin graft rejection, and bone marrow transplant rejection, or immunosuppression.
  • the disease, disorder, or condition may be or include a genitourinary related condition, such as nephritis (interstitial, acute interstitial (allergic), and glomerulonephritis), nephrotic syndrome, cystitis including acute and chronic (interstitial) cystitis and Hunner's ulcer, acute and chronic urethritis, prostatitis, epididymitis, oophoritis, salpingitis, vulvo vaginitis, vulvovaginal candidiasis, Peyronie's disease, and erectile dysfunction, renal disease, renal fibrosis, nephropyelitis, secondary contracted kidney, steroid dependent and steroid-resistant nephrosis, or Goodpasture's syndrome.
  • nephritis interstitial, acute interstitial (allergic), and glomerulonephritis
  • cystitis including acute and chronic (interstitial) cystitis and Hunner's ulcer,
  • the disease, disorder, or condition may be or include a CNS related disease or disorder, such as neurode generative diseases, Alzheimer's disease and other cementing disorders including CID and nvCJD, amyloidosis, and other demyelinating syndromes, cerebral atherosclerosis and vasculitis, temporal arteritis, myasthenia gravis, acute and chronic so pain (acute, intermittent or persistent, whether of central or peripheral origin) including post-operative, visceral pain, headache, migraine, neuralgia (including trigeminal), atypical facial pain, joint and bone pain, pain arising from cancer and tumor invasion, neuropathic pain syndromes including diabetic, post-herpetic, and HIV-associated neuropathies, nemosarcoidosis, to brain injuries, cerebrovascular diseases and their consequences, Parkinson's disease, corticobasal degeneration, motor neuron disease, dementia, including ALS (Amyotrophic-lateral sclerosis), multiple sclerosis, traumatic brain injury, stroke, post-stroke, post
  • the disease, disorder, or condition may be or include an inflammatory or immunological disease or disorder, such as general inflammation (of the ocular, nasal, pulmonary, and gastrointestinal passages), maslocylosis/mast cell disorders (cutaneous, systemic, mast cell activation syndrome, and pediatric mast cell diseases), mastitis (mammary gland), vaginitis, vasculitis (e.g., necrotizing, cutaneous, and hypersensitivity vasculitis). Wegener granulamatosis.
  • an inflammatory or immunological disease or disorder such as general inflammation (of the ocular, nasal, pulmonary, and gastrointestinal passages), maslocylosis/mast cell disorders (cutaneous, systemic, mast cell activation syndrome, and pediatric mast cell diseases), mastitis (mammary gland), vaginitis, vasculitis (e.g., necrotizing, cutaneous, and hypersensitivity vasculitis). Wegener granulamatosis.
  • myyositis including polymyositis, dermatomyositis
  • basophil related diseases including basophilic leukemia and basophilic leukocytosis
  • eosinophil related diseases such as Churg- Strauss syndrome, eosinophilic granuloma, lupus erythematosus (such as, systemic lupus erythematosus, subacute cutaneous lupus erythematosus, and discoid lupus erythematosus), chronic thyroiditis.
  • Hashimoto's thyroiditis Grave's disease, type 1 diabetes, complications arising from diabetes mellitus, other immune disorders, eosinophilia fasciitis, hyper IgE syndrome. Addison's disease, antiphospholipid syndrome, immunodeficiency disease. acquired immune deficiency syndrome (AIDS), leprosy, Sezary 7 syndrome, paraneoplastic syndromes, and other autoimmune disorders, fervescence, myositis, nervous diseases selected from multiple myositis, bursitis, Evans syndrome, leukotriene B4-mediated diseases, idiopathic hypoparathyroidism, nephrotic syndrome lupus, or immunosuppression.
  • AIDS acquired immune deficiency syndrome
  • Sezary 7 syndrome paraneoplastic syndromes
  • fervescence myositis
  • nervous diseases selected from multiple myositis, bursitis, Evans syndrome, leukotriene B4-mediated diseases, idiopathic hypoparathyroidism,
  • the disease, disorder, or condition may be or include a cardiovascular disease or disorder, such as congestive heart failure, myocardial infarction, ischemic diseases of the heart, all kinds of atrial and ventricular arrhythmias, hypertension, cerebral trauma, occlusive vascular disease, stroke, cerebrovascular disorder, atherosclerosis, restenosis, affecting the coronary and peripheral is circulation, pericarditis, myocarditis, inflammatory and auto-immune cardiomyopathies including myocardial sarcoid, endocarditis, valvulitis, and aortitis including infective (e.g.
  • a cardiovascular disease or disorder such as congestive heart failure, myocardial infarction, ischemic diseases of the heart, all kinds of atrial and ventricular arrhythmias, hypertension, cerebral trauma, occlusive vascular disease, stroke, cerebrovascular disorder, atherosclerosis, restenosis, affecting the coronary and peripheral is circulation, pericarditis, myocardi
  • syphilitic hypertensive vascular diseases, peripheral vascular diseases, and atherosclerosis
  • vasculitides disorders of the proximal and peripheral veins including phlebitis and thrombosis, including deep vein thrombosis and complications of varicose veins, aortic aneurism, periarteritis nodosa, cardiac fibrosis, post- myocardial infarction, idiopathic cardiomyopathy, or angioplasty.
  • the disease, disorder, or condition may be or include an oncological disease or disorder, such as common cancers (prostate, breast, lung, ovarian, pancreatic, bowel and colon, abdomen, stomach (and any other digestive system cancers), liver, pancreas, peritoneum, endocrine glands (adrenal, parathyroid, pituitary, testicles, ovary 7 , thymus, thyroid), eye.
  • an oncological disease or disorder such as common cancers (prostate, breast, lung, ovarian, pancreatic, bowel and colon, abdomen, stomach (and any other digestive system cancers), liver, pancreas, peritoneum, endocrine glands (adrenal, parathyroid, pituitary, testicles, ovary 7 , thymus, thyroid), eye.
