US20190292188A1 - Imidazopyrimidines and triazolopyrimidines as a2a / a2b inhibitors - Google Patents

Imidazopyrimidines and triazolopyrimidines as a2a / a2b inhibitors Download PDF

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US20190292188A1
US20190292188A1 US16/285,787 US201916285787A US2019292188A1 US 20190292188 A1 US20190292188 A1 US 20190292188A1 US 201916285787 A US201916285787 A US 201916285787A US 2019292188 A1 US2019292188 A1 US 2019292188A1
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alkyl
aryl
cycloalkyl
membered heterocycloalkyl
membered heteroaryl
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Xiaozhao Wang
Pei Gan
Heeoon Han
Taisheng Huang
Matthew S. McCammant
Chao Qi
Ding-Quan Qian
Liangxing Wu
Wenqing Yao
Zhiyong Yu
Fenglei Zhang
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Incyte Corp
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Incyte Corp
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Assigned to INCYTE CORPORATION reassignment INCYTE CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: QI, Chao, YU, ZHIYONG, GAN, PEI, HAN, Heeoon, HUANG, TAISHENG, MCCAMMANT, Matthew S., QIAN, DING-QUAN, WANG, XIAOZHAO, WU, LIANGXING, YAO, WENQING, ZHANG, FENGLEI
Publication of US20190292188A1 publication Critical patent/US20190292188A1/en
Assigned to INCYTE CORPORATION reassignment INCYTE CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HE, CHUNHONG, ZHAO, Le
Priority to US17/077,713 priority patent/US11673894B2/en
Priority to US18/300,349 priority patent/US20230357255A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring
    • 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

Definitions

  • each R f4 and R g4 is independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14 aryl-C 1-6 alkyl-, C 3-14 cycloalkyl-C 1-6 alkyl-, (5-14 membered heteroaryl)-C 1-6 alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6 alkyl-;
  • each R f2 , R g2 , R f3 , and R g3 is independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14 aryl-C 1-6 alkyl-, C 3-14 cycloalkyl-C 1-6 alkyl-, (5-14 membered heteroaryl)-C 1-6 alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6 alkyl-;
  • each R a6 , R c6 , and R d6 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14 aryl-C 1-6 alkyl-, C 3-14 cycloalkyl-C 1-6 alkyl-, (5-14 membered heteroaryl)-C 1-6 alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14 aryl-C 1-6 alkyl-, C 3-14 cycl
  • each R j6 and R k6 is independently selected from OH, C 1-6 alkoxy, and C 1-6 haloalkoxy;
  • each R b7 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14 aryl-C 1-6 alkyl-, C 3-14 cycloalkyl-C 1-6 alkyl-, (5-14 membered heteroaryl)-C 1-6 alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14 aryl-C 1-6 alkyl-, C 3-14 cycloalkyl-C 1-6 alkyl-,
  • each R j7 and R k7 is independently selected from OH, C 1-6 alkoxy, and C 1-6 haloalkoxy;
  • Cy 1 is C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, or 4-14 membered heterocycloalkyl, wherein the C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, or 4-14 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R E substituents;
  • each R f2 , R g2 , R f3 , and R g3 is independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14 aryl-C 1-6 alkyl-, C 3-14 cycloalkyl-C 1-6 alkyl-, (5-14 membered heteroaryl)-C 1-6 alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6 alkyl-;
  • each R j2 , R k2 , R j3 , and R k3 is independently selected from OH, C 1-6 alkoxy, and C 1-6 haloalkoxy;
  • R j2 and R k2 attached to the same B atom, together with the B atom to which they are attached, form a 5- or 6-membered heterocycloalkyl group optionally substituted with 1, 2, 3, or 4 substituents independently selected from C 1-6 alkyl and C 1-6 haloalkyl;
  • each R B , R C , R D , R E , R F , and R G is independently selected from D, halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14 aryl-C 1-6 alkyl-, C 3-14 cycloalkyl-C 1-6 alkyl-, (5-14 membered heteroaryl)-C 1-6 alkyl-, (4-14 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2 , OR a4 , SR a4 , NHOR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)NR c4 (OR a4 ), C(O)
  • each R e4 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14 aryl-C 1-6 alkyl-, C 3-14 cycloalkyl-C 1-6 alkyl-, (5-14 membered heteroaryl)-C 1-6 alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6 alkyl-;
  • each R j4 and R k4 is independently selected from OH, C 1-6 alkoxy, and C 1-6 haloalkoxy;
  • each R H is independently selected from D, halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14 aryl-C 1-6 alkyl-, C 3-14 cycloalkyl-C 1-6 alkyl-, (5-14 membered heteroaryl)-C 1-6 alkyl-, (4-14 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2 , OR a5 , SR a5 , NHOR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)NR c5 (OR a5 ), C(O)OR a5 , OC(O)R b5 , OC(O
