US20170174671A1 - Heterocyclic compounds as immunomodulators - Google Patents

Heterocyclic compounds as immunomodulators Download PDF

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US20170174671A1
US20170174671A1 US15/381,370 US201615381370A US2017174671A1 US 20170174671 A1 US20170174671 A1 US 20170174671A1 US 201615381370 A US201615381370 A US 201615381370A US 2017174671 A1 US2017174671 A1 US 2017174671A1
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alkyl
ring
cycloalkyl
fused
membered heterocycloalkyl
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Liangxing Wu
Zhiyong Yu
Fenglei Zhang
Wenqing Yao
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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: WU, LIANGXING, YAO, WENQING, YU, ZHIYONG, ZHANG, FENGLEI
Publication of US20170174671A1 publication Critical patent/US20170174671A1/en
Priority to US15/802,850 priority patent/US20180273519A1/en
Priority to US17/125,624 priority patent/US12516044B2/en
Priority to US19/400,272 priority patent/US20260078113A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D241/24—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the present application is concerned with pharmaceutically active compounds.
  • the disclosure provides compounds as well as their compositions and methods of use.
  • the compounds modulate PD-1/PD-L1 protein/protein interaction and are useful in the treatment of various diseases including infectious diseases and cancer.
  • the immune system plays an important role in controlling and eradicating diseases such as cancer.
  • cancer cells often develop strategies to evade or to suppress the immune system in order to favor their growth.
  • One such mechanism is altering the expression of co-stimulatory and co-inhibitory molecules expressed on immune cells (Postow et al, J. Clinical Oncology 2015, 1-9). Blocking the signaling of an inhibitory immune checkpoint, such as PD-1, has proven to be a promising and effective treatment modality.
  • PD-1 Programmed cell death-1
  • CD279 is a cell surface receptor expressed on activated T cells, natural killer T cells, B cells, and macrophages (Greenwald et al, Annu. Rev. Immunol 2005, 23:515-548; Okazaki and Honjo, Trends Immunol 2006, (4): 195-201). It functions as an intrinsic negative feedback system to prevent the activation of T-cells, which in turn reduces autoimmunity and promotes self-tolerance.
  • PD-1 is also known to play a critical role in the suppression of antigen-specific T cell response in diseases like cancer and viral infection (Sharpe et al, Nat Immunol 2007 8, 239-245; Postow et al, J. Clinical Oncol 2015, 1-9).
  • the structure of PD-1 consists of an extracellular immunoglobulin variable-like domain followed by a transmembrane region and an intracellular domain (Parry et al, Mol Cell Biol 2005, 9543-9553).
  • the intracellular domain contains two phosphorylation sites located in an immunoreceptor tyrosine-based inhibitory motif and an immunoreceptor tyrosine-based switch motif, which suggests that PD-1 negatively regulates T cell receptor-mediated signals.
  • PD-1 has two ligands, PD-L1 and PD-L2 (Parry et al, Mol Cell Biol 2005, 9543-9553; Latchman et al, Nat Immunol 2001, 2, 261-268), and they differ in their expression patterns.
  • PD-L1 protein is upregulated on macrophages and dendritic cells in response to lipopolysaccharide and GM-CSF treatment, and on T cells and B cells upon T cell receptor and B cell receptor signaling. PD-L1 is also highly expressed on almost all tumor cells, and the expression is further increased after IFN- ⁇ treatment (Iwai et al, PNAS2002, 99(19):12293-7; Blank et al, Cancer Res 2004, 64(3):1140-5).
  • tumor PD-L1 expression status has been shown to be prognostic in multiple tumor types (Wang et al, Eur J Surg Oncol 2015; Huang et al, Oncol Rep 2015; Sabatier et al, Oncotarget 2015, 6(7): 5449-5464).
  • PD-L2 expression in contrast, is more restricted and is expressed mainly by dendritic cells (Nakae et al, J Immunol 2006, 177:566-73).
  • Ligation of PD-1 with its ligands PD-L1 and PD-L2 on T cells delivers a signal that inhibits IL-2 and IFN- ⁇ production, as well as cell proliferation induced upon T cell receptor activation (Carter et al, Eur J Immunol 2002, 32(3):634-43; Freeman et al, J Exp Med 2000, 192(7): 1027-34).
  • the mechanism involves recruitment of SHP-2 or SHP-1 phosphatases to inhibit T cell receptor signaling such as Syk and Lck phosphorylation (Sharpe et al, Nat Immunol 2007, 8, 239-245).
  • Activation of the PD-1 signaling axis also attenuates PKC- ⁇ activation loop phosphorylation, which is necessary for the activation of NF- ⁇ B and API pathways, and for cytokine production such as IL-2, IFN- ⁇ and TNF (Sharpe et al, Nat Immunol 2007, 8, 239-245; Carter et al, Eur J Immunol 2002, 32(3):634-43; Freeman et al, J Exp Med 2000, 192(7):1027-34).
  • PD-1-deficient mice have been shown to develop lupus-like glomerulonephritis and dilated cardiomyopathy (Nishimura et al, Immunity 1999, 11:141-151; Nishimura et al, Science 2001, 291:319-322).
  • LCMV model of chronic infection it has been shown that PD-1/PD-L1 interaction inhibits activation, expansion and acquisition of effector functions of virus-specific CD8 T cells (Barber et al, Nature 2006, 439, 682-7).
  • the present disclosure further provides, inter alia, a compound of Formula (I):
  • the present disclosure further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the disclosure, or a pharmaceutically acceptable salt or a stereoisomer thereof, and at least one pharmaceutically acceptable carrier or excipient.
  • the present disclosure further provides methods of modulating or inhibiting PD-1/PD-L1 protein/protein interaction, which comprises administering to an individual a compound of the disclosure, or a pharmaceutically acceptable salt or a stereoisomer thereof.
  • the present disclosure further provides methods of treating a disease or disorder in a patient comprising administering to the patient a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt or a stereoisomer thereof.
  • X 1 is N or CR 1 ;
  • X 2 is N or CR 2 ;
  • X 3 is N or CR 3 ;
  • X 4 is N or CR 4 ;
  • X 5 is N or CR 6a ;
  • X 6 is N or CR 6b ;
  • ring B is C 6-10 aryl, C 3-10 cycloalkyl, 5- to 14-membered heteroaryl, or 4- to 10-membered heterocycloalkyl, provided ring B is other than 9-H-carbazol-4-yl, 2,3,4,9-tetrahydro-1H-carbazol-5-yl or 1H-tetrazolyl;
  • R 1 , R 2 , R 3 , R 4 and R 7 are each independently selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, CN, NO 2 , OR a , SR a , NHOR a , C(O)R a , C(O)NR a R a , C(O)OR a , OC(O)R a , OC(O)NR
  • R 5 is halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, CN, NO 2 , OR 11 , SR 11 , NH 2 , —NHR 11 , —NR 11 R 11 , NHOR 11 , C(O)R 11 , C(O)NR 11 R 11 , C(O)OR 11 , OC(O)R 11 , OC(O)NR 11 R 11 , NR 11 C(
  • each R 11 is independently selected from H, CN, C 1-6 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-
  • R 6a , R 6b and R 6c are each independently selected from H, C 1-4 alkyl, C 3-10 cycloalkyl, C 3-10 cycloalkyl-C 1-4 alkyl-, C 6-10 aryl, C 6-10 aryl-C 1-4 alkyl-, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, (5-10 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, C 2-4 alkenyl, C 2-4 alkynyl, halo, CN, OR 10 , C 1-4 haloalkyl, C 1-4 haloalkoxy, NH 2 , —NHR 10 , —NR 10 R 10 , NHOR 10 , C(O)R 10 , C(O)NR 10 R 10 , C(O)OR 10 , OC(O)R 10 , OC(O)NR 10 R 10
  • R 7 substituents taken together with the atoms to which they are attached, form a fused phenyl ring, a fused 4- to 7-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C 3-10 cycloalkyl ring, wherein the fused 4- to 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- to 7-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C 3-10 cycloalkyl ring are each optionally substituted with 1, 2 or 3 independently selected R b substituents, provided
  • R 7 substituents attached to the same ring carbon atom of ring B together with the carbon atom to which they are attached, form a 4- to 7-membered heterocycloalkyl ring having 1-4 heteroatoms as ring members selected from N, O and S or a C 3-6 cycloalkyl ring, wherein the 4- to 7-membered heterocycloalkyl ring and C 3-6 cycloalkyl ring are each optionally substituted with 1, 2 or 3 independently selected R b substituents;
  • each R a is independently selected from H, CN, C 1-6 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl
  • each R d is independently selected from C 1-6 alkyl, C 1-6 haloalkyl, halo, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, CN, NH 2 , NHOR e , OR e , SR e , C(O)R e , C(O)NR e R e , C(O)OR e , OC(O)R e , OC(O)NR e R e , NHR e , NR e R e , NR e C(O)R e , NR e C(O)
  • each R b substituent is independently selected from halo, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, CN, OH, NH 2 , NO 2 , NHOR c , OR c , SR c , C(O)R c , C(O)NR c R c , C(O)OR c , OC(O)R c , OC(O)NR c R c ,
  • each R c is independently selected from H, C 1-6 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5
  • each R g is independently selected from H, C 1-6 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5
  • R c substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected R h substituents;
  • R e substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected R h substituents;
  • R g substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected R h substituents;
  • R i substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected R h substituents;
  • R k substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected R h substituents;
  • R o substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected R h substituents;
  • each R e , R i , R k , R o or R r is independently selected from H, C 1-4 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5 or 6-membered heteroaryl, 4-6 membered heterocycloalkyl, C 1-4 haloalkyl, C 2-4 alkenyl, and C 2-4 alkynyl, wherein the C 1-4 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5 or 6-membered heteroaryl, 4-6 membered heterocycloalkyl, C 2-4 alkenyl, and C 2-4 alkynyl of R e , R i , R k , R o or R r are each optionally substituted with 1, 2 or 3 R q substituents;
  • each R q is independently selected from OH, CN, —COOH, NH 2 , halo, C 1-6 haloalkyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C 3-6 cycloalkyl, NHR 8 , NR 8 R 8 , and C 1-4 haloalkoxy, wherein the C 1-6 alkyl, phenyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl of R q are each optionally substituted with halo, OH, CN, —COOH, NH 2 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, phenyl, C 3-10 cycloalkyl, 5-6 membered heteroaryl
  • ring A is a single bond or a double bond, wherein ring A includes at least one double bond
  • n is an integer of 1, 2, 3, 4 or 5;
  • ring A in Formula (I′) is not 1-methylpyrrolo[2,3-b]pyridine-6-yl;
  • R 5 is 3,5-dimethylphenyl, R 5 is other than 4-amino-1-piperidinyl; and
  • the compound is other than 6-((2R,6S)-2,6-dimethylmorpholino)-N-(2-methyl-4′-(trifluoromethoxy)biphenyl-3-yl)pyridazine-3-carboxamide or N-(3-(3-acetyl-2-oxoimidazolidin-1-yl)-2-methylphenyl)-5,6,7,8-tetrahydroquinoline-2-carboxamide.
  • X 1 is N or CR 1 ;
  • X 2 is N or CR 2 ;
  • X 3 is N or CR 3 ;
  • X 4 is N or CR 4 ;
  • X 5 is N or CR 6a ;
  • X 6 is N or CR 6b ;
  • Ring B is C 6-10 aryl, C 3-10 cycloalkyl, 5- to 14-membered heteroaryl, or 4- to 10-membered heterocycloalkyl, provided ring B is other than 9-H-carbazol-4-yl, 2,3,4,9-tetrahydro-1H-carbazol-5-yl or 1H-tetrazolyl;
  • R 1 , R 2 , R 3 , R 4 and R 7 are each independently selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, CN, NO 2 , OR a , SR a , NHOR a , C(O)R a , C(O)NR a R a , C(O)OR a , OC(O)R a , OC(O)NR
  • R 5 is halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, CN, NO 2 , OR 11 , SR 11 , NH 2 , —NH—C 1-4 alkyl, —N(C 1-4 alkyl) 2 , NHOR 11 , C(O)R 11 , C(O)NR 11 R 11 , C(O)OR 11 , OC(O)R 11 , OC(O)NR
  • each R 11 is independently selected from H, CN, C 1-6 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-
  • R 6a , R 6b and R 6c are each independently selected from H, C 1-4 alkyl, C 3-6 cycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo, CN, OH, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, NH 2 , —NH—C 1-4 alkyl, —N(C 1-4 alkyl) 2 , NHOR 10 , C(O)R 10 , C(O)NR 10 R 10 , C(O)OR 10 , OC(O)R 10 , OC(O)NR 10 R 10 , NR 10 C(O)R 10 , NR 10 C(O)OR 10 , NR 10 C(O)NR 10 R 10 , C( ⁇ NR 10 )R 10 , NR 10 C(O)OR 10 , NR 10 C(O)NR 10 R 10 , C( ⁇ NR 10 )R 10 , C
  • R 7 substituents taken together with the atoms to which they are attached, form a fused phenyl ring, a fused 4- to 7-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C 3-10 cycloalkyl ring, wherein the fused 4- to 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- to 7-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C 3-10 cycloalkyl ring are each optionally substituted with 1 or 2 independently selected R b substituents, provided
  • R 7 substituents attached to the same ring carbon atom of ring B together with the carbon atom to which they are attached, form a 4- to 7-membered heterocycloalkyl ring having 1-4 heteroatoms as ring members selected from N, O and S or a C 3-6 cycloalkyl ring, wherein the 4- to 7-membered heterocycloalkyl ring and C 3-6 cycloalkyl ring are each optionally substituted with 1 or 2 independently selected R b substituents;
  • each R a is independently selected from H, CN, C 1-6 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl
  • each R d is independently selected from C 1-4 alkyl, C 1-4 haloalkyl, halo, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, CN, NH 2 , NHOR e , OR e , SR e , C(O)R e , C(O)NR e R e , C(O)OR e , OC(O)R e , OC(O)NR e R e , NHR e , NR e R e , NR e C(O)R e , NR e C(O)NR e R e , NR e C(O)OR e , NR e C(O)OR e , C( ⁇ NR e )NR e R e , NR e C( ⁇ NR e )NR e R e , S(O)R e , S(O)NR e R
  • each R b substituent is independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, CN, OH, NH 2 , NO 2 , NHOR c , OR c , SR c , C(O)R c , C(O)NR c R c , C(O)OR c , OC(O)R c , OC(O)NR c R c , C( ⁇ NR c )NR c R c ,
  • each R c is independently selected from H, C 1-6 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5
  • each R g is independently selected from H, C 1-6 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5
  • R c substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected R h substituents;
  • R e substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected R h substituents;
  • R g substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected R h substituents;
  • R i substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected R h substituents;
  • R k substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected R h substituents;
  • R o substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected R h substituents;
  • each R e , R i , R k , R o or R p is independently selected from H, C 1-4 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5 or 6-membered heteroaryl, C 1-4 haloalkyl, C 2-4 alkenyl, and C 2-4 alkynyl, wherein the C 1-4 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5 or 6-membered heteroaryl, C 2-4 alkenyl, and C 2-4 alkynyl of R e , R i , R k , R o or R p are each optionally substituted with 1, 2 or 3 R q substituents;
  • each R q is independently selected from OH, CN, —COOH, NH 2 , halo, C 1-6 haloalkyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylthio, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C 3-6 cycloalkyl, NHR 8 , NR 8 R 8 , and C 1-4 haloalkoxy, wherein the C 1-6 alkyl, phenyl, C 3-6 cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl of R q are each optionally substituted with halo, OH, CN, —COOH, NH 2 , C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, phenyl, C 3-10 cycloalkyl and 4-6 membered heterocycloalkyl and each R 8
  • n is an integer of 1, 2, 3, 4 or 5;
  • ring A in Formula (I′) is not 1-methylpyrrolo[2,3-b]pyridine-6-yl;
  • R 5 is 3,5-dimethylphenyl, R 5 is other than 4-amino-1-piperidinyl; and
  • the compound is other than 6-((2R,6S)-2,6-dimethylmorpholino)-N-(2-methyl-4′-(trifluoromethoxy)biphenyl-3-yl)pyridazine-3-carboxamide or N-(3-(3-acetyl-2-oxoimidazolidin-1-yl)-2-methylphenyl)-5,6,7,8-tetrahydroquinoline-2-carboxamide.
  • R 2 is other than C 1-6 alkyl.
  • R 5 is C 1-4 alkyl, halo, CN, OH, cyclopropyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, NH 2 , —NH—C 1-4 alkyl, —N(C 1-4 alkyl) 2 , NHOR 11 , C(O)R 11 , C(O)NR 11 R 11 , C(O)OR 11 , OC(O)R 11 , OC(O)NR 11 R 11 , NR 11 C(O)R 11 , NR 11 C(O)OR 11 , NR 11 C(O)NR 11 R 11 , C( ⁇ NR 11 )R 11 , C( ⁇ NR 11 )NR 11 R 11 , NR 11 C(O)OR 11 , NR 11 C(O)NR 11 R 11 , C( ⁇ NR 11 )R 11 , C( ⁇ NR 11 )NR 11 R 11 , NR
  • ring B is C 6-10 aryl. In certain embodiments, ring B is phenyl or naphthyl. In certain embodiments, ring B is phenyl.
  • R 7 is as defined in any embodiment of compounds of Formula (I′) or Formula (I) as described herein. In certain embodiments, each R 7 is H.
  • ring B is 1-cyclohexenyl, cyclohexyl, 3,4-dihydro-2H-pyridin-5-yl, 1,2,3,4-tetrahydropyridin-5-yl, 1-piperidinyl, 2,3-dihydro-1,4-benzodioxin-6-yl, 3,4-dihydro-2H-pyran-5-yl, 4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl, 3,4-dihydro-2H-1,4-benzoxazin-7-yl, 2,3-dihydro-1-benzofuran-6-yl, 2-methyl-2H-indazol-6-yl, 2H-indazol-6-yl, 1-methyl-1H-indazol-4-yl or 1H-indazol-4-yl.
  • R 7 is as defined in any embodiment of compounds of Formula (I′) or Formula (I) as described herein.
  • ring B is C 3-10 cycloalkyl.
  • ring B is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl or cyclooctyl.
  • R 7 is as defined in any embodiment of compounds of Formula (I′) or Formula (I) as described herein. In certain embodiments, R 7 is H.
  • ring B is 5- to 14-membered heteroaryl.
  • ring B is pyridy, primidinyl, pyrazinyl, pyridazinyl, triazinyl, pyrrolyl, pyrazolyl, azolyl, oxazolyl, thiazolyl, imidazolyl, furanyl, thiophenyl, quinolinyl, isoquinolinyl, naphthyridinyl, indolyl, benzothiophenyl, benzofuranyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl, purinyl, thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazoly
  • ring B is 2-methyl-2H-indazol-6-yl, 1-methyl-1H-indazol-4-yl, 2,3-dihydro-1-benzofuran-6-yl, 4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl or 2,3-dihydro-1,4-benzodioxin-6-yl.
  • R 7 is as defined in any embodiment of compounds of Formula (I′) or Formula (I) as described herein.
  • ring B is 4- to 10-membered heterocycloalkyl.
  • ring B is azetidinyl, azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, morpholino, 3-oxa-9-azaspiro[5.5]undecanyl, 1-oxa-8-azaspiro[4.5]decanyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrolidinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, tropanyl, 2,3-dihydro-1,4-benzodioxin-6-yl, or thiomorpholino.
  • ring B is 3,4-dihydro-2H-pyran-5-yl, 1-piperidinyl or 1,2,3,4-tetrahydropyridin-5-yl.
  • R 7 is as defined in any embodiment of compounds of Formula (I′) or Formula (I) as described herein.
  • ring B is phenyl, 5- or 6-membered heteroaryl, C 3-6 cycloalkyl or 5- or 6-membered heterocycloalkyl.
  • ring B is phenyl, 2-thiophenyl, 3-thiophenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C 3-6 cycloalkyl or 3,6-dihydro-2H-pyran-4-yl.
  • R 7 is as defined in any embodiment of compounds of Formula (I′) or Formula (I) as described herein.
  • X 5 and X 6 are each CH. In certain embodiments, X 5 is N and X 6 is CH. In certain embodiments, X 5 is CH and X 6 is N. In certain embodiments, X 5 and X 6 are each N.
  • R 2 is other than t-butyl or C 1-6 alkyl, wherein each R 12 is independently H or CH 3 and each R 13 is independently phenyl substituted with amino and morpholino, phenyl substituted with a group selected from R 14 , —C(O)R 14 and (2-amino-2-oxo-ethyl)methylcarbamoyl, 2-pyridyl substituted with 4-methylpiperazin-1-yl or 1-methylpyrrolidin-2-yl, 3-pyridizinyl substituted with morpholino or 4-methylpiperazin-1-yl, 5-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-2-yl, 5-trideuteriomethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-2-yl, 5-(2,2-difluoroethyl)-6,7-dihydro-4H-pyrazolo[1,
  • the present disclosure provides compounds of Formula (I):
  • X 1 is N or CR 1 ;
  • X 2 is N or CR 2 ;
  • X 3 is N or CR 3 ;
  • X 4 is N or CR 4 ;
  • R 1 , R 2 , R 3 , R 4 and R 7 are each independently selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, CN, NO 2 , OR a , SR a , NHOR a , C(O)R a , C(O)NR a R a , C(O)OR a , OC(O)R a , OC(O)NR
  • R 5 is C 1-4 alkyl, halo, CN, OH, cyclopropyl, C 2-4 alkynyl, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, NH 2 , —NH—C 1-4 alkyl, —N(C 1-4 alkyl) 2 , NHOR 11 , C(O)R 11 , C(O)NR 11 R 11 , C(O)OR 11 , OC(O)R 11 , OC(O)NR 11 R 11 , NR 11 C(O)R 11 , NR 11 C(O)OR 11 , NR 11 C(O)NR 11 R 11 , C( ⁇ NR 11 )R 11 , C( ⁇ NR 11 )NR 11 R 11 , NR 11 C(O)OR 11 , NR 11 C(O)NR 11 R 11 , C( ⁇ NR 11 )R 11 , C( ⁇ NR 11 )NR 11 R 11 , NR
  • each R 6 is independently selected from H, C 1-4 alkyl, C 3-6 cycloalkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo, CN, OH, C 1-4 alkoxy, C 1-4 haloalkyl, C 1-4 haloalkoxy, NH 2 , —NH—C 1-4 alkyl, —N(C 1-4 alkyl) 2 , NHOR 10 , C(O)R 10 , C(O)NR 10 R 10 , C(O)OR 10 , OC(O)R 10 , OC(O)NR 10 R 10 , NR 10 C(O)R 10 , NR 10 C(O)OR 10 , NR 10 C(O)NR 10 R 10 , C( ⁇ NR 10 )R 10 , C( ⁇ NR 10 )NR 10 R 10 , NR 10 S(O)R 10 , NR 10 S(O)R 10 , NR 10 S(O)R 10 ,
  • R 7 substituents taken together with the carbon atoms to which they are attached, form a fused phenyl ring, a fused 5- to 7-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C 5-6 cycloalkyl ring, wherein the fused 5- to 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- to 7-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C 3-10 cycloalkyl ring are each optionally substituted with 1 or 2 independently selected R q substituents;
  • each R a is independently selected from H, CN, C 1-6 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl
  • each R d is independently selected from C 1-4 alkyl, C 1-4 haloalkyl, halo, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NH 2 , NHOR e , OR e , SR e , C(O)R e , C(O)NR e R e , C(O)OR e , OC(O)R e , OC(O)NR e R e , NHR e , NR e R e , NR e C(O)R e , NR e C(O)NR e R e , NR e C(O)OR e , NR e C(O)OR e , C( ⁇ NR e )NR e R e , NR e C( ⁇ NR e )NR e R e , S(
  • each R b substituent is independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, CN, OH, NH 2 , NO 2 , NHOR c , OR c , SR c , C(O)R c , C(O)NR c R c , C(O)OR c , OC(O)R c , OC(O)NR c R c , C( ⁇ NR c )NR c R c ,
  • each R g is independently selected from H, C 1-6 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5
  • R c substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected R h substituents;
  • R e substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected R h substituents;
  • R g substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected R h substituents;
  • R i substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected R h substituents;
  • R k substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected R h substituents;
  • R o substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected R h substituents;
  • each R e , R i , R k , R o or R p is independently selected from H, C 1-4 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5 or 6-membered heteroaryl, C 1-4 haloalkyl, C 2-4 alkenyl, and C 2-4 alkynyl, wherein the C 1-4 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5 or 6-membered heteroaryl, C 2-4 alkenyl, and C 2-4 alkynyl of R e , R i , R k , R o or R p are each optionally substituted with 1, 2 or 3 R q substituents; each R q is independently selected from OH, CN, —COOH, NH 2 , halo, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylthio, phenyl, 5-6 membered heteroaryl, C 3-6
  • n is an integer of 1, 2, 3, 4 or 5;
  • ring A is a single bond or a double bond, wherein ring A includes at least one double bond
  • the compound is other than 6-((2R,6S)-2,6-dimethylmorpholino)-N-(2-methyl-4′-(trifluoromethoxy)biphenyl-3-yl)pyridazine-3-carboxamide.
  • the subscript m is an integer of 1, 2 or 3.
  • R 5 is halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, CN, NO 2 , OR 11 , SR 11 , NH 2 , —NH—C 1-4 alkyl, —N(C 1-4 alkyl) 2 , NHOR 11 , C(O)R 11 , C(O)NR 11 R 11 , C(O)OR 11 , OC(O)
  • each R 11 is independently selected from H, CN, C 1-6 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-
  • ring A is other than pyridazinyl group.
  • X 2 is CR 2
  • X 3 is CR 3
  • X 4 is CR 4
  • X 1 is other than N.
  • ring A is aromatic.
  • ring A has the formula
  • the present disclosure provides compounds having Formula (II):
  • R 2 is halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, CN, NO 2 , OR a , SR a , NHOR a , C(O)R a , C(O)NR a R a , C(O)OR a , OC(O)R a ,
  • R 5 is CN or C 1-4 alkyl optionally substituted with R q .
  • R 5 is CH 3 or CN.
  • the present disclosure provides compounds having Formula (III):
  • R 2 is halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, CN, NO 2 , OR a , SR a , NHOR a , C(O)R a , C(O)NR a R a , C(O)OR a , OC(O)R a , OC
  • the present disclosure provides compounds having Formula (IV):
  • R 2 is halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, CN, NO 2 , OR a , SR a , NHOR a
  • the present disclosure provides compounds having Formula (V):
  • R 2 is halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, CN, NO 2 , OR a , SR a , NHOR a
  • the present disclosure provides compounds having Formula (VI):
  • R 2 is halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, CN, NO 2 , OR a , SR a , NHOR a
  • the present disclosure provides compounds having Formula (VII):
  • R 3 is halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, CN, NO 2 , OR a , SR a , NHOR
  • R 1 , R 2 , R 3 and R 4 are as defined in Formula (I′), Formula (I′) or Formula (I) or any embodiment of compounds of Formula (I′) or Formula (I) as described herein.
  • R 1 , R 3 and R 4 are each H.
  • R 1 , R 2 , R 3 and R 4 are as defined in Formula (I′), Formula (I) or any embodiment of compounds of Formula (I′) or Formula (I) as described herein.
  • R 1 , R 2 and R 4 are each H.
  • X 1 is CR 1
  • X 3 is CR 3
  • X 4 is CR 4 .
  • X 1 is CR 1
  • X 3 is CR 3
  • X 4 is N.
  • X 1 is CR 1
  • X 3 is N
  • X 4 is CR 4 .
  • X 1 is N
  • X 3 is CR 3
  • X 4 is CR 4 .
  • X 1 is CR 1
  • X 2 is CR 2
  • X 4 is CR 4 .
  • X 1 is CR 1
  • X 2 is CR 2
  • X 4 is N.
  • X 1 is CR 1
  • X 2 is N
  • X 4 is CR 4 .
  • X 1 is N
  • X 2 is CR 2
  • X 4 is CR 4 .
  • R 1 , R 3 and R 4 are each independently selected from H, C 1-6 alkyl, CN, —N(C 1-6 alkyl) 2 and halo.
  • R 1 , R 2 and R 4 are each independently selected from H, C 1-6 alkyl, CN, —N(C 1-6 alkyl) 2 and halo.
  • R 1 , R 2 , R 3 , R 4 , R 6 and R 7 are each H.
  • R 1 , R 3 , R 4 , R 6 and R 7 are each H.
  • R 1 , R 2 , R 4 , R 6 and R 7 are each H.
  • two adjacent R 7 substituents on the phenyl ring taken together with the carbon atoms to which they are attached form a 5-, 6- or 7-membered fused heterocycloalkyl optionally substituted by 1 or 2 R q substituents.
  • the fused heterocycloalkyl has carbon and 1 or 2 heteroatoms as ring members selected from O, N or S, wherein the carbon ring atom is optionally oxidized to form carbonyl, the N ring atom is optionally oxidized to form NO and the S ring atom is optionally oxidized to form SO or SO 2 .
  • the subscript n is 2 and the subscript m is 1.
  • R 5 is C 1-4 alkyl or CN.
  • R 5 is CH 3 or CN.
  • R 6 and R 7 are each H.
  • R 2 is C 1-4 alkyl substituted with R b .
  • R b is NHR c or NR c R c .
  • R b is NR c R c .
  • R b is 2-hydroxyethylamino, 2-hydroxyethyl(methyl)amino, 2-carboxypiperidin-1-yl, (cyanomethyl)amino, (S)-2-carboxypiperidin-1-yl, (R)-2-carboxypiperidin-1-yl or 2-carboxypiperidin-1-yl, each of which is optionally substituted with 1, 2 or 3 R q substituents.
  • R 2 is C 1-4 alkyl substituted with R q .
  • R 2 is C 1-4 alkoxy substituted with R d .
  • R d is phenyl, 3-cyanophenyl, 3-pyridyl, 2-pyridyl, or 4-pyridyl, each of which is optionally substituted with 1, 2 or 3 R q substituents.
  • R 2 is —OCH 2 R d .
  • R d is phenyl, 3-cyanophenyl, 3-pyridyl, 2-pyridyl, 4-pyridyl, each of which is optionally substituted with 1, 2 or 3 R q substituents.
  • X 1 when X 1 is N, X 3 is CH and X 4 is CH, R 2 is other than cis-2,6-dimethylmorpholino. In other embodiments, X 1 is N, X 3 is CH and X 4 is CH, R 2 is other than 2,6-dimethylmorpholino. In other embodiments, X 1 is N, X 3 is CH and X 4 is CH, R 2 is other than 6-membered heterocycloalkyl substituted with 1 or 2 C 1-6 alkyl, wherein the heterocycloalkyl has N and O as ring members. In other embodiments, ring A is other than 6-(2,6-dimethylmorpholino)pyridazin-3-yl.
  • R 3 is C 1-4 alkyl substituted with R b .
  • R b is NHR c or NR c R c .
  • R b is 2-hydroxyethylamino, 2-hydroxyethyl(methyl)amino, 2-carboxypiperidin-1-yl, (cyanomethyl)amino, (S)-2-carboxypiperidin-1-yl, (R)-2-carboxypiperidin-1-yl or 2-carboxypiperidin-1-yl, each of which is optionally substituted with 1, 2 or 3 R q substituents.
  • R 3 is C 1-4 alkyl substituted with R q .
  • R 3 is C 1-4 alkoxy substituted with R d .
  • R d is phenyl, 3-cyanophenyl, 3-pyridyl, 2-pyridyl, or 4-pyridyl, each of which is optionally substituted with 1, 2 or 3 R q substituents.
  • R 3 is —OCH 2 R d .
  • R d is phenyl, 3-cyanophenyl, 3-pyridyl, 2-pyridyl, 4-pyridyl, each of which is optionally substituted with 1, 2 or 3 R q substituents.
  • R 3 is 2-hydroxyethylaminomethyl, 2-hydroxyethyl(methyl)aminomethyl, 2-carboxypiperidin-1-ylmethyl, (cyanomethyl)aminomethyl, (S)-2-carboxypiperidin-1-ylmethyl, (R)-2-carboxypiperidin-1-ylmethyl, 2-carboxypiperidin-1-ylmethyl, benzyloxy, 2-cyanobenzyloxy, 3-cyanobenzyloxy, 4-cyanobenzyloxy, 2-pyridylmethoxy, 3-pyridylmethoxy, or 4-pyridylmethoxy, each of which is optionally substituted with 1, 2 or 3 R q substituents.
  • R 3 is 2-hydroxyethylaminomethyl, 2-carboxypiperidin-1-ylmethyl, (S)-2-carboxypiperidin-1-ylmethyl, (R)-2-carboxypiperidin-1-ylmethyl or (3-cyanobenzyl)oxy, each of which is optionally substituted with 1, 2 or 3 R q substituents.
  • R 6a , R 6b and R 6c are each independently selected from H, halo, CN, N(C 1-6 alkyl) 2 , C 1-6 alkyl and C 1-6 alkoxy, wherein the C 1-6 alkyl are each optionally substituted with 1 or 2 substituents independently selected from halo, OH, CN, C 1-4 alkyl and C 1-4 alkoxy.
  • R 6a , R 6b and R 6c are each independently selected from H, halo, CN, N(CH 3 ) 2 and CH 3 .
  • R 6 is H, halo, CN, N(C 1-6 alkyl) 2 , C 1-6 alkyl or C 1-6 alkoxy, wherein the C 1-6 alkyl and C 1-6 alkoxy are each optionally substituted with 1-3 R q substituents.
  • R 6 is H, halo, CN, N(CH 3 ) 2 or CH 3 .