  • lymphoproliferative systems such as Hodgkin's and nonHodgkin's lymphoma, B-cell lymphoma, follicular lymphoma, metastatic disease and tumor recurrences, and paraneoplastic syndromes, as well as hypergammaglobulinemia, lymphoproliferative diseases, disorders, and/or conditions, paraproteinemias, purpura (including idiopathic thrombocytopenic purpura), Waldenstron's Macroglobulinemia, Gaucher's Disease, histi
  • the disease, disorder, or condition may be or include another disease or disorder, such as pain, migraine, sleep disorders, fever, sepsis, idiopathic thrombocytopenia pupura, post- operative adhesions, flushing, ischemic/reperfusion injury in the heart, brain, peripheral limbs, bacterial infection, viral infection, fungal infection, thrombosis, endotoxin shock, septic shock, thermal regulation including fever, Raynaud's disease, gangrene, diseases requiring anti-coagulation therapy, congestive heart failure, mucus secretion disorders, pulmonary hypotension, prostanoid- induced smooth muscle contract associated with dysmenorrhea and premature labor, premature delivery, reperfusion injury, bum, thermal injury, hemorrhage or traumatic shock, menstrual pain, menstrual cramp, dysmenorrhea, periodontosis, rickettsial infectious disease, protozoal disease, reproduction disease, toothache, pain after tooth extraction, Herpes zoster
  • the disease is selected from the group consisting of an inflammatory disease, an autoimmune disease, an allergic disorder, and an ocular disorder.
  • the disease is selected from the group consisting of pruritus, eczema, asthma, rhinitis, dry eye, ocular inflammation, allergic conjunctivitis, vernal conjunctivitis, vernal keratoconjunctivitis, giant papillary conjunctivitis, fungal keratitis and uveitis.
  • the method may include modulating the activity of one or more kinases in a subject, such as any of the kinase described above.
  • the method may include inhibiting a kinase.
  • the method may include activating, e.g.. stimulating or enhancing the activity of. a kinase.
  • the method may include modulating activity of a single kinase or preferentially modulating activity of a specific kinase over others.
  • the method may include modulating activity of multiple kinases or preferentially modulating activity of two more specific kinases over others.
  • the method may include providing a compound of the invention.
  • the method may include providing multiple compounds of the invention.
  • the method may include contacting cells containing a kinase with one or more compounds of the invention.
  • contacting a cell with a compound may include exposing a cell to a compound, e.g., in a formulation, such as any of those described above; delivering a compound inside a cell; providing a compound to a subject and allowing a cell in the subject to become exposed to the compound.
  • Contacting may be performed in vivo or in vitro. In vitro contact may include exposure of cells or tissue isolated from a subject.
  • the method may include contacting cells with a single compound of the invention.
  • the method may include contact cells with multiple compounds of the invention.
  • the method may include administration of a composition to a subject.
  • the compositions may be provided by any suitable route of administration.
  • the compositions may be administered buccally, by injection, dermally. enterally, intraarterially, intravenously, intranasally. e g., by inhalation, intraocularly, orally, parenterally, pulmonarily, rec tally, subcutaneously, systemically, topically, e.g.. to the skin or eye, transdermally, or with or on an implantable medical device (e.g.. stent or drug-eluting stent or balloon equivalents).
  • an implantable medical device e.g. stent or drug-eluting stent or balloon equivalents.
  • compound III- 1 is brominated to obtain compound III -2, followed by a nucleophilic substitution with compound IV- 1 to afford compound III-3, which undergoes a C-N coupling reaction to give compound III -4, a subsequent deprotection of compound III -4 then occurs to obtain diamine III- 5.
  • the N protection converts compound VI-6 to compound VI-7, followed by a C-N coupling reaction to afford compound VI-8, which undergoes deprotection to afford diamine VI-9.
  • Example 1 4-methoxy-ll-methyl-18-(methylamino)-9-oxa-2, 12,14,16,20- pentazatetracyclo[12.5.2.13,7.017,21]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one
  • Step 1 Synthesis of 2-[(5,7-dichloroimidazo[4,5-b]pyridin-3-yl)methoxy]ethyl-trimethyl-silane ,SEM ypN N
  • Step 2 Synthesis of 5-chloro-N-[(4-methoxyphenyl)methyl]-N-methyl-3-(2- trimethylsilylethoxymethyl)imidazo[4,5-b]pyridin-7-amine
  • Step 3 Synthesis of 5-chloro-N-[(4-methoxyphenyl)methyI]-N-methyl-3H-imidazo[4,5-b]pyridin- 7- amine
  • Step 5 Synthesis of tert-butyl N-[2-[(4-methoxy-3-nitro-phenyl)methoxy]-l-methyl- ethyljcarbamate
  • Step 7 Synthesis of phenyl N-[2-[(4-methoxy-3-nitro-phenyl)methoxy]-l-methyl-ethyl]carbamate
  • Step 8 Synthesis of 5-chloro-N-[2-[(4-methoxy-3-nitro-phenyI)methoxy]-l-methyI-ethyl]-7-[(4- methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridinc-3-carboxamidc
  • Step 9 Synthesis of N-[2-[(3-amino-4-methoxy-phenyl)methoxy]-l-methyl-ethyl]-5-chloro-7-[(4- methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxamide
  • Step 10 Synthesis of 4-methoxy-18-[(4-methoxyphenyl)methyl-methyl-amino]-ll-methyl-9-oxa- 2,12,14,16,20-pentazatetracyclo [12.5.2.13,7.017,21 ] docosa- 1 (19), 3, 5, 7(22), 15,17,20-heptaen-l 3- one
  • Step 11 Synthesis of 4-methoxy-ll-methyl-18-(methylamino)-9-oxa-2,12,14,16,20- pentazatetracyclo[12.5.2.13,7.017,21]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one
  • Gilson 156 UV Detector Column: Phenomenex Gemini-C18 ' 75 ' 40 mm ' 3 um; Mobile phase A: [water-ACN]; Mobile phase B: MeCN; Gradient: B from 43% to 73% in 8 min, hold 100% B for 2 min; Flow Rate: 25 mL/min; Column Temperature: 30 °C; Wavelength: 220 nm) to afford 4-methoxy-ll-methyl-18-(methylamino)-9-oxa-2,12.14,16.20- pentazatetracyclo[12.5.2.13,7.017,21]docosa-l(19),3,5,7(22).15,17.20-heptaen-13-one (8.7 mg, 11.4% yield) as a white solid.