  • R c7 and R d7 attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl or a 4-14 membered heterocycloalkyl group, wherein the 5- or 6-membered heteroaryl or 4-14 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, or 4 independently selected R K substituents;
  • each R h2 , R i2 , R h3 , and R i3 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14 aryl-C 1-6 alkyl-, C 3-14 cycloalkyl-C 1-6 alkyl-, (5-14 membered heteroaryl)-C 1-6 alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6 alkyl-;
  • each R b4 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14 aryl-C 1-6 alkyl-, C 3-14 cycloalkyl-C 1-6 alkyl-, (5-14 membered heteroaryl)-C 1-6 alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14 aryl-C 1-6 alkyl-, C 3-14 cycloalkyl-C 1-6 alkyl-,
  • each R H is independently selected from D, halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14 aryl-C 1-6 alkyl-, C 3-14 cycloalkyl-C 1-6 alkyl-, (5-14 membered heteroaryl)-C 1-6 alkyl-, (4-14 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2 , OR a5 , SR a5 , NHOR a5 , C(O)R b5 , C(O)NR c5 R d5 , C(O)NR c5 (OR a5 ), C(O)OR a5 , OC(O)R b5 , OC(O
  • each R a5 , R c5 , and R d5 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14 aryl-C 1-6 alkyl-, C 3-14 cycloalkyl-C 1-6 alkyl-, (5-14 membered heteroaryl)-C 1-6 alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14 aryl-C 1-6 alkyl-, C 3-14 cycl
  • each R I is independently selected from D, halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14 aryl-C 1-6 alkyl-, C 3-14 cycloalkyl-C 1-6 alkyl-, (5-14 membered heteroaryl)-C 1-6 alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2 , OR a6 , SR a6 , NHOR a6 , C(O)R b6 , C(O)NR c6 R d6 , C(O)NR c6 (OR a6 ), C(O)OR a6 , OC(O)R b6 , OC(
  • X is N
  • each R b6 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14 aryl-C 1-6 alkyl-, C 3-14 cycloalkyl-C 1-6 alkyl-, (5-14 membered heteroaryl)-C 1-6 alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14 aryl-C 1-6 alkyl-, C 3-14 cycloalkyl-C 1-6 alkyl-,
  • X is N
  • R c6 and R d6 attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl or a 4-14 membered heterocycloalkyl group, wherein the 5- or 6-membered heteroaryl or 4-14 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, or 4 independently selected R J substituents;
  • each R J is independently selected from D, halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14 aryl-C 1-6 alkyl-, C 3-14 cycloalkyl-C 1-6 alkyl-, (5-14 membered heteroaryl)-C 1-6 alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6 alkyl-, CN, NO 2 , OR a7 , SR a7 , NHOR a7 , C(O)R b7 , C(O)NR c7 R d7 , C(O)NR c7 (OR a7 ), C(O)OR a7 , OC(O)R b7 , OC(
  • each R b6 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14 aryl-C 1-6 alkyl-, C 3-14 cycloalkyl-C 1-6 alkyl-, (5-14 membered heteroaryl)-C 1-6 alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6 alkyl-.
  • each R H is independently selected from D, halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, CN, C 1-6 alkoxy, C 1-6 haloalkoxy, amino, C 1-6 alkylamino, di-C 1-6 alkylamino, C 1-6 alkylsulfonyl, aminosulfonyl, C 1-6 alkylaminosulfonyl, di-C 1-6 alkylaminosulfonyl, and C 1-6 alkylsulfonylamino; wherein said C 1-6 alkyl is optionally substituted by 1, 2, 3, 4, 5, 6, 7, or 8 independently selected halogens.
  • each R e5 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy;
  • each R h5 and R i5 is independently selected from H, C 1-6 haloalkyl, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, phenyl, C 3-7 cycloalkyl, 5-6 membered heteroaryl, 4-7 membered heterocycloalkyl, phenyl-C 1-6 alkyl-, C 3-7 cycloalkyl-C 1-6 alkyl-, (5-6 membered heteroaryl)-C 1-6 alkyl-, and (4-7 membered heterocycloalkyl)-C 1-6 alkyl-;
  • Cy 1 is not pyridin-4-yl optionally substituted with 1, 2, 3, or 4 independently selected R E substituents;
  • R c2 and R d2 attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl or a 4-14 membered heterocycloalkyl group, wherein the 5- or 6-membered heteroaryl or 4-14 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, or 4 independently selected R G substituents;
  • each R b1 and R b2 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14 aryl-C 1-6 alkyl-, C 3-14 cycloalkyl-C 1-6 alkyl-, (5-14 membered heteroaryl)-C 1-6 alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14 aryl-C 1-6 alkyl-, C 3-14 cycloalkyl-C 1-6
  • each R f4 and R g4 is independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14 aryl-C 1-6 alkyl-, C 3-14 cycloalkyl-C 1-6 alkyl-, (5-14 membered heteroaryl)-C 1-6 alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6 alkyl-;
  • each R h4 and R i4 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14 aryl-C 1-6 alkyl-, C 3-14 cycloalkyl-C 1-6 alkyl-, (5-14 membered heteroaryl)-C 1-6 alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6 alkyl-;