  • X 1 is N or CR 1 ;
  • X 2 is N or CR 2 ;
  • X 3 is N or CR 3 ;
  • X 4 is N or CR 4 ;
  • X 5 is N or CR 6a ;
  • X 6 is CR 6b ;
  • ring B is phenyl, cyclohexyl, piperidinyl, or tetrahydropyridinyl;
  • R 1 , R 2 , R 3 , R 4 and R 7 are each independently selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-14 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, CN, OR a , NHR a , and NR a R a , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered
  • R 5 is C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, C 1-6 haloalkoxy, or CN, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 haloalkyl, and C 1-6 haloalkoxy of R 5 are each optionally substituted with 1, 2 or 3 R b substituents;
  • R 6a , R 6b and R 6c are each independently selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo, CN, OH, C 1-4 alkoxy, C 1-4 haloalkyl, NH 2 , —NH—C 1-4 alkyl, and —N(C 1-4 alkyl) 2 , wherein the C 1-4 alkyl, C 2-4 alkenyl and C 2-4 alkynyl of R 6a , R 6b , and R 6c are each optionally substituted with 1 or 2 substituents independently selected from halo, OH, CN, C 1-4 alkyl and C 1-4 alkoxy;
  • R 7 substituents taken together with the atoms to which they are attached, form a fused 4- to 7-membered heterocycloalkyl ring or a fused 5- or 6-membered heteroaryl ring, wherein the fused 4- to 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N and O and wherein the fused 5- to 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring are each optionally substituted with 1 or 2 independently selected R b substituents;
  • each R a is independently selected from H, CN, C 1-6 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl
  • each R d is independently selected from C 1-4 alkyl, C 1-4 haloalkyl, halo, C 3-10 cycloalkyl, 4-10 membered heterocycloalkyl, CN, NH 2 , OR e , SR e , C(O)R e , C(O)NR e R e , C(O)OR e , OC(O)R e , OC(O)NR e R e , NHR e , NR e R e , and NR e C(O)R e , and S(O) 2 NR e R e , wherein the C 1-4 alkyl, C 3-10 cycloalkyl and 4-10 membered heterocycloalkyl of R d are each further optionally substituted with 1-3 independently selected R f substituents;
  • each R b substituent is independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, CN, OH, NH 2 , NO 2 , NHOR c , OR c , SR c , C(O)R c , C(O)NR c R c , C(O)OR c , OC(O)R c , OC(O)NR c R c , NHR c , NR c R c , NR c C(O)R c , and NR c C(O)OR c ; wherein the C 1-4 alkyl, C 1-4 haloalkyl, and C 1-4 haloalkoxy of R b are each further optionally substituted with 1-3 independently selected R d substituents;
  • each R c is independently selected from H, C 1-6 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl of R c are each optionally substituted with 1, 2, 3, 4, or 5 R f substituents independently selected from C 1-4 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo, CN, NHOR g , OR g , SR g , C(O)R g , C(O)NR g R g , C(O)OR g , OC(O)R g , OC(O)NR g R g , NHR g , NR g R g , and NR g C(O)R g ;
  • each R g is independently selected from H, C 1-6 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl;
  • each R e is independently selected from H, C 1-4 alkyl, C 1-4 haloalkyl, C 2-4 alkenyl, and C 2-4 alkynyl;
  • ring A is a single bond or a double bond, wherein ring A includes at least one double bond
  • n is an integer of 1, 2, 3, 4 or 5.
  • X 1 is N or CR 1 ;
  • X 2 is N or CR 2 ;
  • X 3 is N or CR 3 ;
  • X 4 is N or CR 4 ;
  • X 5 is N or CR 6a ;
  • X 6 is CR 6b ;
  • ring B is phenyl, cyclohexyl, piperidinyl, or tetrahydropyridinyl;
  • R 1 , R 2 , R 3 , R 4 and R 7 are each independently selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, (5-14 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, CN, OR a , NHR a , and NR a R a , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, (5-14 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R 1 , R 2 , R 3 , R 4 and R 7 are each optionally substituted with 1, 2, 3, or 4 R
  • R 5 is C 1-6 alkyl or CN
  • R 6a , R 6b and R 6c are each independently selected from H, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halo, CN, OH, NH 2 , —NH—C 1-4 alkyl, and —N(C 1-4 alkyl) 2 ;
  • R 7 substituents taken together with the atoms to which they are attached, form a fused 4- to 7-membered heterocycloalkyl ring or a fused 5- or 6-membered heteroaryl ring, wherein the fused 4- to 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N and O and wherein the fused 5- to 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring are each optionally substituted with 1 or 2 independently selected R b substituents;
  • each R a is independently selected from H, CN, C 1-6 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl
  • each R d is independently selected from C 1-4 alkyl, C 1-4 haloalkyl, halo, CN, and NH 2 ; each R b substituent is independently selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 haloalkoxy, CN, OH, NH 2 , C(O)OR c , NHR c , and NR c R c ;
  • each R c is independently selected from H, C 1-6 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl of R c are each optionally substituted with 1, 2, 3, 4, or 5 R f substituents independently selected from C 1-4 alkyl, C 1-4 haloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo, CN, OR g , C(O)R g , C(O)NR g R g , C(O)OR g , NHR g , NR g R g , and NR g C(O)R g ;
  • each R g is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl;
  • ring A is a single bond or a double bond, wherein ring A includes at least one double bond
  • n is an integer of 1, 2, 3, 4 or 5.
  • X 1 is N or CR 1 ;
  • X 2 is N or CR 2 ;
  • X 3 is N or CR 3 ;
  • X 4 is N or CR 4 ;
  • X 5 is N or CR 6a ;
  • X 6 is CR 6b ;
  • ring B is phenyl, cyclohexyl, piperidinyl, or tetrahydropyridinyl;
  • R 1 , R 2 , R 3 , R 4 and R 7 are each independently selected from H, halo, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, (5-14 membered heteroaryl)-C 1-4 alkyl-, (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, CN, OR a , NHR a , and NR a R a , wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, (5-14 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl- of R 1 , R 2 , R 3 , R 4 and R 7 are each optionally substituted with 1 or 2, R b
  • R 5 is C 1-6 alkyl or CN
  • R 6a , R 6b and R 6c are each independently selected from H, C 1-4 alkyl and halo;
  • R 7 substituents taken together with the atoms to which they are attached, form a fused 4- to 7-membered heterocycloalkyl ring or a fused 5- or 6-membered heteroaryl ring, wherein the fused 4- to 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N and O and wherein the fused 5- to 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring are each optionally substituted with 1 or 2 independently selected R b substituents;
  • each R a is independently selected from H, CN, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl)-C 1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C 1-4 alkyl-, wherein the C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 6-10 aryl, C 3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C 6-10 aryl-C 1-4 alkyl-, C 3-10 cycloalkyl-C 1-4 alkyl-, (5-10 membered heteroaryl
  • each R d is independently selected from C 1-4 alkyl, halo, CN, and NH 2 ;
  • each R b substituent is independently selected from halo, C 1-4 alkyl, CN, OH, NH 2 , C(O)OR c , NHR c , and NR c R c ;
  • each R c is independently selected from H, C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl, wherein the C 1-6 alkyl, C 2-6 alkenyl, and C 2-6 alkynyl of R c are each optionally substituted with 1, 2 or R f substituents independently selected from C 1-4 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halo, CN, and OR g ;
  • each R g is independently selected from H and C 1-6 alkyl
  • ring A is a single bond or a double bond, wherein ring A includes at least one double bond
  • n is an integer of 1, 2, 3, 4 or 5.
  • C 1-6 alkyl is specifically intended to individually disclose (without limitation) methyl, ethyl, C 3 alkyl, C 4 alkyl, C 5 alkyl and C 6 alkyl.
  • n-membered 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.
  • each linking substituent include both the forward and backward forms of the linking substituent.
  • —NR(CR′R′′) n — includes both —NR(CR′R′′) n — and —(CR′R′′) n NR— and is intended to disclose each of the forms individually.
  • the Markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists “alkyl” or “aryl” then it is understood that the “alkyl” or “aryl” represents a linking alkylene group or arylene group, respectively.
  • substituted means that an atom or group of atoms formally replaces hydrogen as a “substituent” attached to another group.
  • substituted refers to any level of substitution, e.g., mono-, di-, tri-, tetra- or penta-substitution, where such substitution is permitted.
  • the substituents are independently selected, and substitution may be at any chemically accessible position. It is to be understood that substitution at a given atom is limited by valency. It is to be understood that substitution at a given atom results in a chemically stable molecule.
  • the phrase “optionally substituted” means unsubstituted or substituted.
  • substituted means that a hydrogen atom is removed and replaced by a substituent.
  • a single divalent substituent e.g., oxo, can replace two hydrogen atoms.
  • C n-m indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include C 1-4 , C 1-6 and the like.
  • alkyl refers to a saturated hydrocarbon group that may be straight-chained or branched.
  • C n-m alkyl refers to an alkyl group having n to m carbon atoms.
  • An alkyl group formally corresponds to an alkane with one C—H bond replaced by the point of attachment of the alkyl group to the remainder of the compound.
  • the alkyl group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or 1 to 2 carbon atoms.
  • alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl and the like.
  • alkenyl refers to a straight-chain or branched hydrocarbon group corresponding to an alkyl group having one or more double carbon-carbon bonds.
  • An alkenyl group formally corresponds to an alkene with one C—H bond replaced by the point of attachment of the alkenyl group to the remainder of the compound.
  • C n-m alkenyl refers to an alkenyl group having n to m carbons.
  • the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.
  • Example alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl and the like.
  • alkynyl refers to a straight-chain or branched hydrocarbon group corresponding to an alkyl group having one or more triple carbon-carbon bonds.
  • An alkynyl group formally corresponds to an alkyne with one C—H bond replaced by the point of attachment of the alkyl group to the remainder of the compound.
  • C n-m alkynyl refers to an alkynyl group having n to m carbons.
  • Example alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl and the like. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.
  • alkylene employed alone or in combination with other terms, refers to a divalent alkyl linking group.
  • An alkylene group formally corresponds to an alkane with two C—H bond replaced by points of attachment of the alkylene group to the remainder of the compound.
  • C n-m alkylene refers to an alkylene group having n to m carbon atoms.
  • alkylene groups include, but are not limited to, ethan-1,2-diyl, propan-1,3-diyl, propan-1,2-diyl, butan-1,4-diyl, butan-1,3-diyl, butan-1,2-diyl, 2-methyl-propan-1,3-diyl and the like.
  • alkoxy refers to a group of formula —O-alkyl, wherein the alkyl group is as defined above.
  • C n-m alkoxy refers to an alkoxy group, the alkyl group of which has n to m carbons.
  • Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy and the like.
  • the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
  • amino employed alone or in combination with other terms, refers to a group of formula —NH 2 .
  • carboxylate employed alone or in combination with other terms, refers to a group of formula —C(O)NH 2 .
  • carbonyl employed alone or in combination with other terms, refers to a —C( ⁇ O)— group, which also may be written as C(O).
  • cyano or “nitrile,” employed alone or in combination with other terms, refers to a group of formula —C ⁇ N, which also may be written as —CN.
  • halo refers to fluoro, chloro, bromo and iodo.
  • halo refers to a halogen atom selected from F, Cl, or Br.
  • halo groups are F.
  • haloalkyl employed alone or in combination with other terms, as used herein refers to an alkyl group in which one or more of the hydrogen atoms has been replaced by a halogen atom.
  • C n-m haloalkyl refers to a C n-m alkyl group having n to m carbon atoms and from at least one up to ⁇ 2(n to m)+1 ⁇ halogen atoms, which may either be the same or different.
  • the halogen atoms are fluoro atoms.
  • the haloalkyl group has 1 to 6 or 1 to 4 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 haloalkyl group is a fluoroalkyl group.
  • haloalkoxy refers to a group of formula —O-haloalkyl, wherein the haloalkyl group is as defined above.
  • C n-m haloalkoxy refers to a haloalkoxy group, the haloalkyl group of which has n to m carbons.
  • Example haloalkoxy groups include trifluoromethoxy and the like. In some embodiments, the haloalkoxy group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
  • oxo refers to an oxygen atom as a divalent substituent, forming a carbonyl group when attached to carbon, or attached to a heteroatom forming a sulfoxide or sulfone group, or an N-oxide group.
  • heterocyclic groups may be optionally substituted by 1 or 2 oxo ( ⁇ O) substituents.
  • sulfurido refers to a sulfur atom as a divalent substituent, forming a thiocarbonyl group (C ⁇ S) when attached to carbon.
  • aromatic refers to a carbocycle or heterocycle having one or more polyunsaturated rings having aromatic character (i.e., having (4n+2) delocalized ⁇ (pi) electrons where n is an integer).
  • aryl refers to an aromatic hydrocarbon group, which may be monocyclic or polycyclic (e.g., having 2 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, indanyl, indenyl and the like.
  • aryl groups have from 6 to about 10 carbon atoms.
  • aryl groups have 6 carbon atoms.
  • aryl groups have 10 carbon atoms.
  • the aryl group is phenyl.
  • the aryl group is naphthyl.
  • heteroaryl or “heteroaromatic,” employed alone or in combination with other terms, refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from sulfur, oxygen and nitrogen.
  • the heteroaryl ring has 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
  • any ring-forming N in a heteroaryl moiety can be an N-oxide.
  • the heteroaryl has 5-14 ring atoms including carbon atoms and 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen.
  • the heteroaryl has 5-10 ring atoms including carbon atoms and 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl has 5-6 ring atoms and 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl is a five-membered or six-membered heteroaryl ring. In other embodiments, the heteroaryl is an eight-membered, nine-membered or ten-membered fused bicyclic heteroaryl ring.
  • Example heteroaryl groups include, but are not limited to, pyridintl (pyridyl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, azolyl, oxazolyl, thiazolyl, imidazolyl, furanyl, thiophenyl, quinolinyl, isoquinolinyl, naphthyridinyl (including 1,2-, 1,3-, 1,4-, 1,5-, 1,6-, 1,7-, 1,8-, 2,3- and 2,6-naphthyridine), indolyl, benzothiophenyl, benzofuranyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl, purinyl, and the like.
  • pyridintl pyridyl
  • pyrimidinyl pyrazinyl
  • pyridazinyl pyri
  • a five-membered heteroaryl ring is a heteroaryl group having five ring atoms wherein one or more (e.g., 1, 2 or 3) ring atoms are independently selected from N, O and S.
  • Exemplary five-membered ring heteroaryls include thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.
  • a six-membered heteroaryl ring is a heteroaryl group having six ring atoms wherein one or more (e.g., 1, 2 or 3) ring atoms are independently selected from N, O and S.
  • Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.
  • cycloalkyl refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic or polycyclic), including cyclized alkyl and alkenyl groups.
  • C n-m cycloalkyl refers to a cycloalkyl that has n to m ring member carbon atoms.
  • Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) groups and spirocycles. Cycloalkyl groups can have 3, 4, 5, 6 or 7 ring-forming carbons (C 3-7 ).
  • the cycloalkyl group has 3 to 6 ring members, 3 to 5 ring members, or 3 to 4 ring members. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is a C 3-6 monocyclic cycloalkyl group. Ring-forming carbon atoms of a cycloalkyl group can be optionally oxidized to form an oxo or sulfido group. Cycloalkyl groups also include cycloalkylidenes.
  • cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, e.g., benzo or thienyl derivatives of cyclopentane, cyclohexane and the like.
  • a cycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring.
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbomyl, norpinyl, norcamyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, and the like.
  • the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • heterocycloalkyl refers to a non-aromatic ring or ring system, which may optionally contain one or more alkenylene groups as part of the ring structure, which has at least one heteroatom ring member independently selected from nitrogen, sulfur oxygen and phosphorus, and which has 4-10 ring members, 4-7 ring members, or 4-6 ring members. Included within the term “heterocycloalkyl” are monocyclic 4-, 5-, 6- and 7-membered heterocycloalkyl groups. Heterocycloalkyl groups can include mono- or bicyclic (e.g., having two fused or bridged rings) ring systems.
  • the heterocycloalkyl group is a monocyclic group having 1, 2 or 3 heteroatoms independently selected from nitrogen, sulfur and oxygen. Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally oxidized to form an oxo or sulfido group or other oxidized linkage (e.g., C(O), S(O), C(S) or S(O) 2 , N-oxide etc.) or a nitrogen atom can be quaternized.
  • the heterocycloalkyl group can be attached through a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds.
  • the heterocycloalkyl group contains 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the heterocycloalkyl ring, e.g., benzo or thienyl derivatives of piperidine, morpholine, azepine, etc.
  • a heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring.
  • heterocycloalkyl groups include azetidinyl, azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, morpholino, 3-oxa-9-azaspiro[5.5]undecanyl, 1-oxa-8-azaspiro[4.5]decanyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrolidinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, tropanyl, and thiomorpholino.
  • the definitions or embodiments refer to specific rings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwise indicated, these rings can be attached to any ring member provided that the valency of the atom is not exceeded. For example, an azetidine ring may be attached at any position of the ring, whereas an azetidin-3-yl ring is attached at the 3-position.
  • the compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated.
  • Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C ⁇ N double bonds and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms.
  • Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art.
  • One method includes fractional recrystallization using a chiral resolving acid which is an optically active, salt-forming organic acid.
  • Suitable resolving agents for fractional recrystallization methods are, e.g., optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as ⁇ -camphorsulfonic acid.
  • 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.
  • Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine).
  • an optically active resolving agent e.g., dinitrobenzoylphenylglycine
  • Suitable elution solvent composition can be determined by one skilled in the art.
  • the compounds of the invention have the (R)-configuration. In other embodiments, the compounds have the (S)-configuration. In compounds with more than one chiral centers, each of the chiral centers in the compound may be independently (R) or (S), unless otherwise indicated.
  • Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton.
  • Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge.
  • Example prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, e.g., 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole and 1H- and 2H-pyrazole.
  • Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
  • Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include tritium and deuterium.
  • One or more constituent atoms of the compounds of the invention can be replaced or substituted with isotopes of the atoms in natural or non-natural abundance.
  • the compound includes at least one deuterium atom.
  • one or more hydrogen atoms in a compound of the present disclosure can be replaced or substituted by deuterium.
  • the compound includes two or more deuterium atoms.
  • the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 deuterium atoms. Synthetic methods for including isotopes into organic compounds are known in the art.
  • compound as used herein is meant to include all stereoisomers, geometric isomers, tautomers and isotopes of the structures depicted.
  • the term is also meant to refer to compounds of the inventions, regardless of how they are prepared, e.g., synthetically, through biological process (e.g., metabolism or enzyme conversion), or a combination thereof.
  • All compounds, and pharmaceutically acceptable salts thereof can be found together with other substances such as water and solvents (e.g., hydrates and solvates) or can be isolated.
  • solvents e.g., hydrates and solvates
  • the compounds described herein and salts thereof may occur in various forms and may, e.g., take the form of solvates, including hydrates.
  • the compounds may be in any solid state form, such as a polymorph or solvate, so unless clearly indicated otherwise, reference in the specification to compounds and salts thereof should be understood as encompassing any solid state form of the compound.
  • the compounds of the invention, 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, e.g., a composition enriched in the compounds of the invention.
  • 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 of the invention, or salt thereof.
  • phrases “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • ambient temperature and “room temperature,” as used herein, are understood in the art, and refer generally to a temperature, e.g., a reaction temperature, that is about the temperature of the room in which the reaction is carried out, e.g., a temperature from about 20° C. to about 30° C.
  • the present invention 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 invention include the non-toxic salts of the parent compound formed, e.g., from non-toxic inorganic or organic acids.
  • the pharmaceutically acceptable salts of the present invention 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 (MeCN) are preferred.
  • non-aqueous media like ether, ethyl acetate, alcohols (e.g., methanol, ethanol, iso-propanol or butanol) or acetonitrile (MeCN) are preferred.
  • suitable salts are found in Remington's Pharmaceutical Sciences, 17 th Ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J. Pharm. Sci., 1977, 66(1), 1-19 and in Stahl et al., Handbook of Pharmaceutical
  • the reactions for preparing compounds of the invention can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis.
  • suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature.
  • a given reaction can be carried out in one solvent or a mixture of more than one solvent.
  • suitable solvents for a particular reaction step can be selected by the skilled artisan.
  • Preparation of compounds of the invention can involve the protection and deprotection of various chemical groups.
  • the need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art.
  • the chemistry of protecting groups is described, e.g., in Kocienski, Protecting Groups , (Thieme, 2007); Robertson, Protecting Group Chemistry , (Oxford University Press, 2000); Smith et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6 th Ed. (Wiley, 2007); Peturssion et al., “Protecting Groups in Carbohydrate Chemistry,” J Chem. Educ., 1997, 74(11), 1297; and Wuts et al., Protective Groups in Organic Synthesis, 4th Ed., (Wiley, 2006).
  • Reactions can be monitored according to any suitable method known in the art.
  • product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry or by chromatographic methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC).
  • spectroscopic means such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13 C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry or by chromatographic methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC).
  • HPLC high performance liquid chromatography
  • TLC thin layer chromatography
  • the compound of formula 7 can be synthesized by coupling the halo group (W 2 ) of 6 with a vinyl reagent (e.g., vinyl boronic acid pinacol ester) under standard coupling reaction conditions (such as Suzuki coupling reaction, e.g., in the presence of a palladium catalyst (e.g., 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)) and a base (e.g., a bicarbonate or a carbonate base)).
  • a vinyl reagent e.g., vinyl boronic acid pinacol ester
  • a palladium catalyst e.g., 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
  • base e.g., a bicarbonate or a carbonate base
  • the vinyl group in compound 7 is oxidatively cleaved to afford an aldehyde of formula 8 in the presence of suitable reagents such as, but not limited to, OsO 4 and NaIO 4 .
  • suitable reagents such as, but not limited to, OsO 4 and NaIO 4 .
  • compounds of formula 8a are obtained by a reductive amination between the compound of formula 8 and a suitable amine in a proper solvent such as THF or DCM using a reducing agent such as, but not limited to, sodium triacetoxyborohydride, optionally in the presence of an acid such as acetic acid.
  • Compounds of formula 8a can be alternatively synthesized using a process shown in Scheme 3.
  • the aromatic amine 3 is reacted with an acid of formula 9 under suitable conditions to form an amide bond providing the product of formula 10, using coupling reagents such as, but not limited to, HATU and DIPEA.
  • Subsequent reduction of the ester group in compound 10 can give an alcohol of formula 11 using a suitable reducing agent such as, but not limited to, lithium aluminum hydride.
  • the alcohol unit in compound 11 was oxidized to aldehyde in compound 8 with a suitable oxidant such as, but not limited to, Dess-Martin periodinane.
  • the compound of formula 8a was obtained by a reductive amination between formula 8 and a suitable amine in a proper solvent such as THF or DCM using a reducing agent such as, but not limited to, sodium triacetoxyborohydride, optionally in the presence of an acid such as acetic acid.
  • a proper solvent such as THF or DCM
  • a reducing agent such as, but not limited to, sodium triacetoxyborohydride, optionally in the presence of an acid such as acetic acid.
  • the compound of formula 14 can be synthesized by coupling the halo group (W 3 ) of 13 with a vinyl reagent (e.g., vinyl boronic acid pinacol ester) under standard coupling reaction conditions (such as Suzuki coupling reaction, e.g., in the presence of a palladium catalyst (e.g., 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)) and a base (e.g., a bicarbonate or a carbonate base)).
  • a vinyl reagent e.g., vinyl boronic acid pinacol ester
  • a palladium catalyst e.g., 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
  • base e.g., a bicarbonate or a carbonate base
  • the vinyl group in compound 14 is oxidatively cleaved to afford an aldehyde of formula 15 in the presence of suitable reagents such as, but not limited to, OsO 4 and NaIO 4 .
  • suitable reagents such as, but not limited to, OsO 4 and NaIO 4 .
  • the compound of formula 15a is obtained by a reductive amination between the compound of formula 15 and a suitable amine in a proper solvent such as THF or DCM using a reducing agent such as, but not limited to, sodium triacetoxyborohydride, optionally in the presence of an acid such as acetic acid.
  • Acids of formula 4 can react with aromatic amines of formula 16 under amide coupling conditions [e.g., in the presence of 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) and a suitable base such as N,N-Diisopropylethylamine (DIPEA)] to give amide derivatives of formula 17.
  • HATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate
  • DIPEA N,N-Diisopropylethylamine
  • M is a boronic acid, boronic ester or an appropriately substituted metal
  • M is B(OR) 2 , Sn(Alkyl) 4 , or Zn-Hal
  • Suzuki coupling conditions e.g., in the presence of a palladium catalyst and a suitable base
  • Stille coupling conditions e.
  • compound 18 can be a cyclic amine (where M is H and attached to an amine nitrogen in ring A) and the coupling of aryl halide 17 with the cyclic amine 18 can be performed under Buchwald amination conditions (e.g., in the presence of a palladium catalyst and a base such as sodium tert-butoxide).
  • Buchwald amination conditions e.g., in the presence of a palladium catalyst and a base such as sodium tert-butoxide.
  • compounds of formula 19 can also be prepared using reaction sequence as outlined in Scheme 6. Coupling of aromatic halides of formula 16 with compounds of formula 18 can be achieved under similar conditions as described in Scheme 5 (e.g., conditions used for coupling of compounds 17 and compounds 18) to give compounds of formula 20. Acids of formula 4 can react with aromatic amines of formula 20 under amide coupling conditions to give compounds of formula 19.
  • Compounds of the present disclosure can inhibit the activity of PD-1/PD-L1 protein/protein interaction and, thus, are useful in treating diseases and disorders associated with activity of PD-1 and the diseases and disorders associated with PD-L1 including its interaction with other proteins such as PD-1 and B7-1 (CD80).
  • the compounds of the present disclosure, or pharmaceutically acceptable salts or stereoisomers thereof are useful for therapeutic administration to enhance stimulate and/or increase immunity in cancer or chronic infection, including enhancement of response to vaccination.
  • the present disclosure provides a method for inhibiting the PD-1/PD-L1 protein/protein interaction.
  • the method includes administering to an individual or a patient a compound of Formula (I′), Formula (I) or of any of the formulas as described herein, or of a compound as recited in any of the claims and described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof.
  • the compounds of the present disclosure can be used alone, in combination with other agents or therapies or as an adjuvant or neoadjuvant for the treatment of diseases or disorders, including cancer or infection diseases.
  • any of the compounds of the disclosure including any of the embodiments thereof, may be used.
  • the compounds of the present disclosure inhibit the PD-1/PD-L1 protein/protein interaction, resulting in a PD-1 pathway blockade.
  • the blockade of PD-1 can enhance the immune response to cancerous cells and infectious diseases in mammals, including humans.
  • the present disclosure provides treatment of an individual or a patient in vivo using a compound of Formula (I′), Formula (I) or a salt or stereoisomer thereof such that growth of cancerous tumors is inhibited.
  • a compound of Formula (I′), Formula (I) or of any of the formulas as described herein, or a compound as recited in any of the claims and described herein, or a salt or stereoisomer thereof, can be used to inhibit the growth of cancerous tumors.
  • a compound of Formula (I′), Formula (I) or of any of the formulas as described herein, or a compound as recited in any of the claims and described herein, or a salt or stereoisomer thereof can be used in conjunction with other agents or standard cancer treatments, as described below.
  • the present disclosure provides a method for inhibiting growth of tumor cells in vitro. The method includes contacting the tumor cells in vitro with a compound of Formula (I′), Formula (I) or of any of the formulas as described herein, or of a compound as recited in any of the claims and described herein, or of a salt or stereoisomer thereof.
  • the present disclosure provides a method for inhibiting growth of tumor cells in an individual or a patient.
  • the method includes administering to the individual or patient in need thereof a therapeutically effective amount of a compound of Formula (I′), Formula (I) or of any of the formulas as described herein, or of a compound as recited in any of the claims and described herein, or a salt or a stereoisomer thereof.
  • a method for treating cancer includes administering to a patient in need thereof, a therapeutically effective amount of a compound of Formula (I′), Formula (I) or any of the formulas as described herein, a compound as recited in any of the claims and described herein, or a salt thereof.
  • cancers include those whose growth may be inhibited using compounds of the disclosure and cancers typically responsive to immunotherapy.
  • the present disclosure provides a method of enhancing, stimulating and/or increasing the immune response in a patient.
  • the method includes administering to the patient in need thereof a therapeutically effective amount of a compound of Formula (I′), Formula (I) or any of the formulas as described herein, a compound or composition as recited in any of the claims and described herein, or a salt thereof.
  • cancers that are treatable using the compounds or combinations of the present disclosure include, but are not limited to, ewing sarcoma, cholangiocarcinoma, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, endometrial cancer, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemias including acute mye
  • cancers treatable with compounds or combinations of the present disclosure include melanoma (e.g., metastatic malignant melanoma), renal cancer (e.g. clear cell carcinoma), prostate cancer (e.g. hormone refractory prostate adenocarcinoma), breast cancer, colon cancer and lung cancer (e.g. non-small cell lung cancer). Additionally, the disclosure includes refractory or recurrent malignancies whose growth may be inhibited using the compounds of the disclosure.
  • melanoma e.g., metastatic malignant melanoma
  • renal cancer e.g. clear cell carcinoma
  • prostate cancer e.g. hormone refractory prostate adenocarcinoma
  • breast cancer e.g. hormone refractory prostate adenocarcinoma
  • colon cancer e.g. non-small cell lung cancer
  • lung cancer e.g. non-small cell lung cancer
  • cancers that are treatable using the compounds or combinations of the present disclosure include, but are not limited to, solid tumors (e.g., prostate cancer, colon cancer, esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer, renal cancer, hepatic cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancers of the head and neck, thyroid cancer, glioblastoma, sarcoma, bladder cancer, etc.), hematological cancers (e.g., lymphoma, leukemia such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), DLBCL, mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed or refractory NHL and recurrent follicular), Hodgkin lymphoma or multiple myeloma)
  • PD-1 pathway blockade with compounds of the present disclosure can also be used for treating infections such as viral, bacteria, fungus and parasite infections.
  • the present disclosure provides a method for treating infections such as viral infections. The method includes administering to a patient in need thereof, a therapeutically effective amount of a compound of Formula (I′), Formula (I) or any of the formulas as described herein, a compound as recited in any of the claims and described herein, a salt thereof.
  • viruses causing infections treatable by methods of the present disclosure include, but are not limit to, human immunodeficiency virus, human papillomavirus, influenza, hepatitis A, B, C or D viruses, adenovirus, poxvirus, herpes simplex viruses, human cytomegalovirus, severe acute respiratory syndrome virus, ebola virus, and measles virus.
  • viruses causing infections treatable by methods of the present disclosure include, but are not limit to, hepatitis (A, B, or C), herpes virus (e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus), adenovirus, influenza virus, flaviviruses, echovirus, rhinovirus, coxsackie virus, comovirus, respiratory syncytial virus, mumpsvirus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus and arboviral encephalitis virus.
  • herpes virus e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus
  • adenovirus e.g., adenovirus
  • influenza virus flaviviruses
  • the present disclosure provides a method for treating bacterial infections.
  • the method includes administering to a patient in need thereof, a therapeutically effective amount of a compound of Formula (I′), Formula (I) or any of the formulas as described herein, a compound as recited in any of the claims and described herein, or a salt thereof.
  • Non-limiting examples of pathogenic bacteria causing infections treatable by methods of the disclosure include chlamydia , rickettsial bacteria, mycobacteria, staphylococci, streptococci, pneumonococci, meningococci and conococci, klebsiella, proteus, serratia, pseudomonas, legionella , diphtheria, salmonella , bacilli, cholera, tetanus, botulism, anthrax, plague, leptospirosis, and Lyme's disease bacteria.
  • the present disclosure provides a method for treating fungus infections.
  • the method includes administering to a patient in need thereof, a therapeutically effective amount of a compound of Formula (I′), Formula (I) or any of the formulas as described herein, a compound as recited in any of the claims and described herein, or a salt thereof.
  • Non-limiting examples of pathogenic fungi causing infections treatable by methods of the disclosure include Candida ( albicans, krusei, glabrata, tropicalis , etc.), Cryptococcus neoformans, Aspergillus ( fumigatus, niger , etc.), Genus Mucorales ( mucor, absidia, rhizophus ), Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis and Histoplasma capsulatum.
  • Candida albicans, krusei, glabrata, tropicalis , etc.
  • Cryptococcus neoformans Aspergillus ( fumigatus, niger , etc.)
  • Genus Mucorales mucor, absidia, rhizophus
  • Sporothrix schenkii Blastomyces dermatitidis
  • the present disclosure provides a method for treating parasite infections.
  • the method includes administering to a patient in need thereof, a therapeutically effective amount of a compound of Formula (I′), Formula (I) or any of the formulas as described herein, a compound as recited in any of the claims and described herein, or a salt thereof.
  • Non-limiting examples of pathogenic parasites causing infections treatable by methods of the disclosure include Entamoeba histolytica, Balantidium coli, Naegleriafowleri, Acanthamoeba sp., Giardia lambia, Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi , and Nippostrongylus brasiliensis.
  • mice refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • terapéuticaally effective amount refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • treating refers to one or more of (1) inhibiting the disease; e.g., inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology); and (2) ameliorating the disease; e.g., ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) such as decreasing the severity of disease.
  • the compounds of the invention are useful in preventing or reducing the risk of developing any of the diseases referred to herein; e.g., preventing or reducing the risk of developing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease.
  • Cancer cell growth and survival can be impacted by multiple signaling pathways.
  • Targeting more than one signaling pathway (or more than one biological molecule involved in a given signaling pathway) may reduce the likelihood of drug-resistance arising in a cell population, and/or reduce the toxicity of treatment.
  • the compounds of the present disclosure can be used in combination with one or more other enzyme/protein/receptor inhibitors for the treatment of diseases, such as cancer or infections.
  • diseases such as cancer or infections.
  • cancers include solid tumors and liquid tumors, such as blood cancers.
  • infections include viral infections, bacterial infections, fungus infections or parasite infections.
  • the compounds of the present disclosure can be combined with one or more inhibitors of the following kinases for the treatment of cancer: Akt1, Akt2, Akt3, TGF- ⁇ R, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGF ⁇ R, PDGF ⁇ R, CSFIR, KIT, FLK-II, KDR/FLK-1, FLK-4, fit-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron, Sea, TRKA, TRKB, TRKC, FLT3, VEGFR/Flt2, Flt4, EphA1, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK,
  • the compounds of the present disclosure can be combined with one or more of the following inhibitors for the treatment of cancer or infections.
  • inhibitors that can be combined with the compounds of the present disclosure for treatment of cancer and infections include an FGFR inhibitor (FGFR1, FGFR2, FGFR3 or FGFR4, e.g., INCB54828, INCB62079 and INCB63904), a JAK inhibitor (JAK1 and/or JAK2, e.g., ruxolitinib, baricitinib or INCB39110), an IDO inhibitor (e.g., epacadostat and NLG919), an LSD1 inhibitor (e.g., INCB59872 and INCB60003), a TDO inhibitor, a PI3K-delta inhibitor, a PI3K-gamma inhibitor, such as PI3K-gamma selective inhibitor (e.g., INCB50797), a Pim inhibitor, a CSF1R inhibitor, a
  • immune checkpoint inhibitors include inhibitors against immune checkpoint molecules such as CD27, CD28, CD40, CD122, CD96, CD73, CD47, OX40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, CD137 (also known as 4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, PD-1, PD-L1 and PD-L2.
  • immune checkpoint inhibitors include inhibitors against immune checkpoint molecules such as CD27, CD28, CD40, CD122, CD96, CD73, CD47, OX40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, CD137 (also known as 4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM
  • the immune checkpoint molecule is a stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS, OX40, GITR and CD137.
  • the immune checkpoint molecule is an inhibitory checkpoint molecule selected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, and VISTA.
  • the compounds provided herein can be used in combination with one or more agents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors and TGFR beta inhibitors.
  • the inhibitor of an immune checkpoint molecule is anti-PD1 antibody, anti-PD-L1 antibody, or anti-CTLA-4 antibody.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody.
  • the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, or AMP-224.
  • the anti-PD-1 monoclonal antibody is nivolumab or pembrolizumab.
  • the anti-PD1 antibody is pembrolizumab.
  • the anti PD-1 antibody is SHR-1210.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody.
  • the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C.
  • the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody.
  • the anti-CTLA-4 antibody is ipilimumab.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of LAG3, e.g., an anti-LAG3 antibody.
  • the anti-LAG3 antibody is BMS-986016 or LAG525.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of GITR, e.g., an anti-GITR antibody.
  • the anti-GITR antibody is TRX518 or MK-4166.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of OX40, e.g., an anti-OX40 antibody or OX40L fusion protein.