  • Example 4 4-(difluoromethoxy)-ll-methyl-18-(methylamino)-9-oxa-2,12,14,16,20- pentazatetracyclo[12.5.2.1 3 ’ 7 .0 17 ' 21 ]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one
  • Step 3 Synthesis of tert-butyl A-[2-[[4-(difhioroinethoxy)-3-nitro-phenyl]methoxy]-l-methyl- ethyl]carbamate
  • Step 4 Synthesis of l-[[4-(difluoromethoxy)-3-nitro-phenyl]methoxy]propan-2-amine
  • Step 5 Synthesis of 5-chloro-N-[2-[[4-(difhioromethoxy)-3-nitro-phenyl]methoxy]-l-methyI- ethyl]-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxamide
  • Step 7 Synthesis of A r -
  • Step 8 Synthesis of 4-(difluoromethoxy)-18-[(4-methoxyphenyl)methyl-methyl-amino]-ll- methyl-9-oxa-2,12,14,16,20-pentazatetracyclo[12.5.2.1 3 ’ 7 .0 17 ' 21 ]docosa-l(19),3,5,7(22),15,17,20- heptaen-13-one
  • Step 9 Synthesis of 4-(difluoromethoxy)-ll-methyl-18-(methylamino)-9-oxa-2,12,14,16,20- pentazatetracyclo[12.5.2.1 3 ’ 7 .0 17 ’ 21 ]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one
  • Step 1 Synthesis of l-(bromomethyl)-3-fluoro-5-nitro-benzene NO
  • Step 2 Synthesis of tert-butyl M
  • Step 4 Synthesis of 5-chloro-7V-[(lR)-2-[(3-fliioro-5-nitro-phenyl)methoxy]-l-methyl-ethyl]-7- [(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxamide
  • Step 5 Synthesis of /V-[(l R)-2-[(3-amino-5-fluoro-phenyl)mcthoxy
  • Step 6 Synthesis of (llR)-5-fhioro-18-[(4-methoxyphenyl)methyl-methyl-amino]-ll-inethyl-9- oxa-2,12,14,16,20-pentazatetracyclo[12.5.2.1 3 ’ 7 .0 17 ’ 21 ]docosa-l(19),3,5,7(22),15,17,20-heptaen-13- one
  • Step 7 Synthesis of (HR)-5-fluoro-ll-methyl-18-(methylamino)-9-oxa-2,12,14,16,20- pentazatetracyclo[12.5.2.1 3 ’ 7 .0 17 ’ 21 ]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one
  • TFA 292 mg, 2.56 mmol
  • triethylsilane (306 mg, 2.63 mmol) in DCM (50 mL) was added ( 1 lR)-5 -fluoro- 18-[(4-methoxy pheny l)methy 1-methyl-amino] -11 -methy l-9-oxa-2, 12,14,16,20- pentazatetracyclo[12.5.2.1 3 7 ,0 1 7 - 21 ]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one (130
  • Example 88 (10R,14R)-6-methoxy-21-(methylamino)-9-oxa-2,15,17,19,23- pentazapentacyclo[15.5.2.1 3 ’ 7 .0 1014 .0 2024 ]pentacosa-l(23),3,5,7(25),18,20(24),21-heptaen-16-one
  • Step 11 Synthesis of tert-butyl N- [(1 R,2R)-2- [(2-methoxy-5-nitro- phenyl) methoxy] cyclopentyl] carbamate
  • Step 3 Synthesis of 5-chloro-7V-[(lR,2R)-2-[(2-methoxy-5- nitro-phenyl)methoxy] cyclopentyl] -7- [(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxamide
  • Step 4 Synthesis of N-[(lR,2R)-2-[(5-amino-2-methoxy-phenyl)methoxy]cyclopentyl]-5-chloro-7-
  • Step 5 Synthesis of (10R,14R)-6-methoxy-21-[(4-methoxyphenyl)methyl-methyl-amino]-9-oxa- 2,15,17,19,23-pentazapentacyclo[15.5.2.1 3 ’ 7 .0 1014 .0 2024 ]pentacosa-l(23),3,5,7(25),18,20(24),21- heptaen-16-one
  • Step 6 Synthesis of (10R,14R)-6-methoxy-21-(methylamino)-9-oxa-2,15,17,19,23- pentazapentacyclo[15.5.2.1 3 ’ 7 .0 1014 .0 20 ' 24 ]pentacosa-l(23),3,5,7(25),18,20(24),21-heptaen-16-one
  • Step 4 Synthesis of 5-chloro-N-[(4-inethoxyphenyl)methyl]-N,2-dimethyl-3-(2- trimethylsilylethoxymethyl)imidazo[4,5-b]pyridin-7-amine
  • Step 5 Synthesis of 5-chloro-N-[(4-methoxyphenyl)methyl]-N,2-dimethyl-3H-imidazo[4,5- b]pyridin-7-amine
  • Step 6 Synthesis of 5-chloro-N-[(lR)-2-[(4-methoxy-3-nitro-phenyl)methoxy]-l-methyl-ethyl]-7- [(4-methoxyphenyl)methyl-methyl-amino] -2-methyl-imidazo [4,5-b] pyridine-3-carboxamide
  • Step 7 Synthesis of N-[(lR)-2-[(3-amino-4-methoxy-phenyl)methoxy]-l-methyl-ethyI]-5-chloro- 7-[(4-methoxyphenyl)methyl-methyl-amino]-2-methyI-imidazo[4,5-b]pyridine-3-carboxamide
  • Step 8 Synthesis of (llR)-4-methoxy-18-[(4-methoxyphenyl)methyl-methyl-amino]-ll,15- dimethyl-9-oxa-2,l 2,14,16,20-pentazatetracyclo [12.5.2.13,7.017,21] docosa- l(19),3,5,7(22),15,17,20-heptaen-13-one
  • Step 9 Synthesis of (llR)-4-methoxy-ll,15-dimethyl-18-(methylamino)-9-oxa-2,12,14,16,20- pentazatetracyclo[12.5.2.13,7.017,21]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one
  • Example 10 (10R,14R)-5-fluoro-21-(methylamino)-9-oxa-2,15,17,19,23- pentazapentacyclo[15.5.2.1 3 ’ 7 .0 1014 .0 2024 ]pentacosa-l(23),3,5,7(25),18,20(24),21-heptaen-16-one
  • Step 1 Synthesis of tert-butyl 7V-[(lR,2R)-2-[(3-fluoro-5- nitrophenyl)methoxy]cyclopentyl]carbamate