  • each R e5 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14 aryl-C 1-6 alkyl-, C 3-14 cycloalkyl-C 1-6 alkyl-, (5-14 membered heteroaryl)-C 1-6 alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6 alkyl-;
  • R c6 and R d6 attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl or a 4-14 membered heterocycloalkyl group, wherein the 5- or 6-membered heteroaryl or 4-14 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, or 4 independently selected R J substituents;
  • each R b7 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14 aryl-C 1-6 alkyl-, C 3-14 cycloalkyl-C 1-6 alkyl-, (5-14 membered heteroaryl)-C 1-6 alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14 aryl-C 1-6 alkyl-, C 3-14 cycloalkyl-C 1-6 alkyl-,
  • R 1 is selected from H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, and C 1-6 haloalkyl;
  • Cy 2 is C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, or 4-14 membered heterocycloalkyl, wherein the C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, or 4-14 membered heterocycloalkyl is optionally substituted with 1, 2, 3, 4, 5, 6, 7, or 8 independently selected R E substituents;
  • each R h4 and R i4 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14 aryl-C 1-6 alkyl-, C 3-14 cycloalkyl-C 1-6 alkyl-, (5-14 membered heteroaryl)-C 1-6 alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6 alkyl-;
  • each R f5 and R g5 is independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14 aryl-C 1-6 alkyl-, C 3-14 cycloalkyl-C 1-6 alkyl-, (5-14 membered heteroaryl)-C 1-6 alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6 alkyl-;
  • R c6 and R d6 attached to the same N atom, together with the N atom to which they are attached, form a 5- or 6-membered heteroaryl or a 4-14 membered heterocycloalkyl group, wherein the 5- or 6-membered heteroaryl or 4-14 membered heterocycloalkyl group is optionally substituted with 1, 2, 3, or 4 independently selected R J substituents;
  • each R j6 and R k6 is independently selected from OH, C 1-6 alkoxy, and C 1-6 haloalkoxy;
  • each R j7 and R k7 is independently selected from OH, C 1-6 alkoxy, and C 1-6 haloalkoxy;
  • each R j2 and R k2 is independently selected from OH, C 1-6 alkoxy, and C 1-6 haloalkoxy;
  • each R f5 and R g5 is independently selected from H, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14 aryl-C 1-6 alkyl-, C 3-14 cycloalkyl-C 1-6 alkyl-, (5-14 membered heteroaryl)-C 1-6 alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6 alkyl-;
  • each R e6 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 2-6 alkenyl, C 2-6 alkynyl, C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14 aryl-C 1-6 alkyl-, C 3-14 cycloalkyl-C 1-6 alkyl-, (5-14 membered heteroaryl)-C 1-6 alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6 alkyl-;
  • C 3-6 cycloalkyl, phenyl, 5-10 membered heteroaryl, and 5-10 membered heterocycloalkyl are each optionally substituted with 1, 2, or 3 substituents selected from C 1-3 alkyl, C 1-3 alkyl-OH, halo, CN, C 1-3 alkoxy, and C(O)NH 2
  • Cy 2 is selected from C 3-6 cycloalkyl, phenyl, 5-10 membered heteroaryl, and 5-10 membered heterocycloalkyl;
  • the optionally substituted Cy 2 is selected from 2,6-dimethylpyridin-4-yl, pyridin-4-yl, 2-methylpyridin-4-yl, 1-carbamoyl-1,2,3,6-tetrahydropyridin-4-yl, 1-carbamoylpiperidin-4-yl, 2-methoxypyridin-4-yl, 2-methoxy-6-methylpyridin-4-yl, 2,6-dimethylpyridin-4-yl-1-oxide, 1-ethyl-6-oxo-1,6-dihydropyridin-3-yl, 3-methylpyridin-4-yl, 3-fluoropyridin-4-yl, 3-chloropyridin-4-yl, 3-methoxypyridin-4-yl, 3-cyanopyridin-4-yl, 4-carbamoylphenyl, pyrazolo[1,5-a]pyridin-3-yl, pyrazolo[1,5-didin
  • the optionally substituted Cy 2 is selected from 2,6-dimethylpyridin-4-yl, pyridin-4-yl, 2-methylpyridin-4-yl, 1-carbamoyl-1,2,3,6-tetrahydropyridin-4-yl, 1-carbamoylpiperidin-4-yl, 2-methoxypyridin-4-yl, 2,6-dimethylpyridin-4-yl-1-oxide, 1-ethyl-6-oxo-1,6-dihydropyridin-3-yl, 3-methylpyridin-4-yl, 3-fluoropyridin-4-yl, 3-chloropyridin-4-yl, 3-methoxypyridin-4-yl, 3-cyanopyridin-4-yl, 4-carbamoylphenyl, pyrazolo[1,5-a]pyridin-3-yl, 5-methyl-1H-pyrazol-4-yl, 1-ethyl-1H-pyra
  • R 1 is selected from H, C 1-6 alkyl, and 5-8 membered heteroaryl, wherein the 5-8 membered heteroaryl is optionally substituted by 1 or 2 independently selected R B substituents.
  • R 1 is H or C 1-6 alkyl.
  • R 1 is H, ethyl, or nicotinonitrile.
  • R 1 is pyridyl which is optionally substituted by cyano.
  • R 1 is 3-cyanopyridyl.
  • R 2 is selected from C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14 aryl-C 1-6 alkyl-, C 3-14 cycloalkyl-C 1-6 alkyl-, (5-14 membered heteroaryl)-C 1-6 alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6 alkyl-, wherein the C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14 aryl-C 1-6 alkyl-, C 3-14 cycloalkyl-C 1-6 alkyl-, (5-14 membered heteroaryl)-C 1-6 alkyl-, and (4-14 membered heterocycloalkyl)-C 1-6 alkyl- are each optionally substituted with 1, 2, 3, 4, or 5 independently selected R C substituents.