  • OX40 e.g., an anti-OX40 antibody or OX40L fusion protein.
  • the anti-OX40 antibody is MEDI0562.
  • the OX40L fusion protein is MEDI6383.
  • the agent is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulatory agent.
  • an alkylating agent examples include cyclophosphamide (CY), melphalan (MEL), and bendamustine.
  • the proteasome inhibitor is carfilzomib.
  • the corticosteroid is dexamethasone (DEX).
  • the immunomodulatory agent is lenalidomide (LEN) or pomalidomide (POM).
  • the compounds of the present disclosure can further be used in combination with other methods of treating cancers, for example by chemotherapy, irradiation therapy, tumor-targeted therapy, adjuvant therapy, immunotherapy or surgery.
  • immunotherapy include cytokine treatment (e.g., interferons, GM-CSF, G-CSF, IL-2), CRS-207 immunotherapy, cancer vaccine, monoclonal antibody, adoptive T cell transfer, oncolytic virotherapy and immunomodulating small molecules, including thalidomide or JAK1/2 inhibitor and the like.
  • the compounds can be administered in combination with one or more anti-cancer drugs, such as a chemotherapeutics.
  • Example chemotherapeutics include any of: abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bevacizumab, bexarotene, baricitinib, bleomycin, bortezombi, bortezomib, busulfan intravenous, busulfan oral, calusterone, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazox
  • anti-cancer agent(s) include antibody therapeutics such as trastuzumab (Herceptin), antibodies to costimulatory molecules such as CTLA-4 (e.g., ipilimumab), 4-IBB, antibodies to PD-1 and PD-L1, or antibodies to cytokines (IL-10, TGF- ⁇ , etc.).
  • Examples of antibodies to PD-1 and/or PD-L1 that can be combined with compounds of the present disclosure for the treatment of cancer or infections such as viral, bacteria, fungus and parasite infections include, but are not limited to, nivolumab, pembrolizumab, MPDL3280A, MEDI-4736 and SHR-1210.
  • the anti-cancer agent is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulatory agent.
  • an alkylating agent include cyclophosphamide (CY), melphalan (MEL), and bendamustine.
  • the proteasome inhibitor is carfilzomib.
  • the corticosteroid is dexamethasone (DEX).
  • the immunomodulatory agent is lenalidomide (LEN) or pomalidomide (POM).
  • immune checkpoint inhibitors include inhibitors against immune checkpoint molecules such as CD27, CD28, CD40, CD122, CD96, CD73, CD47, OX40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, CD137 (also known as 4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, PD-1, PD-L1 and PD-L2.
  • immune checkpoint inhibitors include inhibitors against immune checkpoint molecules such as CD27, CD28, CD40, CD122, CD96, CD73, CD47, OX40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, CD137 (also known as 4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM
  • the immune checkpoint molecule is a stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS, OX40, GITR and CD137.
  • the immune checkpoint molecule is an inhibitory checkpoint molecule selected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, and VISTA.
  • the compounds provided herein can be used in combination with one or more agents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors and TGFR beta inhibitors.
  • the inhibitor of an immune checkpoint molecule is anti-PD1 antibody, anti-PD-L1 antibody, or anti-CTLA-4 antibody.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody.
  • the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, or AMP-224.
  • the anti-PD-1 monoclonal antibody is nivolumab or pembrolizumab.
  • the anti-PD1 antibody is pembrolizumab.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody.
  • the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C.
  • the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody.
  • the anti-CTLA-4 antibody is ipilimumab.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of LAG3, e.g., an anti-LAG3 antibody.
  • the anti-LAG3 antibody is BMS-986016 or LAG525.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of GITR, e.g., an anti-GITR antibody.
  • the anti-GITR antibody is TRX518 or MK-4166.
  • the inhibitor of an immune checkpoint molecule is an inhibitor of OX40, e.g., an anti-OX40 antibody or OX40L fusion protein.
  • OX40 e.g., an anti-OX40 antibody or OX40L fusion protein.
  • the anti-OX40 antibody is MEDI0562.
  • the OX40L fusion protein is MEDI6383.
  • the compounds of the present disclosure can further be used in combination with one or more anti-inflammatory agents, steroids, immunosuppressants or therapeutic antibodies.
  • the compounds of Formula (I′), Formula (I) or any of the formulas as described herein, a compound as recited in any of the claims and described herein, or salts thereof can be combined with another immunogenic agent, such as cancerous cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immune stimulating cytokines.
  • tumor vaccines include peptides of melanoma antigens, such as peptides of gp100, MAGE antigens, Trp-2, MARTI and/or tyrosinase, or tumor cells transfected to express the cytokine GM-CSF.
  • tumor vaccines include the proteins from viruses implicated in human cancers such as Human Papilloma Viruses (HPV), Hepatitis Viruses (HBV and HCV) and Kaposi's Herpes Sarcoma Virus (KHSV).
  • HPV Human Papilloma Viruses
  • HBV and HCV Hepatitis Viruses
  • KHSV Kaposi's Herpes Sarcoma Virus
  • the compounds of the present disclosure can be used in combination with tumor specific antigen such as heat shock proteins isolated from tumor tissue itself.
  • the compounds of Formula (I′), Formula (I) or any of the formulas as described herein, a compound as recited in any of the claims and described herein, or salts thereof can be combined with dendritic cells immunization to activate potent anti-tumor responses.
  • the compounds of the present disclosure can be used in combination with bispecific macrocyclic peptides that target Fe alpha or Fe gamma receptor-expressing effectors cells to tumor cells.
  • the compounds of the present disclosure can also be combined with macrocyclic peptides that activate host immune responsiveness.
  • 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 Formula (I′), Formula (I) or any of the formulas as described herein, a compound as recited in any of the claims and described herein, or salts thereof can be used in combination with vaccines, to stimulate the immune response to pathogens, toxins, and self antigens.
  • pathogens for which this therapeutic approach may be particularly useful include pathogens for which there is currently no effective vaccine, or pathogens for which conventional vaccines are less than completely effective. These include, but are not limited to, HIV, Hepatitis (A, B, & C), Influenza, Herpes, Giardia , Malaria, Leishmania, Staphylococcus aureus, Pseudomonas Aeruginosa.
  • Viruses causing infections treatable by methods of the present disclosure include, but are not limit to human papillomavirus, influenza, hepatitis A, B, C or D viruses, adenovirus, poxvirus, herpes simplex viruses, human cytomegalovirus, severe acute respiratory syndrome virus, ebola virus, measles virus, herpes virus (e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus), flaviviruses, echovirus, rhinovirus, coxsackie virus, cornovirus, respiratory syncytial virus, mumpsvirus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus and arboviral encephalitis virus.
  • human papillomavirus influenza, hepatitis A,
  • Pathogenic bacteria causing infections treatable by methods of the disclosure include, but are not limited to, chlamydia , rickettsial bacteria, mycobacteria, staphylococci, streptococci, pneumonococci, meningococci and conococci, klebsiella, proteus, serratia, pseudomonas, legionella , diphtheria, salmonella , bacilli, cholera, tetanus, botulism, anthrax, plague, leptospirosis, and Lyme's disease bacteria.
  • Pathogenic fungi causing infections treatable by methods of the disclosure include, but are not limited to, Candida ( albicans, krusei, glabrata, tropicalis , etc.), Cryptococcus neoformans, Aspergillus ( fumigatus, niger , etc.), Genus Mucorales ( mucor, absidia, rhizophus ), Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis and Histoplasma capsulatum.
  • Candida albicans, krusei, glabrata, tropicalis , etc.
  • Cryptococcus neoformans Aspergillus ( fumigatus, niger , etc.)
  • Genus Mucorales mucor, absidia, rhizophus
  • Sporothrix schenkii Blastomyces dermatitidis
  • Pathogenic parasites causing infections treatable by methods of the disclosure include, but are not limited to, Entamoeba histolytica, Balantidium coli, Naegleriafowleri, Acanthamoeba sp., Giardia lambia, Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi , and Nippostrongylus brasiliensis.
  • more than one pharmaceutical agent When more than one pharmaceutical agent is administered to a patient, they can be administered simultaneously, separately, sequentially, or in combination (e.g., for more than two agents).
  • the compounds of the present disclosure can be administered in the form of pharmaceutical compositions.
  • a composition comprising a compound of Formula (I′), Formula (I) or any of the formulas as described herein, a compound as recited in any of the claims and described herein, or a pharmaceutically acceptable salt thereof, or any of the embodiments thereof, and at least one pharmaceutically acceptable carrier or excipient.
  • 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 indicated 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.
  • Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal intramuscular or injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration.
  • Parenteral administration can be in the form of a single bolus dose, or may be, e.g., by a continuous perfusion pump.
  • compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders.
  • Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.
  • compositions which contain, as the active ingredient, the compound of the present disclosure or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers or excipients.
  • the composition is suitable for topical administration.
  • the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, e.g., a capsule, sachet, paper, or other container.
  • the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, e.g., up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.
  • the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g., about 40 mesh.
  • the compounds of the invention may be milled using known milling procedures such as wet milling to obtain a particle size appropriate for tablet formation and for other formulation types.
  • Finely divided (nanoparticulate) preparations of the compounds of the invention can be prepared by processes known in the art see, e.g., WO 2002/000196.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents.
  • the compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • the pharmaceutical composition comprises silicified microcrystalline cellulose (SMCC) and at least one compound described herein, or a pharmaceutically acceptable salt thereof.
  • SMCC silicified microcrystalline cellulose
  • the silicified microcrystalline cellulose comprises about 98% microcrystalline cellulose and about 2% silicon dioxide w/w.
  • the composition is a sustained release composition comprising at least one compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient.
  • the composition comprises at least one compound described herein, or a pharmaceutically acceptable salt thereof, and at least one component selected from microcrystalline cellulose, lactose monohydrate, hydroxypropyl methylcellulose and polyethylene oxide.
  • the composition comprises at least one compound described herein, or a pharmaceutically acceptable salt thereof, and microcrystalline cellulose, lactose monohydrate and hydroxypropyl methylcellulose.
  • the composition comprises at least one compound described herein, or a pharmaceutically acceptable salt thereof, and microcrystalline cellulose, lactose monohydrate and polyethylene oxide.
  • the composition further comprises magnesium stearate or silicon dioxide.
  • the microcrystalline cellulose is Avicel PH102TM.
  • the lactose monohydrate is Fast-flo 316TM.
  • the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose 2208 K4M (e.g., Methocel K4 M PremierTM) and/or hydroxypropyl methylcellulose 2208 K100LV (e.g., Methocel K00LVTM).
  • the polyethylene oxide is polyethylene oxide WSR 1105 (e.g., Polyox WSR 1105TM).
  • a wet granulation process is used to produce the composition. In some embodiments, a dry granulation process is used to produce the composition.
  • compositions can be formulated in a unit dosage form, each dosage containing from about 5 to about 1,000 mg (1 g), more usually about 100 mg to about 500 mg, of the active ingredient. In some embodiments, each dosage contains about 10 mg of the active ingredient. In some embodiments, each dosage contains about 50 mg of the active ingredient. In some embodiments, each dosage contains about 25 mg of the active ingredient.
  • unit dosage forms refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the components used to formulate the pharmaceutical compositions are of high purity and are substantially free of potentially harmful contaminants (e.g., at least National Food grade, generally at least analytical grade, and more typically at least pharmaceutical grade).
  • the composition is preferably manufactured or formulated under Good Manufacturing Practice standards as defined in the applicable regulations of the U.S. Food and Drug Administration.
  • suitable formulations may be sterile and/or substantially isotonic and/or in full compliance with all Good Manufacturing Practice regulations of the U.S. Food and Drug Administration.
  • the active compound may be effective over a wide dosage range and is generally administered in a therapeutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms and the like.
  • the therapeutic dosage of a compound of the present invention can vary according to, e.g., the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician.
  • the proportion or concentration of a compound of the invention in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration.
  • the compounds of the invention can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w/v of the compound for parenteral administration. Some typical dose ranges are from about 1 ⁇ g/kg to about 1 g/kg of body weight per day.
  • the dose range is from about 0.01 mg/kg to about 100 mg/kg of body weight per day.
  • the dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.
  • the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
  • a solid preformulation composition containing a homogeneous mixture of a compound of the present invention.
  • the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, e.g., about 0.1 to about 1000 mg of the active ingredient of the present invention.
  • the tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
  • liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra.
  • the compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • Compositions can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face mask, tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.
  • Topical formulations can contain one or more conventional carriers.
  • ointments can contain water and one or more hydrophobic carriers selected from, e.g., liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white Vaseline, and the like.
  • Carrier compositions of creams can be based on water in combination with glycerol and one or more other components, e.g., glycerinemonostearate, PEG-glycerinemonostearate and cetylstearyl alcohol.
  • Gels can be formulated using isopropyl alcohol and water, suitably in combination with other components such as, e.g., glycerol, hydroxyethyl cellulose, and the like.
  • topical formulations contain at least about 0.1, at least about 0.25, at least about 0.5, at least about 1, at least about 2 or at least about 5 wt % of the compound of the invention.
  • the topical formulations can be suitably packaged in tubes of, e.g., 100 g which are optionally associated with instructions for the treatment of the select indication, e.g., psoriasis or other skin condition.
  • compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient and the like.
  • compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration.
  • the pH of the compound preparations typically will be between 3 and 11, more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers or stabilizers will result in the formation of pharmaceutical salts.
  • the therapeutic dosage of a compound of the present invention can vary according to, e.g., the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician.
  • the proportion or concentration of a compound of the invention in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration.
  • the compounds of the invention can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w/v of the compound for parenteral administration. Some typical dose ranges are from about 1 ⁇ g/kg to about 1 g/kg of body weight per day.
  • the dose range is from about 0.01 mg/kg to about 100 mg/kg of body weight per day.
  • the dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.
  • the compounds of the present disclosure can further be useful in investigations of biological processes in normal and abnormal tissues.
  • another aspect of the present invention relates to labeled compounds of the invention (radio-labeled, fluorescent-labeled, etc.) that would be useful not only in imaging techniques but also in assays, both in vitro and in vivo, for localizing and quantitating PD-1 or PD-L1 protein in tissue samples, including human, and for identifying PD-L1 ligands by inhibition binding of a labeled compound.
  • the present invention includes PD-1/PD-L1 binding assays that contain such labeled compounds.
  • the present invention further includes isotopically-substituted compounds of the disclosure.
  • An “isotopically-substituted” compound is a compound of the invention where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring). It is to be understood that a “radio-labeled” compound is a compound that has incorporated at least one isotope that is radioactive (e.g., radionuclide).
  • Suitable radionuclides that may be incorporated in compounds of the present invention include but are not limited to 3 H (also written as T for tritium), 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 18 F, 35 S, 36 Cl, 82 Br, 75 Br, 76 Br, 77 Br, 123 I, 124 I, 125 I and 131 I.
  • the radionuclide that is incorporated in the instant radio-labeled compounds will depend on the specific application of that radio-labeled compound. For example, for in vitro PD-L1 protein labeling and competition assays, compounds that incorporate 3 H, 14 C, 82 Br, 125 I, 131 I, 35 S or will generally be most useful.
  • radionuclide is selected from the group consisting of 3 H, 14 C, 125 I, 35 S and 82 Br. Synthetic methods for incorporating radio-isotopes into organic compounds are known in the art.
  • a labeled compound of the invention can be used in a screening assay to identify and/or evaluate compounds.
  • a newly synthesized or identified compound i.e., test compound
  • a test compound which is labeled can be evaluated for its ability to bind a PD-L1 protein by monitoring its concentration variation when contacting with the PD-L1 protein, 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 a PD-L1 protein (i.e., standard compound). Accordingly, the ability of a test compound to compete with the standard compound for binding to the PD-L1 protein directly correlates to its binding affinity.
  • the standard compound is labeled and test compounds are unlabeled. Accordingly, the concentration of the labeled standard compound is monitored in order to evaluate the competition between the standard compound and the test compound, and the relative binding affinity of the test compound is thus ascertained.
  • kits useful useful, e.g., in the treatment or prevention of diseases or disorders associated with the activity of PD-L1 including its interaction with other proteins such as PD-1 and B7-1 (CD80), such as cancer or infections, which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I′), Formula (I), or any of the embodiments thereof.
  • kits can further include one or more of various conventional pharmaceutical kit components, such as, e.g., containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art.
  • Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit.
  • Step 2 methyl 6- ⁇ [(2-methylbiphenyl-3-yl)amino]carbonyl ⁇ nicotinate
  • N,N-Diisopropylethylamine 200 ⁇ L, 1 mmol was added to a mixture of 2-methylbiphenyl-3-amine (70 mg, 0.4 mmol), 5-(methoxycarbonyl)pyridine-2-carboxylic acid (Oakwood Chemical, cat#017196, 75 mg, 0.42 mmol), and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (220 mg, 0.57 mmol) in N,N-dimethylformamide (2 mL, 20 mmol). The reaction mixture was allowed to stir at room temperature (rt) overnight.
  • Step 4 (2S)-1-[(5-methyl-6- ⁇ [(2-methylbiphenyl-3-yl)amino]carbonyl ⁇ pyridin-3-yl)methyl]piperidine-2-carboxylic acid
  • This compound was prepared using a similar procedure as described for Example 1, Step 5, with 5-formyl-3-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide replacing 5-formyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide.
  • LC-MS calculated for C 27 H 30 N 3 O 3 (M+H) + : m/z 444.2; found 444.2.
  • Step 4 (2S)-1-[(2- ⁇ [(2-methylbiphenyl-3-yl)amino]carbonyl ⁇ pyrimidin-5-yl)methyl]piperidine-2-carboxylic acid
  • This compound was prepared using a similar procedure as described for Example 1, Step 5, with 5-formyl-N-(2-methylbiphenyl-3-yl)pyrimidine-2-carboxamide replacing 5-formyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide.
  • LC-MS calculated for C 25 H 27 N 4 O 3 (M+H) + : m/z 431.2; found 431.1.
  • N,N-Diisopropylethylamine 200 ⁇ L, 1 mmol was added to a mixture of 3-aminobiphenyl-2-carbonitrile (80 mg, 0.4 mmol), 5-bromopyridine-2-carboxylic acid (Frontier Scientific cat#B 1704, 96 mg, 0.47 mmol), and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (250 mg, 0.65 mmol) in N,N-dimethylformamide (2 mL, 20 mmol). The reaction mixture was allowed to stir at rt overnight.
  • This compound was prepared using a similar procedure as described for Example 1, Step 5, with N-(2-cyanobiphenyl-3-yl)-5-formylpyridine-2-carboxamide replacing 5-formyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide.
  • LC-MS calculated for C 26 H 25 N 4 O 3 (M+H) + : m/z 441.2; found 441.1.
  • This compound was prepared using a similar procedure as described for Example 1, Step 1, with 2,3-dihydro-1,4-benzodioxin-6-ylboronic acid (Sigma-Aldrich, cat#635995) replacing phenylboronic acid, and with 2-amino-6-bromobenzonitrile (Astatech, cat#CL8148) replacing 3-bromo-2-methylaniline.
  • N,N-Diisopropylethylamine 200 ⁇ L, 1 mmol was added to a mixture of 2-amino-6-(2,3-dihydro-1,4-benzodioxin-6-yl)benzonitrile (100 mg, 0.4 mmol), 5-bromopyridine-2-carboxylic acid (Frontier Scientific cat#B1704, 96 mg, 0.47 mmol), and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (250 mg, 0.65 mmol) in N,N-dimethylformamide (2 mL, 20 mmol).
  • Step 3 N-[2-cyano-3-(2, 3-dihydro-1, 4-benzodioxin-6-yl)phenyl]-5-vinylpyridine-2-carboxamide
  • Step 4 N-[2-cyano-3-(2, 3-dihydro-1, 4-benzodioxin-6-yl)phenyl]-5-formylpyridine-2-carboxamide
  • This compound was prepared using a similar procedure as described for Example 1, Step 5, with N-[2-cyano-3-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]-5-formylpyridine-2-carboxamide replacing 5-formyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide.
  • LC-MS calculated for C 28 H 27 N 4 O 5 (M+H) + : m/z 499.2; found 499.2.
  • Step 1 pyrazine-2,5-dicarboxylic acid
  • Step 2 methyl 5- ⁇ [(2-methylbiphenyl-3-yl)amino]carbonyl ⁇ pyrazine-2-carboxylate
  • Step 5 5- ⁇ [(2-hydroxyethyl)amino]methyl ⁇ -N-(2-methylbiphenyl-3-yl)pyrazine-2-carboxamide
  • This compound was prepared using a similar procedure as described for Example 4 with 5-formyl-N-(2-methylbiphenyl-3-yl)pyrazine-2-carboxamide replacing 5-formyl-3-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide.
  • LC-MS calculated for C 21 H 23 N 4 O 2 (M+H) + : m/z 363.2; found 363.2.
  • This compound was prepared using a similar procedure as described for Example 11, Step 1, with pyridazine-3,6-dicarboxylic acid (Astatech, cat#37156) replacing pyrazine-2,5-dicarboxylic acid.
  • Step 2 methyl 6- ⁇ [(2-methylbiphenyl-3-yl)amino]carbonyl ⁇ pyridazine-3-carboxylate
  • Step 5 6- ⁇ [(2-hydroxyethyl)amino]methyl ⁇ -N-(2-methylbiphenyl-3-yl)pyridazine-3-carboxamide
  • This compound was prepared using a similar procedure as described for Example 4 with 6-formyl-N-(2-methylbiphenyl-3-yl)pyridazine-3-carboxamide replacing 5-formyl-3-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide.
  • LC-MS calculated for C 21 H 23 N 4 O 2 (M+H) + : m/z 363.2; found 363.2.
  • Step 4 (2S)-1-[(2-methyl-6- ⁇ [(2-methylbiphenyl-3-yl)amino]carbonyl ⁇ pyridin-3-yl)methyl]piperidine-2-carboxylic acid
  • This compound was prepared using a similar procedure as described for Example 1, Step 5, with 5-formyl-6-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide replacing 5-formyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide.
  • LC-MS calculated for C 27 H 30 N 3 O 3 (M+H) + : m/z 444.2; found 444.2.
  • Step 4 (2S)-1-[(5-chloro-6- ⁇ [(2-methylbiphenyl-3-yl)amino]carbonyl ⁇ pyridin-3-yl)methyl]piperidine-2-carboxylic acid
  • This compound was prepared using a similar procedure as described for Example 1, Step 5 with 3-chloro-5-formyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide replacing 5-formyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide.
  • LC-MS calculated for C 26 H 27 ClN 3 O 3 (M+H) + : m/z 464.2; found 464.0.
  • Step 4 3-fluoro-5- ⁇ [(2-hydroxyethyl)amino]methyl ⁇ -N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide
  • This compound was prepared using a similar procedure as described for Example 4 with 3-fluoro-5-formyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide replacing 5-formyl-3-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide.
  • LC-MS calculated for C 22 H 23 FN 3 O 2 (M+H) + : m/z 380.2; found 380.2.
  • Step 3 4-[(3-cyanobenzyl)oxy]-N-(2-methylbiphenyl-3-yl)-5-vinylpyridine-2-carboxamide
  • Step 4 4-[(3-cyanobenzyl)oxy]-5-formyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide
  • Step 5 4-[(3-cyanobenzyl)oxy]-5- ⁇ [(2-hydroxyethyl)amino]methyl ⁇ -N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide
  • This compound was prepared using a similar procedure as described for Example 4 with 4-[(3-cyanobenzyl)oxy]-5-formyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide replacing 5-formyl-3-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide.
  • LC-MS calculated for C 30 H 29 N 4 O 3 (M+H) + : m/z 493.2; found 493.2.
  • Step 4 5- ⁇ [(2-hydroxyethyl)amino]methyl ⁇ -N-(2-methylbiphenyl-3-yl)-4-(pyridin-3-ylmethoxy)pyridine-2-carboxamide
  • Step 4 5- ⁇ [(2-hydroxyethyl)amino]methyl ⁇ -N-(2-methylbiphenyl-3-yl)-4-(pyridin-2-ylmethoxy)pyridine-2-carboxamide
  • Step 4 3-(dimethylamino)-5- ⁇ [(2-hydroxyethyl)amino]methyl ⁇ -N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide
  • This compound was prepared using a similar procedure as described for Example 4 with 3-(dimethylamino)-5-formyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide replacing 5-formyl-3-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide.
  • LC-MS calculated for C 24 H 29 N 4 O 2 (M+H) + : m/z 405.2; found 405.2.
  • Step 4 (2S)-1-[(2- ⁇ [(2-methylbiphenyl-3-yl)amino]carbonyl ⁇ pyridin-4-yl)methyl]piperidine-2-carboxylic acid
  • This compound was prepared using a similar procedure as described for Example 1, Step 5, with 4-formyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide replacing 5-formyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide.
  • LC-MS calculated for C 26 H 28 N 3 O 3 (M+H) + : m/z 430.2; found 430.2.
  • This compound was prepared using a similar procedure as described for Example 1, Step 2, with 4-cyanopyridine-2-carboxylic acid (Bionet Intermediates, cat#BB-0608) replacing 5-(methoxycarbonyl)pyridine-2-carboxylic acid.
  • This compound was prepared using a similar procedure as described for Example 1, Step 2, with 2-pyrazinecarboxylic acid (Sigma-Aldrich, cat#P56100) replacing 5-(methoxycarbonyl)pyridine-2-carboxylic acid.
  • This compound was prepared using a similar procedure as described for Example 1, Step 2, with pyrimidine-4-carboxylic acid (VWR International, cat#101390) replacing 5-(methoxycarbonyl)pyridine-2-carboxylic acid.
  • This compound was prepared using a similar procedure as described for Example 1, Step 2, with pyrimidine-2-carboxylic acid (Ark Pham, cat#AK-24353) replacing 5-(methoxycarbonyl)pyridine-2-carboxylic acid.
  • This compound was prepared using a similar procedure as described for Example 1, Step 2, with pyridazine-3-carboxylic acid (Ark Pham, cat#AK-28139) replacing 5-(methoxycarbonyl)pyridine-2-carboxylic acid.
  • This compound was prepared using a similar procedure as described for Example 1, Step 2, with 2-(pyridin-3-ylmethoxy)pyrimidine-4-carboxylic acid replacing 5-(methoxycarbonyl)pyridine-2-carboxylic acid.
  • Step 1 N-(2-methylbiphenyl-3-yl)-5-vinyl-4, 4′-bipyridine-2-carboxamide
  • Step 3 5- ⁇ [(2-hydroxyethyl)amino]methyl ⁇ -N-(2-methylbiphenyl-3-yl)-4,4′-bipyridine-2-carboxamide
  • Step 2 This compound was prepared using a similar procedure as described for Example 4 with 5-formyl-N-(2-methylbiphenyl-3-yl)-4,4′-bipyridine-2-carboxamide (Step 2) replacing 5-formyl-3-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide.
  • Step 4 (2S)-1-[(4-methyl-6- ⁇ [(2-methylbiphenyl-3-yl)amino]carbonyl ⁇ pyridin-3-yl)methyl]piperidine-2-carboxylic acid
  • This compound was prepared using a similar procedure as described for Example 1, Step 5 with 5-formyl-4-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide replacing 5-formyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide.
  • LC-MS calculated for C 27 H 30 N 3 O 3 (M+H) + : m/z 444.2; found 444.2.
  • Step 2 4-(cyclopropylmethoxy)-N-(2-methylbiphenyl-3-yl)-5-vinylpicolinamide
  • Step 3 4-(cyclopropylmethoxy)-5-formyl-N-(2-methylbiphenyl-3-yl)picolinamide
  • Step 4 4-(cyclopropylmethoxy)-5-((2-hydroxyethylamino)methyl)-N-(2-methylbiphenyl-3-yl)picolinamide
  • This compound was prepared using a similar procedure as described for Example 4 with 4-(cyclopropylmethoxy)-5-formyl-N-(2-methylbiphenyl-3-yl)picolinamide replacing 5-formyl-3-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide.
  • LC-MS calculated for C 26 H 30 N 3 O 3 (M+H) + : m/z 432.2; found 432.2.
  • Step 2 4-methoxy-N-(2-methylbiphenyl-3-yl)-5-vinylpyridine-2-carboxamide
  • Step 4 5- ⁇ [(2-hydroxyethyl)amino]methyl ⁇ -4-methoxy-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide
  • This compound was prepared using a similar procedure as described for Example 4 with 5-formyl-4-methoxy-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide replacing 5-formyl-3-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide.
  • LC-MS calculated for C 23 H 26 N 3 O 3 (M+H) + : m/z 392.2; found 392.2.
  • Step 4 (2S)-1-[(5-methyl-2- ⁇ [(2-methylbiphenyl-3-yl)amino]carbonyl ⁇ pyridin-4-yl)methyl]piperidine-2-carboxylic acid
  • This compound was prepared using a similar procedure as described for Example 1, Step 5 with 4-formyl-5-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide replacing 5-formyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide.
  • LC-MS calculated for C 27 H 30 N 3 O 3 (M+H) + : m/z 444.2; found 444.2.
  • Step 6 N-(2-cyano-3-cyclohex-1-en-1-ylphenyl)-5- ⁇ [(2-hydroxyethyl)amino]methyl ⁇ pyridine-2-carboxamide
  • This compound was prepared using a similar procedure as described for Example 1, Step 1 with 2-cyclohex-1-en-1-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane replacing phenylboronic acid, and with 2-amino-6-bromobenzonitrile (Astatech, cat#CL8148) replacing 3-bromo-2-methylaniline.
  • Step 2 methyl 6- ⁇ [(2-chloro-3-methylpyridin-4-yl)amino]carbonyl ⁇ nicotinate
  • Step 3 methyl 6- ⁇ [(3-methyl-2-phenylpyridin-4-yl)amino]carbonyl ⁇ nicotinate
  • Step 6 (S)-1-((6-(3-methyl-2-phenylpyridin-4-ylcarbamoyl)pyridin-3-yl)methyl)piperidine-2-carboxylic acid
  • This compound was prepared using a similar procedure as described for Example 1, Step 5 with 5-formyl-N-(3-methyl-2-phenylpyridin-4-yl)pyridine-2-carboxamide replacing 5-formyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide.
  • LC-MS calculated for C 25 H 27 N 4 O 3 (M+H) + : m/z 431.2; found 431.2.
  • This compound was prepared using a similar procedure as described for Example 41, Step 4 with 3-bromo-5-fluoro-2-methylaniline (Combi-Blocks, cat# ST-8934) replacing 2-amino-6-cyclohexylbenzonitrile.
  • Step 3 N-[3-(2, 3-dihydro-1, 4-benzodioxin-6-yl)-5-fluoro-2-methylphenyl]-5- ⁇ [(2-hydroxyethyl)amino]methyl ⁇ pyridine-2-carboxamide
  • This compound was prepared using a similar procedure as described for Example 38, Step 6 with 2,3-dihydro-1,4-benzodioxin-6-ylboronic acid (Sigma-Aldrich, cat#635995) replacing 2-cyclohex-1-en-1-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, and with N-(3-bromo-5-fluoro-2-methylphenyl)-5- ⁇ [(2-hydroxyethyl)amino]methyl ⁇ pyridine-2-carboxamide replacing N-(3-bromo-2-cyanophenyl)-5- ⁇ [(2-hydroxyethyl)amino]methyl ⁇ pyridine-2-carboxamide.
  • 2,3-dihydro-1,4-benzodioxin-6-ylboronic acid Sigma-Aldrich, cat#635995
  • Example A PD-1/PD-L1 Homogeneous Time-Resolved Fluorescence (HTRF) Binding Assay
  • the assays were conducted in a standard black 384-well polystyrene plate with a final volume of 20 ⁇ L. Inhibitors were first serially diluted in DMSO and then added to the plate wells before the addition of other reaction components. The final concentration of DMSO in the assay was 1%. The assays were carried out at 25° C. in the PBS buffer (pH 7.4) with 0.05% Tween-20 and 0.1% BSA. Recombinant human PD-L1 protein (19-238) with a His-tag at the C-terminus was purchased from AcroBiosystems (PD1-H5229).
  • Recombinant human PD-1 protein (25-167) with Fc tag at the C-terminus was also purchased from AcroBiosystems (PD1-H5257).
  • PD-L1 and PD-1 proteins were diluted in the assay buffer and 10 ⁇ L was added to the plate well. Plates were centrifuged and proteins were preincubated with inhibitors for 40 minutes. The incubation was followed by the addition of 10 ⁇ L of HTRF detection buffer supplemented with Europium cryptate-labeled anti-human IgG (PerkinElmer-AD0212) specific for Fc and anti-His antibody conjugated to SureLight®-Allophycocyanin (APC, PerkinElmer-AD0059H).
  • IC 50 determination was performed by fitting the curve of percent control activity versus the log of the inhibitor concentration using the GraphPad Prism 5.0 software.
  • Example 1 Data obtained for the Example compounds using the PD-1/PD-L1 homogenous time-resolved fluorescence (HTRF) binding assay described in Example A is provided in Table 1.
  • Table 1 Data obtained for the Example compounds using the PD-1/PD-L1 homogenous time-resolved fluorescence (HTRF) binding assay described in Example A is provided in Table 1.

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Abstract

Disclosed are compounds of Formula (I′), methods of using the compounds as immunomodulators, and pharmaceutical compositions comprising such compounds. The compounds are useful in treating, preventing or ameliorating diseases or disorders such as cancer or infections.
Figure US20170174671A1-20170622-C00001

Description

    FIELD OF THE INVENTION
  • The present application is concerned with pharmaceutically active compounds. The disclosure provides compounds as well as their compositions and methods of use. The compounds modulate PD-1/PD-L1 protein/protein interaction and are useful in the treatment of various diseases including infectious diseases and cancer.
    • BACKGROUND OF THE INVENTION
  • The immune system plays an important role in controlling and eradicating diseases such as cancer. However, cancer cells often develop strategies to evade or to suppress the immune system in order to favor their growth. One such mechanism is altering the expression of co-stimulatory and co-inhibitory molecules expressed on immune cells (Postow et al, J. Clinical Oncology 2015, 1-9). Blocking the signaling of an inhibitory immune checkpoint, such as PD-1, has proven to be a promising and effective treatment modality.
  • Programmed cell death-1 (PD-1), also known as CD279, is a cell surface receptor expressed on activated T cells, natural killer T cells, B cells, and macrophages (Greenwald et al, Annu. Rev. Immunol 2005, 23:515-548; Okazaki and Honjo, Trends Immunol 2006, (4): 195-201). It functions as an intrinsic negative feedback system to prevent the activation of T-cells, which in turn reduces autoimmunity and promotes self-tolerance. In addition, PD-1 is also known to play a critical role in the suppression of antigen-specific T cell response in diseases like cancer and viral infection (Sharpe et al, Nat Immunol 2007 8, 239-245; Postow et al, J. Clinical Oncol 2015, 1-9).