  • Step 3 Synthesis of 5-chloro-A-[(lR,2R)-2-[(3-fluoro-5-nitro-phenyl)methoxy]cyclopentyl]-7-[(4- methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxamide
  • Step 4 Synthesis of 7V-[(lR,2R)-2-[(3-amino-5-fhioro-phenyl)inethoxy]cyclopentyl]-5-chloro-7- [(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxamide
  • Step 5 Synthesis of (10R,14R)-5-fluoro-21-[(4-methoxyphenyI)methyI-methyl-amino]-9-oxa- 2,15,17,19,23-pentazapentacyclo[15.5.2.1 37 .0 1014 .0 2024 ]pentacosa-l(23),3,5,7(25),18,20(24),21- heptaen-16-one
  • M-[(lR,2R)-2-[(3-amino-5-fluoro-phenyl)methoxy]cyclopentyl]-5-chloro-7-[(4- methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxamide 180 mg, 0.325 mmol
  • K3PO4 207 mg, 0.975 mmol
  • dioxane 30 mL
  • Step 6 Synthesis of (10R,14R)-5-fhioro-21-(methylamino)-9-oxa-2,15,17,19,23- pentazapentacyclo[15.5.2.1 3 ’ 7 .0 1014 .0 20 ’ 24 ]pentacosa-l(23),3,5,7(25),18,20(24),21-heptaen-16-one
  • Example 1111 (10R,14R)-21-(methylamino)-5-(2-methyltriazol-4-yl)-9-oxa-2,l 5,17,19,23- pentazapentacyclo [15.5.2.13,7.010,14.020,24] pentacosa-1 (23), 3(25), 4, 6,18, 20(24), 21 -heptaen-16- one
  • Step 3 Synthesis of tert-butyl N-[(lR,2R)-2-[[3-(2-methyltriazol-4-yl)-5-nitro- phenyl] methoxy] cyclopentyl] carbamate
  • Step 4 Synthesis of (lR,2R)-2-[[3-(2-methyltriazol-4-yl)-5-nitro phenyl]methoxy]cyclopentan amine
  • the crude product was purified by a reversed-phase HPLC (Column: SepaFlash® Sphercial CIS, 25 g, 40-60 pm, 120A; MeCN/water with MeCN from 0-45%, flow rate: 25 mL/min, 254 nm). The fraction was concentrated under reduced pressure and then lyophilized for overnight. The desired product (lR,2R)-2-[[3-(2-mcthyltriazol-4-yl)-5-nitro- phenyl]methoxy]cyclopentanamine (270 mg, 58.3% yield) was obtained as a yellow oil. LCMS (ESI) m/z 318.4 [M+H] + .
  • Step 5 Synthesis of phenyl 5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5- b] py ridine-3-carboxy late
  • Step 6 Synthesis of 5-chloro-7-[(4-inethoxyphenyl)methyl-methyl-amino]-N-[(lR,2R)-2-[[3-(2- methyltriazol-4-yl)-5-nitro-phenyl]inethoxy]cyclopentyl]imidazo[4,5-b]pyridine-3-carboxamide
  • Step 7 Synthesis of N-[(lR,2R)-2-[[3-amino-5-(2-methyltriazol-4- yl)phenyl] methoxy]cyclopentyl] -5-chloro-7- [(4-methoxyphenyl)methyl-methyl- amino]imidazo[4,5-b]pyridine-3-carboxamide
  • Step 8 Synthesis of (10R,14R)-21-[(4-methoxyphenyl)methyl-methyl-amino]-5-(2-methyltriazol- 4-yl)-9-oxa-2,l 5,17,19,23-pentazapentacyclo[l 5.5.2.13,7.010,14.020, 24]pentacosa- 1 (23), 3(25), 4, 6, 18, 20(24), 21 -heptaen-16-one
  • Step 9 Synthesis of (10R,14R)-21-(methylamino)-5-(2-methyltriazol-4-yl)-9-oxa-2, 15, 17,19,23- pentazapentacyclo [15.5.2.13,7.010,14.020,24] pentacosa-1 (23), 3(25), 4, 6,18, 20(24), 21 -heptaen-16- one
  • Example 1122 : (11 R)-4-methoxy-ll -methyl- 18-(methylamino)-9-thia-2,12,l 4,16,20- pentazatetracyclo[12.5.2.1 3 ' 7 .0 17 ’ 21 ]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one
  • Step 1 Synthesis of [(2R)-2-(tert-butoxycarbonylamino)propyl] 4- methylbenzenesulfonate
  • Step 2 Synthesis of S-[(2R)-2-(tert-butoxycarbonylamino)propyl] ethanethioate
  • Step 3 Synthesis of tert-butyl N-[(lR)-l-methyl-2-sulfanyl-ethyl]carbamate
  • Step 4 Synthesis of tert-butyl N-[(lR)-2-[(4-methoxy-3-nitro-phenyl)methylsulfanyl]-l-methyl- ethyl]carbamate
  • Step 6 Synthesis of 5-chloro-N-[(lR)-2-[(4-methoxy-3-nitro-phenyl)methylsulfanyl]-l-methyl- ethyl]-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxamide
  • TEA 0.690 mL, 4.95 mmol
  • phenyl carbonochloridate 310 mg, 1.98 mmol
  • Step 7 Synthesis of N-[(lR)-2-[(3-amino-4-methoxy-phenyl)methylsulfanyl]-l-methyl-ethyl]-5- chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxamide
  • Step 8 Synthesis of (llR)-4-methoxy-18-[(4-methoxyphenyl)methyl-methyl-amino]-ll-methyl-9- thia-2,12,14,16,20-pentazatetracyclo[12.5.2.13,7.017,21]docosa-l(19),3,5,7(22),15,17,20-heptaen- 13-one
  • reaction mixture was cooled to room temperature and quenched by H 2 O (20 mL) and extracted with DCM (50 mL ' 3). The combined organic layers were washed with brine (50 mL), dried over Na 2 SO4, filtered and concentrated under reduced pressure.