  • R 2 is selected from H, C 1-6 alkyl, C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14 aryl-C 1-6 alkyl-, C 3-14 cycloalkyl-C 1-6 alkyl-, (5-14 membered heteroaryl)-C 1-6 alkyl-, (4-14 membered heterocycloalkyl)-C 1-6 alkyl-, OR a2 , NR c2 R d2 , C(O)R b2 , C(O)NR c2 R d2 , and C(O)OR a2 , wherein the C 1-6 alkyl, C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14 aryl-C 1-6 alkyl-, C 3-14 cycloalkyl-C
  • R 2 is selected from H, C 1-6 alkyl, C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14 aryl-C 1-6 alkyl-, C 3-14 cycloalkyl-C 1-6 alkyl-, (5-14 membered heteroaryl)-C 1-6 alkyl-, (4-14 membered heterocycloalkyl)-C 1-6 alkyl-, OR a2 , NR c2 R d2 , C(O)R b2 , C(O)NR c2 R d2 , and C(O)OR a2 , wherein the C 1-6 alkyl, C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, C 6-14 aryl-C 1-6 alkyl-, C 3-14 cycloalkyl-C
  • R 2 is selected from H, C 6-14 aryl, 5-14 membered heteroaryl, C(O)R b2 , C(O)NR c2 R d2 , and C(O)OR a2 , wherein the C 6-14 aryl and 5-14 membered heteroaryl are each optionally substituted with 1, 2, or 3 independently selected R C substituents.
  • the optionally substituted R 2 is selected from pyridinylmethyl, hydroxy(phenyl)methyl, hydroxyethylamino(phenyl)ethyl, cyclohexylmethyl, fluorobenzyl, hydroxy(fluorophenyl)methyl, (methylpyridinyl)methyl, (fluoropyridinyl)methyl, (trifluoromethylpyridinyl)methyl, ((hydroxymethyl)pyridinyl)methyl, (methoxypyridinyl)methyl, (methylpyrazolyl)benzyl, (methylpyrazolyl)methyl, benzoisoxazolylmethyl, (methylindazolyl)methyl, (hydroxyazetidinyl)methyl, benzoyl, phenylcyclopropyl, (cyano(phenyl)methyl)amino, tetrahydrofuranyl, phenyl(pyridinyloxy)methyl, fluoro ((fluorohydroxypyrrol)methyl,
  • R 2 is selected from pyridinylmethyl, hydroxy(phenyl)methyl, hydroxyethylamino(phenyl)ethyl, cyclohexylmethyl, fluorobenzyl, hydroxy(fluorophenyl)methyl, (methylpyridinyl)methyl, (fluoropyridinyl)methyl, (methoxypyridinyl)methyl, (methylpyrazolyl)benzyl, benzoisoxazolylmethyl, (methylindazolyl)methyl, (hydroxyazetidinyl)methyl, benzoyl, phenylcyclopropyl, (cyano(phenyl)methyl)amino, tetrahydrofuranyl, and phenyl(pyridinyloxy)methyl.
  • R 2 is selected from pyridin-2-ylmethyl, hydroxy(phenyl)methyl, (2-hydroxyethylamino)(phenyl)methyl, cyclohexylmethyl, 2-fluorobenzyl, (2-fluorophenyl)(hydroxy)methyl, (6-methylpyridin-2-yl)methyl, (3-fluoropyridin-2-yl)methyl, (3-methoxypyridin-2-yl)methyl, 2-(1-methyl-1H-pyrazol-4-yl)benzyl, benzo[d]isoxazol-3-ylmethyl, (1-methyl-1H-indazol-3-yl)methyl, (3-hydroxyazetidin-1-yl)methyl, benzoyl, 1-phenylcyclopropyl, (cyano(phenyl)methyl)amino, tetrahydrofuran-3-yl, phenyl(pyridin-2-yloxy)methyl, 2-fluoro-6-((((())
  • R c2 and R d2 are each independently selected from H, C 1-6 alkyl, 5-14 membered heteroaryl, and C 6-14 aryl-C 1-6 alkyl-, wherein the C 1-6 alkyl, 5-14 membered heteroaryl, and C 6-14 aryl-C 1-6 alkyl- are each optionally substituted with 1, 2, or 3 independently selected R G substituents.
  • each R c4 and R d4 are independently selected from H and C 1-6 alkyl, wherein the C 1-6 alkyl is optionally substituted by 1, 2, or 3 independently selected R H substituents.
  • each R a5 , and R c5 is selected from H and C 1-6 alkyl.