  • The structure of PD-1 consists of an extracellular immunoglobulin variable-like domain followed by a transmembrane region and an intracellular domain (Parry et al, Mol Cell Biol 2005, 9543-9553). The intracellular domain contains two phosphorylation sites located in an immunoreceptor tyrosine-based inhibitory motif and an immunoreceptor tyrosine-based switch motif, which suggests that PD-1 negatively regulates T cell receptor-mediated signals. PD-1 has two ligands, PD-L1 and PD-L2 (Parry et al, Mol Cell Biol 2005, 9543-9553; Latchman et al, Nat Immunol 2001, 2, 261-268), and they differ in their expression patterns. PD-L1 protein is upregulated on macrophages and dendritic cells in response to lipopolysaccharide and GM-CSF treatment, and on T cells and B cells upon T cell receptor and B cell receptor signaling. PD-L1 is also highly expressed on almost all tumor cells, and the expression is further increased after IFN-γ treatment (Iwai et al, PNAS2002, 99(19):12293-7; Blank et al, Cancer Res 2004, 64(3):1140-5). In fact, tumor PD-L1 expression status has been shown to be prognostic in multiple tumor types (Wang et al, Eur J Surg Oncol 2015; Huang et al, Oncol Rep 2015; Sabatier et al, Oncotarget 2015, 6(7): 5449-5464). PD-L2 expression, in contrast, is more restricted and is expressed mainly by dendritic cells (Nakae et al, J Immunol 2006, 177:566-73). Ligation of PD-1 with its ligands PD-L1 and PD-L2 on T cells delivers a signal that inhibits IL-2 and IFN-γ production, as well as cell proliferation induced upon T cell receptor activation (Carter et al, Eur J Immunol 2002, 32(3):634-43; Freeman et al, J Exp Med 2000, 192(7): 1027-34). The mechanism involves recruitment of SHP-2 or SHP-1 phosphatases to inhibit T cell receptor signaling such as Syk and Lck phosphorylation (Sharpe et al, Nat Immunol 2007, 8, 239-245). Activation of the PD-1 signaling axis also attenuates PKC-θ activation loop phosphorylation, which is necessary for the activation of NF-κB and API pathways, and for cytokine production such as IL-2, IFN-γ and TNF (Sharpe et al, Nat Immunol 2007, 8, 239-245; Carter et al, Eur J Immunol 2002, 32(3):634-43; Freeman et al, J Exp Med 2000, 192(7):1027-34).
  • Several lines of evidence from preclinical animal studies indicate that PD-1 and its ligands negatively regulate immune responses. PD-1-deficient mice have been shown to develop lupus-like glomerulonephritis and dilated cardiomyopathy (Nishimura et al, Immunity 1999, 11:141-151; Nishimura et al, Science 2001, 291:319-322). Using an LCMV model of chronic infection, it has been shown that PD-1/PD-L1 interaction inhibits activation, expansion and acquisition of effector functions of virus-specific CD8 T cells (Barber et al, Nature 2006, 439, 682-7). Together, these data support the development of a therapeutic approach to block the PD-1-mediated inhibitory signaling cascade in order to augment or “rescue” T cell response. Accordingly, there is a need for new compounds that block PD-1/PD-L1 protein/protein interaction.
    • SUMMARY
  • The present disclosure provides, inter alia, a compound of Formula (I′):
  • Figure US20170174671A1-20170622-C00002
  • or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein constituent variables are defined herein.
  • The present disclosure further provides, inter alia, a compound of Formula (I):
  • Figure US20170174671A1-20170622-C00003
  • or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein constituent variables are defined herein.
  • The present disclosure further provides a pharmaceutical composition comprising a compound of the disclosure, or a pharmaceutically acceptable salt or a stereoisomer thereof, and at least one pharmaceutically acceptable carrier or excipient.
  • The present disclosure further provides methods of modulating or inhibiting PD-1/PD-L1 protein/protein interaction, which comprises administering to an individual a compound of the disclosure, or a pharmaceutically acceptable salt or a stereoisomer thereof.
  • The present disclosure further provides methods of treating a disease or disorder in a patient comprising administering to the patient a therapeutically effective amount of a compound of the disclosure, or a pharmaceutically acceptable salt or a stereoisomer thereof.
    • DETAILED DESCRIPTION I. Compounds
  • The present disclosure provides compounds of Formula (I′):
  • Figure US20170174671A1-20170622-C00004
  • or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:
  • X1 is N or CR1;
  • X2 is N or CR2;
  • X3 is N or CR3;
  • X4 is N or CR4;
  • wherein no more than two of X1, X2, X3 and X4 are simultaneously N;
  • X5 is N or CR6a;
  • X6 is N or CR6b;
  • ring B is C6-10 aryl, C3-10 cycloalkyl, 5- to 14-membered heteroaryl, or 4- to 10-membered heterocycloalkyl, provided ring B is other than 9-H-carbazol-4-yl, 2,3,4,9-tetrahydro-1H-carbazol-5-yl or 1H-tetrazolyl;
  • R1, R2, R3, R4 and R7 are each independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, CN, NO2, ORa, SRa, NHORa, C(O)Ra, C(O)NRaRa, C(O)ORa, OC(O)Ra, OC(O)NRaRa, NHRa, NRaRa, NRaC(O)Ra, NRaC(O)ORa, NRaC(O)NRaRa, C(═NRa)Ra, C(═NRa)NRaRa, NRaC(═NRa)NRaRa, NRaS(O)Ra, NRaS(O)2Ra, NRaS(O)2NRaRa, S(O)Ra, S(O)NRaRa, S(O)2Ra, and S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of R1, R2, R3, R4 and R7 are each optionally substituted with 1, 2, 3, or 4 Rb substituents;
  • R5 is halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, CN, NO2, OR11, SR11, NH2, —NHR11, —NR11R11, NHOR11, C(O)R11, C(O)NR11R11, C(O)OR11, OC(O)R11, OC(O)NR11R11, NR11C(O)R11, NR11C(O)OR11, NR11C(O)NR11R11, C(═NR11)R11, C(═NR11)NR11R11, NR11C(═NR11)NR11R11, NR11S(O)R11, NR11S(O)2R11, NR11S(O)2NR11R11, S(O)R11, S(O)NR11R11, S(O)2R11, and S(O)2NR11R11, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of R5 are each optionally substituted with 1, 2 or 3 Rb substituents; wherein R5 is other than F when ring B is C3-10 cycloalkyl, 5- to 14-membered heteroaryl or 4- to 10-membered heterocycloalkyl;
  • each R11 is independently selected from H, CN, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of R11 are each optionally substituted with 1, 2 or 3 Rb substituents;
  • R6a, R6b and R6c are each independently selected from H, C1-4 alkyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl-, C6-10 aryl, C6-10 aryl-C1-4 alkyl-, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, C2-4 alkenyl, C2-4 alkynyl, halo, CN, OR10, C1-4 haloalkyl, C1-4 haloalkoxy, NH2, —NHR10, —NR10R10, NHOR10, C(O)R10, C(O)NR10R10, C(O)OR10, OC(O)R10, OC(O)NR10R10, NR10C(O)R10, NR10C(O)OR10, NR10C(O)NR10R10, C(═NR10)R10, C(═NR10)NR10R10, NR10C(═NR10)NR10R10, NR10S(O)R10, NR10S(O)2R10, NR10S(O)2NR10R10, S(O)R10, S(O)NR10R10, S(O)2R10, and S(O)2NR10R10, wherein each R10 is independently selected from H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl-, C6-10 aryl, C6-10 aryl-C1-4 alkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl-, C6-10 aryl, C6-10 aryl-C1-4 alkyl-, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of R6a, R6b, R6c and R10 are each optionally substituted with 1, 2 or 3 independently selected Rd substituents;
  • or two adjacent R7 substituents, taken together with the atoms to which they are attached, form a fused phenyl ring, a fused 4- to 7-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C3-10 cycloalkyl ring, wherein the fused 4- to 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- to 7-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C3-10 cycloalkyl ring are each optionally substituted with 1, 2 or 3 independently selected Rb substituents, provided
  • Figure US20170174671A1-20170622-C00005
  • is other than 9-H-carbazol-4-yl or 2,3,4,9-tetrahydro-1H-carbazol-5-yl, each of which is optionally substituted by 1, 2 or 3 independently selected Rb substituents;
  • or two R7 substituents attached to the same ring carbon atom of ring B, together with the carbon atom to which they are attached, form a 4- to 7-membered heterocycloalkyl ring having 1-4 heteroatoms as ring members selected from N, O and S or a C3-6 cycloalkyl ring, wherein the 4- to 7-membered heterocycloalkyl ring and C3-6 cycloalkyl ring are each optionally substituted with 1, 2 or 3 independently selected Rb substituents;
  • or R1 and X2 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C5-6 cycloalkyl ring are each optionally substituted with 1, 2 or 3 independently selected Rb substituents;
  • or R2 and X1 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C5-6 cycloalkyl ring are each optionally substituted with 1, 2 or 3 independently selected Rb substituents;
  • or R2 and X3 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C5-6 cycloalkyl ring are each optionally substituted with 1, 2 or 3 independently selected Rb substituents;
  • or R3 and X2 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C5-6 cycloalkyl ring are each optionally substituted with 1, 2 or 3 independently selected Rb substituents;
  • or R3 and X4 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C5-6 cycloalkyl ring are each optionally substituted with 1, 2 or 3 independently selected Rb substituents;
  • or R4 and X3 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C5-6 cycloalkyl ring are each optionally substituted with 1, 2 or 3 independently selected Rb substituents;
  • each Ra is independently selected from H, CN, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Ra are each optionally substituted with 1, 2, 3, 4, or 5 Rd substituents;
  • each Rd is independently selected from C1-6 alkyl, C1-6 haloalkyl, halo, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, CN, NH2, NHORe, ORe, SRe, C(O)Re, C(O)NReRe, C(O)ORe, OC(O)Re, OC(O)NReRe, NHRe, NReRe, NReC(O)Re, NReC(O)NReRe, NReC(O)ORe, C(═NRe)NReRe, NReC(═NRe)NReRe, NReC(═NOH)NReRe, NReC(═NCN)NReRe, S(O)Re, S(O)NReRe, S(O)2Re, NReS(O)2Re, NReS(O)2NReRe, and S(O)2NReRe, wherein the C1-6 alkyl, C1-6 haloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Rd are each optionally substituted with 1-3 independently selected Rf substituents;
  • each Rb substituent is independently selected from halo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, CN, OH, NH2, NO2, NHORc, ORc, SRc, C(O)Rc, C(O)NRcRc, C(O)ORc, OC(O)Rc, OC(O)NRcRc, C(═NRc)NRcRc, NRcC(═NRc)NRcRc, NHRc, NRcRc, NRcC(O)Rc, NRcC(O)ORc, NRcC(O)NRcRc, NRcS(O)Rc, NRcS(O)2Rc, NRcS(O)2NRcRc, S(O)Rc, S(O)NRcRc, S(O)2Rc and S(O)2NRcRc; wherein the C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Rb are each further optionally substituted with 1-3 independently selected Rd substituents;
  • each Rc is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Rc are each optionally substituted with 1, 2, 3, 4, or 5 Rf substituents independently selected from C1-4 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, halo, CN, NHORg, ORg, SRg, C(O)Rg, C(O)NRgRg, C(O)ORg, OC(O)Rg, OC(O)NRgRg, NHRg, NRgRg, NRgC(O)Rg, NRgC(O)NRgRg, NRgC(O)ORg, C(═NRg)NRgRg, NRgC(═NRg)NRgRg, S(O)Rg, S(O)NRgRg, S(O)2Rg, NRgS(O)2Rg, NRgS(O)2NRgRg, and S(O)2NRgRg; wherein the C1-4 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Rf are each optionally substituted with 1, 2, 3, 4, or 5 Rn substituents independently selected from C1-4 alkyl, C3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl-, (4-7 membered heterocycloalkyl)-C1-4 alkyl-, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, halo, CN, Ro, NHORo, ORo, SRo, C(O)Ro, C(O)NRoRo, C(O)ORo, OC(O)Ro, OC(O)NRoRo, NHRo, NRoRo, NRoC(O)Ro, NRoC(O)NRoRo, NRoC(O)ORo, C(═NR)NRoRo, NRoC(═NR)NRoRo, S(O)Ro, S(O)NRoRo, S(O)2Ro, NRoS(O)2Ro, NRoS(O)2NRoRo, and S(O)2NRoRo, wherein the C1-4 alkyl, C3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl-, (4-7 membered heterocycloalkyl)-C1-4 alkyl-, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl and C1-4 haloalkyl of Rn are each optionally substituted with 1, 2 or 3 Rq substituents;
  • each Rg is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Rg are each optionally substituted with 1-3 Rp substituents independently selected from C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, halo, CN, NHORr, ORr, SRr, C(O)Rr, C(O)NRrRr, C(O)ORr, OC(O)Rr, OC(O)NRrRr, NHRr, NRrRr, NRrC(O)Rr, NRrC(O)NRrRr, NRrC(O)ORr, C(═NRr)NRrRr, NRrC(═NRr)NRrRr, NRrC(═NOH)NRrRr, NRrC(═NCN)NRrRr, S(O)Rr, S(O)NRrRr, S(O)2Rr, NRrS(O)2Rr, NRrS(O)2NRrRr and S(O)2NRrRr, wherein the C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Rp are each optionally substituted with 1, 2 or 3 Rq substituents;
  • or any two Ra substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 Rh substituents independently selected from C1-6 alkyl, C3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl-, (4-7 membered heterocycloalkyl)-C1-4 alkyl-, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, halo, CN, ORi, SRi, NHORi, C(O)Ri, C(O)NRiRi, C(O)ORi, OC(O)Ri, OC(O)NRiRi, NHRi, NRiRi, NRiC(O)Ri, NRiC(O)NRiRi, NRiC(O)ORi, C(═NRi)NRiRi, NRiC(═NRi)NRiRi, S(O)Ri, S(O)NRiRi, S(O)2Ri, NRiS(O)2Ri, NRiS(O)2NRiRi, and S(O)2NRiRi, wherein the C1-6 alkyl, C3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl-, and (4-7 membered heterocycloalkyl)-C1-4 alkyl- of Rh are each further optionally substituted by 1, 2, or 3 Rj substituents independently selected from C3-6 cycloalkyl, C6-10 aryl, 5 or 6-membered heteroaryl, 4-7 membered heterocycloalkyl, C2-4 alkenyl, C2-4 alkynyl, halo, C1-4 alkyl, C1-4 haloalkyl, C1-4haloalkoxy, CN, NHORk, ORk, SRk, C(O)Rk, C(O)NRkRk, C(O)ORk, OC(O)Rk, OC(O)NRkRk, NHRk, NRkRk, NRkC(O)Rk, NRkC(O)NRkRk, NRkC(O)ORk, C(═NRk)NRkRk, NRkC(═NRk)NRkRk, S(O)Rk, S(O)NRkRk, S(O)2Rk, NRkS(O)2Rk, NRkS(O)2NRkRk, and S(O)2NRkRk, wherein the C1-4 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5- or 6-membered heteroaryl, 4-7 membered heterocycloalkyl, C2-4 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, and C1-4haloalkoxy of Rj are each optionally substituted with 1, 2 or 3 independently selected Rq substituents; or two Rh groups attached to the same carbon atom of the 4- to 10-membered heterocycloalkyl taken together with the carbon atom to which they are attached form a C3-6 cycloalkyl or 4- to 6-membered heterocycloalkyl having 1-2 heteroatoms as ring members selected from O, N or S;
  • or any two Rc substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;
  • or any two Re substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;
  • or any two Rg substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;
  • or any two Ri substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;
  • or any two Rk substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;
  • or any two Ro substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents; and
  • each Re, Ri, Rk, Ro or Rr is independently selected from H, C1-4 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5 or 6-membered heteroaryl, 4-6 membered heterocycloalkyl, C1-4 haloalkyl, C2-4 alkenyl, and C2-4 alkynyl, wherein the C1-4 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5 or 6-membered heteroaryl, 4-6 membered heterocycloalkyl, C2-4 alkenyl, and C2-4 alkynyl of Re, Ri, Rk, Ro or Rr are each optionally substituted with 1, 2 or 3 Rq substituents;
  • each Rq is independently selected from OH, CN, —COOH, NH2, halo, C1-6 haloalkyl, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C3-6 cycloalkyl, NHR8, NR8R8, and C1-4 haloalkoxy, wherein the C1-6 alkyl, phenyl, C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl of Rq are each optionally substituted with halo, OH, CN, —COOH, NH2, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, phenyl, C3-10 cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl and each R8 is independently C1-6 alkyl;
  • Figure US20170174671A1-20170622-P00001
    is a single bond or a double bond, wherein ring A includes at least one double bond;
  • the subscript n is an integer of 1, 2, 3, 4 or 5; and
  • with the proviso (i) when
  • Figure US20170174671A1-20170622-C00006
  • is 2,6-dioxohexahydropyrimidin-1-yl, 2-oxopyrrolidin-1-yl, benzo[d]thiazol-2-yl, 2-amino-4-methyl-5,6-dihydro-1,3-thiazin-4-yl, 4-methyl-6-[4-(morpholine-4-carbonyl)anilino]-5-oxo-pyrazin-2-yl, 5,7-dimethylbenzo[d]oxazol-2-yl, 6-[4-(morpholine-4-carbonyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl, 8-[4-(morpholine-4-carbonyl)anilino]imidazo[1,2-a]pyrazin-6-yl, oxazolo[4,5-b]pyridine-2-yl, or 1-methyl-2-oxo-1,6-naphthridin-3-yl, ring A in Formula (I′) is not 2-pyridyl or 2-pyridyl optionally substituted with halo, methylcarboxy, 1,2,4-triazol-4-yl, 1-piperidinyl, or cyclopropyl;
  • (ii) when ring B is thiazolo[5,4-b]pyridin-2-yl or 6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl, ring A in Formula (I′) is other than 2-quinolyl;
  • (iii) when ring B is 1-piperazinyl, ring A in Formula (I′) is not 3-(4-benzyloxyphenyl)pyrazolo[1,5-a]pyrimidin-5-yl;
  • (iv) when
  • Figure US20170174671A1-20170622-C00007
  • is 6-[1-(dimethylcarbamoyl)-3,6-dihydro-2H-pyridin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl, ring A in Formula (I′) is not 1-methylpyrrolo[2,3-b]pyridine-6-yl;
  • (v) when ring B is 2-oxo-1,2-dihydropyridin-5-yl, 2-oxo-1,2-dihydropyrazin-5-yl or 6-oxo-1H-pyridazin-3-yl, R2 is other than t-butyl;
  • (vi) when
  • Figure US20170174671A1-20170622-C00008
  • is 3,5-dimethylphenyl, R5 is other than 4-amino-1-piperidinyl; and
  • (vii) the compound is other than 6-((2R,6S)-2,6-dimethylmorpholino)-N-(2-methyl-4′-(trifluoromethoxy)biphenyl-3-yl)pyridazine-3-carboxamide or N-(3-(3-acetyl-2-oxoimidazolidin-1-yl)-2-methylphenyl)-5,6,7,8-tetrahydroquinoline-2-carboxamide.
  • The present disclosure provides compounds of Formula (I′), or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:
  • X1 is N or CR1;
  • X2 is N or CR2;
  • X3 is N or CR3;
  • X4 is N or CR4;
  • wherein no more than two of X1, X2, X3 and X4 are simultaneously N;
  • X5 is N or CR6a;
  • X6 is N or CR6b;
  • Ring B is C6-10 aryl, C3-10 cycloalkyl, 5- to 14-membered heteroaryl, or 4- to 10-membered heterocycloalkyl, provided ring B is other than 9-H-carbazol-4-yl, 2,3,4,9-tetrahydro-1H-carbazol-5-yl or 1H-tetrazolyl;
  • R1, R2, R3, R4 and R7 are each independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, CN, NO2, ORa, SRa, NHORa, C(O)Ra, C(O)NRaRa, C(O)ORa, OC(O)Ra, OC(O)NRaRa, NHRa, NRaRa, NRaC(O)Ra, NRaC(O)ORa, NRaC(O)NRaRa, C(═NRa)Ra, C(═NRa)NRaRa, NRaC(═NRa)NRaRa, NRaS(O)Ra, NRaS(O)2Ra, NRaS(O)2NRaRa, S(O)Ra, S(O)NRaRa, S(O)2Ra, and S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of R1, R2, R3, R4 and R7 are each optionally substituted with 1, 2, 3, or 4 Rb substituents;
  • R5 is halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, CN, NO2, OR11, SR11, NH2, —NH—C1-4 alkyl, —N(C1-4 alkyl)2, NHOR11, C(O)R11, C(O)NR11R11, C(O)OR11, OC(O)R11, OC(O)NR11R11, NR11C(O)R11, NR11C(O)OR11, NR11C(O)NR11R11, C(═NR)R11, C(═NR11)NR11R11, NR11C(═NR11)NR11R , NR11S(O)R11, NR11S(O)2R11, NR11S(O)2NR11R , S(O)R11, S(O)NR11R , S(O)2R11, and S(O)2NR11R , wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of R5 are each optionally substituted with 1, 2 or 3 Rb substituents; wherein R5 is other than F when ring B is C3-10 cycloalkyl, 5- to 14-membered heteroaryl or 4- to 10-membered heterocycloalkyl;
  • each R11 is independently selected from H, CN, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of R11 are each optionally substituted with 1, 2 or 3 Rb substituents;
  • R6a, R6b and R6c are each independently selected from H, C1-4 alkyl, C3-6 cycloalkyl, C2-4 alkenyl, C2-4 alkynyl, halo, CN, OH, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, NH2, —NH—C1-4 alkyl, —N(C1-4 alkyl)2, NHOR10, C(O)R10, C(O)NR10R10, C(O)OR10, OC(O)R10, OC(O)NR10R10, NR10C(O)R10, NR10C(O)OR10, NR10C(O)NR10R10, C(═NR10)R10, C(═NR10)NR10R10, NR10C(═NR10)NR10R10, NR10S(O)R10, NR10S(O)2R10, NR10S(O)2NR10R10, S(O)R10, S(O)NR10R10, S(O)2R10, and S(O)2NR10R10, wherein each R10 is independently H or C1-4 alkyl optionally substituted with 1 or 2 groups independently selected from halo, OH, CN and C1-4 alkoxy, and wherein the C1-4 alkyl, C3-6 cycloalkyl, C2-4 alkenyl and C2-4 alkynyl of R6a, R6b, and R6c are each optionally substituted with 1 or 2 substituents independently selected from halo, OH, CN, C1-4 alkyl and C1-4 alkoxy;
  • or two adjacent R7 substituents, taken together with the atoms to which they are attached, form a fused phenyl ring, a fused 4- to 7-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C3-10 cycloalkyl ring, wherein the fused 4- to 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- to 7-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C3-10 cycloalkyl ring are each optionally substituted with 1 or 2 independently selected Rb substituents, provided
  • Figure US20170174671A1-20170622-C00009
  • is other than 9-H-carbazol-4-yl or 2,3,4,9-tetrahydro-1H-carbazol-5-yl, each of which is optionally substituted by 1 or 2 independently selected Rb substituents;
  • or two R7 substituents attached to the same ring carbon atom of ring B, together with the carbon atom to which they are attached, form a 4- to 7-membered heterocycloalkyl ring having 1-4 heteroatoms as ring members selected from N, O and S or a C3-6 cycloalkyl ring, wherein the 4- to 7-membered heterocycloalkyl ring and C3-6 cycloalkyl ring are each optionally substituted with 1 or 2 independently selected Rb substituents;
  • or R1 and X2 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C5-6 cycloalkyl ring are each optionally substituted with 1 or 2 independently selected Rb substituents;
  • or R2 and X1 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C5-6 cycloalkyl ring are each optionally substituted with 1 or 2 independently selected Rb substituents;
  • or R2 and X3 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C5-6 cycloalkyl ring are each optionally substituted with 1 or 2 independently selected Rb substituents;
  • or R3 and X2 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C5-6 cycloalkyl ring are each optionally substituted with 1 or 2 independently selected Rb substituents;
  • or R3 and X4 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C5-6 cycloalkyl ring are each optionally substituted with 1 or 2 independently selected Rb substituents;
  • or R4 and X3 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C5-6 cycloalkyl ring are each optionally substituted with 1 or 2 independently selected Rb substituents;
  • each Ra is independently selected from H, CN, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Ra are each optionally substituted with 1, 2, 3, 4, or 5 Rd substituents;
  • each Rd is independently selected from C1-4 alkyl, C1-4 haloalkyl, halo, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, CN, NH2, NHORe, ORe, SRe, C(O)Re, C(O)NReRe, C(O)ORe, OC(O)Re, OC(O)NReRe, NHRe, NReRe, NReC(O)Re, NReC(O)NReRe, NReC(O)ORe, C(═NRe)NReRe, NReC(═NRe)NReRe, S(O)Re, S(O)NReRe, S(O)2Re, NReS(O)2Re, NReS(O)2NReRe, and S(O)2NReRe, wherein the C1-4 alkyl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl of Rd are each further optionally substituted with 1-3 independently selected Rf substituents;
  • each Rb substituent is independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, CN, OH, NH2, NO2, NHORc, ORc, SRc, C(O)Rc, C(O)NRcRc, C(O)ORc, OC(O)Rc, OC(O)NRcRc, C(═NRc)NRcRc, NRcC(═NRc)NRcRc, NHRc, NRcRc, NRcC(O)Rc, NRcC(O)ORc, NRcC(O)NRcRc, NRcS(O)Rc, NRcS(O)2Rc, NRcS(O)2NRcRc, S(O)Rc, S(O)NRcRc, S(O)2Rc and S(O)2NRcRc; wherein the C1-4 alkyl, C1-4 haloalkyl, C1-4 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Rb are each further optionally substituted with 1-3 independently selected Rd substituents;
  • each Rc is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Rc are each optionally substituted with 1, 2, 3, 4, or 5 Rf substituents independently selected from C1-4 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, halo, CN, NHORg, ORg, SRg, C(O)Rg, C(O)NRgRg, C(O)ORg, OC(O)Rg, OC(O)NRgRg, NHRg, NRgRg, NRgC(O)Rg, NRgC(O)NRgRg, NRgC(O)ORg, C(═NRg)NRgRg, NRgC(═NR)NRgRg, S(O)Rg, S(O)NRgRg, S(O)2Rg, NRgS(O)2Rg, NRgS(O)2NRgRg, and S(O)2NRgRg; wherein the C1-4 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Rf are each optionally substituted with 1, 2, 3, 4, or 5 Rn substituents independently selected from C1-4 alkyl, C1-4 haloalkyl, halo, CN, Ro, NHORo, ORo, SRo, C(O)Ro, C(O)NRoRo, C(O)ORo, OC(O)Ro, OC(O)NRoRo, NHRo, NRoRo, NRoC(O)Ro, NRoC(O)NRoRo, NRoC(O)ORo, C(═NR)NRoRo, NRoC(═NR)NRoRo, S(O)Ro, S(O)NRoRo, S(O)2Ro, NRoS(O)2Ro, NRoS(O)2NRoRo, and S(O)2NRoRo;
  • each Rg is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Rg are each optionally substituted with 1-3 independently selected Rp substituents;
  • or any two Ra substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 Rh substituents independently selected from C1-6 alkyl, C3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl-, (4-7 membered heterocycloalkyl)-C1-4 alkyl-, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, halo, CN, ORi, SRi, NHORi, C(O)Ri, C(O)NRiRi, C(O)ORi, OC(O)Ri, OC(O)NRiRi, NHRi, NRiRi, NRiC(O)Ri, NRiC(O)NRiRi, NRiC(O)ORi, C(═NRi)NRiRi, NRiC(═NRi)NRiRi, S(O)Ri, S(O)NRiRi, S(O)2Ri, NRiS(O)2Ri, NRiS(O)2NRiRi, and S(O)2NRiRi, wherein the C1-6 alkyl, C3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl-, and (4-7 membered heterocycloalkyl)-C1-4 alkyl- of Rh are each further optionally substituted by 1, 2, or 3 Rj substituents independently selected from C3-6 cycloalkyl, C6-10 aryl, 5 or 6-membered heteroaryl, C2-4 alkenyl, C2-4 alkynyl, halo, C1-4 alkyl, C1-4 haloalkyl, CN, NHORk, ORk, SRk, C(O)Rk, C(O)NRkRk, C(O)ORk, OC(O)Rk, OC(O)NRkRk, NHRk, NRkRk, NRkC(O)Rk, NRkC(O)NRkRk, NRkC(O)ORk, C(═NRk)NRkRk, NRkC(═NRk)NRkRk, S(O)Rk, S(O)NRkRk, S(O)2Rk, NRkS(O)2Rk, NRkS(O)2NRkRk, and S(O)2NRkRk; or two Rh groups attached to the same carbon atom of the 4- to 10-membered heterocycloalkyl taken together with the carbon atom to which they are attached form a C3-6 cycloalkyl or 4- to 6-membered heterocycloalkyl having 1-2 heteroatoms as ring members selected from O, N or S;
  • or any two Rc substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;
  • or any two Re substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;
  • or any two Rg substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;
  • or any two Ri substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;
  • or any two Rk substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;
  • or any two Ro substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents; and
  • each Re, Ri, Rk, Ro or Rp is independently selected from H, C1-4 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5 or 6-membered heteroaryl, C1-4 haloalkyl, C2-4 alkenyl, and C2-4 alkynyl, wherein the C1-4 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5 or 6-membered heteroaryl, C2-4 alkenyl, and C2-4 alkynyl of Re, Ri, Rk, Ro or Rp are each optionally substituted with 1, 2 or 3 Rq substituents;
  • each Rq is independently selected from OH, CN, —COOH, NH2, halo, C1-6 haloalkyl, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C3-6 cycloalkyl, NHR8, NR8R8, and C1-4 haloalkoxy, wherein the C1-6 alkyl, phenyl, C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl of Rq are each optionally substituted with halo, OH, CN, —COOH, NH2, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, phenyl, C3-10 cycloalkyl and 4-6 membered heterocycloalkyl and each R8 is independently C1-6 alkyl;
  • Figure US20170174671A1-20170622-P00001
    is a single bond or a double bond, wherein ring A includes at least one double bond; the subscript n is an integer of 1, 2, 3, 4 or 5; and
  • with the proviso (i) when
  • Figure US20170174671A1-20170622-C00010
  • is 2,6-dioxohexahydropyrimidin-1-yl, 2-oxopyrrolidin-1-yl, benzo[d]thiazol-2-yl, 2-amino-4-methyl-5,6-dihydro-1,3-thiazin-4-yl, 4-methyl-6-[4-(morpholine-4-carbonyl)anilino]-5-oxo-pyrazin-2-yl, 5,7-dimethylbenzo[d]oxazol-2-yl, 6-[4-(morpholine-4-carbonyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl, 8-[4-(morpholine-4-carbonyl)anilino]imidazo[1,2-a]pyrazin-6-yl, oxazolo[4,5-b]pyridine-2-yl, or 1-methyl-2-oxo-1,6-naphthridin-3-yl, ring A in Formula (I′) is not 2-pyridyl or 2-pyridyl optionally substituted with halo, methylcarboxy, 1,2,4-triazol-4-yl, 1-piperidinyl, or cyclopropyl;
  • (ii) when ring B is thiazolo[5,4-b]pyridin-2-yl or 6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl, ring A in Formula (I′) is other than 2-quinolyl;
  • (iii) when ring B is 1-piperazinyl, ring A in Formula (I′) is not 3-(4-benzyloxyphenyl)pyrazolo[1,5-a]pyrimidin-5-yl;
  • (iv) when
  • Figure US20170174671A1-20170622-C00011
  • is 6-[1-(dimethylcarbamoyl)-3,6-dihydro-2H-pyridin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl, ring A in Formula (I′) is not 1-methylpyrrolo[2,3-b]pyridine-6-yl;
  • (v) when ring B is 2-oxo-1,2-dihydropyridin-5-yl, 2-oxo-1,2-dihydropyrazin-5-yl or 6-oxo-1H-pyridazin-3-yl, R2 is other than t-butyl;
  • (vi) when
  • Figure US20170174671A1-20170622-C00012
  • is 3,5-dimethylphenyl, R5 is other than 4-amino-1-piperidinyl; and
  • (vii) the compound is other than 6-((2R,6S)-2,6-dimethylmorpholino)-N-(2-methyl-4′-(trifluoromethoxy)biphenyl-3-yl)pyridazine-3-carboxamide or N-(3-(3-acetyl-2-oxoimidazolidin-1-yl)-2-methylphenyl)-5,6,7,8-tetrahydroquinoline-2-carboxamide.
  • In some embodiments, when Cy is 2-oxo-1,2-dihydropyridin-5-yl, 2-oxo-1, 2-dihydropyrazin-5-yl or 6-oxo-1,5-dihydropyridazin-3-yl, each of which is optionally substituted, R2 is other than C1-6 alkyl.
  • In some embodiments of compounds of Formula (I′), R5 is C1-4 alkyl, halo, CN, OH, cyclopropyl, C2-4 alkynyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, NH2, —NH—C1-4 alkyl, —N(C1-4 alkyl)2, NHOR11, C(O)R11, C(O)NR11R11, C(O)OR11, OC(O)R11, OC(O)NR11R11, NR11C(O)R11, NR11C(O)OR11, NR11C(O)NR11R11, C(═NR11)R11, C(═NR11)NR11R11, NR11C(═NR11)NR11R11, NR11S(O)R11, NR11S(O)2R11, NR11S(O)2NR11R11, S(O)R11, S(O)NR11R11, S(O)2R11, and S(O)2NR11R11, wherein C1-4 alkyl, cyclopropyl, C2-4 alkynyl and C1-4 alkoxy of R5 are each optionally substituted with 1 or 2 halo, OH, CN or OCH3 substituent and each R11 is independently selected from H and C1-4 alkyl optionally substituted with 1 or 2 halo, OH, CN or OCH3; wherein R5 is other than F when ring B is C3-10 cycloalkyl, 5- to 14-membered heteroaryl, or 4- to 10-membered heterocycloalkyl. In some embodiments of compounds of Formula (I′), ring A is aromatic.
  • In some embodiments of compounds of Formula (I′), ring B is C6-10 aryl. In certain embodiments, ring B is phenyl or naphthyl. In certain embodiments, ring B is phenyl. R7 is as defined in any embodiment of compounds of Formula (I′) or Formula (I) as described herein. In certain embodiments, each R7 is H.
  • In some embodiments, ring B is 1-cyclohexenyl, cyclohexyl, 3,4-dihydro-2H-pyridin-5-yl, 1,2,3,4-tetrahydropyridin-5-yl, 1-piperidinyl, 2,3-dihydro-1,4-benzodioxin-6-yl, 3,4-dihydro-2H-pyran-5-yl, 4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl, 3,4-dihydro-2H-1,4-benzoxazin-7-yl, 2,3-dihydro-1-benzofuran-6-yl, 2-methyl-2H-indazol-6-yl, 2H-indazol-6-yl, 1-methyl-1H-indazol-4-yl or 1H-indazol-4-yl. R7 is as defined in any embodiment of compounds of Formula (I′) or Formula (I) as described herein. In some embodiments, R7 is t-butoxycarbonyl or C1-6 alkyl. In certain embodiments,
  • Figure US20170174671A1-20170622-C00013
  • is 1-cyclohexenyl, cyclohexyl, 1-t-butoxycarbonyl-3,4-dihydro-2H-pyridin-5-yl, 1,2,3,4-tetrahydropyridin-5-yl, 1-piperidinyl, 2,3-dihydro-1,4-benzodioxin-6-yl, 3,4-dihydro-2H-pyran-5-yl, 4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl, 3,4-dihydro-2H-1,4-benzoxazin-7-yl, 2,3-dihydro-1-benzofuran-6-yl, 2-methyl-2H-indazol-6-yl, 2H-indazol-6-yl, 1-methyl-1H-indazol-4-yl or 1H-indazol-4-yl.