  • Step 9 Synthesis of (llR)-4-methoxy-ll-methyl-18-(methylamino)-9-thia-2,12,14,16,20- pentazatetracyclo[12.5.2.13,7.017,21]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one
  • reaction mixture was quenched with a saturated NaHCCh aqueous solution (20 mL) and extracted with DCM (50 mL ' 3). The combined organic layers were washed with brine (50 mL). dried over Na 2 SO4, filtered, and concentrated under reduced pressure.
  • Example 1133 (10R,14R)-5-(5-fluoropyrimidin-2-yl)-21-(methylamino)-9-oxa-2,15,17,19,23- pentazapentacyclo[15.5.2.1 3 ’ 7 .0 1014 .0 20 ' 24 ]pentacosa-l(23),3(25),4,6,18,20(24),21-heptaen-16-one
  • Step 4 Synthesis of tert-butyl N-[(lR,2R)-2-[[3-(5-fhioropyrimidin-2-yl)-5- nitrophenyl] methoxy] cyclopentyl] carbamate
  • Step 5 Synthesis of (lR,2R)-2-[[3-(5-fluoropyrimidin-2-yl)-5-nitro- phenyl]methoxy]cyclopentanamine tert-Butyl N-[(lR,2R)-2-[[3-(5-fhioropyrimidin-2-yl)-5-nitro-phenyl]methoxy]cyclopentyl] carbamate (430 mg, 0.994 mmol) was dissolved in a solution of HC1 in dioxane (2M, 15 mL). The resulting mixture was stirred at 20 °C for 1 h under N 2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove solvent.
  • Step 6 Synthesis ooff 5-chloro-N-[(lR,2R)-2-[[3-(5-fluoropyrimidin-2-yl)-5-nitro- phenyl] methoxy] cyclopentyl] - 7- [ (4-methoxyphenyl)met hyl- methyl- amino] imidazo [ 4,5- b] py ridine-3-carboxamide
  • Step 7 Synthesis of N-[(lR,2R)-2-[[3-amino-5-(5-fluoropyrimidin-2- yl)phenyl] methoxy]cyclopentyl] -5-chloro-7- [(4-methoxyphenyl)methyl-methyl- amino]imidazo[4,5-b]pyridine-3-carboxamide
  • Step 8 Synthesis of (10R,14R)-5-(5-fluoropyrimidin-2-yl)-21-[(4-inethoxyphenyl)niethyl-methyl- amino
  • Step 9 Synthesis of (10R,14R)-5-(5-fluoropyrimidin-2-yl)-21-(methylamino)-9-oxa-2,15,17,19,23- pentazapentacyclo[15.5.2.13, 7.010,14.020, 24]pentacosa-l(23), 3(25), 4, 6, 18, 20(24), 21-heptaen-16- one
  • Step 1 Synthesis of tert-butyl N-[(lR,2R)-2-[[7-bromo-3-(trideuteriomethyl)benzotriazol-5- yl]methoxy]cyclobutyl]carbamate
  • Step 2 Synthesis of tert-butyl N-[6-[[(lR,2R)-2-(tert-butoxycarbonylamino)cyclobutoxy]methyl]- l-(trideuteriomethyl)benzotriazol-4-yl] carbamate
  • Step 3 Synthesis of 6-[[(lR,2R)-2-aminocyclobutoxy]methyl]-l-(trideuteriomethyl)benzotriazol- 4- amine tert-Butyl N-[6-[[(lR,2R)-2-(tert-butoxycarbonylamino)cyclobutoxy]methyl]-l-
  • Step 4 Synthesis ooff N-[(lR,2R)-2-[[7-amino-3-(trideuteriomethyl)benzotriazol-5- yl]methoxy]cyclobutyl]-5-chloro-7-[(4-methoxyphenyl)inethyl-methyl-amino]imidazo[4,5- b] py ridine-3-carboxamide
  • Step 6 Synthesis of (13R,16R)-23-(methylamino)-7-(trideuteriomethyl)-12-oxa- 2, 5, 6, 7,17,19,21 ,25-octazahexacyclo[l 7.5.2.13,10.04,8.013,16.022, 26]heptacosa- 1(25), 3,: 5,8, 10(27), 20, 22(26), 23-octaen-18-one
  • Example 1155 : (llR)-ll-cyclopropyl-4-methoxy-18-(methylamino)-9-oxa-2,12,14,16,20- pentazatetracyclo[12.5.2.1 3 ' 7 .0 17 ’ 21 ]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one
  • Step 11 Synthesis of tert-butyl N-[(lR)-l-cyclopropyl-2-[(4-methoxy-3-nitro- phenyl)methoxy] ethyl] carbamate
  • Step 2 Synthesis of (1R)-1 -cyclopropyl- 2- [(4-methoxy-3-nitro-phenyl)methoxy] ethanamine tert- Butyl N-[(lR)-l-cyclopropyl-2-[(4-methoxy-3-nitro-phenyl)methoxy]ethyl]carbamate (1.00 g, 2.73 mmol) was dissolved in a solution of HC1 in dioxane (10 mL, 2M) and stirred at 20°C for 2 h. The reaction mixture was adjusted to pH - 8 with a saturated Na 2 COs aqueous solution, and then extracted with DCM (100 mL ' 5).