  • R 3 is selected from H, D, halo, C 1-6 alkyl, C 1-6 haloalkyl, C 6-14 aryl, 5-14 membered heteroaryl, CN, and OR a3 , wherein the C 1-6 alkyl, C 6-14 aryl, and 5-14 membered heteroaryl of R 3 are each optionally substituted with 1, 2, 3, or 4 independently selected R D substituents;
  • Cy 1 is phenyl optionally substituted with 1, 2, 3, or 4 independently selected R M substituents, or C 10-14 aryl or 5-14 membered heteroaryl, wherein the C 10-14 aryl and 5-14 membered heteroaryl of Cy 1 is optionally substituted with 1, 2, 3, or 4 independently selected R E substituents;
  • each R a2 , R c2 , R d2 , and R a3 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, and 4-14 membered heterocycloalkyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, and 4-14 membered heterocycloalkyl of R a2 , R c2 , R d2 , and R a3 are each optionally substituted with 1, 2, 3, or 4 independently selected R G substituents;
  • each R J is independently selected from D, halo, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, CN, NO 2 , OR a7 , SR a7 , NHOR a7 , C(O)R b7 , C(O)NR c7 R d7 , C(O)OR a7 , OC(O)R b7 , OC(O)NR c7 R d7 , NR c7 R d7 , NR c7 C(O)R b7 , NR c7 C(O)OR a7 , NR c7 C(O)NR c7 R d7 , C( ⁇ NR e7 )R b7 , C
  • each R a7 , R c7 , and R d7 is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, and 4-14 membered heterocycloalkyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, and 4-14 membered heterocycloalkyl of R a7 , R c7 , and R d7 are each optionally substituted with 1, 2, 3, or 4 independently selected R K substituents;
  • each R b7 is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, and 4-14 membered heterocycloalkyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, and 4-14 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R K substituents;
  • X is CR 3 ;
  • each R e4 is independently selected from H, OH, CN, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, and C 1-6 haloalkoxy;
  • each R b2 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-7 cycloalkyl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted with 1, 2, 3, or 4 independently selected R G substituents;
  • Cy 2 is C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl or 4-14 membered heterocycloalkyl, wherein the C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl and 4-14 membered heterocycloalkyl of Cy 2 are each optionally substituted with 1, 2, 3, or 4 independently selected R E substituents;
  • each R B , R C , R E , R F , and R G is independently selected from D, halo, oxo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-14 aryl, C 3-14 cycloalkyl, 5-14 membered heteroaryl, 4-14 membered heterocycloalkyl, CN, NO 2 , OR a4 , SR a4 , NHOR a4 , C(O)R b4 , C(O)NR c4 R d4 , C(O)OR a4 , OC(O)R b4 , OC(O)NR c4 R d4 , NR c4 R d4 , NR c4 C(O)R b4 , NR c4 C(O)OR a4 , NR c4 C(O)NR c4 R d4 , C( ⁇ NR e4 )
  • X is N
  • each R E is independently selected from D, halo, oxo, C 1-6 alkyl, C 2-6 alkenyl, CN, NO 2 , and OR a4 , wherein the C 1-6 alkyl and C 2-6 alkenyl of R E are each optionally substituted with 1, 2, or 3 independently selected R H substituents;
  • each R a4 is independently selected from H, C 1-6 alkyl and C 1-6 alkoxy;
  • each R H is independently selected from D, halo, oxo, C 1-6 alkyl, CN, NO 2 and OH.
  • each R E is independently selected from D, halo, oxo, C 1-6 alkyl, C 2-6 alkenyl, CN, NO 2 , and OR a4 , wherein the C 1-6 alkyl and C 2-6 alkenyl of R E are each optionally substituted with 1, 2, or 3 independently selected R H substituents;
  • Cy 1 is cyanophenyl
  • n-membered where n is an integer typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n.
  • piperidinyl is an example of a 6-membered heterocycloalkyl ring
  • pyrazolyl is an example of a 5-membered heteroaryl ring
  • pyridyl is an example of a 6-membered heteroaryl ring
  • 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.
  • C n-m alkynyl refers to an alkyl group having one or more triple carbon-carbon bonds and having n to m carbons.
  • Example alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl, and the like.
  • the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.
  • aryl refers to an aromatic hydrocarbon group, which may be monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings).
  • C n-m aryl refers to an aryl group having from n to m ring carbon atoms.
  • Aryl groups include, e.g., phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and the like.
  • aryl groups have from 5 to 14 carbon atoms.
  • the aryl group has from 5 to 10 carbon atoms.
  • the aryl group is phenyl or naphthyl.
  • the aryl group is phenyl.
  • halo refers to F, Cl, Br, or I. In some embodiments, a halo is F, Cl, or Br. In some embodiments, a halo is F or Cl. In some embodiments, a halo is F. In some embodiments, a halo is Cl.
  • C n-m haloalkyl refers to an alkyl group having from one halogen atom to 2s+1 halogen atoms which may be the same or different, where “s” is the number of carbon atoms in the alkyl group, wherein the alkyl group has n to m carbon atoms.
  • the haloalkyl group is fluorinated only.
  • the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
  • Example haloalkyl groups include CF 3 , C 2 F 5 , CHF 2 , CCl 3 , CHCl 2 , C 2 Cl 5 and the like.
  • the cycloalkyl is a C 3-14 monocyclic or bicyclic cycloalkyl. In some embodiments, the cycloalkyl is a C 3-7 monocyclic cycloalkyl. In some embodiments, the cycloalkyl is a C 4-7 monocyclic cycloalkyl. In some embodiments, the cycloalkyl is a C 4-10 spirocycle or bridged cycloalkyl (e.g., a bridged bicycloalkyl group).
  • heteroaryl refers to a monocyclic or polycyclic (e.g., having 2, 3, or 4 fused rings) aromatic heterocycle having at least one heteroatom ring member selected from N, O, S, and B.