  • In some embodiments of compounds of Formula (I′), ring B is C3-10 cycloalkyl. In certain embodiments, ring B is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl or cyclooctyl. R7 is as defined in any embodiment of compounds of Formula (I′) or Formula (I) as described herein. In certain embodiments, R7 is H.
  • In some embodiments of compounds of Formula (I′), ring B is 5- to 14-membered heteroaryl. In certain embodiments, ring B is pyridy, primidinyl, pyrazinyl, pyridazinyl, triazinyl, pyrrolyl, pyrazolyl, azolyl, oxazolyl, thiazolyl, imidazolyl, furanyl, thiophenyl, quinolinyl, isoquinolinyl, naphthyridinyl, indolyl, benzothiophenyl, benzofuranyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl, purinyl, thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl. In certain embodiments, ring B is 2-methyl-2H-indazol-6-yl, 1-methyl-1H-indazol-4-yl, 2,3-dihydro-1-benzofuran-6-yl, 4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl or 2,3-dihydro-1,4-benzodioxin-6-yl. R7 is as defined in any embodiment of compounds of Formula (I′) or Formula (I) as described herein.
  • In some embodiments of compounds of Formula (I′), ring B is 4- to 10-membered heterocycloalkyl. In certain embodiments, ring B is azetidinyl, azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, morpholino, 3-oxa-9-azaspiro[5.5]undecanyl, 1-oxa-8-azaspiro[4.5]decanyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrolidinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, tropanyl, 2,3-dihydro-1,4-benzodioxin-6-yl, or thiomorpholino. In some embodiments, ring B is 3,4-dihydro-2H-pyran-5-yl, 1-piperidinyl or 1,2,3,4-tetrahydropyridin-5-yl. R7 is as defined in any embodiment of compounds of Formula (I′) or Formula (I) as described herein.
  • In some embodiments of compounds of Formula (I′), ring B is phenyl, 5- or 6-membered heteroaryl, C3-6 cycloalkyl or 5- or 6-membered heterocycloalkyl. In certain instances, ring B is phenyl, 2-thiophenyl, 3-thiophenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, C3-6 cycloalkyl or 3,6-dihydro-2H-pyran-4-yl. R7 is as defined in any embodiment of compounds of Formula (I′) or Formula (I) as described herein.
  • In some embodiments of compounds of Formula (I′), X5 and X6 are each CH. In certain embodiments, X5 is N and X6 is CH. In certain embodiments, X5 is CH and X6 is N. In certain embodiments, X5 and X6 are each N.
  • In some embodiments of compounds of Formula (I′), when
  • Figure US20170174671A1-20170622-C00014
  • R2 is other than t-butyl or C1-6 alkyl, wherein each R12 is independently H or CH3 and each R13 is independently phenyl substituted with amino and morpholino, phenyl substituted with a group selected from R14, —C(O)R14 and (2-amino-2-oxo-ethyl)methylcarbamoyl, 2-pyridyl substituted with 4-methylpiperazin-1-yl or 1-methylpyrrolidin-2-yl, 3-pyridizinyl substituted with morpholino or 4-methylpiperazin-1-yl, 5-methyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-2-yl, 5-trideuteriomethyl-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-2-yl, 5-(2,2-difluoroethyl)-6,7-dihydro-4H-pyrazolo[1,5-a]pyrazine-2-yl, 1-methylpyrazol-3-yl, 4-pyrimidinyl, wherein R14 is selected from morpholino, 4-ethylpiperazin-1-yl, 1,1-dioxo-1,4-thiazinan-4-yl, 4-oxo-1-piperidinyl, 4-methyl-1-piperidinyl, 4-oxo-piperidin-1-yl, 2-(hydroxymethyl)morpholin-4-yl.
  • In some embodiments, the present disclosure provides compounds of Formula (I):
  • Figure US20170174671A1-20170622-C00015
  • or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:
  • X1 is N or CR1;
  • X2 is N or CR2;
  • X3 is N or CR3;
  • X4 is N or CR4;
  • wherein no more than two of X1, X2, X3 and X4 are simultaneously N;
  • R1, R2, R3, R4 and R7 are each independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, CN, NO2, ORa, SRa, NHORa, C(O)Ra, C(O)NRaRa, C(O)ORa, OC(O)Ra, OC(O)NRaRa, NHRa, NRaRa, NRaC(O)Ra, NRaC(O)ORa, NRaC(O)NRaRa, C(═NRa)Ra, C(═NRa)NRaRa, NRaC(═NRa)NRaRa, NRaS(O)Ra, NRaS(O)2Ra, NRaS(O)2NRaRa, S(O)Ra, S(O)NRaRa, S(O)2Ra, and S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of R1, R2, R3, R4 and R7 are each optionally substituted with 1, 2, 3, or 4 Rb substituents;
  • R5 is C1-4 alkyl, halo, CN, OH, cyclopropyl, C2-4 alkynyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, NH2, —NH—C1-4 alkyl, —N(C1-4 alkyl)2, NHOR11, C(O)R11, C(O)NR11R11, C(O)OR11, OC(O)R11, OC(O)NR11R11, NR11C(O)R11, NR11C(O)OR11, NR11C(O)NR11R11, C(═NR11)R11, C(═NR11)NR11R11, NR11C(═NR11)NR11R11NR11S(O)R11, NR11S(O)2R11, NR11S(O)2NR11R11, S(O)R11, S(O)NR11R11, S(O)2R11, and S(O)2NR11R11, wherein each R11 is independently selected from H and C1-4 alkyl optionally substituted with 1 or 2 halo, OH, CN or OCH3;
  • each R6 is independently selected from H, C1-4 alkyl, C3-6 cycloalkyl, C2-4 alkenyl, C2-4 alkynyl, halo, CN, OH, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, NH2, —NH—C1-4 alkyl, —N(C1-4 alkyl)2, NHOR10, C(O)R10, C(O)NR10R10, C(O)OR10, OC(O)R10, OC(O)NR10R10, NR10C(O)R10, NR10C(O)OR10, NR10C(O)NR10R10, C(═NR10)R10, C(═NR10)NR10R10, NR10C(═NR10)NR10R10, NR10S(O)R10, NR10S(O)2R10, NR10S(O)2NR10R10, S(O)R10, S(O)NR10R10, S(O)2R10, and S(O)2NR10R10, wherein each R10 is independently H or C1-4 alkyl optionally substituted with 1 or 2 groups independently selected from halo, OH, CN and C1-4 alkoxy, and wherein the C1-4 alkyl, C3-4 cycloalkyl, C2-4 alkenyl and C2-4 alkynyl of R6 are each optionally substituted with 1 or 2 substituents independently selected from halo, OH, CN, C1-4 alkyl and C1-4 alkoxy;
  • or two adjacent R7 substituents, taken together with the carbon atoms to which they are attached, form a fused phenyl ring, a fused 5- to 7-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C5-6 cycloalkyl ring, wherein the fused 5- to 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- to 7-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C3-10 cycloalkyl ring are each optionally substituted with 1 or 2 independently selected Rq substituents;
  • or R1 and X2 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C5-6 cycloalkyl ring are each optionally substituted with 1 or 2 independently selected Rb substituents;
  • or R2 and X1 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C5-6 cycloalkyl ring are each optionally substituted with 1 or 2 independently selected Rb substituents;
  • or R2 and X3 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C5-6 cycloalkyl ring are each optionally substituted with 1 or 2 independently selected Rb substituents;
  • or R3 and X2 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C5-6 cycloalkyl ring are each optionally substituted with 1 or 2 independently selected Rb substituents;
  • or R3 and X4 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C5-6 cycloalkyl ring are each optionally substituted with 1 or 2 independently selected Rb substituents;
  • or R4 and X3 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C5-6 cycloalkyl ring are each optionally substituted with 1 or 2 independently selected Rb substituents;
  • each Ra is independently selected from H, CN, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Ra are each optionally substituted with 1, 2, 3, 4, or 5 Rd substituents;
  • each Rd is independently selected from C1-4 alkyl, C1-4 haloalkyl, halo, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, CN, NH2, NHORe, ORe, SRe, C(O)Re, C(O)NReRe, C(O)ORe, OC(O)Re, OC(O)NReRe, NHRe, NReRe, NReC(O)Re, NReC(O)NReRe, NReC(O)ORe, C(═NRe)NReRe, NReC(═NRe)NReRe, S(O)Re, S(O)NReRe, S(O)2Re, NReS(O)2Re, NReS(O)2NReRe, and S(O)2NReRe, wherein the C1-4 alkyl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl of Rd are each further optionally substituted with 1-3 independently selected Rq substituents or 1-3 independently selected Rf substituents;
  • each Rb substituent is independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, CN, OH, NH2, NO2, NHORc, ORc, SRc, C(O)Rc, C(O)NRcRc, C(O)ORc, OC(O)Rc, OC(O)NRcRc, C(═NRc)NRcRc, NRcC(═NRc)NRcRc, NHRc, NRcRc, NRcC(O)Rc, NRcC(O)ORc, NRcC(O)NRcRc, NRcS(O)Rc, NRcS(O)2Rc, NRcS(O)2NRcRc, S(O)Rc, S(O)NRcRc, S(O)2Rc and S(O)2NRcRc; wherein the C1-4 alkyl, C1-4 haloalkyl, C1-4 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Rb are each further optionally substituted with 1-3 independently selected Rd substituents; each Rc is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Rc are each optionally substituted with 1, 2, 3, 4, or 5 Rf substituents independently selected from C1-4 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, halo, CN, NHORg, ORg, SRg, C(O)Rg, C(O)NRgRg, C(O)ORg, OC(O)Rg, OC(O)NRgRg, NHRg, NRgRg, NRgC(O)Rg, NRgC(O)NRgRg, NRgC(O)ORg, C(═NRg)NRgRg, NRgC(═NRg)NRgRg, S(O)Rg, S(O)NRgRg, S(O)2Rg, NRgS(O)2Rg, NRgS(O)2NRgRg, and S(O)2NRgRg; wherein the C1-4 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Rf are each optionally substituted with 1, 2, 3, 4, or 5 Rn substituents independently selected from C1-4 alkyl, C1-4 haloalkyl, halo, CN, Ro, NHORo, ORo, SRo, C(O)Ro, C(O)NRoRo, C(O)ORo, OC(O)Ro, OC(O)NRoRo, NHRo, NRoRo, NRoC(O)Ro, NRoC(O)NRoRo, NRoC(O)ORo, C(═NR)NRoRo, NRoC(═NR)NRoRo, S(O)Ro, S(O)NRoRo, S(O)2Ro, NRoS(O)2Ro, NRoS(O)2NRoRo, and S(O)2NRoRo;
  • each Rg is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Rg are each optionally substituted with 1-3 independently selected Rp substituents; or any two Ra substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 Rh substituents independently selected from C1-6 alkyl, C3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl-, (4-7 membered heterocycloalkyl)-C1-4 alkyl-, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, halo, CN, ORi, SRi, NHORi, C(O)Ri, C(O)NRiRi, C(O)ORi, OC(O)Ri, OC(O)NRiRi, NHRi, NRiRi, NRiC(O)Ri, NRiC(O)NRiRi, NRiC(O)ORi, C(═NRi)NRiRi, NRiC(═NRi)NRiRi, S(O)Ri, S(O)NRiRi, S(O)2Ri, NRiS(O)2Ri, NRiS(O)2NRiRi, and S(O)2NRiRi, wherein the C1-6 alkyl, C3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl-, and (4-7 membered heterocycloalkyl)-C1-4 alkyl- of Rh are each further optionally substituted by 1, 2, or 3 Rj substituents independently selected from C3-6 cycloalkyl, C6-10 aryl, 5 or 6-membered heteroaryl, C2-4 alkenyl, C2-4 alkynyl, halo, C1-4 alkyl, C1-4 haloalkyl, CN, NHORk, ORk, SRk, C(O)Rk, C(O)NRkRk, C(O)ORk, OC(O)Rk, OC(O)NRkRk, NHRk, NRkRk, NRkC(O)Rk, NRkC(O)NRkRk, NRkC(O)ORk, C(═NRk)NRkRk, NRkC(═NRk)NRkRk, S(O)Rk, S(O)NRkRk, S(O)2Rk, NRkS(O)2Rk, NRkS(O)2NRkRk, and S(O)2NRkRk; or two Rh groups attached to the same carbon atom of the 4- to 10-membered heterocycloalkyl taken together with the carbon atom to which they are attached form a C3-6 cycloalkyl or 4- to 6-membered heterocycloalkyl having 1-2 heteroatoms as ring members selected from O, N or S;
  • or any two Rc substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;
  • or any two Re substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;
  • or any two Rg substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;
  • or any two Ri substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;
  • or any two Rk substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;
  • or any two Ro substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents; and
  • each Re, Ri, Rk, Ro or Rp is independently selected from H, C1-4 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5 or 6-membered heteroaryl, C1-4 haloalkyl, C2-4 alkenyl, and C2-4 alkynyl, wherein the C1-4 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5 or 6-membered heteroaryl, C2-4 alkenyl, and C2-4 alkynyl of Re, Ri, Rk, Ro or Rp are each optionally substituted with 1, 2 or 3 Rq substituents; each Rq is independently selected from OH, CN, —COOH, NH2, halo, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, phenyl, 5-6 membered heteroaryl, C3-6 cycloalkyl, NHR8, NR8R8, and C1-4 haloalkoxy, wherein the C1-4 alkyl, phenyl and 5-6 membered heteroaryl of Rq are each optionally substituted with OH, CN, —COOH, NH2, C1-4 alkoxy, C3-10 cycloalkyl and 4-, 5-, or 6-membered heterocycloalkyl and each R8 is independently C1-6 alkyl;
  • the subscript n is an integer of 1, 2, 3, 4 or 5;
  • the subscript m is an integer of 1, 2, 3 or 4; and
  • Figure US20170174671A1-20170622-P00001
    is a single bond or a double bond, wherein ring A includes at least one double bond;
  • with the proviso that the compound is other than 6-((2R,6S)-2,6-dimethylmorpholino)-N-(2-methyl-4′-(trifluoromethoxy)biphenyl-3-yl)pyridazine-3-carboxamide. In some embodiments of compounds of Formula (I), the subscript m is an integer of 1, 2 or 3. The compounds, or pharmaceutically acceptable salts or stereoisomers thereof, as described herein are useful as inhibitors of the PD-1/PD-L1 protein/protein interaction. For example, compounds or pharmaceutically acceptable salts or stereoisomers thereof as described herein can disrupt the PD-1/PD-L1 protein/protein interaction in the PD-1 pathway.
  • In some embodiments of compounds of Formula (I), R5 is halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, CN, NO2, OR11, SR11, NH2, —NH—C1-4 alkyl, —N(C1-4 alkyl)2, NHOR11, C(O)R11, C(O)NR11R11, C(O)OR11, OC(O)R11, OC(O)NR11R11, NR11C(O)R11, NR11C(O)OR11, NR11C(O)NR11R11, C(═NR11)R11, C(═NR11)NR11R11, NR11C(═NR11)NR11R11, NR11S(O)R11, NR11S(O)2R11, NR11S(O)2NR11R11, S(O)R11, S(O)NR11R11, S(O)2R11, and S(O)2NR11R11, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of R5 are each optionally substituted with 1, 2 or 3 Rb substituents; wherein R5 is other than F when Cy is C3-10 cycloalkyl, 5- to 14-membered heteroaryl, or 4- to 10-membered heterocycloalkyl;
  • each R11 is independently selected from H, CN, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of R11 are each optionally substituted with 1, 2 or 3 Rb substituents.
  • In some embodiments, ring A is other than pyridazinyl group. In some instances, when X2 is CR2, X3 is CR3 and X4 is CR4, X1 is other than N.
  • In some embodiments, ring A is aromatic.
  • In some embodiments, ring A has the formula
  • Figure US20170174671A1-20170622-C00016
  • In some embodiments, R1 and R2 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C5-6 cycloalkyl ring are each optionally substituted with 1 or 2 independently selected Rb substituents.
  • In some embodiments, R2 and R3 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C5-6 cycloalkyl ring are each optionally substituted with 1 or 2 independently selected Rb substituents.
  • In some embodiments, R3 and R4 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C5-6 cycloalkyl ring are each optionally substituted with 1 or 2 independently selected Rb substituents.
  • In some embodiments, the present disclosure provides compounds having Formula (II):
  • Figure US20170174671A1-20170622-C00017
  • or a pharmaceutically acceptable salt or a stereoisomer thereof. In certain embodiments of compounds of Formula (II), R2 is halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, CN, NO2, ORa, SRa, NHORa, C(O)Ra, C(O)NRaRa, C(O)ORa, OC(O)Ra, OC(O)NRaRa, NHRa, NRaRa, NRaC(O)Ra, NRaC(O)ORa, NRaC(O)NRaRa, C(═NRa)Ra, C(═NRa)NRaRa, NRaC(═NRa)NRaRa, NRaS(O)Ra, NRaS(O)2Ra, NRaS(O)2NRaRa, S(O)Ra, S(O)NRaRa, S(O)2Ra, and S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of R2 are each optionally substituted with 1, 2, 3, or 4 Rb substituents, or a pharmaceutically acceptable salt or a stereoisomer thereof. Other variables of Formula (II) are as defined in Formula (I′), Formula (I) or any embodiment of compounds of Formula (I′) or Formula (I) as described herein. In one embodiment of compounds of Formula (II), R5 is CN or C1-4 alkyl optionally substituted with Rq. In another embodiment, R5 is CH3 or CN.
  • In some embodiments, the present disclosure provides compounds having Formula (III):
  • Figure US20170174671A1-20170622-C00018
  • or a pharmaceutically acceptable salt or a stereoisomer thereof. In certain embodiments of compounds of Formula (III), R2 is halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, CN, NO2, ORa, SRa, NHORa, C(O)Ra, C(O)NRaRa, C(O)ORa, OC(O)Ra, OC(O)NRaRa, NHRa, NRaRa, NRaC(O)Ra, NRaC(O)ORa, NRaC(O)NRaRa, C(═NRa)Ra, C(═NRa)NRaRa, NRaC(═NRa)NRaRa, NRaS(O)Ra, NRaS(O)2Ra, NRaS(O)2NRaRa, S(O)Ra, S(O)NRaRa, S(O)2Ra, and S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of R2 are each optionally substituted with 1, 2, 3, or 4 Rb substituents, or a pharmaceutically acceptable salt or a stereoisomer thereof. Other variables of Formula (III) are as defined in Formula (I′), Formula (I) or any embodiment of compounds of Formula (I′) or Formula (I) as described herein.
  • In some embodiments, the present disclosure provides compounds having Formula (IV):
  • Figure US20170174671A1-20170622-C00019
  • or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein the variables of Formula (IV) are as defined in Formula (I′), Formula (I) or any embodiment of compounds of Formula (I′) or Formula (I) as described herein. In certain embodiments of compounds of Formula (II), R2 is halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, CN, NO2, ORa, SRa, NHORa, C(O)Ra, C(O)NRaRa, C(O)ORa, OC(O)Ra, OC(O)NRaRa, NHRa, NRaRa, NRaC(O)Ra, NRaC(O)ORa, NRaC(O)NRaRa, C(═NRa)Ra, C(═NRa)NRaRa, NRaC(═NRa)NRaRa, NRaS(O)Ra, NRaS(O)2Ra, NRaS(O)2NRaRa, S(O)Ra, S(O)NRaRa, S(O)2Ra, and S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of R2 are each optionally substituted with 1, 2, 3, or 4 Rb substituents, or a pharmaceutically acceptable salt or a stereoisomer thereof.
  • In some embodiments, the present disclosure provides compounds having Formula (V):
  • Figure US20170174671A1-20170622-C00020
  • or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein the variables of Formula (V) are as defined in Formula (I′), Formula (I) or any embodiment of compounds of Formula (I′) or Formula (I) as described herein. In certain embodiments of compounds of Formula (V), R2 is halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, CN, NO2, ORa, SRa, NHORa, C(O)Ra, C(O)NRaRa, C(O)ORa, OC(O)Ra, OC(O)NRaRa, NHRa, NRaRa, NRaC(O)Ra, NRaC(O)ORa, NRaC(O)NRaRa, C(═NRa)Ra, C(═NRa)NRaRa, NRaC(═NRa)NRaRa, NRaS(O)Ra, NRaS(O)2Ra, NRaS(O)2NRaRa, S(O)Ra, S(O)NRaRa, S(O)2Ra, and S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of R2 are each optionally substituted with 1, 2, 3, or 4 Rb substituents, or a pharmaceutically acceptable salt or a stereoisomer thereof.
  • In some embodiments, the present disclosure provides compounds having Formula (VI):
  • Figure US20170174671A1-20170622-C00021
  • or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein the variables of Formula (VI) are as defined in Formula (I′), Formula (I) or any embodiment of compounds of Formula (I′) or Formula (I) as described herein. In certain embodiments of compounds of Formula (VI), R2 is halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, CN, NO2, ORa, SRa, NHORa, C(O)Ra, C(O)NRaRa, C(O)ORa, OC(O)Ra, OC(O)NRaRa, NHRa, NRaRa, NRaC(O)Ra, NRaC(O)ORa, NRaC(O)NRaRa, C(═NRa)Ra, C(═NRa)NRaRa, NRaC(═NRa)NRaRa, NRaS(O)Ra, NRaS(O)2Ra, NRaS(O)2NRaRa, S(O)Ra, S(O)NRaRa, S(O)2Ra, and S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of R2 are each optionally substituted with 1, 2, 3, or 4 Rb substituents, or a pharmaceutically acceptable salt or a stereoisomer thereof.
  • In some embodiments, the present disclosure provides compounds having Formula (VII):
  • Figure US20170174671A1-20170622-C00022
  • or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein the variables of Formula (VII) are as defined in Formula (I′), Formula (I) or any embodiment of compounds of Formula (I′) or Formula (I) as described herein. In certain embodiments of compounds of Formula (VII), R3 is halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, CN, NO2, ORa, SRa, NHORa, C(O)Ra, C(O)NRaRa, C(O)ORa, OC(O)Ra, OC(O)NRaRa, NHRa, NRaRa, NRaC(O)Ra, NRaC(O)ORa, NRaC(O)NRaRa, C(═NRa)Ra, C(═NRa)NRaRa, NRaC(═NRa)NRaRa, NRaS(O)Ra, NRaS(O)2Ra, NRaS(O)2NRaRa, S(O)Ra, S(O)NRaRa, S(O)2Ra, and S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-C3-10 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of R2 are each optionally substituted with 1, 2, 3, or 4 Rb substituents, or a pharmaceutically acceptable salt or a stereoisomer thereof.
  • In some embodiments of compounds of Formula I′, I, II, III, IV, V or VI, or a pharmaceutically acceptable salt or a stereoisomer thereof, the moiety
  • Figure US20170174671A1-20170622-C00023
  • is selected from:
  • Figure US20170174671A1-20170622-C00024
  • wherein the substituents R1, R2, R3 and R4 are as defined in Formula (I′), Formula (I′) or Formula (I) or any embodiment of compounds of Formula (I′) or Formula (I) as described herein. In certain embodiments, at each occurrence, R1, R3 and R4 are each H.
  • In some embodiments of compounds of Formula I′, I or VII, or a pharmaceutically acceptable salt or a stereoisomer thereof, the moiety the moiety
  • Figure US20170174671A1-20170622-C00025
  • is selected from:
  • Figure US20170174671A1-20170622-C00026
  • wherein the substituents R1, R2, R3 and R4 are as defined in Formula (I′), Formula (I) or any embodiment of compounds of Formula (I′) or Formula (I) as described herein. In certain embodiments, at each occurrence, R1, R2 and R4 are each H.
  • In some embodiments of compounds of Formula I′, I, II, III, IV, V or VI, or a pharmaceutically acceptable salt or a stereoisomer thereof, X1 is CR1, X3 is CR3 and X4 is CR4.
  • In some embodiments of compounds of Formula I′, I, II, III, IV, V or VI, or a pharmaceutically acceptable salt or a stereoisomer thereof, X1 is CR1, X3 is CR3 and X4 is N.
  • In some embodiments of compounds of Formula I′, I, II, III, IV, V or VI, or a pharmaceutically acceptable salt or a stereoisomer thereof, X1 is CR1, X3 is N and X4 is CR4.
  • In some embodiments of compounds of Formula I′, I, II, III, IV, V or VI, or a pharmaceutically acceptable salt or a stereoisomer thereof, X1 is N, X3 is CR3 and X4 is CR4.
  • In some embodiments of compounds of Formula I′, I or VII, or a pharmaceutically acceptable salt or a stereoisomer thereof, X1 is CR1, X2 is CR2 and X4 is CR4.
  • In some embodiments of compounds of Formula I′, I or VII, or a pharmaceutically acceptable salt or a stereoisomer thereof, X1 is CR1, X2 is CR2 and X4 is N.
  • In some embodiments of compounds of Formula I′, I or VII, or a pharmaceutically acceptable salt or a stereoisomer thereof, X1 is CR1, X2 is N and X4 is CR4.
  • In some embodiments of compounds of Formula I′, I or VII, or a pharmaceutically acceptable salt or a stereoisomer thereof, X1 is N, X2 is CR2 and X4 is CR4.
  • In some embodiments, R1, R3 and R4, are each independently selected from H, C1-6 alkyl, CN, —N(C1-6 alkyl)2 and halo.
  • In some embodiments, R1, R2 and R4, are each independently selected from H, C1-6 alkyl, CN, —N(C1-6 alkyl)2 and halo.
  • In some embodiments, R1, R2, R3, R4, R6 and R7 are each H.
  • In some embodiments, R1, R3, R4, R6 and R7 are each H.
  • In some embodiments, R1, R2, R4, R6 and R7 are each H.
  • In some embodiments, two adjacent R7 substituents on the phenyl ring taken together with the carbon atoms to which they are attached form a 5-, 6- or 7-membered fused heterocycloalkyl optionally substituted by 1 or 2 Rq substituents. In certain instances, the fused heterocycloalkyl has carbon and 1 or 2 heteroatoms as ring members selected from O, N or S, wherein the carbon ring atom is optionally oxidized to form carbonyl, the N ring atom is optionally oxidized to form NO and the S ring atom is optionally oxidized to form SO or SO2.
  • In some embodiments, the subscript n is 2 and the subscript m is 1.
  • In some embodiments, R5 is C1-4 alkyl or CN.
  • In some embodiments, R5 is CH3 or CN.
  • In some embodiments, R6 and R7 are each H.
  • In some embodiments of compounds of Formula I′, I, II, III, III, IV, V or VI, R2 is C1-4 alkyl substituted with Rb. In certain embodiments, Rb is NHRc or NRcRc. In certain embodiments, Rb is NRcRc. In other embodiments, Rb is 2-hydroxyethylamino, 2-hydroxyethyl(methyl)amino, 2-carboxypiperidin-1-yl, (cyanomethyl)amino, (S)-2-carboxypiperidin-1-yl, (R)-2-carboxypiperidin-1-yl or 2-carboxypiperidin-1-yl, each of which is optionally substituted with 1, 2 or 3 Rq substituents. In other embodiments, R2 is C1-4 alkyl substituted with Rq.
  • In some embodiments of compounds of Formula I′, I, II, III, III, IV, V or VI, R2 is C1-4 alkoxy substituted with Rd. In certain embodiments, Rd is phenyl, 3-cyanophenyl, 3-pyridyl, 2-pyridyl, or 4-pyridyl, each of which is optionally substituted with 1, 2 or 3 Rq substituents.
  • In some embodiments of compounds of Formula I′, I, II, III, III, IV, V or VI, R2 is —OCH2Rd. In certain embodiments, Rd is phenyl, 3-cyanophenyl, 3-pyridyl, 2-pyridyl, 4-pyridyl, each of which is optionally substituted with 1, 2 or 3 Rq substituents.
  • In some embodiments, when X1 is N, X3 is CH and X4 is CH, R2 is other than cis-2,6-dimethylmorpholino. In other embodiments, X1 is N, X3 is CH and X4 is CH, R2 is other than 2,6-dimethylmorpholino. In other embodiments, X1 is N, X3 is CH and X4 is CH, R2 is other than 6-membered heterocycloalkyl substituted with 1 or 2 C1-6 alkyl, wherein the heterocycloalkyl has N and O as ring members. In other embodiments, ring A is other than 6-(2,6-dimethylmorpholino)pyridazin-3-yl.
  • In some embodiments of compounds of Formula I′, I or VII, R3 is C1-4 alkyl substituted with Rb. In certain embodiments, Rb is NHRc or NRcRc. In other embodiments, Rb is 2-hydroxyethylamino, 2-hydroxyethyl(methyl)amino, 2-carboxypiperidin-1-yl, (cyanomethyl)amino, (S)-2-carboxypiperidin-1-yl, (R)-2-carboxypiperidin-1-yl or 2-carboxypiperidin-1-yl, each of which is optionally substituted with 1, 2 or 3 Rq substituents. In other embodiments, R3 is C1-4 alkyl substituted with Rq.
  • In some embodiments of compounds of Formula I′, I or VII, R3 is C1-4 alkoxy substituted with Rd. In certain embodiments, Rd is phenyl, 3-cyanophenyl, 3-pyridyl, 2-pyridyl, or 4-pyridyl, each of which is optionally substituted with 1, 2 or 3 Rq substituents.
  • In some embodiments of compounds of Formula I′, I or VII, R3 is —OCH2Rd. In certain embodiments, Rd is phenyl, 3-cyanophenyl, 3-pyridyl, 2-pyridyl, 4-pyridyl, each of which is optionally substituted with 1, 2 or 3 Rq substituents.
  • In some embodiments of compounds of Formula I′, I, II, III, IV, V or VI, R3 is 2-hydroxyethylaminomethyl, 2-hydroxyethyl(methyl)aminomethyl, 2-carboxypiperidin-1-ylmethyl, (cyanomethyl)aminomethyl, (S)-2-carboxypiperidin-1-ylmethyl, (R)-2-carboxypiperidin-1-ylmethyl, 2-carboxypiperidin-1-ylmethyl, benzyloxy, 2-cyanobenzyloxy, 3-cyanobenzyloxy, 4-cyanobenzyloxy, 2-pyridylmethoxy, 3-pyridylmethoxy, or 4-pyridylmethoxy, each of which is optionally substituted with 1, 2 or 3 Rq substituents. In certain embodiments, R3 is 2-hydroxyethylaminomethyl, 2-carboxypiperidin-1-ylmethyl, (S)-2-carboxypiperidin-1-ylmethyl, (R)-2-carboxypiperidin-1-ylmethyl or (3-cyanobenzyl)oxy, each of which is optionally substituted with 1, 2 or 3 Rq substituents.
  • In some embodiments of compounds of Formula I′, R6a, R6b and R6c are each independently selected from H, halo, CN, N(C1-6 alkyl)2, C1-6 alkyl and C1-6 alkoxy, wherein the C1-6 alkyl are each optionally substituted with 1 or 2 substituents independently selected from halo, OH, CN, C1-4 alkyl and C1-4 alkoxy.
  • In some embodiments of compounds of Formula I′, R6a, R6b and R6c are each independently selected from H, halo, CN, N(CH3)2 and CH3.
  • In some embodiments of compounds of Formula I, II, III, V, or VII, R6 is H, halo, CN, N(C1-6 alkyl)2, C1-6 alkyl or C1-6 alkoxy, wherein the C1-6 alkyl and C1-6 alkoxy are each optionally substituted with 1-3 Rq substituents.
  • In some embodiments of compounds of Formula I, II, III, V or VIII, R6 is H, halo, CN, N(CH3)2 or CH3.
  • In some embodiments, provided herein is a compound of Formula (I′):
  • Figure US20170174671A1-20170622-C00027
  • or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:
  • X1 is N or CR1;
  • X2 is N or CR2;
  • X3 is N or CR3;
  • X4 is N or CR4;
  • wherein no more than two of X1, X2, X3 and X4 are simultaneously N;
  • X5 is N or CR6a;
  • X6 is CR6b;
  • ring B is phenyl, cyclohexyl, piperidinyl, or tetrahydropyridinyl;
  • R1, R2, R3, R4 and R7 are each independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, CN, ORa, NHRa, and NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of R1, R2, R3, R4 and R7 are each optionally substituted with 1, 2, 3, or 4 Rb substituents;
  • R5 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, or CN, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, and C1-6 haloalkoxy of R5 are each optionally substituted with 1, 2 or 3 Rb substituents;
  • R6a, R6b and R6c are each independently selected from H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, halo, CN, OH, C1-4 alkoxy, C1-4 haloalkyl, NH2, —NH—C1-4 alkyl, and —N(C1-4 alkyl)2, wherein the C1-4 alkyl, C2-4 alkenyl and C2-4 alkynyl of R6a, R6b, and R6c are each optionally substituted with 1 or 2 substituents independently selected from halo, OH, CN, C1-4 alkyl and C1-4 alkoxy;
  • or two adjacent R7 substituents, taken together with the atoms to which they are attached, form a fused 4- to 7-membered heterocycloalkyl ring or a fused 5- or 6-membered heteroaryl ring, wherein the fused 4- to 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N and O and wherein the fused 5- to 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring are each optionally substituted with 1 or 2 independently selected Rb substituents;
  • each Ra is independently selected from H, CN, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Ra are each optionally substituted with 1, 2, 3, 4, or 5 Rd substituents;
  • each Rd is independently selected from C1-4 alkyl, C1-4 haloalkyl, halo, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, CN, NH2, ORe, SRe, C(O)Re, C(O)NReRe, C(O)ORe, OC(O)Re, OC(O)NReRe, NHRe, NReRe, and NReC(O)Re, and S(O)2NReRe, wherein the C1-4 alkyl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl of Rd are each further optionally substituted with 1-3 independently selected Rf substituents;
  • each Rb substituent is independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 haloalkoxy, CN, OH, NH2, NO2, NHORc, ORc, SRc, C(O)Rc, C(O)NRcRc, C(O)ORc, OC(O)Rc, OC(O)NRcRc, NHRc, NRcRc, NRcC(O)Rc, and NRcC(O)ORc; wherein the C1-4 alkyl, C1-4 haloalkyl, and C1-4 haloalkoxy of Rb are each further optionally substituted with 1-3 independently selected Rd substituents;
  • each Rc is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein the C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl of Rc are each optionally substituted with 1, 2, 3, 4, or 5 Rf substituents independently selected from C1-4 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, halo, CN, NHORg, ORg, SRg, C(O)Rg, C(O)NRgRg, C(O)ORg, OC(O)Rg, OC(O)NRgRg, NHRg, NRgRg, and NRgC(O)Rg;
  • each Rg is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl;
  • each Re is independently selected from H, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, and C2-4 alkynyl;
  • Figure US20170174671A1-20170622-P00001
    is a single bond or a double bond, wherein ring A includes at least one double bond; and
  • the subscript n is an integer of 1, 2, 3, 4 or 5.