  • Step 3 Synthesis ooff 5-chloro-N-[(lR)-l-cyclopropyl-2-[(4-methoxy-3-nitro- phenyl)methoxy]ethyl]-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3- carboxamide
  • Step 5 Synthesis of N-[(lR)-2-[(3-amino-4-methoxy-phenyl)methoxy]-l-cyclopropyl-ethyl]-5- chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxamide
  • Step 6 Synthesis of (llR)-ll-cycIopropyI-4-methoxy-18-[(4-methoxyphenyl)methyI-methyI- amino]-9-oxa-2,12,14,16,20-pentazatetracyclo[12.5.2.1 3 ' 7 .0 17 ’ 21 ]docosa-l(19),3,5,7(22),15,17,20- heptaen-13-one
  • reaction mixture was quenched by H 2 O (20 mL) and extracted with DCM (50mL ' 3). The combined organic layers were washed with brine (50mL), dried over anhydrous Na2SO4. filtered, and concentrated under reduced pressure.
  • Step 7 Synthesis of (HR)-ll-cyclopropyl-4-methoxy-18-(methylamino)-9-oxa-2,12,14,16,20- pentazatetracyclo[12.5.2.1 3 ’ 7 .0 17 ’ 21 ]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one
  • the reaction mixture was filtered and concentrated under reduced pressure to give a residue.
  • Step 2 Synthesis of (E,S)-A'-
  • Step 3 Synthesis of (S)-IV-[(lR)-4-(4-methoxyphenyl)-l-methyl-butyl]-2-methyl-propane-2- sulfinamide
  • Step 7 Synthesis of tert-butyl 7V-[2-methoxy-5-[(4R)-4-(tert- butoxycarbonylamino)pentyl]phenyl]carbamate
  • Step 9 Synthesis of 5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]-/V-[(lR)-4-(3-amino-4- methoxy-phenyl)-! -methyl-butyl] imidazo [4, 5-b]pyridine-3-carboxamide
  • Step 10 Synthesis of (llR)-4-methoxy-18-[(4-methoxyphenyl)methyl-methyl-amino]-ll-methyl- 2,12,14,16,20-pentazatetracyclo[12.5.2.1 3 ’ 7 .0 17 ’ 21 ]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one
  • Step 11 Synthesis of (HR)-4-methoxy-ll-methyl-18-(methylamino)-2,12,14,16,20- pentazatetracyclo[12.5.2.1 3 ’ 7 .0 17 ’ 21 ]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one
  • Example 1177 (10R,14R)-6-fluoro-4-methoxy-21 -(methylamino)-9-oxa-2,l 5,17,19,23- pentazapentacyclo[15.5.2.1 3 ’ 7 .0 1014 .0 20 ’ 24 ]pcntacosa-l(23),3(25),4,6,18,20(24),21-hcptacn-16-one
  • Step 2 Synthesis of l-(bromomethyl)-2-fluoro-4-methoxy- 5- nitro-benzene
  • Step 3 Synthesis of tert-butyl 2V-[(lR,2R)-2-[(2-fluoro-4-niethoxy-5-nitro- phenyl) methoxy] cyclopentyl] carbamate
  • Step 4 Synthesis of (lR,2R)-2-[(2-fluoro-4-methoxy-5-nitro-phenyl)methoxy]cyclopentanamine tert-Butyl A r -[(lR,2R)-2-[(2-fluoro-4-methoxy-5-nitro-phenyl)methoxy]cyclopentyl]carbamate (420 mg. 1.09 mmol) was dissolved in a solution of HC1 in dioxane (2M, 10 mL) and the resulting mixture was stirred at 20 °C for 1 hr. The reaction mixture was concentrated under reduced pressure to remove solvent.
  • Step 5 Synthesis of 5-chloro-/V-[(lR,2R)-2-[(2-fluoro-4-methoxy-5-nitro- phenyl)methoxy]cyclopentyI]-7-[(4-methoxyphenyl)methyLmethyI-amino]imidazo[4,5- b] py ridine-3-carboxamide
  • Step 6 Synthesis of N- [(lR,2R)-2- [(5- amino- 2-fluoro-4-methoxy-phenyl)methoxy] cyclopentyl] -5- chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]imidazo[4,5-b]pyridine-3-carboxamide
  • Step 7 Synthesis of (10R,14R)-6-fluoro-4-methoxy-21-[(4-methoxyphenyl)methyl-methyl- amino]-9-oxa-2,15,17,19,23-pentazapentacyclo[15.5.2.1 3 ' 7 .0 10 14 .0 20 ' 24 ]pentacosa-
  • Step 8 Synthesis of (10R,14R)-6-fluoro-4-methoxy-21-(methylamino)-9-oxa-2,15,17,19,23- pentazapentacyclo[15.5.2.1 3 ’ 7 .0 10 14 .0 20 ’ 24 ]pentacosa-l(23),3(25),4,6,18,20(24),21-heptaen-16-one
  • LCMS (ESI) m/z 427.3 [M+H] + ; *H NMR (400 MHz, DMSO-Je) ⁇ 5 ppm 9.62 (d, J 3.4 Hz.