  • the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, S and B.
  • any ring-forming N in a heteroaryl moiety can be an N-oxide.
  • the heteroaryl is a 5-10 membered monocyclic or bicyclic heteroaryl having 1, 2, 3, or 4 heteroatom ring members independently selected from N, O, S, and B.
  • the heteroaryl is a 5-6 monocyclic heteroaryl having 1, 2, or 3 heteroatom ring members independently selected from N, O, S, and B.
  • the heteroaryl is a five-membered or six-membered heteroaryl ring.
  • a five-membered heteroaryl ring is a heteroaryl with a ring having five ring atoms wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, O, S, and B.
  • the heteroaryl group contains 3 to 14, 4 to 14, 3 to 7, or 5 to 6 ring-forming atoms.
  • Example heteroaryl groups include, but are not limited to, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, pyrazole, azolyl, oxazole, isoxazole, thiazole, isothiazole, imidazole, furan, thiophene, triazole, tetrazole, thiadiazole, quinoline, isoquinoline, indole, benzothiophene, benzofuran, benzisoxazole, imidazo[1, 2-b]thiazole, purine, triazine, thieno[3,2-b]pyridine, imidazo[1,2-a]pyridine, 1,5-naphthyridine, 1H-pyrazolo[4,3-b]pyridine, and the like.
  • Heterocycloalkyl groups include monocyclic and polycyclic (e.g., having 2, 3, or 4 fused rings) systems. Included in heterocycloalkyl are monocyclic and polycyclic 3-14-, 4-14-, 3-10-, 4-10-, 5-10-, 4-7-, 5-7-, 5-6-, 5- or 6-membered heterocycloalkyl groups. Heterocycloalkyl groups can also include spirocycles and bridged rings (e.g., a 5-14 membered bridged biheterocycloalkyl ring having one or more ring-forming carbon atoms replaced by a heteroatom independently selected from N, O, S, and B).
  • spirocycles and bridged rings e.g., a 5-14 membered bridged biheterocycloalkyl ring having one or more ring-forming carbon atoms replaced by a heteroatom independently selected from N, O, S, and B).
  • alkyl linking groups or “alkylene groups” include methylene, ethan-1,1-diyl, ethan-1,2-diyl, propan-1,3-dilyl, propan-1,2-diyl, propan-1,1-diyl and the like.
  • resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of ⁇ -methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.
  • the compounds provided herein, or salts thereof are substantially isolated.
  • substantially isolated is meant that the compound is at least partially or substantially separated from the environment in which it was formed or detected.
  • Partial separation can include, for example, a composition enriched in the compounds provided herein.
  • Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compounds provided herein, or salt thereof. Methods for isolating compounds and their salts are routine in the art.
  • the present application also includes pharmaceutically acceptable salts of the compounds described herein.
  • pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by converting an existing acid or base moiety to its salt form.
  • examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the pharmaceutically acceptable salts of the present disclosure include the conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the present disclosure can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods.
  • such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) or acetonitrile (ACN) are preferred.
  • non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) or acetonitrile (ACN) are preferred.
  • non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol, or butanol) or acetonitrile (ACN) are preferred.
  • ACN acetonitrile
  • Compound of formula 10 can be prepared via the synthetic route as outlined in Scheme 1.
  • the commercially available starting material 1 can undergo a halogenation reaction, such as electrophilic aromatic substitution (S E Ar), with an appropriate reagent, such as N-bromosuccinimide (NBS), to afford compound 2 (Hal is a halide, such as F, Cl, Br, or I).
  • Condensation of compound 2 with a carbonyl adduct of formula 3 at elevated temperature can generate the bicyclic compound 4.
  • Selective chloride displacement of compound 4 via either nucleophilic substitution, or a coupling reaction, with compound 5 can deliver compound 6.
  • compound of formula 10 can be prepared via the synthetic route as outlined in Scheme 2.
  • the commercially available starting material 11 can undergo a coupling reaction with an adduct of formula 9, in which M is a boronic acid, a boronic ester or an appropriately substituted metal [e.g., M is B(OR) 2 , Sn(Alkyl) 3 , Zn-Hal, etc.], under standard Suzuki cross-coupling conditions (e.g., in the presence of a palladium catalyst and a suitable base), or standard Stille cross-coupling conditions (e.g., in the presence of a palladium catalyst), or standard Negishi cross-coupling conditions (e.g., in the presence of a palladium catalyst), to give a derivative of formula 12.
  • M is a boronic acid, a boronic ester or an appropriately substituted metal
  • Compound 21 can then be subjected to a halogenation reaction, such as electrophilic aromatic substitution (S E Ar), with an appropriate reagent, such as N-bromosuccinimide (NBS), to afford compound 22 (Hal is a halide, such as F, Cl, Br, or I).
  • a halogenation reaction such as electrophilic aromatic substitution (S E Ar)
  • NBS N-bromosuccinimide
  • Condensation of compound 22 with a carbonyl adduct of formula 3a at elevated temperature can generate the bicyclic compound of formula 23.
  • Oxidation of compound 23 with an appropriate oxidant, such as mCPBA, followed by nucleophilic substitution with a protected amine adduct 24 can deliver compound 25.