  • In some embodiments, provided herein is a compound of Formula (I′):
  • Figure US20170174671A1-20170622-C00028
  • or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:
  • X1 is N or CR1;
  • X2 is N or CR2;
  • X3 is N or CR3;
  • X4 is N or CR4;
  • wherein no more than two of X1, X2, X3 and X4 are simultaneously N;
  • X5 is N or CR6a;
  • X6 is CR6b;
  • ring B is phenyl, cyclohexyl, piperidinyl, or tetrahydropyridinyl;
  • R1, R2, R3, R4 and R7 are each independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, (5-14 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, CN, ORa, NHRa, and NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, (5-14 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of R1, R2, R3, R4 and R7 are each optionally substituted with 1, 2, 3, or 4 Rb substituents;
  • R5 is C1-6 alkyl or CN;
  • R6a, R6b and R6c are each independently selected from H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, halo, CN, OH, NH2, —NH—C1-4 alkyl, and —N(C1-4 alkyl)2;
  • or two adjacent R7 substituents, taken together with the atoms to which they are attached, form a fused 4- to 7-membered heterocycloalkyl ring or a fused 5- or 6-membered heteroaryl ring, wherein the fused 4- to 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N and O and wherein the fused 5- to 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring are each optionally substituted with 1 or 2 independently selected Rb substituents;
  • each Ra is independently selected from H, CN, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Ra are each optionally substituted with 1, 2, 3, 4, or 5 Rd substituents;
  • each Rd is independently selected from C1-4 alkyl, C1-4 haloalkyl, halo, CN, and NH2; each Rb substituent is independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 haloalkoxy, CN, OH, NH2, C(O)ORc, NHRc, and NRcRc;
  • each Rc is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein the C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl of Rc are each optionally substituted with 1, 2, 3, 4, or 5 Rf substituents independently selected from C1-4 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, halo, CN, ORg, C(O)Rg, C(O)NRgRg, C(O)ORg, NHRg, NRgRg, and NRgC(O)Rg;
  • each Rg is independently selected from H, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;
  • Figure US20170174671A1-20170622-P00001
    is a single bond or a double bond, wherein ring A includes at least one double bond; and
  • the subscript n is an integer of 1, 2, 3, 4 or 5.
  • In some embodiments, provided herein is a compound of Formula (I′):
  • Figure US20170174671A1-20170622-C00029
  • or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:
  • X1 is N or CR1;
  • X2 is N or CR2;
  • X3 is N or CR3;
  • X4 is N or CR4;
  • wherein no more than two of X1, X2, X3 and X4 are simultaneously N;
  • X5 is N or CR6a;
  • X6 is CR6b;
  • ring B is phenyl, cyclohexyl, piperidinyl, or tetrahydropyridinyl;
  • R1, R2, R3, R4 and R7 are each independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, (5-14 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, CN, ORa, NHRa, and NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, (5-14 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of R1, R2, R3, R4 and R7 are each optionally substituted with 1 or 2, Rb substituents;
  • R5 is C1-6 alkyl or CN;
  • R6a, R6b and R6c are each independently selected from H, C1-4 alkyl and halo;
  • or two adjacent R7 substituents, taken together with the atoms to which they are attached, form a fused 4- to 7-membered heterocycloalkyl ring or a fused 5- or 6-membered heteroaryl ring, wherein the fused 4- to 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N and O and wherein the fused 5- to 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring are each optionally substituted with 1 or 2 independently selected Rb substituents;
  • each Ra is independently selected from H, CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Ra are each optionally substituted with 1 or 2 Rd substituents;
  • each Rd is independently selected from C1-4 alkyl, halo, CN, and NH2;
  • each Rb substituent is independently selected from halo, C1-4 alkyl, CN, OH, NH2, C(O)ORc, NHRc, and NRcRc;
  • each Rc is independently selected from H, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein the C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl of Rc are each optionally substituted with 1, 2 or Rf substituents independently selected from C1-4 alkyl, C2-6 alkenyl, C2-6 alkynyl, halo, CN, and ORg;
  • each Rg is independently selected from H and C1-6 alkyl;
  • Figure US20170174671A1-20170622-P00001
    is a single bond or a double bond, wherein ring A includes at least one double bond; and
  • the subscript n is an integer of 1, 2, 3, 4 or 5.
  • It is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment (while the embodiments are intended to be combined as if written in multiply dependent form). Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination. Thus, it is contemplated as features described as embodiments of the compounds of Formula (I′) or formula (I) can be combined in any suitable combination.
  • At various places in the present specification, certain features of the compounds are disclosed in groups or in ranges. It is specifically intended that such a disclosure include each and every individual subcombination of the members of such groups and ranges. For example, the term “C1-6 alkyl” is specifically intended to individually disclose (without limitation) methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl and C6 alkyl.
  • The term “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. For example, 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 and 1,2,3,4-tetrahydro-naphthalene is an example of a 10-membered cycloalkyl group.
  • At various places in the present specification, variables defining divalent linking groups may be described. It is specifically intended that each linking substituent include both the forward and backward forms of the linking substituent. For example, —NR(CR′R″)n— includes both —NR(CR′R″)n— and —(CR′R″)nNR— and is intended to disclose each of the forms individually. Where the structure requires a linking group, the Markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists “alkyl” or “aryl” then it is understood that the “alkyl” or “aryl” represents a linking alkylene group or arylene group, respectively.
  • The term “substituted” means that an atom or group of atoms formally replaces hydrogen as a “substituent” attached to another group. The term “substituted”, unless otherwise indicated, refers to any level of substitution, e.g., mono-, di-, tri-, tetra- or penta-substitution, where such substitution is permitted. The substituents are independently selected, and substitution may be at any chemically accessible position. It is to be understood that substitution at a given atom is limited by valency. It is to be understood that substitution at a given atom results in a chemically stable molecule. The phrase “optionally substituted” means unsubstituted or substituted. The term “substituted” means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent, e.g., oxo, can replace two hydrogen atoms.
  • The term “Cn-m” indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include C1-4, C1-6 and the like.
  • The term “alkyl,” employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chained or branched. The term “Cn-m alkyl”, refers to an alkyl group having n to m carbon atoms. An alkyl group formally corresponds to an alkane with one C—H bond replaced by the point of attachment of the alkyl group to the remainder of the compound. In some embodiments, the alkyl group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or 1 to 2 carbon atoms. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl; higher homologs such as 2-methyl-1-butyl, n-pentyl, 3-pentyl, n-hexyl, 1,2,2-trimethylpropyl and the like.
  • The term “alkenyl,” employed alone or in combination with other terms, refers to a straight-chain or branched hydrocarbon group corresponding to an alkyl group having one or more double carbon-carbon bonds. An alkenyl group formally corresponds to an alkene with one C—H bond replaced by the point of attachment of the alkenyl group to the remainder of the compound. The term “Cn-m alkenyl” refers to an alkenyl group having n to m carbons. In some embodiments, the alkenyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms. Example alkenyl groups include, but are not limited to, ethenyl, n-propenyl, isopropenyl, n-butenyl, sec-butenyl and the like.
  • The term “alkynyl,” employed alone or in combination with other terms, refers to a straight-chain or branched hydrocarbon group corresponding to an alkyl group having one or more triple carbon-carbon bonds. An alkynyl group formally corresponds to an alkyne with one C—H bond replaced by the point of attachment of the alkyl group to the remainder of the compound. The term “Cn-m alkynyl” refers to an alkynyl group having n to m carbons. Example alkynyl groups include, but are not limited to, ethynyl, propyn-1-yl, propyn-2-yl and the like. In some embodiments, the alkynyl moiety contains 2 to 6, 2 to 4, or 2 to 3 carbon atoms.
  • The term “alkylene,” employed alone or in combination with other terms, refers to a divalent alkyl linking group. An alkylene group formally corresponds to an alkane with two C—H bond replaced by points of attachment of the alkylene group to the remainder of the compound. The term “Cn-m alkylene” refers to an alkylene group having n to m carbon atoms. Examples of alkylene groups include, but are not limited to, ethan-1,2-diyl, propan-1,3-diyl, propan-1,2-diyl, butan-1,4-diyl, butan-1,3-diyl, butan-1,2-diyl, 2-methyl-propan-1,3-diyl and the like.
  • The term “alkoxy,” employed alone or in combination with other terms, refers to a group of formula —O-alkyl, wherein the alkyl group is as defined above. The term “Cn-m alkoxy” refers to an alkoxy group, the alkyl group of which has n to m carbons. Example alkoxy groups include methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), t-butoxy and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
  • The term “amino,” employed alone or in combination with other terms, refers to a group of formula —NH2.
  • The term “carbamyl,” employed alone or in combination with other terms, refers to a group of formula —C(O)NH2.
  • The term “carbonyl,” employed alone or in combination with other terms, refers to a —C(═O)— group, which also may be written as C(O).
  • The term “cyano” or “nitrile,” employed alone or in combination with other terms, refers to a group of formula —C≡N, which also may be written as —CN.
  • The terms “halo” or “halogen,” used alone or in combination with other terms, refers to fluoro, chloro, bromo and iodo. In some embodiments, “halo” refers to a halogen atom selected from F, Cl, or Br. In some embodiments, halo groups are F.
  • The term “haloalkyl,” employed alone or in combination with other terms, as used herein refers to an alkyl group in which one or more of the hydrogen atoms has been replaced by a halogen atom. The term “Cn-m haloalkyl” refers to a Cn-m alkyl group having n to m carbon atoms and from at least one up to {2(n to m)+1} halogen atoms, which may either be the same or different. In some embodiments, the halogen atoms are fluoro atoms. In some embodiments, the haloalkyl group has 1 to 6 or 1 to 4 carbon atoms. Example haloalkyl groups include CF3, C2F5, CHF2, CCl3, CHCl2, C2Cl5 and the like. In some embodiments, the haloalkyl group is a fluoroalkyl group.
  • The term “haloalkoxy,” employed alone or in combination with other terms, refers to a group of formula —O-haloalkyl, wherein the haloalkyl group is as defined above. The term “Cn-m haloalkoxy” refers to a haloalkoxy group, the haloalkyl group of which has n to m carbons. Example haloalkoxy groups include trifluoromethoxy and the like. In some embodiments, the haloalkoxy group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.
  • The term “oxo” refers to an oxygen atom as a divalent substituent, forming a carbonyl group when attached to carbon, or attached to a heteroatom forming a sulfoxide or sulfone group, or an N-oxide group. In some embodiments, heterocyclic groups may be optionally substituted by 1 or 2 oxo (═O) substituents.
  • The term “sulfido” refers to a sulfur atom as a divalent substituent, forming a thiocarbonyl group (C═S) when attached to carbon.
  • The term “aromatic” refers to a carbocycle or heterocycle having one or more polyunsaturated rings having aromatic character (i.e., having (4n+2) delocalized π (pi) electrons where n is an integer).
  • The term “aryl,” employed alone or in combination with other terms, refers to an aromatic hydrocarbon group, which may be monocyclic or polycyclic (e.g., having 2 fused rings). The term “Cn-m aryl” refers to an aryl group having from n to m ring carbon atoms. Aryl groups include, e.g., phenyl, naphthyl, indanyl, indenyl and the like. In some embodiments, aryl groups have from 6 to about 10 carbon atoms. In some embodiments aryl groups have 6 carbon atoms. In some embodiments aryl groups have 10 carbon atoms. In some embodiments, the aryl group is phenyl. In some embodiments, the aryl group is naphthyl.
  • The term “heteroaryl” or “heteroaromatic,” employed alone or in combination with other terms, refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from sulfur, oxygen and nitrogen. In some embodiments, the heteroaryl ring has 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, any ring-forming N in a heteroaryl moiety can be an N-oxide. In some embodiments, the heteroaryl has 5-14 ring atoms including carbon atoms and 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl has 5-10 ring atoms including carbon atoms and 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl has 5-6 ring atoms and 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl is a five-membered or six-membered heteroaryl ring. In other embodiments, the heteroaryl is an eight-membered, nine-membered or ten-membered fused bicyclic heteroaryl ring. Example heteroaryl groups include, but are not limited to, pyridintl (pyridyl), pyrimidinyl, pyrazinyl, pyridazinyl, pyrrolyl, pyrazolyl, azolyl, oxazolyl, thiazolyl, imidazolyl, furanyl, thiophenyl, quinolinyl, isoquinolinyl, naphthyridinyl (including 1,2-, 1,3-, 1,4-, 1,5-, 1,6-, 1,7-, 1,8-, 2,3- and 2,6-naphthyridine), indolyl, benzothiophenyl, benzofuranyl, benzisoxazolyl, imidazo[1,2-b]thiazolyl, purinyl, and the like.
  • A five-membered heteroaryl ring is a heteroaryl group having five ring atoms wherein one or more (e.g., 1, 2 or 3) ring atoms are independently selected from N, O and S. Exemplary five-membered ring heteroaryls include thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl and 1,3,4-oxadiazolyl.
  • A six-membered heteroaryl ring is a heteroaryl group having six ring atoms wherein one or more (e.g., 1, 2 or 3) ring atoms are independently selected from N, O and S. Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.
  • The term “cycloalkyl,” employed alone or in combination with other terms, refers to a non-aromatic hydrocarbon ring system (monocyclic, bicyclic or polycyclic), including cyclized alkyl and alkenyl groups. The term “Cn-m cycloalkyl” refers to a cycloalkyl that has n to m ring member carbon atoms. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) groups and spirocycles. Cycloalkyl groups can have 3, 4, 5, 6 or 7 ring-forming carbons (C3-7). In some embodiments, the cycloalkyl group has 3 to 6 ring members, 3 to 5 ring members, or 3 to 4 ring members. In some embodiments, the cycloalkyl group is monocyclic. In some embodiments, the cycloalkyl group is monocyclic or bicyclic. In some embodiments, the cycloalkyl group is a C3-6 monocyclic cycloalkyl group. Ring-forming carbon atoms of a cycloalkyl group can be optionally oxidized to form an oxo or sulfido group. Cycloalkyl groups also include cycloalkylidenes. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, e.g., benzo or thienyl derivatives of cyclopentane, cyclohexane and the like. A cycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbomyl, norpinyl, norcamyl, bicyclo[1.1.1]pentanyl, bicyclo[2.1.1]hexanyl, and the like. In some embodiments, the cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • The term “heterocycloalkyl,” employed alone or in combination with other terms, refers to a non-aromatic ring or ring system, which may optionally contain one or more alkenylene groups as part of the ring structure, which has at least one heteroatom ring member independently selected from nitrogen, sulfur oxygen and phosphorus, and which has 4-10 ring members, 4-7 ring members, or 4-6 ring members. Included within the term “heterocycloalkyl” are monocyclic 4-, 5-, 6- and 7-membered heterocycloalkyl groups. Heterocycloalkyl groups can include mono- or bicyclic (e.g., having two fused or bridged rings) ring systems. In some embodiments, the heterocycloalkyl group is a monocyclic group having 1, 2 or 3 heteroatoms independently selected from nitrogen, sulfur and oxygen. Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally oxidized to form an oxo or sulfido group or other oxidized linkage (e.g., C(O), S(O), C(S) or S(O)2, N-oxide etc.) or a nitrogen atom can be quaternized. The heterocycloalkyl group can be attached through a ring-forming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the heterocycloalkyl ring, e.g., benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. A heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring. Examples of heterocycloalkyl groups include azetidinyl, azepanyl, dihydrobenzofuranyl, dihydrofuranyl, dihydropyranyl, morpholino, 3-oxa-9-azaspiro[5.5]undecanyl, 1-oxa-8-azaspiro[4.5]decanyl, piperidinyl, piperazinyl, oxopiperazinyl, pyranyl, pyrrolidinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,2,3,4-tetrahydroquinolinyl, tropanyl, and thiomorpholino.
  • At certain places, the definitions or embodiments refer to specific rings (e.g., an azetidine ring, a pyridine ring, etc.). Unless otherwise indicated, these rings can be attached to any ring member provided that the valency of the atom is not exceeded. For example, an azetidine ring may be attached at any position of the ring, whereas an azetidin-3-yl ring is attached at the 3-position.
  • The compounds described herein can be asymmetric (e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C═N double bonds and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms.
  • Resolution of racemic mixtures of compounds can be carried out by any of numerous methods known in the art. One method includes fractional recrystallization using a chiral resolving acid which is an optically active, salt-forming organic acid. Suitable resolving agents for fractional recrystallization methods are, e.g., optically active acids, such as the D and L forms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid or the various optically active camphorsulfonic acids such as β-camphorsulfonic acid. Other resolving agents suitable for fractional crystallization methods include stereoisomerically pure forms of α-methylbenzylamine (e.g., S and R forms, or diastereomerically pure forms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine, cyclohexylethylamine, 1,2-diaminocyclohexane and the like.
  • Resolution of racemic mixtures can also be carried out by elution on a column packed with an optically active resolving agent (e.g., dinitrobenzoylphenylglycine). Suitable elution solvent composition can be determined by one skilled in the art.
  • In some embodiments, the compounds of the invention have the (R)-configuration. In other embodiments, the compounds have the (S)-configuration. In compounds with more than one chiral centers, each of the chiral centers in the compound may be independently (R) or (S), unless otherwise indicated.
  • Compounds of the invention also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone-enol pairs, amide-imidic acid pairs, lactam-lactim pairs, enamine-imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, e.g., 1H- and 3H-imidazole, 1H-, 2H- and 4H-1,2,4-triazole, 1H- and 2H-isoindole and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.
  • Compounds of the invention can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. One or more constituent atoms of the compounds of the invention can be replaced or substituted with isotopes of the atoms in natural or non-natural abundance. In some embodiments, the compound includes at least one deuterium atom. For example, one or more hydrogen atoms in a compound of the present disclosure can be replaced or substituted by deuterium. In some embodiments, the compound includes two or more deuterium atoms. In some embodiments, the compound includes 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 deuterium atoms. Synthetic methods for including isotopes into organic compounds are known in the art.
  • The term, “compound,” as used herein is meant to include all stereoisomers, geometric isomers, tautomers and isotopes of the structures depicted. The term is also meant to refer to compounds of the inventions, regardless of how they are prepared, e.g., synthetically, through biological process (e.g., metabolism or enzyme conversion), or a combination thereof.
  • All compounds, and pharmaceutically acceptable salts thereof, can be found together with other substances such as water and solvents (e.g., hydrates and solvates) or can be isolated. When in the solid state, the compounds described herein and salts thereof may occur in various forms and may, e.g., take the form of solvates, including hydrates. The compounds may be in any solid state form, such as a polymorph or solvate, so unless clearly indicated otherwise, reference in the specification to compounds and salts thereof should be understood as encompassing any solid state form of the compound.
  • In some embodiments, the compounds of the invention, or salts thereof, are substantially isolated. By “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, e.g., a composition enriched in the compounds of the invention. 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 of the invention, or salt thereof.
  • The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • The expressions, “ambient temperature” and “room temperature,” as used herein, are understood in the art, and refer generally to a temperature, e.g., a reaction temperature, that is about the temperature of the room in which the reaction is carried out, e.g., a temperature from about 20° C. to about 30° C.
  • The present invention also includes pharmaceutically acceptable salts of the compounds described herein. The term “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 invention include the non-toxic salts of the parent compound formed, e.g., from non-toxic inorganic or organic acids. The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, 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 (MeCN) are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th Ed., (Mack Publishing Company, Easton, 1985), p. 1418, Berge et al., J. Pharm. Sci., 1977, 66(1), 1-19 and in Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection, and Use, (Wiley, 2002). In some embodiments, the compounds described herein include the N-oxide forms.
    • II. Synthesis
  • Compounds of the invention, including salts thereof, can be prepared using known organic synthesis techniques and can be synthesized according to any of numerous possible synthetic routes, such as those in the Schemes below.
  • The reactions for preparing compounds of the invention can be carried out in suitable solvents which can be readily selected by one of skill in the art of organic synthesis. Suitable solvents can be substantially non-reactive with the starting materials (reactants), the intermediates or products at the temperatures at which the reactions are carried out, e.g., temperatures which can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step can be selected by the skilled artisan.
  • Preparation of compounds of the invention can involve the protection and deprotection of various chemical groups. The need for protection and deprotection, and the selection of appropriate protecting groups, can be readily determined by one skilled in the art. The chemistry of protecting groups is described, e.g., in Kocienski, Protecting Groups, (Thieme, 2007); Robertson, Protecting Group Chemistry, (Oxford University Press, 2000); Smith et al., March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 6th Ed. (Wiley, 2007); Peturssion et al., “Protecting Groups in Carbohydrate Chemistry,” J Chem. Educ., 1997, 74(11), 1297; and Wuts et al., Protective Groups in Organic Synthesis, 4th Ed., (Wiley, 2006).
  • Reactions can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1H or 13C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry or by chromatographic methods such as high performance liquid chromatography (HPLC) or thin layer chromatography (TLC).
  • The Schemes below provide general guidance in connection with preparing the compounds of the invention. One skilled in the art would understand that the preparations shown in the Schemes can be modified or optimized using general knowledge of organic chemistry to prepare various compounds of the invention.
  • Compounds of Formula (I′) and Formula (I) can be synthesized using a process shown in Scheme 1. In Scheme 1, a suitable halo (W1)-substituted aromatic amine 1 is reacted with a suitable coupling reagent 2 (where M is, e.g., —B(OH)2) to produce compound 3 under standard metal catalyzed cross-coupling reaction conditions (such as Suzuki coupling reaction, e.g., in the presence of a palladium catalyst (e.g., 1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II)) and a base (e.g., a bicarbonate or a carbonate base)). Then the aromatic amine 3 is reacted with an acid of formula 4 under suitable conditions forming an amide bond to provide the product of formula (I) using coupling reagents such as, but not limited to, HATU and DIPEA.
  • Figure US20170174671A1-20170622-C00030
  • Compounds of the invention (8a) can be synthesized using a process shown in Scheme 2. The aromatic amine 3 is reacted with an acid of formula 5 under suitable conditions forming an amide bond to provide the product 6, using coupling reagents such as, but not limited to, HATU and DIPEA. The compound of formula 7 can be synthesized by coupling the halo group (W2) of 6 with a vinyl reagent (e.g., vinyl boronic acid pinacol ester) under standard coupling reaction conditions (such as Suzuki coupling reaction, e.g., in the presence of a palladium catalyst (e.g., 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)) and a base (e.g., a bicarbonate or a carbonate base)). The vinyl group in compound 7 is oxidatively cleaved to afford an aldehyde of formula 8 in the presence of suitable reagents such as, but not limited to, OsO4 and NaIO4. Then compounds of formula 8a are obtained by a reductive amination between the compound of formula 8 and a suitable amine in a proper solvent such as THF or DCM using a reducing agent such as, but not limited to, sodium triacetoxyborohydride, optionally in the presence of an acid such as acetic acid.
  • Figure US20170174671A1-20170622-C00031
  • Compounds of formula 8a can be alternatively synthesized using a process shown in Scheme 3. The aromatic amine 3 is reacted with an acid of formula 9 under suitable conditions to form an amide bond providing the product of formula 10, using coupling reagents such as, but not limited to, HATU and DIPEA. Subsequent reduction of the ester group in compound 10 can give an alcohol of formula 11 using a suitable reducing agent such as, but not limited to, lithium aluminum hydride. The alcohol unit in compound 11 was oxidized to aldehyde in compound 8 with a suitable oxidant such as, but not limited to, Dess-Martin periodinane. Then the compound of formula 8a was obtained by a reductive amination between formula 8 and a suitable amine in a proper solvent such as THF or DCM using a reducing agent such as, but not limited to, sodium triacetoxyborohydride, optionally in the presence of an acid such as acetic acid.
  • Figure US20170174671A1-20170622-C00032
  • Compounds of the invention (15a) can be synthesized using a process shown in Scheme 4. The aromatic amine 3 is reacted with an acid of formula 12 under suitable conditions forming an amide bond to provide the product of formula 13, using coupling reagents such as, but not limited to, HATU and DIPEA. The compound of formula 14 can be synthesized by coupling the halo group (W3) of 13 with a vinyl reagent (e.g., vinyl boronic acid pinacol ester) under standard coupling reaction conditions (such as Suzuki coupling reaction, e.g., in the presence of a palladium catalyst (e.g., 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)) and a base (e.g., a bicarbonate or a carbonate base)). The vinyl group in compound 14 is oxidatively cleaved to afford an aldehyde of formula 15 in the presence of suitable reagents such as, but not limited to, OsO4 and NaIO4. Then the compound of formula 15a is obtained by a reductive amination between the compound of formula 15 and a suitable amine in a proper solvent such as THF or DCM using a reducing agent such as, but not limited to, sodium triacetoxyborohydride, optionally in the presence of an acid such as acetic acid.
  • Figure US20170174671A1-20170622-C00033
  • Compounds of Formula 19 can be prepared using procedures as outlined in Scheme 5. Acids of formula 4 can react with aromatic amines of formula 16 under amide coupling conditions [e.g., in the presence of 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU) and a suitable base such as N,N-Diisopropylethylamine (DIPEA)] to give amide derivatives of formula 17. The halide (e.g., Hal1=Cl, Br, I) in compounds 17 can be coupled to compounds of formula 18, in which M is a boronic acid, boronic ester or an appropriately substituted metal [e.g., M is B(OR)2, Sn(Alkyl)4, or Zn-Hal], under Suzuki coupling conditions (e.g., in the presence of a palladium catalyst and a suitable base) or Stille coupling conditions (e.g., in the presence of a palladium catalyst), or Negishi coupling conditions (e.g., in the presence of a palladium catalyst) to give derivatives of formula 19. Alternatively, compound 18 can be a cyclic amine (where M is H and attached to an amine nitrogen in ring A) and the coupling of aryl halide 17 with the cyclic amine 18 can be performed under Buchwald amination conditions (e.g., in the presence of a palladium catalyst and a base such as sodium tert-butoxide).
  • Figure US20170174671A1-20170622-C00034
  • Alternatively, compounds of formula 19 can also be prepared using reaction sequence as outlined in Scheme 6. Coupling of aromatic halides of formula 16 with compounds of formula 18 can be achieved under similar conditions as described in Scheme 5 (e.g., conditions used for coupling of compounds 17 and compounds 18) to give compounds of formula 20. Acids of formula 4 can react with aromatic amines of formula 20 under amide coupling conditions to give compounds of formula 19.
  • Figure US20170174671A1-20170622-C00035
    • III. Uses of the Compounds
  • Compounds of the present disclosure can inhibit the activity of PD-1/PD-L1 protein/protein interaction and, thus, are useful in treating diseases and disorders associated with activity of PD-1 and the diseases and disorders associated with PD-L1 including its interaction with other proteins such as PD-1 and B7-1 (CD80). In certain embodiments, the compounds of the present disclosure, or pharmaceutically acceptable salts or stereoisomers thereof, are useful for therapeutic administration to enhance stimulate and/or increase immunity in cancer or chronic infection, including enhancement of response to vaccination. In some embodiments, the present disclosure provides a method for inhibiting the PD-1/PD-L1 protein/protein interaction. The method includes administering to an individual or a patient a compound of Formula (I′), Formula (I) or of any of the formulas as described herein, or of a compound as recited in any of the claims and described herein, or a pharmaceutically acceptable salt or a stereoisomer thereof. The compounds of the present disclosure can be used alone, in combination with other agents or therapies or as an adjuvant or neoadjuvant for the treatment of diseases or disorders, including cancer or infection diseases. For the uses described herein, any of the compounds of the disclosure, including any of the embodiments thereof, may be used.
  • The compounds of the present disclosure inhibit the PD-1/PD-L1 protein/protein interaction, resulting in a PD-1 pathway blockade. The blockade of PD-1 can enhance the immune response to cancerous cells and infectious diseases in mammals, including humans. In some embodiments, the present disclosure provides treatment of an individual or a patient in vivo using a compound of Formula (I′), Formula (I) or a salt or stereoisomer thereof such that growth of cancerous tumors is inhibited. A compound of Formula (I′), Formula (I) or of any of the formulas as described herein, or a compound as recited in any of the claims and described herein, or a salt or stereoisomer thereof, can be used to inhibit the growth of cancerous tumors. Alternatively, a compound of Formula (I′), Formula (I) or of any of the formulas as described herein, or a compound as recited in any of the claims and described herein, or a salt or stereoisomer thereof, can be used in conjunction with other agents or standard cancer treatments, as described below. In one embodiment, the present disclosure provides a method for inhibiting growth of tumor cells in vitro. The method includes contacting the tumor cells in vitro with a compound of Formula (I′), Formula (I) or of any of the formulas as described herein, or of a compound as recited in any of the claims and described herein, or of a salt or stereoisomer thereof. In another embodiment, the present disclosure provides a method for inhibiting growth of tumor cells in an individual or a patient. The method includes administering to the individual or patient in need thereof a therapeutically effective amount of a compound of Formula (I′), Formula (I) or of any of the formulas as described herein, or of a compound as recited in any of the claims and described herein, or a salt or a stereoisomer thereof.
  • In some embodiments, provided herein is a method for treating cancer. The method includes administering to a patient in need thereof, a therapeutically effective amount of a compound of Formula (I′), Formula (I) or any of the formulas as described herein, a compound as recited in any of the claims and described herein, or a salt thereof. Examples of cancers include those whose growth may be inhibited using compounds of the disclosure and cancers typically responsive to immunotherapy.
  • In some embodiments, the present disclosure provides a method of enhancing, stimulating and/or increasing the immune response in a patient. The method includes administering to the patient in need thereof a therapeutically effective amount of a compound of Formula (I′), Formula (I) or any of the formulas as described herein, a compound or composition as recited in any of the claims and described herein, or a salt thereof.
  • Examples of cancers that are treatable using the compounds or combinations of the present disclosure include, but are not limited to, ewing sarcoma, cholangiocarcinoma, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular malignant melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, testicular cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, endometrial cancer, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, non-Hodgkin's lymphoma, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, chronic or acute leukemias including acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, solid tumors of childhood, lymphocytic lymphoma, cancer of the bladder, cancer of the kidney or urethra, carcinoma of the renal pelvis, neoplasm of the central nervous system (CNS), primary CNS lymphoma, tumor angiogenesis, spinal axis tumor, brain stem glioma, pituitary adenoma, Kaposi's sarcoma, epidermoid cancer, squamous cell cancer, T-cell lymphoma, environmentally induced cancers including those induced by asbestos, and combinations of said cancers. The compounds of the present disclosure are also useful for the treatment of metastatic cancers, especially metastatic cancers that express PD-L1.
  • In some embodiments, cancers treatable with compounds or combinations of the present disclosure include melanoma (e.g., metastatic malignant melanoma), renal cancer (e.g. clear cell carcinoma), prostate cancer (e.g. hormone refractory prostate adenocarcinoma), breast cancer, colon cancer and lung cancer (e.g. non-small cell lung cancer). Additionally, the disclosure includes refractory or recurrent malignancies whose growth may be inhibited using the compounds of the disclosure.
  • In some embodiments, cancers that are treatable using the compounds or combinations of the present disclosure include, but are not limited to, solid tumors (e.g., prostate cancer, colon cancer, esophageal cancer, endometrial cancer, ovarian cancer, uterine cancer, renal cancer, hepatic cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, cancers of the head and neck, thyroid cancer, glioblastoma, sarcoma, bladder cancer, etc.), hematological cancers (e.g., lymphoma, leukemia such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), DLBCL, mantle cell lymphoma, Non-Hodgkin lymphoma (including relapsed or refractory NHL and recurrent follicular), Hodgkin lymphoma or multiple myeloma) and combinations of said cancers.
  • PD-1 pathway blockade with compounds of the present disclosure can also be used for treating infections such as viral, bacteria, fungus and parasite infections. The present disclosure provides a method for treating infections such as viral infections. The method includes administering to a patient in need thereof, a therapeutically effective amount of a compound of Formula (I′), Formula (I) or any of the formulas as described herein, a compound as recited in any of the claims and described herein, a salt thereof. Examples of viruses causing infections treatable by methods of the present disclosure include, but are not limit to, human immunodeficiency virus, human papillomavirus, influenza, hepatitis A, B, C or D viruses, adenovirus, poxvirus, herpes simplex viruses, human cytomegalovirus, severe acute respiratory syndrome virus, ebola virus, and measles virus. In some embodiments, viruses causing infections treatable by methods of the present disclosure include, but are not limit to, hepatitis (A, B, or C), herpes virus (e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus), adenovirus, influenza virus, flaviviruses, echovirus, rhinovirus, coxsackie virus, comovirus, respiratory syncytial virus, mumpsvirus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus and arboviral encephalitis virus.
  • The present disclosure provides a method for treating bacterial infections. The method includes administering to a patient in need thereof, a therapeutically effective amount of a compound of Formula (I′), Formula (I) or any of the formulas as described herein, a compound as recited in any of the claims and described herein, or a salt thereof. Non-limiting examples of pathogenic bacteria causing infections treatable by methods of the disclosure include chlamydia, rickettsial bacteria, mycobacteria, staphylococci, streptococci, pneumonococci, meningococci and conococci, klebsiella, proteus, serratia, pseudomonas, legionella, diphtheria, salmonella, bacilli, cholera, tetanus, botulism, anthrax, plague, leptospirosis, and Lyme's disease bacteria.
  • The present disclosure provides a method for treating fungus infections. The method includes administering to a patient in need thereof, a therapeutically effective amount of a compound of Formula (I′), Formula (I) or any of the formulas as described herein, a compound as recited in any of the claims and described herein, or a salt thereof. Non-limiting examples of pathogenic fungi causing infections treatable by methods of the disclosure include Candida (albicans, krusei, glabrata, tropicalis, etc.), Cryptococcus neoformans, Aspergillus (fumigatus, niger, etc.), Genus Mucorales (mucor, absidia, rhizophus), Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis and Histoplasma capsulatum.
  • The present disclosure provides a method for treating parasite infections. The method includes administering to a patient in need thereof, a therapeutically effective amount of a compound of Formula (I′), Formula (I) or any of the formulas as described herein, a compound as recited in any of the claims and described herein, or a salt thereof. Non-limiting examples of pathogenic parasites causing infections treatable by methods of the disclosure include Entamoeba histolytica, Balantidium coli, Naegleriafowleri, Acanthamoeba sp., Giardia lambia, Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi, and Nippostrongylus brasiliensis.
  • The terms “individual” or “patient,” used interchangeably, refer to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.
  • The phrase “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • As used herein, the term “treating” or “treatment” refers to one or more of (1) inhibiting the disease; e.g., inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology); and (2) ameliorating the disease; e.g., ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology) such as decreasing the severity of disease.
  • In some embodiments, the compounds of the invention are useful in preventing or reducing the risk of developing any of the diseases referred to herein; e.g., preventing or reducing the risk of developing a disease, condition or disorder in an individual who may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease.
    • Combination Therapies
  • Cancer cell growth and survival can be impacted by multiple signaling pathways. Thus, it is useful to combine different enzyme/protein/receptor inhibitors, exhibiting different preferences in the targets which they modulate the activities of, to treat such conditions. Targeting more than one signaling pathway (or more than one biological molecule involved in a given signaling pathway) may reduce the likelihood of drug-resistance arising in a cell population, and/or reduce the toxicity of treatment.