  • Example 1188 (10R,l 4R)-5-tluoro-4-methoxy-21 -(methylamino)-9-oxa-2,l 5,17,19,23- pentazapentacyclo[15.5.2.1 3 ’ 7 .0 1014 .0 20 ’ 24 ]pentacosa-l(23),3(25),4,6,18,20(24),21-heptaen-16-one
  • Step 2 Synthesis ooff tert-butyl N-[(lR,2R)-2-[(3-fhioro-4-methoxy-5-nitro- phenyl) methoxy] cyclopentyl] carbamate Boc HN
  • Step 3 Synthesis of (lR,2R)-2-[(3-fluoro-4-methoxy-5-nitro-phenyl)methoxy]cyclopentanamine tert-Butyl N-[(lR,2R)-2-[(3-fluoro-4-methoxy-5-nitro-phenyl)methoxy]cyclopentyl]carbamate (900 mg. 2.34 mmol) was dissolved in a solution of HC1 in dioxane (10 mL) and the reaction mixture was stirred at 20 °C for 1 h. The resulting mixture was quenched by addition of a saturated NaHCO;, aqueous solution (20 mL) and extracted with EtOAc (50 mL ' 3).
  • Step 4 Synthesis of 5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]-N-[(lR,2R)-2-[(3- fluoro-4-methoxy-5-nitro-phenyl)methoxy]cydopentyl]imidazo[4,5-b]pyridine-3-carboxamide
  • Step 5 Synthesis of 5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]-N-[(lR,2R)-2-[(3- amino-5-fluoro-4-methoxy-phenyl)methoxy]cyclopentyl]imidazo[4,5-b]pyridine-3-carboxamide
  • Step 6 Synthesis of (10R,14R)-5-fluoro-4-methoxy-21-[(4-methoxyphenyl)methyI-methyI- amino]-9-oxa-2,15,17,19,23-pentazapentacyclo[15.5.2.1 3 ’ 7 .0 1014 .0 20 ’ 24 ]pentacosa-
  • Step 7 Synthesis of (10R,14R)-5-fluoro-4-methoxy-21-(methylamino)-9-oxa-2,15,17,19,23- pentazapentacyclo[15.5.2.1 3 ’ 7 .0 1014 .0 20 ’ 24 ]pentacosa-l(23),3(25),4,6,18,20(24),21-heptaen-16-one
  • Example 19 19-deuterio-4-methoxy-ll-methyl-18-(methylamino)-9-oxa-2,12,14,16,20- pentazatetracyclo[12.5.2.13,7.017,21]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one
  • Step 1 Synthesis of 19-bromo-4-methoxy-ll-methyl-18-(methylamino)-9-oxa-2,12,14,16,20- pentazatetracyclo[12.5.2.13,7.017,21]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one
  • reaction mixture was diluted with water (30 mL) and extracted with EtOAc (50 mL ' 3). The combined organic phase was washed with brine (30 mL ' 3), dried over anhydrous Na2SO 4 , fdtcrcd and concentrated under reduced pressure.
  • Step 2 Synthesis of 19-deuterio-4-methoxy-ll-methyl-18-(methylamino)-9-oxa-2,12,14,16,20- pentazatetracyclo[12.5.2.13,7.017,21]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one 19-Bromo-4-methoxy- 11 -methyl- 18-(methylamino)-9-oxa-2, 12,14,16,20- pentazatetracyclo[12.5.2.13,7.017,21]docosa-l(19),3,5,7(22),15,17,20-heptaen-13-one (12 mg, 0.026 mmol), Pd 2 (dba) 2 (5 mg, 0.005 mmol), SPhos (7 mg, 0.017 mmol) and K 2 CO 2 (8 mg, 0.058 mmol) were taken up into a microwave tube in 2-propanol-D8 (3 mL).
  • Example 20 (6 1 R,6 2 R)-3 6 -methoxy-17-(methylamino)-13H-5-oxa-2,7-diaza-l(5,3)-imidazo[4,5- b]pyridina-3(l,3)-benzena-6(l,2)-cyclobutanacyclooctaphan-8-one
  • Step 2 Synthesis of tert-butyl ((lR,2R)-2-((4-methoxy-3-nitrobenzyl)oxy)cyclobutyl)carbamate
  • Step 3 Synthesis of (lR,2R)-2-((4-methoxy-3-nitrobenzyl)oxy)cyclobutan-l-amine tert-Butyl N-[(lR,2R)-2-[(4-methoxy-3-nitro-phenyl)methoxy]cyclobutyl]carbamate (400 mg, 1.14 mmol) was dissolved in a solution of HC1 in dioxane (2N, 10 mL) and the reaction mixture was stirred at 20 °C for 12 h under N 2 atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give a residue.
  • Step 4 Synthesis of 5-chloro-N-((lR,2R)-2-((4-methoxy-3-nitrobenzyI)oxy)cyclobutyl)-7-((4- methoxybenzyl)(methyl)amino)-3H-imidazo[4,5-b]pyridine-3-carboxamide
  • reaction mixture was quenched with H 2 O (50 mL) at 25 °C, extracted with EtOAc (50 mL ' 3). The combined organic layers were washed with brine (50 mL ' 3), dried overNa2SO4, filtered and concentrated under reduced pressure to give a residue.
  • the residue was purified by flash chromatography (ISCO®; 20 g SepaFlash® 1 Silica Flash Column, petroleum ether/EtOAc with EtOAc from 0 ⁇ 40%, flow rate: 65 mL/min, 254 nm).
  • Step 5 Synthesis of N-((lR,2R)-2-((3-amino-4-methoxybenzyl)oxy)cyclobutyl)-5-chloro-7-((4- methoxybenzyl)(methyl)amino)-3H-imidazo[4,5-b]pyridine-3-carboxamide
  • reaction mixture was quenched with H 2 O (50 mL) at 25 °C, extracted with EtOAc (50 mL ' 3). The combined organic layers were washed with brine (50 mL ' 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue.
  • the residue was purified by flash chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, petroleum ether/EtOAc with EtOAc from 0 ⁇ 40%, flow rate: 65 mL/min, 254 nm).