  • Compound 10c can also be prepared using the synthetic route as outlined in Scheme 6.
  • Compound 22 (prepared as described in Scheme 5) can first undergo a coupling reaction with an adduct of formula 7, in which M is a boronic acid, a boronic ester or an appropriately substituted metal [e.g., M is B(OR) 2 , Sn(Alkyl) 3 , Zn-Hal, etc.], under standard Suzuki cross-coupling conditions (e.g., in the presence of a palladium catalyst and a suitable base), or standard Stille cross-coupling conditions (e.g., in the presence of a palladium catalyst), or standard Negishi cross-coupling conditions (e.g., in the presence of a palladium catalyst), to give a derivative of formula 27.
  • Condensation of compound 27 with a carbonyl adduct of formula 3a at elevated temperature can generate the bicyclic compound of formula 28.
  • Compound 28 can then react with amine 19 and amine 5, in either
  • Compounds 10d can be prepared using the synthetic route as outlined in Scheme 7. Condensation of commercially available starting material 29 with a carbonyl adduct of formula 3a at elevated temperature can generate the bicyclic compound of formula 30. Compound 30 can then undergo a coupling reaction with an adduct of formula 9, in which M is a boronic acid, a boronic ester or an appropriately substituted metal [e.g., M is B(OR) 2 , Sn(Alkyl) 3 , Zn-Hal, etc.], under standard Suzuki cross-coupling conditions (e.g., in the presence of a palladium catalyst and a suitable base), or standard Stille cross-coupling conditions (e.g., in the presence of a palladium catalyst), or standard Negishi cross-coupling conditions (e.g., in the presence of a palladium catalyst), to give a derivative of formula 31.
  • M is a boronic acid, a boronic ester or an appropriately substituted metal
  • Compound 31 can then be subjected to a halogenation reaction, such as electrophilic aromatic substitution (S E Ar), with an appropriate reagent, such as N-bromosuccinimide (NBS), to afford compound 32 (Hal is a halide, such as F, Cl, Br, or I).
  • a halogenation reaction such as electrophilic aromatic substitution (S E Ar)
  • NSS N-bromosuccinimide
  • Ester hydrolysis of compound 32 in the presence of an appropriate reagent, such as lithium hydroxide (LiOH) can generate the corresponding carboxylic acid, which can then be coupled with an amine adduct of formula 19, using an appropriate coupling reagent (such as HATU, BOP, or PyBOP), to afford compound 33.
  • an appropriate coupling reagent such as HATU, BOP, or PyBOP
  • Cy 2 can then be achieved by the coupling of compound 33 with an adduct of formula 7, using similar conditions as described for the preparation of compound 31 from compound 30, to
  • M is a boronic acid, boronic ester or an appropriately substituted metal [e.g., M is B(OR) 2 , Sn(Alkyl) 3 , or Zn-Hal], under standard Suzuki cross-coupling conditions (e.g., in the presence of a palladium catalyst and a suitable base), or standard Stille cross-coupling conditions (e.g., in the presence of a palladium catalyst), or standard Negishi cross-coupling conditions (e.g., in the presence of a palladium catalyst).
  • M is a boronic acid, boronic ester or an appropriately substituted metal
  • M is B(OR) 2 , Sn(Alkyl) 3 , or Zn-Hal
  • Suzuki cross-coupling conditions e.g., in the presence of a palladium catalyst and a suitable base
  • Stille cross-coupling conditions e.g., in the presence of a palladium catalyst
  • Negishi cross-coupling conditions e.g
  • the compounds or salts described herein can be selective.
  • selective it is meant that the compound binds to or inhibits an adenosine receptor with greater affinity or potency, respectively, compared to at least one other receptor, kinase, etc.
  • the compounds of the present disclosure can also be dual antagonists (i.e., inhibitors) of adenosine receptors, e.g., A2A and A2B adenosine receptors.
  • the disease or disorder is lung cancer (e.g., non-small cell lung cancer), melanoma, pancreatic cancer, breast cancer, head and neck squamous cell carcinoma, prostate cancer, liver cancer, color cancer, endometrial cancer, bladder cancer, skin cancer, cancer of the uterus, renal cancer, gastric cancer, or sarcoma.
  • lung cancer e.g., non-small cell lung cancer
  • melanoma pancreatic cancer
  • breast cancer head and neck squamous cell carcinoma
  • prostate cancer liver cancer
  • color cancer endometrial cancer
  • bladder cancer skin cancer
  • cancer of the uterus cancer of the uterus
  • renal cancer gastric cancer
  • sarcoma sarcoma
  • immune checkpoint inhibitors include inhibitors against immune checkpoint molecules such as CD20, CD28, CD40, CD122, CD96, CD73, CD47, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, HPK1, CD137 (also known as 4-1BB), ICOS, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, TIGIT, PD-1, PD-L1 and PD-L2.
  • the immune checkpoint molecule is a stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS, OX40, GITR and CD137.
  • the anti-PD-1 monoclonal antibody is MGA012. In some embodiments, the anti-PD1 antibody is SHR-1210.
  • Other anti-cancer agent(s) include antibody therapeutics such as 4-1BB (e.g. urelumab, utomilumab.