  • The compounds of the present disclosure can be used in combination with one or more other enzyme/protein/receptor inhibitors for the treatment of diseases, such as cancer or infections. Examples of cancers include solid tumors and liquid tumors, such as blood cancers. Examples of infections include viral infections, bacterial infections, fungus infections or parasite infections. For example, the compounds of the present disclosure can be combined with one or more inhibitors of the following kinases for the treatment of cancer: Akt1, Akt2, Akt3, TGF-βR, PKA, PKG, PKC, CaM-kinase, phosphorylase kinase, MEKK, ERK, MAPK, mTOR, EGFR, HER2, HER3, HER4, INS-R, IGF-1R, IR-R, PDGFαR, PDGFβR, CSFIR, KIT, FLK-II, KDR/FLK-1, FLK-4, fit-1, FGFR1, FGFR2, FGFR3, FGFR4, c-Met, Ron, Sea, TRKA, TRKB, TRKC, FLT3, VEGFR/Flt2, Flt4, EphA1, EphA2, EphA3, EphB2, EphB4, Tie2, Src, Fyn, Lck, Fgr, Btk, Fak, SYK, FRK, JAK, ABL, ALK and B-Raf. In some embodiments, the compounds of the present disclosure can be combined with one or more of the following inhibitors for the treatment of cancer or infections. Non-limiting examples of inhibitors that can be combined with the compounds of the present disclosure for treatment of cancer and infections include an FGFR inhibitor (FGFR1, FGFR2, FGFR3 or FGFR4, e.g., INCB54828, INCB62079 and INCB63904), a JAK inhibitor (JAK1 and/or JAK2, e.g., ruxolitinib, baricitinib or INCB39110), an IDO inhibitor (e.g., epacadostat and NLG919), an LSD1 inhibitor (e.g., INCB59872 and INCB60003), a TDO inhibitor, a PI3K-delta inhibitor, a PI3K-gamma inhibitor, such as PI3K-gamma selective inhibitor (e.g., INCB50797), a Pim inhibitor, a CSF1R inhibitor, a TAM receptor tyrosine kinases (Tyro-3, Ax1, and Mer), an angiogenesis inhibitor, an interleukin receptor inhibitor, bromo and extra terminal family members inhibitors (for example, bromodomain inhibitors or BET inhibitors such as INCB54329 and INCB57643) and an adenosine receptor antagonist or combinations thereof.
  • Compounds of the present disclosure can be used in combination with one or more immune checkpoint inhibitors. Exemplary immune checkpoint inhibitors include inhibitors against immune checkpoint molecules such as CD27, CD28, CD40, CD122, CD96, CD73, CD47, OX40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, CD137 (also known as 4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, PD-1, PD-L1 and PD-L2. In some embodiments, the immune checkpoint molecule is a stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS, OX40, GITR and CD137. In some embodiments, the immune checkpoint molecule is an inhibitory checkpoint molecule selected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, and VISTA. In some embodiments, the compounds provided herein can be used in combination with one or more agents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors and TGFR beta inhibitors.
  • In some embodiments, the inhibitor of an immune checkpoint molecule is anti-PD1 antibody, anti-PD-L1 antibody, or anti-CTLA-4 antibody.
  • In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, or AMP-224. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab or pembrolizumab. In some embodiments, the anti-PD1 antibody is pembrolizumab. In some embodiments, the anti PD-1 antibody is SHR-1210.
  • In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments, the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736.
  • In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab.
  • In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is BMS-986016 or LAG525.
  • In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of GITR, e.g., an anti-GITR antibody. In some embodiments, the anti-GITR antibody is TRX518 or MK-4166.
  • In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of OX40, e.g., an anti-OX40 antibody or OX40L fusion protein. In some embodiments, the anti-OX40 antibody is MEDI0562. In some embodiments, the OX40L fusion protein is MEDI6383.
  • Compounds of the present disclosure can be used in combination with one or more agents for the treatment of diseases such as cancer. In some embodiments, the agent is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulatory agent.
  • Examples of an alkylating agent include cyclophosphamide (CY), melphalan (MEL), and bendamustine. In some embodiments, the proteasome inhibitor is carfilzomib. In some embodiments, the corticosteroid is dexamethasone (DEX). In some embodiments, the immunomodulatory agent is lenalidomide (LEN) or pomalidomide (POM).
  • The compounds of the present disclosure can further be used in combination with other methods of treating cancers, for example by chemotherapy, irradiation therapy, tumor-targeted therapy, adjuvant therapy, immunotherapy or surgery. Examples of immunotherapy include cytokine treatment (e.g., interferons, GM-CSF, G-CSF, IL-2), CRS-207 immunotherapy, cancer vaccine, monoclonal antibody, adoptive T cell transfer, oncolytic virotherapy and immunomodulating small molecules, including thalidomide or JAK1/2 inhibitor and the like. The compounds can be administered in combination with one or more anti-cancer drugs, such as a chemotherapeutics. Example chemotherapeutics include any of: abarelix, aldesleukin, alemtuzumab, alitretinoin, allopurinol, altretamine, anastrozole, arsenic trioxide, asparaginase, azacitidine, bevacizumab, bexarotene, baricitinib, bleomycin, bortezombi, bortezomib, busulfan intravenous, busulfan oral, calusterone, capecitabine, carboplatin, carmustine, cetuximab, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, dalteparin sodium, dasatinib, daunorubicin, decitabine, denileukin, denileukin diftitox, dexrazoxane, docetaxel, doxorubicin, dromostanolone propionate, eculizumab, epirubicin, erlotinib, estramustine, etoposide phosphate, etoposide, exemestane, fentanyl citrate, filgrastim, floxuridine, fludarabine, fluorouracil, fulvestrant, gefitinib, gemcitabine, gemtuzumab ozogamicin, goserelin acetate, histrelin acetate, ibritumomab tiuxetan, idarubicin, ifosfamide, imatinib mesylate, interferon alfa 2a, irinotecan, lapatinib ditosylate, lenalidomide, letrozole, leucovorin, leuprolide acetate, levamisole, lomustine, meclorethamine, megestrol acetate, melphalan, mercaptopurine, methotrexate, methoxsalen, mitomycin C, mitotane, mitoxantrone, nandrolone phenpropionate, nelarabine, nofetumomab, oxaliplatin, paclitaxel, pamidronate, panitumumab, pegaspargase, pegfilgrastim, pemetrexed disodium, pentostatin, pipobroman, plicamycin, procarbazine, quinacrine, rasburicase, rituximab, ruxolitinib, sorafenib, streptozocin, sunitinib, sunitinib maleate, tamoxifen, temozolomide, teniposide, testolactone, thalidomide, thioguanine, thiotepa, topotecan, toremifene, tositumomab, trastuzumab, tretinoin, uracil mustard, valrubicin, vinblastine, vincristine, vinorelbine, vorinostat and zoledronate.
  • Other anti-cancer agent(s) include antibody therapeutics such as trastuzumab (Herceptin), antibodies to costimulatory molecules such as CTLA-4 (e.g., ipilimumab), 4-IBB, antibodies to PD-1 and PD-L1, or antibodies to cytokines (IL-10, TGF-β, etc.). Examples of antibodies to PD-1 and/or PD-L1 that can be combined with compounds of the present disclosure for the treatment of cancer or infections such as viral, bacteria, fungus and parasite infections include, but are not limited to, nivolumab, pembrolizumab, MPDL3280A, MEDI-4736 and SHR-1210.
  • In some embodiments, the anti-cancer agent is an alkylating agent, a proteasome inhibitor, a corticosteroid, or an immunomodulatory agent. Examples of an alkylating agent include cyclophosphamide (CY), melphalan (MEL), and bendamustine. In some embodiments, the proteasome inhibitor is carfilzomib. In some embodiments, the corticosteroid is dexamethasone (DEX). In some embodiments, the immunomodulatory agent is lenalidomide (LEN) or pomalidomide (POM).
  • Compounds of the present disclosure can be used in combination with one or more immune checkpoint inhibitors for the treatment of diseases, such as cancer or infections. Exemplary immune checkpoint inhibitors include inhibitors against immune checkpoint molecules such as CD27, CD28, CD40, CD122, CD96, CD73, CD47, OX40, GITR, CSF1R, JAK, PI3K delta, PI3K gamma, TAM, arginase, CD137 (also known as 4-1BB), ICOS, A2AR, B7-H3, B7-H4, BTLA, CTLA-4, LAG3, TIM3, VISTA, PD-1, PD-L1 and PD-L2. In some embodiments, the immune checkpoint molecule is a stimulatory checkpoint molecule selected from CD27, CD28, CD40, ICOS, OX40, GITR and CD137. In some embodiments, the immune checkpoint molecule is an inhibitory checkpoint molecule selected from A2AR, B7-H3, B7-H4, BTLA, CTLA-4, IDO, KIR, LAG3, PD-1, TIM3, and VISTA. In some embodiments, the compounds provided herein can be used in combination with one or more agents selected from KIR inhibitors, TIGIT inhibitors, LAIR1 inhibitors, CD160 inhibitors, 2B4 inhibitors and TGFR beta inhibitors.
  • In some embodiments, the inhibitor of an immune checkpoint molecule is anti-PD1 antibody, anti-PD-L1 antibody, or anti-CTLA-4 antibody.
  • In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-1, e.g., an anti-PD-1 monoclonal antibody. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab, pembrolizumab (also known as MK-3475), pidilizumab, SHR-1210, PDR001, or AMP-224. In some embodiments, the anti-PD-1 monoclonal antibody is nivolumab or pembrolizumab. In some embodiments, the anti-PD1 antibody is pembrolizumab.
  • In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of PD-L1, e.g., an anti-PD-L1 monoclonal antibody. In some embodiments, the anti-PD-L1 monoclonal antibody is BMS-935559, MEDI4736, MPDL3280A (also known as RG7446), or MSB0010718C. In some embodiments, the anti-PD-L1 monoclonal antibody is MPDL3280A or MEDI4736.
  • In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of CTLA-4, e.g., an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab.
  • In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of LAG3, e.g., an anti-LAG3 antibody. In some embodiments, the anti-LAG3 antibody is BMS-986016 or LAG525.
  • In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of GITR, e.g., an anti-GITR antibody. In some embodiments, the anti-GITR antibody is TRX518 or MK-4166.
  • In some embodiments, the inhibitor of an immune checkpoint molecule is an inhibitor of OX40, e.g., an anti-OX40 antibody or OX40L fusion protein. In some embodiments, the anti-OX40 antibody is MEDI0562. In some embodiments, the OX40L fusion protein is MEDI6383.
  • The compounds of the present disclosure can further be used in combination with one or more anti-inflammatory agents, steroids, immunosuppressants or therapeutic antibodies.
  • The compounds of Formula (I′), Formula (I) or any of the formulas as described herein, a compound as recited in any of the claims and described herein, or salts thereof can be combined with another immunogenic agent, such as cancerous cells, purified tumor antigens (including recombinant proteins, peptides, and carbohydrate molecules), cells, and cells transfected with genes encoding immune stimulating cytokines. Non-limiting examples of tumor vaccines that can be used include peptides of melanoma antigens, such as peptides of gp100, MAGE antigens, Trp-2, MARTI and/or tyrosinase, or tumor cells transfected to express the cytokine GM-CSF.
  • The compounds of Formula (I′), Formula (I) or any of the formulas as described herein, a compound as recited in any of the claims and described herein, or salts thereof can be used in combination with a vaccination protocol for the treatment of cancer. In some embodiments, the tumor cells are transduced to express GM-CSF. In some embodiments, tumor vaccines include the proteins from viruses implicated in human cancers such as Human Papilloma Viruses (HPV), Hepatitis Viruses (HBV and HCV) and Kaposi's Herpes Sarcoma Virus (KHSV). In some embodiments, the compounds of the present disclosure can be used in combination with tumor specific antigen such as heat shock proteins isolated from tumor tissue itself. In some embodiments, the compounds of Formula (I′), Formula (I) or any of the formulas as described herein, a compound as recited in any of the claims and described herein, or salts thereof can be combined with dendritic cells immunization to activate potent anti-tumor responses.
  • The compounds of the present disclosure can be used in combination with bispecific macrocyclic peptides that target Fe alpha or Fe gamma receptor-expressing effectors cells to tumor cells. The compounds of the present disclosure can also be combined with macrocyclic peptides that activate host immune responsiveness.
  • 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 Formula (I′), Formula (I) or any of the formulas as described herein, a compound as recited in any of the claims and described herein, or salts thereof can be used in combination with vaccines, to stimulate the immune response to pathogens, toxins, and self antigens. Examples of pathogens for which this therapeutic approach may be particularly useful, include pathogens for which there is currently no effective vaccine, or pathogens for which conventional vaccines are less than completely effective. These include, but are not limited to, HIV, Hepatitis (A, B, & C), Influenza, Herpes, Giardia, Malaria, Leishmania, Staphylococcus aureus, Pseudomonas Aeruginosa.
  • Viruses causing infections treatable by methods of the present disclosure include, but are not limit to human papillomavirus, influenza, hepatitis A, B, C or D viruses, adenovirus, poxvirus, herpes simplex viruses, human cytomegalovirus, severe acute respiratory syndrome virus, ebola virus, measles virus, herpes virus (e.g., VZV, HSV-1, HAV-6, HSV-II, and CMV, Epstein Barr virus), flaviviruses, echovirus, rhinovirus, coxsackie virus, cornovirus, respiratory syncytial virus, mumpsvirus, rotavirus, measles virus, rubella virus, parvovirus, vaccinia virus, HTLV virus, dengue virus, papillomavirus, molluscum virus, poliovirus, rabies virus, JC virus and arboviral encephalitis virus.
  • Pathogenic bacteria causing infections treatable by methods of the disclosure include, but are not limited to, chlamydia, rickettsial bacteria, mycobacteria, staphylococci, streptococci, pneumonococci, meningococci and conococci, klebsiella, proteus, serratia, pseudomonas, legionella, diphtheria, salmonella, bacilli, cholera, tetanus, botulism, anthrax, plague, leptospirosis, and Lyme's disease bacteria.
  • Pathogenic fungi causing infections treatable by methods of the disclosure include, but are not limited to, Candida (albicans, krusei, glabrata, tropicalis, etc.), Cryptococcus neoformans, Aspergillus (fumigatus, niger, etc.), Genus Mucorales (mucor, absidia, rhizophus), Sporothrix schenkii, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Coccidioides immitis and Histoplasma capsulatum.
  • Pathogenic parasites causing infections treatable by methods of the disclosure include, but are not limited to, Entamoeba histolytica, Balantidium coli, Naegleriafowleri, Acanthamoeba sp., Giardia lambia, Cryptosporidium sp., Pneumocystis carinii, Plasmodium vivax, Babesia microti, Trypanosoma brucei, Trypanosoma cruzi, Leishmania donovani, Toxoplasma gondi, and Nippostrongylus brasiliensis.
  • When more than one pharmaceutical agent is administered to a patient, they can be administered simultaneously, separately, sequentially, or in combination (e.g., for more than two agents).
    • IV. Formulation, Dosage Forms and Administration
  • When employed as pharmaceuticals, the compounds of the present disclosure can be administered in the form of pharmaceutical compositions. Thus the present disclosure provides a composition comprising a compound of Formula (I′), Formula (I) or any of the formulas as described herein, a compound as recited in any of the claims and described herein, or a pharmaceutically acceptable salt thereof, or any of the embodiments thereof, and at least one pharmaceutically acceptable carrier or excipient. 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 indicated 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. Parenteral administration includes intravenous, intraarterial, subcutaneous, intraperitoneal intramuscular or injection or infusion; or intracranial, e.g., intrathecal or intraventricular, administration. Parenteral administration can be in the form of a single bolus dose, or may be, e.g., by a continuous perfusion pump. Pharmaceutical compositions and formulations for topical administration may include transdermal patches, ointments, lotions, creams, gels, drops, suppositories, sprays, liquids and powders. Conventional pharmaceutical carriers, aqueous, powder or oily bases, thickeners and the like may be necessary or desirable.
  • This invention also includes pharmaceutical compositions which contain, as the active ingredient, the compound of the present disclosure or a pharmaceutically acceptable salt thereof, in combination with one or more pharmaceutically acceptable carriers or excipients. In some embodiments, the composition is suitable for topical administration. In making the compositions of the invention, the active ingredient is typically mixed with an excipient, diluted by an excipient or enclosed within such a carrier in the form of, e.g., a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, e.g., up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions and sterile packaged powders.
  • In preparing a formulation, the active compound can be milled to provide the appropriate particle size prior to combining with the other ingredients. If the active compound is substantially insoluble, it can be milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size can be adjusted by milling to provide a substantially uniform distribution in the formulation, e.g., about 40 mesh.
  • The compounds of the invention may be milled using known milling procedures such as wet milling to obtain a particle size appropriate for tablet formation and for other formulation types. Finely divided (nanoparticulate) preparations of the compounds of the invention can be prepared by processes known in the art see, e.g., WO 2002/000196.
  • Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup and methyl cellulose. The formulations can additionally include: lubricating agents such as talc, magnesium stearate and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxy-benzoates; sweetening agents; and flavoring agents. The compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • In some embodiments, the pharmaceutical composition comprises silicified microcrystalline cellulose (SMCC) and at least one compound described herein, or a pharmaceutically acceptable salt thereof. In some embodiments, the silicified microcrystalline cellulose comprises about 98% microcrystalline cellulose and about 2% silicon dioxide w/w.
  • In some embodiments, the composition is a sustained release composition comprising at least one compound described herein, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier or excipient. In some embodiments, the composition comprises at least one compound described herein, or a pharmaceutically acceptable salt thereof, and at least one component selected from microcrystalline cellulose, lactose monohydrate, hydroxypropyl methylcellulose and polyethylene oxide. In some embodiments, the composition comprises at least one compound described herein, or a pharmaceutically acceptable salt thereof, and microcrystalline cellulose, lactose monohydrate and hydroxypropyl methylcellulose. In some embodiments, the composition comprises at least one compound described herein, or a pharmaceutically acceptable salt thereof, and microcrystalline cellulose, lactose monohydrate and polyethylene oxide. In some embodiments, the composition further comprises magnesium stearate or silicon dioxide. In some embodiments, the microcrystalline cellulose is Avicel PH102™. In some embodiments, the lactose monohydrate is Fast-flo 316™. In some embodiments, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose 2208 K4M (e.g., Methocel K4 M Premier™) and/or hydroxypropyl methylcellulose 2208 K100LV (e.g., Methocel K00LV™). In some embodiments, the polyethylene oxide is polyethylene oxide WSR 1105 (e.g., Polyox WSR 1105™).
  • In some embodiments, a wet granulation process is used to produce the composition. In some embodiments, a dry granulation process is used to produce the composition.
  • The compositions can be formulated in a unit dosage form, each dosage containing from about 5 to about 1,000 mg (1 g), more usually about 100 mg to about 500 mg, of the active ingredient. In some embodiments, each dosage contains about 10 mg of the active ingredient. In some embodiments, each dosage contains about 50 mg of the active ingredient. In some embodiments, each dosage contains about 25 mg of the active ingredient. The term “unit dosage forms” refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • The components used to formulate the pharmaceutical compositions are of high purity and are substantially free of potentially harmful contaminants (e.g., at least National Food grade, generally at least analytical grade, and more typically at least pharmaceutical grade). Particularly for human consumption, the composition is preferably manufactured or formulated under Good Manufacturing Practice standards as defined in the applicable regulations of the U.S. Food and Drug Administration. For example, suitable formulations may be sterile and/or substantially isotonic and/or in full compliance with all Good Manufacturing Practice regulations of the U.S. Food and Drug Administration.
  • The active compound may be effective over a wide dosage range and is generally administered in a therapeutically effective amount. It will be understood, however, that the amount of the compound actually administered will usually be determined by a physician, according to the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms and the like.
  • The therapeutic dosage of a compound of the present invention can vary according to, e.g., the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the invention in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. For example, the compounds of the invention can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w/v of the compound for parenteral administration. Some typical dose ranges are from about 1 μg/kg to about 1 g/kg of body weight per day. In some embodiments, the dose range is from about 0.01 mg/kg to about 100 mg/kg of body weight per day. The dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.
  • For preparing solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound of the present invention. When referring to these preformulation compositions as homogeneous, the active ingredient is typically dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules. This solid preformulation is then subdivided into unit dosage forms of the type described above containing from, e.g., about 0.1 to about 1000 mg of the active ingredient of the present invention.
  • The tablets or pills of the present invention can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action. For example, the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
  • The liquid forms in which the compounds and compositions of the present invention can be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • Compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described supra. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. Compositions can be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebulizing device or the nebulizing device can be attached to a face mask, tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered orally or nasally from devices which deliver the formulation in an appropriate manner.
  • Topical formulations can contain one or more conventional carriers. In some embodiments, ointments can contain water and one or more hydrophobic carriers selected from, e.g., liquid paraffin, polyoxyethylene alkyl ether, propylene glycol, white Vaseline, and the like. Carrier compositions of creams can be based on water in combination with glycerol and one or more other components, e.g., glycerinemonostearate, PEG-glycerinemonostearate and cetylstearyl alcohol. Gels can be formulated using isopropyl alcohol and water, suitably in combination with other components such as, e.g., glycerol, hydroxyethyl cellulose, and the like. In some embodiments, topical formulations contain at least about 0.1, at least about 0.25, at least about 0.5, at least about 1, at least about 2 or at least about 5 wt % of the compound of the invention. The topical formulations can be suitably packaged in tubes of, e.g., 100 g which are optionally associated with instructions for the treatment of the select indication, e.g., psoriasis or other skin condition.
  • The amount of compound or composition administered to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, the state of the patient, the manner of administration and the like. In therapeutic applications, compositions can be administered to a patient already suffering from a disease in an amount sufficient to cure or at least partially arrest the symptoms of the disease and its complications. Effective doses will depend on the disease condition being treated as well as by the judgment of the attending clinician depending upon factors such as the severity of the disease, the age, weight and general condition of the patient and the like.
  • The compositions administered to a patient can be in the form of pharmaceutical compositions described above. These compositions can be sterilized by conventional sterilization techniques, or may be sterile filtered. Aqueous solutions can be packaged for use as is, or lyophilized, the lyophilized preparation being combined with a sterile aqueous carrier prior to administration. The pH of the compound preparations typically will be between 3 and 11, more preferably from 5 to 9 and most preferably from 7 to 8. It will be understood that use of certain of the foregoing excipients, carriers or stabilizers will result in the formation of pharmaceutical salts.
  • The therapeutic dosage of a compound of the present invention can vary according to, e.g., the particular use for which the treatment is made, the manner of administration of the compound, the health and condition of the patient, and the judgment of the prescribing physician. The proportion or concentration of a compound of the invention in a pharmaceutical composition can vary depending upon a number of factors including dosage, chemical characteristics (e.g., hydrophobicity), and the route of administration. For example, the compounds of the invention can be provided in an aqueous physiological buffer solution containing about 0.1 to about 10% w/v of the compound for parenteral administration. Some typical dose ranges are from about 1 μg/kg to about 1 g/kg of body weight per day. In some embodiments, the dose range is from about 0.01 mg/kg to about 100 mg/kg of body weight per day. The dosage is likely to depend on such variables as the type and extent of progression of the disease or disorder, the overall health status of the particular patient, the relative biological efficacy of the compound selected, formulation of the excipient, and its route of administration. Effective doses can be extrapolated from dose-response curves derived from in vitro or animal model test systems.
    • V. Labeled Compounds and Assay Methods
  • The compounds of the present disclosure can further be useful in investigations of biological processes in normal and abnormal tissues. Thus, another aspect of the present invention relates to labeled compounds of the invention (radio-labeled, fluorescent-labeled, etc.) that would be useful not only in imaging techniques but also in assays, both in vitro and in vivo, for localizing and quantitating PD-1 or PD-L1 protein in tissue samples, including human, and for identifying PD-L1 ligands by inhibition binding of a labeled compound. Accordingly, the present invention includes PD-1/PD-L1 binding assays that contain such labeled compounds.
  • The present invention further includes isotopically-substituted compounds of the disclosure. An “isotopically-substituted” compound is a compound of the invention where one or more atoms are replaced or substituted by an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring). It is to be understood that a “radio-labeled” compound is a compound that has incorporated at least one isotope that is radioactive (e.g., radionuclide). Suitable radionuclides that may be incorporated in compounds of the present invention include but are not limited to 3H (also written as T for tritium), 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 18F, 35S, 36Cl, 82Br, 75Br, 76Br, 77Br, 123I, 124I, 125I and 131I. The radionuclide that is incorporated in the instant radio-labeled compounds will depend on the specific application of that radio-labeled compound. For example, for in vitro PD-L1 protein labeling and competition assays, compounds that incorporate 3H, 14C, 82Br, 125I, 131I, 35S or will generally be most useful. For radio-imaging applications 11C, 18F, 125I, 123I, 124I, 131I, 75Br, 76Br or 77Br will generally be most useful. In some embodiments the radionuclide is selected from the group consisting of 3H, 14C, 125I, 35S and 82Br. Synthetic methods for incorporating radio-isotopes into organic compounds are known in the art.
  • Specifically, a labeled compound of the invention can be used in a screening assay to identify and/or evaluate compounds. For example, a newly synthesized or identified compound (i.e., test compound) which is labeled can be evaluated for its ability to bind a PD-L1 protein by monitoring its concentration variation when contacting with the PD-L1 protein, through tracking of the labeling. For example, a test compound (labeled) can be evaluated for its ability to reduce binding of another compound which is known to bind to a PD-L1 protein (i.e., standard compound). Accordingly, the ability of a test compound to compete with the standard compound for binding to the PD-L1 protein directly correlates to its binding affinity. Conversely, in some other screening assays, the standard compound is labeled and test compounds are unlabeled. Accordingly, the concentration of the labeled standard compound is monitored in order to evaluate the competition between the standard compound and the test compound, and the relative binding affinity of the test compound is thus ascertained.
    • VI. Kits
  • The present disclosure also includes pharmaceutical kits useful, e.g., in the treatment or prevention of diseases or disorders associated with the activity of PD-L1 including its interaction with other proteins such as PD-1 and B7-1 (CD80), such as cancer or infections, which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I′), Formula (I), or any of the embodiments thereof. Such kits can further include one or more of various conventional pharmaceutical kit components, such as, e.g., containers with one or more pharmaceutically acceptable carriers, additional containers, etc., as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, can also be included in the kit.
  • The invention will be described in greater detail by way of specific examples. The following examples are offered for illustrative purposes, and are not intended to limit the invention in any manner. Those of skill in the art will readily recognize a variety of non-critical parameters which can be changed or modified to yield essentially the same results. The compounds of the Examples have been found to inhibit the activity of PD-1/PD-L1 protein/protein interaction according to at least one assay described herein.
    • EXAMPLES
  • Experimental procedures for compounds of the invention are provided below. Open Access Preparative LCMS Purification of some of the compounds prepared was performed on Waters mass directed fractionation systems. The basic equipment setup, protocols and control software for the operation of these systems have been described in detail in literature. See, e.g., Blom, “Two-Pump At Column Dilution Configuration for Preparative LC-MS”, K. Blom, J Combi. Chem., 2002, 4, 295-301; Blom et al., “Optimizing Preparative LC-MS Configurations and Methods for Parallel Synthesis Purification”, J Combi. Chem., 2003, 5, 670-83; and Blom et al., “Preparative LC-MS Purification: Improved Compound Specific Method Optimization”, J. Combi. Chem., 2004, 6, 874-883.
    • Example 1: (2S)-1-[(6-{[(2-methylbiphenyl-3-yl)amino]carbonyl}pyridin-3-yl)methyl]piperidine-2-carboxylic acid
  • Figure US20170174671A1-20170622-C00036
    • Step 1: 2-methylbiphenyl-3-amine
  • Figure US20170174671A1-20170622-C00037
  • Tetrakis(triphenylphosphine)palladium(0) (300 mg, 0.3 mmol) was added to a mixture of 3-bromo-2-methylaniline (1000 mg, 5 mmol), phenylboronic acid (600 mg, 5 mmol), 1,4-dioxane (20 mL, 200 mmol) and water (3 mL, 200 mmol), and the mixture was allowed to stir at 100° C. overnight. After concentration, the residue was dissolved in dichloromethane (DCM) and washed with brine. The organic layer was dried and concentrated to afford the desired product as a brown solid, which was used in the next step without further purification. LC-MS calculated for C13H14N (M+H)+: m/z=184.1; found 184.1.
    • Step 2: methyl 6-{[(2-methylbiphenyl-3-yl)amino]carbonyl}nicotinate
  • Figure US20170174671A1-20170622-C00038
  • N,N-Diisopropylethylamine (200 μL, 1 mmol) was added to a mixture of 2-methylbiphenyl-3-amine (70 mg, 0.4 mmol), 5-(methoxycarbonyl)pyridine-2-carboxylic acid (Oakwood Chemical, cat#017196, 75 mg, 0.42 mmol), and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (220 mg, 0.57 mmol) in N,N-dimethylformamide (2 mL, 20 mmol). The reaction mixture was allowed to stir at room temperature (rt) overnight. The reaction mixture was quenched with saturated aqueous NaHCO3, and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-35%) to afford the desired product. LC-MS calculated for C21H19N2O3 (M+H)+: m/z=347.1; found 347.1.
    • Step 3: 5-(hydroxymethyl)-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00039
  • 1.0 M Lithium tetrahydroaluminate in THF (0.6 mL, 0.6 mmol) was added to a THF (4.0 mL) solution of methyl 6-{[(2-methylbiphenyl-3-yl)amino]carbonyl}nicotinate (100 mg, 0.3 mmol) at 0° C. The reaction mixture was allowed to stir at 0° C. for 1 h to reach full conversion. The mixture was quenched with aqueous potassium sodium tartrate. The mixture was allowed to stir at rt for 2 h. The reaction mixture was extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The mixture was dried, concentrated, and the residue was used in the next step without further purification. LC-MS calculated for C20H19N2O2 (M+H)+: m/z=319.1; found 319.0.
    • Step 4: 5-formyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00040
  • Dess-Martin periodinane (76 mg, 0.18 mmol) was added to a mixture of 5-(hydroxymethyl)-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide (48 mg, 0.15 mmol), sodium bicarbonate (40 mg, 0.4 mmol), and methylene chloride (1 mL, 20 mmol), and the mixture was allowed to stir at rt for 2 h to reach full conversion. After concentration, the residue was dissolved in DCM and filtered. The organic layer was concentrated to afford desired product which was used in the next step without further purification. LC-MS calculated for C20H17N2O2 (M+H)+: m/z=317.1; found 317.0.
    • Step 5: (2S)-1-[(6-{[(2-methylbiphenyl-3-yl)amino]carbonyl}pyridin-3-yl)methyl]piperidine-2-carboxylic acid
  • Figure US20170174671A1-20170622-C00041
  • (2S)-Piperidine-2-carboxylic acid (20 mg, 0.1 mmol), sodium triacetoxyborohydride (60 mg, 0.3 mmol) and one drop of acetic acid were added to a methylene chloride (1 mL) solution of 5-formyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide, and the mixture was allowed to stir at rt overnight. The reaction mixture was purified by prep-HPLC (pH=10, acetonitrile/water+NH4OH) to give the desired product. LC-MS calculated for C26H28N3O3 (M+H)+: m/z=430.2; found 430.2.
    • Example 2: 5-{[(2-hydroxyethyl)amino]methyl}-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00042
  • Ethanolamine (20 μL, 0.3 mmol) and sodium triacetoxyborohydride (60 mg, 0.3 mmol) were added to a methylene chloride (1 mL) solution of 5-formyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide (Example 1, Step 4), and the mixture was allowed to stir at rt overnight. The reaction mixture was purified by prep-HPLC (pH=10, acetonitrile/water+NH4OH) to give the desired product. LC-MS calculated for C22H24N3O2 (M+H)+: m/z=362.2; found 362.2.
    • Example 3: (2S)-1-[(5-methyl-6-{[(2-methylbiphenyl-3-yl)amino]carbonyl}pyridin-3-yl)methyl]piperidine-2-carboxylic acid
  • Figure US20170174671A1-20170622-C00043
    • Step 1: 5-bromo-3-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00044
  • This compound was prepared using a similar procedure as described for Example 1, Step 2 with 5-bromo-2-carboxy-3-methylpyridine replacing 5-(methoxycarbonyl)pyridine-2-carboxylic acid. LC-MS calculated for C20H18BrN2O (M+H)+: m/z=381.0; found: 381.1.
    • Step 2: 3-methyl-N-(2-methylbiphenyl-3-yl)-5-vinylpyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00045
  • A mixture of 5-bromo-3-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide (150 mg, 0.39 mmol), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with DCM (20 mg, 0.02 mmol), sodium bicarbonate, and 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (70 μL, 0.4 mmol) in dioxane (2.83 mL, 29.6 mmol) and water (1 mL, 60 mmol) was degassed and sealed. It was stirred at 95° C. overnight. The reaction mixture was diluted with EtOAc and washed with water and brine. The organic layer was separated and concentrated to afford desired product, which was used in the next step without further purification. LC-MS calculated for C22H21N2O (M+H)+: m/z=329.2; found: 329.2.
    • Step 3: 5-formyl-3-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00046
  • 3-Methyl-N-(2-methylbiphenyl-3-yl)-5-vinylpyridine-2-carboxamide (100 mg, 0.4 mmol) was dissolved in 1,4-dioxane (6 mL, 80 mmol) and water (1 mL, 70 mmol). To this mixture was added a mixture of osmium tetraoxide (4% w/w in water, 0.38 mL, 0.06 mmol). After stirring for 5 min, sodium periodate (342 mg, 1.60 mmol) was added and the mixture was allowed to stir for 1 h to reach full conversion. The reaction mixture was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford desired product, which was used in the next step without further purification. LC-MS calculated for C21H19N2O2 (M+H)+: m/z=331.1; found: 331.1.
    • Step 4: (2S)-1-[(5-methyl-6-{[(2-methylbiphenyl-3-yl)amino]carbonyl}pyridin-3-yl)methyl]piperidine-2-carboxylic acid
  • Figure US20170174671A1-20170622-C00047
  • This compound was prepared using a similar procedure as described for Example 1, Step 5, with 5-formyl-3-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide replacing 5-formyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide. The reaction mixture was purified by prep-HPLC (pH=10, acetonitrile/water+NH4OH) to give the desired product. LC-MS calculated for C27H30N3O3 (M+H)+: m/z=444.2; found 444.2.
    • Example 4: 5-{[(2-hydroxyethyl)amino]methyl}-3-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00048
  • Ethanolamine (20 μL, 0.3 mmol) and sodium triacetoxyborohydride (60 mg, 0.3 mmol) were added to a methylene chloride (1 mL) solution of 5-formyl-3-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide (Example 3, Step 3), and the mixture was allowed to stir at rt overnight. The reaction mixture was purified by prep-HPLC (pH=10, acetonitrile/water+NH4OH) to give the desired product. LC-MS calculated for C23H26N3O2 (M+H)+: m/z=376.2; found 376.1.