  • Step 6 Synthesis of (61R,62R)-36-methoxy-17-((4-methoxybenzyl)(methyl)amino)-13H-5-oxa- 2,7-diaza-l(5,3)-imidazo[4,5-b]pyridina-3(l,3)-benzena-6(l,2)-cyclobutanacyclooctaphan-8-one
  • EPlios Pd G4 (46.0 mg, 50.1 pmol) and K3PO4 (175 mg, 0.824 mmol) in dioxane (10 mL) was degassed and purged with N 2 for 3 times, and then the mixture was stirred at 100 °C until complete by LCMS ( ⁇ 2 h) under N 2 atmosphere.
  • the reaction mixture was quenched by addition of H 2 O (50 mL) at 25 °C. extracted with EtOAc (50 mL ' 3). The combined organic layers were washed with brine (50 mL ' 3), dried over Na 2 SC>4, filtered and concentrated under reduced pressure to give a residue.
  • Step 7 Synthesis of (61R, 62R)-36-methoxy-17-(methylamino)-13H-5-oxa-2,7-diaza-l(5,3)- imidazo[4,5-b]pyridina-3(l,3)-benzena-6(l,2)-cyclobutanacycIooctaphan-8-one
  • Example 21 (10R,l 4R)-4-methoxy-21 -(methylamino)-9-oxa-2,l 5,17,19,23- pentazapentacyclo [15.5.2.13, 7.010,14.020, 24]pentacosa-l(23), 3, 5, 7(25), 18, 20(24), 21-heptaen-16- one
  • Step 11 Synthesis of tert-butyl N- [(lR,2R)-2- [(4-methoxy-3-nitro- phenyl) methoxy] cyclopentyl] carbamate
  • Step 3 Synthesis of 5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]-N-[(lR,2R)-2-[(4- methoxy-3-nitro-phenyl)methoxy]cyclopentyl]imidazo[4,5-b]pyridine-3-carboxamide
  • Step 4 Synthesis of 5-chloro-7-[(4-methoxyphenyl)methyl-methyl-amino]-N-[(lR,2R)-2-[(3- amino-4-methoxy-phenyl)methoxy]cyclopentyl]imidazo[4,5-b]pyridine-3-carboxamide
  • Step 5 Synthesis of (10R,14R)-4-methoxy-21-[(4-methoxyphenyl)methyl-methyl-amino]-9-oxa- 2, 15, 17, 19,23- pentazapentacyclo[15.5.2.13, 7.010, 14.020, 24]pentacosa-
  • Step 8 Synthesis of (10R,14R)-4-methoxy-21-(methylamino)-9-oxa-2,15,17,19,23- pentazapentacyclo[15.5.2.13, 7.010,14.020, 24]pentacosa-l(23), 3, 5, 7(25), 18, 20(24), 21-heptaen-16- one
  • Gilson 322 Pump, Gilson 156 UV Detector; Column: Phenomenex Gemini-C18 ' 75 ' 40 mm ' 3 um; Mobile phase A: [water(NH4HCO3)-ACN];Mobile phase B: MeCN; Gradient: B from 50% to 80% in 8 min, hold 100% B for 2 min; Flow Rate: 25 mL/min; Column Temperature: 30 °C; Wavelength: 220 nm) to afford (10R,14R)-4-methoxy-21-(methylamino)-9-oxa-2,15,17,19,23- pentazapentacyclo[15.5.2.13,7.010,14.020,24]pentacosa-l (23),3,5,7(25),18.20(24),21 -heptaen-16-one (28.3 mg, 28.2% yield) as a white solid.
  • Example 22 (10R,l 5R)-4-methoxy-22-(methylamino)-9-oxa-2,l 6,18,20,24- pentazapentacyclo[16.5.2.1 37 .0 1015 .0 212S ]hexacosa-l(24),3,5,7(26),19,21(25),22-heptaen-17-one
  • Step 11 Synthesis of tert-butyl N-[(lR,2R)-2-[(4-methoxy-3-nitro- phenyl)methoxy] cyclohexyl] carbamate
  • Step 3 Synthesis of 5-chloro-N-[(lR,2R)-2-[(4-methoxy-3-nitro-phenyI)methoxy]cyclohexyl]-7- [(4-methoxyphenyl)methyI-methyI-amino]imidazo[4,5-b]pyridine-3-carboxamide
  • Step 5 Synthesis of N-[(lR,2R)-2-[(3-amino-4-methoxy-phenyl)methoxy]cyclohexyl]-5-chloro-7-
  • Step 6 Synthesis of (10R,15R)-4-methoxy-22-[(4-methoxyphenyl)methyl-methyl-amino]-9-oxa- 2,16,18, 20, 24-pentazapentacyclo[16.5.2.1 3 ’ 7 .0 1015 .0 2125 ]hexacosa-l(24),3, 5,' 7(26), 19, 21(25), 22- heptaen-17-one
  • reaction mixture was cooled to room temperature and diluted with H 2 O (50 mL) and extracted with EtOAc (100 mL ' 3). The combined organic layers were washed with brine (100 mL), dried over anhydrous Na 2 SO i. filtered and concentrated under reduced pressure.
  • Step 7 Synthesis ooff (10R,15R)-4-methoxy-22-(methylamino)-9-oxa-2,16,18,20,24- pentazapentacyclo[16.5.2.1 3 ’ 7 .0 1015 .0 21 ' 2S ]hexacosa-l(24),3,5,7(26),19,21(25),22-heptaen-17-one
  • the reaction mixture was filtered and concentrated under reduced pressure.
  • the residue was purified by flash chromatography (Biotage®, Column; SepaFlash®Sphercial Cis, 40 g, 40-60 pm.

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Abstract

L'invention concerne des composés qui modulent l'activité de matrice de protéines kinases qui sont associées à des maladies, des troubles et des états humains. En particulier, les composés de l'invention inhibent TYK2, un élément de la famille Janus Kinase (JAK) de protéines kinases non réceptrices.
PCT/US2025/019990 2024-03-15 2025-03-14 Modulateurs de kinase et leurs procédés d'utilisation Pending WO2025194074A1 (fr)

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