  • the inhibitor of an immune checkpoint molecule is an agonist of OX40, e.g., OX40 agonist antibody or OX40L fusion protein.
  • OX40 e.g., OX40 agonist antibody or OX40L fusion protein.
  • the anti-OX40 antibody is MEDI0562, MOXR-0916, PF-04518600, GSK3174998, or BMS-986178.
  • the OX40L fusion protein is MEDI6383.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of CD20, e.g., an anti-CD20 antibody.
  • the anti-CD20 antibody is obinutuzumab or rituximab.
  • the compounds of the disclosure can be used in combination with one or more metabolic enzyme inhibitors.
  • the metabolic enzyme inhibitor is an inhibitor of IDO1, TDO, or arginase.
  • IDO1 inhibitors include epacadostat, NLG919, BMS-986205, PF-06840003, IOM2983, RG-70099 and LY338196.
  • the additional compounds, inhibitors, agents, etc. can be combined with the present compound in a single or continuous dosage form, or they can be administered simultaneously or sequentially as separate dosage forms.
  • the compounds of the present disclosure can be used in combination with one or more other enzyme/protein/receptor inhibitors or one or more therapies for the treatment of diseases, such as cancer.
  • diseases and indications treatable with combination therapies include those as described herein.
  • Example antibodies for use in combination therapy include but are not limited to Trastuzumab (e.g. anti-HER2), Ranibizumab (e.g. anti-VEGF-A), Bevacizumab (trade name Avastin, e.g. anti-VEGF, Panitumumab (e.g. anti-EGFR), Cetuximab (e.g. anti-EGFR), Rituxan (anti-CD20) and antibodies directed to c-MET.
  • Trastuzumab e.g. anti-HER2
  • Ranibizumab e.g. anti-VEGF-A
  • Bevacizumab trade name Avastin, e.g. anti-VEGF, Panitumumab (e.g. anti-EGFR), Cetuximab (e.g. anti-EGFR), Rituxan (anti-CD20) and antibodies directed to c-MET.
  • cytostatic agent cisplatin, doxorubicin, taxotere, taxol, etoposide, irinotecan, camptostar, topotecan, paclitaxel, docetaxel, epothilones, tamoxifen, 5-fluorouracil, methoxtrexate, temozolomide, cyclophosphamide, SCH 66336, R115777, L778,123, BMS 214662, IRESSATM, (gefitinib), TARCEVATM, (erlotinib), antibodies to EGFR, GLEEVECTM, intron, ara-C, adriamycin, cytoxan, gemcitabine, uracil mustard, chlormethine, ifosfamide, melphalan, chlorambucil, pipobroman,
  • Example Bcr-Abl inhibitors include imatinib mesylate (GLEEVACTM), nilotinib, dasatinib, bosutinib, and ponatinib, and pharmaceutically acceptable salts.
  • Other example suitable Bcr-Abl inhibitors include the compounds, and pharmaceutically acceptable salts thereof, of the genera and species disclosed in U.S. Pat. No. 5,521,184, WO 04/005281, and U.S. Ser. No. 60/578,491.
  • Example suitable Flt-3 inhibitors include midostaurin, lestaurtinib, linifanib, sunitinib, sunitinib, maleate, sorafenib, quizartinib, crenolanib, pacritinib, tandutinib, PLX3397 and ASP2215, and their pharmaceutically acceptable salts.
  • Other example suitable Flt-3 inhibitors include compounds, and their pharmaceutically acceptable salts, as disclosed in WO 03/037347, WO 03/099771, and WO 04/046120.
  • the agents can be combined with the present compound in a single or continuous dosage form, or the agents can be administered simultaneously or sequentially as separate dosage forms.
  • combinations of the compounds of the disclosure with other therapeutic agents can be administered to a patient prior to, during, and/or after a bone marrow transplant or stem cell transplant.
  • the compounds of the present disclosure can be used in combination with bone marrow transplant for the treatment of a variety of tumors of hematopoietic origin.
  • the compounds of the disclosure can be administered in the form of pharmaceutical compositions.
  • These compositions can be prepared in a manner well known in the pharmaceutical art, and can be administered by a variety of routes, depending upon whether local or systemic treatment is desired and upon the area to be treated. Administration may be topical (including transdermal, epidermal, ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery), pulmonary (e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal), oral, or parenteral.
  • topical including transdermal, epidermal, ophthalmic and to mucous membranes including intranasal, vaginal and rectal delivery
  • pulmonary e.g., by inhalation or insufflation of powders or aerosols, including by nebulizer; intratracheal or intranasal
  • oral or parenteral.
  • compositions of the disclosure contain from about 50 to about 500 mg of the active ingredient.
  • all of the hydrogen atoms in a compound can be replaced or substituted by deuterium atoms.
  • a labeled compound of the disclosure can be used in a screening assay to identify/evaluate compounds.
  • a newly synthesized or identified compound (i.e., test compound) which is labeled can be evaluated for its ability to bind an adenosine receptor by monitoring its concentration variation when contacting with the adenosine receptor, through tracking of the labeling.
  • a test compound (labeled) can be evaluated for its ability to reduce binding of another compound which is known to bind to an adenosine receptor (i.e., standard compound). Accordingly, the ability of a test compound to compete with the standard compound for binding to the adenosine receptor directly correlates to its binding affinity.

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