    • Example 5: (2S)-1-[(2-{[(2-methylbiphenyl-3-yl)amino]carbonyl}pyrimidin-5-yl)methyl]piperidine-2-carboxylic acid
  • Figure US20170174671A1-20170622-C00049
    • Step 1: 5-bromo-N-(2-methylbiphenyl-3-yl)pyrimidine-2-carboxamide
  • Figure US20170174671A1-20170622-C00050
  • This compound was prepared using a similar procedure as described for Example 1, Step 2, with 5-bromopyrimidine-2-carboxylic acit (Art Pharma, cat#AK-21808) replacing 5-(methoxycarbonyl) pyridine-2-carboxylic acit. LC-MS calculated for C18H15BrN3O (M+H)+: m/z=368.0; found 368.0.
    • Step 2: N-(2-methylbiphenyl-3-yl)-5-vinylpyrimidine-2-carboxamide
  • Figure US20170174671A1-20170622-C00051
  • This compound was prepared using a similar procedure as described for Example 3, Step 2, with 5-bromo-N-(2-methylbiphenyl-3-yl)pyrimidine-2-carboxamide replacing 5-bromo-3-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide. LC-MS calculated for C20H18N3O (M+H)+: m/z=316.1; found 316.1.
    • Step 3: 5-formyl-N-(2-methylbiphenyl-3-yl)pyrimidine-2-carboxamide
  • Figure US20170174671A1-20170622-C00052
  • This compound was prepared using a similar procedure as described for Example 3, Step 3, with N-(2-methylbiphenyl-3-yl)-5-vinylpyrimidine-2-carboxamide replacing 3-methyl-N-(2-methylbiphenyl-3-yl)-5-vinylpyridine-2-carboxamide. LC-MS calculated for C19H16N3O2 (M+H)+: m/z=318.2; found 318.1.
    • Step 4: (2S)-1-[(2-{[(2-methylbiphenyl-3-yl)amino]carbonyl}pyrimidin-5-yl)methyl]piperidine-2-carboxylic acid
  • Figure US20170174671A1-20170622-C00053
  • This compound was prepared using a similar procedure as described for Example 1, Step 5, with 5-formyl-N-(2-methylbiphenyl-3-yl)pyrimidine-2-carboxamide replacing 5-formyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide. The reaction mixture was purified by prep-HPLC (pH=10, acetonitrile/water+NH4OH) to give the desired product. LC-MS calculated for C25H27N4O3 (M+H)+: m/z=431.2; found 431.1.
    • Example 6: 5-{[(2-hydroxyethyl)amino]methyl}-N-(2-methylbiphenyl-3-yl)pyrimidine-2-carboxamide
  • Figure US20170174671A1-20170622-C00054
  • This compound was prepared using a similar procedure as described for Example 4 with 5-formyl-N-(2-methylbiphenyl-3-yl)pyrimidine-2-carboxamide (Example 5, Step 3) replacing 5-formyl-3-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide. The reaction mixture was purified by prep-HPLC (pH=10, acetonitrile/water+NH4OH) to give the desired product. LC-MS calculated for C21H23N4O2 (M+H)+: m/z=363.2; found 363.2.
    • Example 7: (2S)-1-[(6-{[(2-cyanobiphenyl-3-yl)amino]carbonyl}pyridin-3-yl)methyl]piperidine-2-carboxylic acid
  • Figure US20170174671A1-20170622-C00055
    • Step 1: 3-aminobiphenyl-2-carbonitrile
  • Figure US20170174671A1-20170622-C00056
  • This compound was prepared using a similar procedure as described for Example 1, Step 1, with 2-amino-6-bromobenzonitrile (Astatech, cat#CL8148) replacing 3-bromo-2-methylaniline. LC-MS calculated for C13H11N2 (M+H)+: m/z=195.1; found 195.1.
    • Step 2: 5-bromo-N-(2-cyanobiphenyl-3-yl)pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00057
  • N,N-Diisopropylethylamine (200 μL, 1 mmol) was added to a mixture of 3-aminobiphenyl-2-carbonitrile (80 mg, 0.4 mmol), 5-bromopyridine-2-carboxylic acid (Frontier Scientific cat#B 1704, 96 mg, 0.47 mmol), and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (250 mg, 0.65 mmol) in N,N-dimethylformamide (2 mL, 20 mmol). The reaction mixture was allowed to stir at rt overnight. The reaction mixture was quenched with saturated aqueous NaHCO3, and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-35%) to afford the desired product. LC-MS calculated for C19H13BrN3O (M+H)+: m/z=378.0; found 378.0.
    • Step 3: N-(2-cyanobiphenyl-3-yl)-5-vinylpyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00058
  • This compound was prepared using a similar procedure as described for Example 3, Step 2, with 5-bromo-N-(2-cyanobiphenyl-3-yl)pyridine-2-carboxamide replacing 5-bromo-3-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide. LC-MS calculated for C21H16N3O (M+H)+: m/z=326.1; found 326.1.
    • Step 4: N-(2-cyanobiphenyl-3-yl)-5-formylpyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00059
  • This compound was prepared using a similar procedure as described for Example 3, Step 3, with N-(2-cyanobiphenyl-3-yl)-5-vinylpyridine-2-carboxamide replacing 3-methyl-N-(2-methylbiphenyl-3-yl)-5-vinylpyridine-2-carboxamide. LC-MS calculated for C20H14N3O2 (M+H)+: m/z=328.1; found 328.1.
    • Step 5: (2S)-1-[(6-{[(2-cyanobiphenyl-3-yl)amino]carbonyl}pyridin-3-yl)methyl]piperidine-2-carboxylic acid
  • Figure US20170174671A1-20170622-C00060
  • This compound was prepared using a similar procedure as described for Example 1, Step 5, with N-(2-cyanobiphenyl-3-yl)-5-formylpyridine-2-carboxamide replacing 5-formyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide. The reaction mixture was purified by prep-HPLC (pH=10, acetonitrile/water+NH4OH) to give the desired product. LC-MS calculated for C26H25N4O3 (M+H)+: m/z=441.2; found 441.1.
    • Example 8: N-(2-cyanobiphenyl-3-yl)-5-{[(2-hydroxyethyl)amino]methyl}pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00061
  • This compound was prepared using a similar procedure as described for Example 4 with N-(2-cyanobiphenyl-3-yl)-5-formylpyridine-2-carboxamide (Example 7, Step 4) replacing 5-formyl-3-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide. The reaction mixture was purified by prep-HPLC (pH=10, acetonitrile/water+NH4OH) to give the desired product. LC-MS calculated for C22H21N4O2 (M+H)+: m/z=373.2; found 373.2.
    • Example 9: (2S)-1-{[6-({[2-cyano-3-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]amino}carbonyl)pyridin-3-yl]methyl}piperidine-2-carboxylic acid
  • Figure US20170174671A1-20170622-C00062
    • Step 1: 2-amino-6-(2, 3-dihydro-1,4-benzodioxin-6-yl)benzonitrile
  • Figure US20170174671A1-20170622-C00063
  • This compound was prepared using a similar procedure as described for Example 1, Step 1, with 2,3-dihydro-1,4-benzodioxin-6-ylboronic acid (Sigma-Aldrich, cat#635995) replacing phenylboronic acid, and with 2-amino-6-bromobenzonitrile (Astatech, cat#CL8148) replacing 3-bromo-2-methylaniline. LC-MS calculated for C15H13N2O2 (M+H)+: m/z=253.1; found 253.1.
    • Step 2: 5-bromo-N-[2-cyano-3-(2, 3-dihydro-1, 4-benzodioxin-6-yl)phenyl]pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00064
  • N,N-Diisopropylethylamine (200 μL, 1 mmol) was added to a mixture of 2-amino-6-(2,3-dihydro-1,4-benzodioxin-6-yl)benzonitrile (100 mg, 0.4 mmol), 5-bromopyridine-2-carboxylic acid (Frontier Scientific cat#B1704, 96 mg, 0.47 mmol), and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (250 mg, 0.65 mmol) in N,N-dimethylformamide (2 mL, 20 mmol). The reaction mixture was allowed to stir at rt overnight. The reaction mixture was quenched with saturated aqueous NaHCO3, and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexanes (0-35%) to afford the desired product. LC-MS calculated for C21H15BrN3O3 (M+H)+: m/z=436.0; found 436.0.
    • Step 3: N-[2-cyano-3-(2, 3-dihydro-1, 4-benzodioxin-6-yl)phenyl]-5-vinylpyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00065
  • This compound was prepared using a similar procedure as described for Example 3, Step 2, with 5-bromo-N-[2-cyano-3-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]pyridine-2-carboxamide replacing 5-bromo-3-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide. LC-MS calculated for C23H18N3O3 (M+H)+: m/z=384.1; found 384.1.
    • Step 4: N-[2-cyano-3-(2, 3-dihydro-1, 4-benzodioxin-6-yl)phenyl]-5-formylpyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00066
  • This compound was prepared using a similar procedure as described for Example 3, Step 3, with N-[2-cyano-3-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]-5-vinylpyridine-2-carboxamide replacing 3-methyl-N-(2-methylbiphenyl-3-yl)-5-vinylpyridine-2-carboxamide. LC-MS calculated for C22H16N3O4 (M+H)+: m/z=386.1; found 386.1.
    • Step 5: (2S)-1-{[6-({[2-cyano-3-(2, 3-dihydro-1, 4-benzodioxin-6-yl)phenyl]amino}carbonyl)pyridin-3-yl]methyl}piperidine-2-carboxylic acid
  • Figure US20170174671A1-20170622-C00067
  • This compound was prepared using a similar procedure as described for Example 1, Step 5, with N-[2-cyano-3-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]-5-formylpyridine-2-carboxamide replacing 5-formyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide. The reaction mixture was purified by prep-HPLC (pH=10, acetonitrile/water+NH4OH) to give the desired product. LC-MS calculated for C28H27N4O5 (M+H)+: m/z=499.2; found 499.2.
    • Example 10: N-(2-cyano-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)phenyl)-5-((2-hydroxyethylamino)methyl)picolinamide
  • Figure US20170174671A1-20170622-C00068
  • This compound was prepared using a similar procedure as described for Example 4 with N-[2-cyano-3-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]-5-formylpyridine-2-carboxamide (Example 9, Step 4) replacing 5-formyl-3-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide. The reaction mixture was purified by prep-HPLC (pH=10, acetonitrile/water+NH4OH) to give the desired product. LC-MS calculated for C22H21N4O2 (M+H)+: m/z=431.2; found 431.2.
    • Example 11: 5-{[(2-hydroxyethyl)amino]methyl}-N-(2-methylbiphenyl-3-yl)pyrazine-2-carboxamide
  • Figure US20170174671A1-20170622-C00069
    • Step 1: pyrazine-2,5-dicarboxylic acid
  • Figure US20170174671A1-20170622-C00070
  • Sulfuric acid (19 μL, 0.36 mmol) was added to a methanol (1.2 mL, 29 mmol) solution of pyrazine-2,5-dicarboxylic acid (Ark Pharma cat# AK-76746, 100 mg, 0.6 mmol). Then the mixture was allowed to stir at 90° C. overnight. After cooling to rt, the mixture was diluted with methanol and basified with NaOH aq. Then the mixture was allowed to stir at rt for 5 h to reach ˜50% conversion to afford the mono-ester. Then the mixture was acidified with HCl aq, and extracted with DCM/iPrOH×3. The organic layer was dried and concentrated to afford desired product, which was used in the next step without further purification. LC-MS calculated for C7H7N2O4 (M+H)+: m/z=183.0; found 183.0.
    • Step 2: methyl 5-{[(2-methylbiphenyl-3-yl)amino]carbonyl}pyrazine-2-carboxylate
  • Figure US20170174671A1-20170622-C00071
  • This compound was prepared using a similar procedure as described for Example 1, Step 2, with pyrazine-2,5-dicarboxylic acid replacing 5-(methoxycarbonyl)pyridine-2-carboxylic acid. LC-MS calculated for C20H18N3O3 (M+H)+: m/z=348.1; found 348.1.
    • Step 3: 5-(hydroxymethyl)-N-(2-methylbiphenyl-3-yl)pyrazine-2-carboxamide
  • Figure US20170174671A1-20170622-C00072
  • This compound was prepared using a similar procedure as described for Example 1, Step 3, with methyl 5-{[(2-methylbiphenyl-3-yl)amino]carbonyl}pyrazine-2-carboxylate replacing methyl 6-{[(2-methylbiphenyl-3-yl)amino]carbonyl}nicotinate. Part of the reaction mixture was purified by prep-HPLC (pH=10, acetonitrile/water+NH4OH) to give the desired product. LC-MS calculated for C19H18N3O2 (M+H)+: m/z=320.1; found 320.1.
    • Step 4: 5-formyl-N-(2-methylbiphenyl-3-yl)pyrazine-2-carboxamide
  • Figure US20170174671A1-20170622-C00073
  • This compound was prepared using a similar procedure as described for Example 1, Step 4, with 5-(hydroxymethyl)-N-(2-methylbiphenyl-3-yl)pyrazine-2-carboxamide replacing 5-(hydroxymethyl)-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide. LC-MS calculated for C19H16N3O2 (M+H)+: m/z=318.1; found 318.1.
    • Step 5: 5-{[(2-hydroxyethyl)amino]methyl}-N-(2-methylbiphenyl-3-yl)pyrazine-2-carboxamide
  • Figure US20170174671A1-20170622-C00074
  • This compound was prepared using a similar procedure as described for Example 4 with 5-formyl-N-(2-methylbiphenyl-3-yl)pyrazine-2-carboxamide replacing 5-formyl-3-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide. The reaction mixture was purified by prep-HPLC (pH=10, acetonitrile/water+NH4OH) to give the desired product. LC-MS calculated for C21H23N4O2 (M+H)+: m/z=363.2; found 363.2.
    • Example 12: 6-{[(2-hydroxyethyl)amino]methyl}-N-(2-methylbiphenyl-3-yl)pyridazine-3-carboxamide
  • Figure US20170174671A1-20170622-C00075
    • Step 1: 6-(methoxycarbonyl)pyridazine-3-carboxylic acid
  • Figure US20170174671A1-20170622-C00076
  • This compound was prepared using a similar procedure as described for Example 11, Step 1, with pyridazine-3,6-dicarboxylic acid (Astatech, cat#37156) replacing pyrazine-2,5-dicarboxylic acid. The reaction mixture was purified by prep-HPLC (pH=10, acetonitrile/water+NH4OH) to give the desired product. LC-MS calculated for C7H7N2O4 (M+H)+: m/z=183.0; found 183.0.
    • Step 2: methyl 6-{[(2-methylbiphenyl-3-yl)amino]carbonyl}pyridazine-3-carboxylate
  • Figure US20170174671A1-20170622-C00077
  • This compound was prepared using a similar procedure as described for Example 1, Step 2, with 6-(methoxycarbonyl)pyridazine-3-carboxylic acid replacing 5-(methoxycarbonyl)pyridine-2-carboxylic acid. LC-MS calculated for C21H17N3O3 (M+H)+: m/z=348.1; found 348.1.
    • Step 3: 6-(hydroxymethyl)-N-(2-methylbiphenyl-3-yl)pyridazine-3-carboxamide
  • Figure US20170174671A1-20170622-C00078
  • This compound was prepared using a similar procedure as described for Example 1, Step 3, with methyl 6-{[(2-methylbiphenyl-3-yl)amino]carbonyl}pyridazine-3-carboxylate replacing methyl 6-{[(2-methylbiphenyl-3-yl)amino]carbonyl}nicotinate. LC-MS calculated for C19H18N3O2 (M+H)+: m/z=320.1; found 320.1.
    • Step 4: 6-formyl-N-(2-methylbiphenyl-3-yl)pyridazine-3-carboxamide
  • Figure US20170174671A1-20170622-C00079
  • This compound was prepared using a similar procedure as described for Example 1, Step 4, with 6-(hydroxymethyl)-N-(2-methylbiphenyl-3-yl)pyridazine-3-carboxamide replacing 5-(hydroxymethyl)-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide. LC-MS calculated for C19H16N3O2 (M+H)+: m/z=318.1; found 318.1.
    • Step 5: 6-{[(2-hydroxyethyl)amino]methyl}-N-(2-methylbiphenyl-3-yl)pyridazine-3-carboxamide
  • Figure US20170174671A1-20170622-C00080
  • This compound was prepared using a similar procedure as described for Example 4 with 6-formyl-N-(2-methylbiphenyl-3-yl)pyridazine-3-carboxamide replacing 5-formyl-3-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide. The reaction mixture was purified by prep-HPLC (pH=10, acetonitrile/water+NH4OH) to give the desired product. LC-MS calculated for C21H23N4O2 (M+H)+: m/z=363.2; found 363.2.
    • Example 13: (2S)-1-[(2-methyl-6-{[(2-methylbiphenyl-3-yl)amino]carbonyl}pyridin-3-yl)methyl]piperidine-2-carboxylic acid
  • Figure US20170174671A1-20170622-C00081
    • Step 1: 5-bromo-6-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00082
  • This compound was prepared using a similar procedure as described for Example 1, Step 2, with 5-bromo-6-methylpyridine-2-carboxylic acid (Ark Pharma cat#Ak-61563) replacing 5-(methoxycarbonyl)pyridine-2-carboxylic acid. LC-MS calculated for C20H18BrN2O (M+H)+: m/z=381.0; found 381.0.
    • Step 2: 6-methyl-N-(2-methylbiphenyl-3-yl)-5-vinylpyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00083
  • This compound was prepared using a similar procedure as described for Example 3, Step 2, with 5-bromo-6-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide replacing 5-bromo-3-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide. LC-MS calculated for C22H21N2O (M+H)+: m/z=329.2; found 329.2.
    • Step 3: 5-formyl-6-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00084
  • This compound was prepared using a similar procedure as described for Example 3, Step 3, with 6-methyl-N-(2-methylbiphenyl-3-yl)-5-vinylpyridine-2-carboxamide replacing 3-methyl-N-(2-methylbiphenyl-3-yl)-5-vinylpyridine-2-carboxamide. LC-MS calculated for C21H19N2O2 (M+H)+: m/z=331.1; found 331.1.
    • Step 4: (2S)-1-[(2-methyl-6-{[(2-methylbiphenyl-3-yl)amino]carbonyl}pyridin-3-yl)methyl]piperidine-2-carboxylic acid
  • Figure US20170174671A1-20170622-C00085
  • This compound was prepared using a similar procedure as described for Example 1, Step 5, with 5-formyl-6-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide replacing 5-formyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide. The reaction mixture was purified by prep-HPLC (pH=10, acetonitrile/water+NH4OH) to give the desired product. LC-MS calculated for C27H30N3O3 (M+H)+: m/z=444.2; found 444.2.
    • Example 14: 5-{[(2-hydroxyethyl)amino]methyl}-6-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00086
  • This compound was prepared using a similar procedure as described for Example 4 with 5-formyl-6-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide (Example 13, Step 3) replacing 5-formyl-3-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide. The reaction mixture was purified by prep-HPLC (pH=10, acetonitrile/water+NH4OH) to give the desired product. LC-MS calculated for C23H26N3O2 (M+H)+: m/z=376.2; found 376.2.
    • Example 15: (2S)-1-[(5-chloro-6-{[(2-methylbiphenyl-3-yl)amino]carbonyl}pyridin-3-yl)methyl]piperidine-2-carboxylic acid
  • Figure US20170174671A1-20170622-C00087
    • Step 1: 5-bromo-3-chloro-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00088
  • This compound was prepared using a similar procedure as described for Example 1, Step 2, with 5-bromo-3-chloropyridine-2-carboxylic acid (Ark Pharma cat#AK-53906) replacing 5-(methoxycarbonyl)pyridine-2-carboxylic acid. LC-MS calculated for C19H15BrClN2O (M+H)+: m/z=401.0; found 401.1.
    • Step 2: 3-chloro-N-(2-methylbiphenyl-3-yl)-5-vinylpyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00089
  • This compound was prepared using a similar procedure as described for Example 3, Step 2, with 5-bromo-3-chloro-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide replacing 5-bromo-3-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide. LC-MS calculated for C21H18ClN2O (M+H)+: m/z=349.1; found 349.0.
    • Step 3: 3-chloro-5-formyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00090
  • This compound was prepared using a similar procedure as described for Example 3, Step 3, with 3-chloro-N-(2-methylbiphenyl-3-yl)-5-vinylpyridine-2-carboxamide replacing 3-methyl-N-(2-methylbiphenyl-3-yl)-5-vinylpyridine-2-carboxamide. LC-MS calculated for C20H16ClN2O2 (M+H)+: m/z=351.1; found 351.0.
    • Step 4: (2S)-1-[(5-chloro-6-{[(2-methylbiphenyl-3-yl)amino]carbonyl}pyridin-3-yl)methyl]piperidine-2-carboxylic acid
  • Figure US20170174671A1-20170622-C00091
  • This compound was prepared using a similar procedure as described for Example 1, Step 5 with 3-chloro-5-formyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide replacing 5-formyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide. The reaction mixture was purified by prep-HPLC (pH=10, acetonitrile/water+NH4OH) to give the desired product. LC-MS calculated for C26H27ClN3O3 (M+H)+: m/z=464.2; found 464.0.
    • Example 16: 3-chloro-5-{[(2-hydroxyethyl)amino]methyl}-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00092
  • This compound was prepared using a similar procedure as described for Example 4 with 3-chloro-5-formyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide (Example 15, Step 3) replacing 5-formyl-3-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide. The reaction mixture was purified by prep-HPLC (pH=10, acetonitrile/water+NH4OH) to give the desired product. LC-MS calculated for C22H23ClN3O2 (M+H)+: m/z=396.1; found 396.1.
    • Example 17: 3-fluoro-5-{[(2-hydroxyethyl)amino]methyl}-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00093
    • Step 1: 5-bromo-3-fluoro-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00094
  • This compound was prepared using a similar procedure as described for Example 1, Step 2, with 5-bromo-3-fluoropyridine-2-carboxylic acid (Aldrich, cat#753483) replacing 5-(methoxycarbonyl)pyridine-2-carboxylic acid and prolong the reaction time to 3 days. LC-MS calculated for C19H15BrFN2O (M+H)+: m/z=385.0; found 385.0.
    • Step 2: 3-fluoro-N-(2-methylbiphenyl-3-yl)-5-vinylpyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00095
  • This compound was prepared using a similar procedure as described for Example 3, Step 2, with 5-bromo-3-fluoro-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide replacing 5-bromo-3-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide. LC-MS calculated for C21H18FN2O (M+H)+: m/z=333.1; found 333.1.
    • Step 3: 3-fluoro-5-formyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00096
  • This compound was prepared using a similar procedure as described for Example 3, Step 3, with 3-fluoro-N-(2-methylbiphenyl-3-yl)-5-vinylpyridine-2-carboxamide replacing 3-methyl-N-(2-methylbiphenyl-3-yl)-5-vinylpyridine-2-carboxamide. LC-MS calculated for C20H16FN2O2 (M+H)+: m/z=335.1; found 335.1.
    • Step 4: 3-fluoro-5-{[(2-hydroxyethyl)amino]methyl}-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00097
  • This compound was prepared using a similar procedure as described for Example 4 with 3-fluoro-5-formyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide replacing 5-formyl-3-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide. The reaction mixture was purified by prep-HPLC (pH=10, acetonitrile/water+NH4OH) to give the desired product. LC-MS calculated for C22H23FN3O2 (M+H)+: m/z=380.2; found 380.2.
    • Example 18: 4-[(3-cyanobenzyl)oxy]-5-{[(2-hydroxyethyl)amino]methyl}-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00098
    • Step 1: 5-bromo-4-chloro-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00099
  • This compound was prepared using a similar procedure as described for Example 1, Step 2 with 5-bromo-4-chloropyridine-2-carboxylic acid (Ark Pharma, cat#AK-55136) replacing 5-(methoxycarbonyl)pyridine-2-carboxylic acid. LC-MS calculated for C19H15BrClN2O (M+H)+: m/z=401.0; found 401.0.
    • Step 2: 5-bromo-4-[(3-cyanobenzyl)oxy]-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00100
  • Sodium hydride (60% w/w in oil, 9 mg, 0.4 mmol) was added to a mixture of 5-bromo-4-chloro-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide (50 mg, 0.1 mmol), 3-(hydroxymethyl)benzonitrile (TCI cat#C1510, 40 mg, 0.30 mmol) and N,N-dimethylformamide (1 mL, 10 mmol) at rt. Then the mixture was allowed to stir at room temperature for 4 h to reach full conversion. The mixture was quenched with water and extracted with EtOAc×3, and the combined organic layers were dried and concentrated to afford desired product. LC-MS calculated for C27H21BrN3O2 (M+H)+: m/z=498.1; found 498.1.
    • Step 3: 4-[(3-cyanobenzyl)oxy]-N-(2-methylbiphenyl-3-yl)-5-vinylpyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00101
  • This compound was prepared using a similar procedure as described for Example 3, Step 2, with 5-bromo-4-[(3-cyanobenzyl)oxy]-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide replacing 5-bromo-3-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide. LC-MS calculated for C29H24N3O2 (M+H)+: m/z=446.2; found 446.1.
    • Step 4: 4-[(3-cyanobenzyl)oxy]-5-formyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00102
  • This compound was prepared using a similar procedure as described for Example 3, Step 3, with 4-[(3-cyanobenzyl)oxy]-N-(2-methylbiphenyl-3-yl)-5-vinylpyridine-2-carboxamide replacing 3-methyl-N-(2-methylbiphenyl-3-yl)-5-vinylpyridine-2-carboxamide. LC-MS calculated for C28H22N3O3 (M+H)+: m/z=448.2; found 448.1.
    • Step 5: 4-[(3-cyanobenzyl)oxy]-5-{[(2-hydroxyethyl)amino]methyl}-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00103
  • This compound was prepared using a similar procedure as described for Example 4 with 4-[(3-cyanobenzyl)oxy]-5-formyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide replacing 5-formyl-3-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide. The reaction mixture was purified by prep-HPLC (pH=10, acetonitrile/water+NH4OH) to give the desired product. LC-MS calculated for C30H29N4O3 (M+H)+: m/z=493.2; found 493.2.
    • Example 19: 5-{[(2-hydroxyethyl)amino]methyl}-N-(2-methylbiphenyl-3-yl)-4-(pyridin-3-ylmethoxy)pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00104
    • Step 1: 5-bromo-N-(2-methylbiphenyl-3-yl)-4-(pyridin-3-ylmethoxy-pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00105
  • This compound was prepared using a similar procedure as described for Example 18, Step 2, with nicotinyl alcohol replacing 3-(hydroxymethyl)benzonitrile. LC-MS calculated for C25H21BrN3O2 (M+H)+: m/z=474.0; found 474.1.
    • Step 2: N-(2-methylbiphenyl-3-yl)-4-(pyridin-3-ylmethoxy)-5-vinylpyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00106
  • This compound was prepared using a similar procedure as described for Example 3, Step 2, with 5-bromo-N-(2-methylbiphenyl-3-yl)-4-(pyridin-3-ylmethoxy)pyridine-2-carboxamide replacing 5-bromo-3-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide. LC-MS calculated for C27H24N3O2 (M+H)+: m/z=422.2; found 422.1.
    • Step 3: 5-formyl-N-(2-methylbiphenyl-3-yl)-4-(pyridin-3-ylmethoxy)pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00107
  • This compound was prepared using a similar procedure as described for Example 3, Step 3, with N-(2-methylbiphenyl-3-yl)-4-(pyridin-3-ylmethoxy)-5-vinylpyridine-2-carboxamide replacing 3-methyl-N-(2-methylbiphenyl-3-yl)-5-vinylpyridine-2-carboxamide. LC-MS calculated for C26H22N3O3 (M+H)+: m/z=424.2; found 424.2.
    • Step 4: 5-{[(2-hydroxyethyl)amino]methyl}-N-(2-methylbiphenyl-3-yl)-4-(pyridin-3-ylmethoxy)pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00108
  • This compound was prepared using a similar procedure as described for Example 4 with 5-formyl-N-(2-methylbiphenyl-3-yl)-4-(pyridin-3-ylmethoxy)pyridine-2-carboxamide replacing 5-formyl-3-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide. The reaction mixture was purified by prep-HPLC (pH=10, acetonitrile/water+NH4OH) to give the desired product, which was further purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as its TFA salt. LC-MS calculated for C28H29N4O3 (M+H)+: m/z=469.2; found 469.2.
    • Example 20: 5-{[(2-hydroxyethyl)amino]methyl}-N-(2-methylbiphenyl-3-yl)-4-(pyridin-2-ylmethoxy)pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00109
    • Step 1: 5-bromo-N-(2-methylbiphenyl-3-yl)-4-(pyridin-2-ylmethoxy)pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00110
  • This compound was prepared using a similar procedure as described for Example 18, Step 2, with pyridin-2-ylmethanol replacing 3-(hydroxymethyl)benzonitrile. LC-MS calculated for C25H21BrN3O2 (M+H)+: m/z=474.0; found 474.1.
    • Step 2: N-(2-methylbiphenyl-3-yl)-4-(pyridin-2-ylmethoxy)-5-vinylpyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00111
  • This compound was prepared using a similar procedure as described for Example 3, Step 2, with 5-bromo-N-(2-methylbiphenyl-3-yl)-4-(pyridin-2-ylmethoxy)pyridine-2-carboxamide replacing 5-bromo-3-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide. LC-MS calculated for C27H24N3O2 (M+H)+: m/z=422.2; found 422.1.
    • Step 3: 5-formyl-N-(2-methylbiphenyl-3-yl)-4-(pyridin-2-ylmethoxy)pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00112
  • This compound was prepared using a similar procedure as described for Example 3, Step 3, with N-(2-methylbiphenyl-3-yl)-4-(pyridin-2-ylmethoxy)-5-vinylpyridine-2-carboxamide replacing 3-methyl-N-(2-methylbiphenyl-3-yl)-5-vinylpyridine-2-carboxamide. LC-MS calculated for C26H22N3O3 (M+H)+: m/z=424.2; found 424.2.
    • Step 4: 5-{[(2-hydroxyethyl)amino]methyl}-N-(2-methylbiphenyl-3-yl)-4-(pyridin-2-ylmethoxy)pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00113
  • This compound was prepared using a similar procedure as described for Example 4 with 5-formyl-N-(2-methylbiphenyl-3-yl)-4-(pyridin-2-ylmethoxy)pyridine-2-carboxamide replacing 5-formyl-3-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide. The reaction mixture was purified by prep-HPLC (pH=10, acetonitrile/water+NH4OH) to give the desired product. LC-MS calculated for C28H29N4O3 (M+H)+: m/z=469.2; found 469.2.
    • Example 21: 3-(dimethylamino)-5-{[(2-hydroxyethyl)amino]methyl}-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00114
    • Step 1: 5-bromo-3-(dimethylamino)-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00115
  • 1.0 M Dimethylamine in THF (0.3 mL, 0.3 mmol) was added to 5-bromo-3-fluoro-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide (Example 17, Step 1, 40 mg, 0.1 mmol) at rt, then the reaction was allowed to stir at rt overnight. The reaction was concentrated to afford desired product, which was used in the next step without further purification. LC-MS calculated for C21H21BrN3O (M+H)+: m/z=410.1; found 410.1.
    • Step 2: 3-(dimethylamino)-N-(2-methylbiphenyl-3-yl)-5-vinylpyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00116
  • This compound was prepared using a similar procedure as described for Example 3, Step 2, with 5-bromo-3-(dimethylamino)-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide replacing 5-bromo-3-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide. LC-MS calculated for C23H24N3O (M+H)+: m/z=358.2; found 358.1.
    • Step 3: 3-(dimethylamino)-5-formyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00117
  • This compound was prepared using a similar procedure as described for Example 3, Step 3, with 3-(dimethylamino)-N-(2-methylbiphenyl-3-yl)-5-vinylpyridine-2-carboxamide replacing 3-methyl-N-(2-methylbiphenyl-3-yl)-5-vinylpyridine-2-carboxamide. LC-MS calculated for C22H22N3O2 (M+H)+: m/z=360.2; found 360.1.
    • Step 4: 3-(dimethylamino)-5-{[(2-hydroxyethyl)amino]methyl}-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00118
  • This compound was prepared using a similar procedure as described for Example 4 with 3-(dimethylamino)-5-formyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide replacing 5-formyl-3-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide. The reaction mixture was purified by prep-HPLC (pH=10, acetonitrile/water+NH4OH) to give the desired product. LC-MS calculated for C24H29N4O2 (M+H)+: m/z=405.2; found 405.2.
    • Example 22: (2S)-1-[(2-{[(2-methylbiphenyl-3-yl)amino]carbonyl}pyridin-4-yl)methyl]piperidine-2-carboxylic acid
  • Figure US20170174671A1-20170622-C00119
    • Step 1: 4-bromo-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00120
  • This compound was prepared using a similar procedure as described for Example 1, Step 2, with 4-bromopyridine-2-carboxylic acid (Ark Pharm, cat#AK-23753) replacing 5-(methoxycarbonyl)pyridine-2-carboxylic acid. LC-MS calculated for C19H16BrN2O (M+H)+: m/z=367.0; found 367.0.
    • Step 2: N-(2-methylbiphenyl-3-yl)-4-vinylpyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00121
  • This compound was prepared using a similar procedure as described for Example 3, Step 2, with 4-bromo-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide replacing 5-bromo-3-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide. LC-MS calculated for C21H19N2O (M+H)+: m/z=315.1; found 315.2.
    • Step 3: 4-formyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00122
  • This compound was prepared using a similar procedure as described for Example 3, Step 3, with N-(2-methylbiphenyl-3-yl)-4-vinylpyridine-2-carboxamide replacing 3-methyl-N-(2-methylbiphenyl-3-yl)-5-vinylpyridine-2-carboxamide. LC-MS calculated for C20H17N2O2 (M+H)+: m/z=317.1; found 317.1.
    • Step 4: (2S)-1-[(2-{[(2-methylbiphenyl-3-yl)amino]carbonyl}pyridin-4-yl)methyl]piperidine-2-carboxylic acid
  • Figure US20170174671A1-20170622-C00123
  • This compound was prepared using a similar procedure as described for Example 1, Step 5, with 4-formyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide replacing 5-formyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide. The reaction mixture was purified by prep-HPLC (pH=10, acetonitrile/water+NH4OH) to give the desired product. LC-MS calculated for C26H28N3O3 (M+H)+: m/z=430.2; found 430.2.
    • Example 23: 4-{[(2-hydroxyethyl)amino]methyl}-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00124
  • This compound was prepared using a similar procedure as described for Example 4 with 4-formyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide (Example 25, Step 3) replacing 5-formyl-3-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide. The reaction mixture was purified by prep-HPLC (pH=10, acetonitrile/water+NH4OH) to give the desired product, which was concentrated and further purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as its TFA salt. LC-MS calculated for C22H24N3O2 (M+H)+: m/z=362.2; found 362.2.
    • Example 24: N-(2-methylbiphenyl-3-yl)-6-(pyridin-3-ylmethoxy)pyrimidine-4-carboxamide
  • Figure US20170174671A1-20170622-C00125
    • Step 1: 6-(pyridin-3-ylmethoxy)pyrimidine-4-carboxylic acid
  • Figure US20170174671A1-20170622-C00126
  • Nicotinyl alcohol (73 μL, 0.76 mmol) was added to a suspension of sodium hydride (20 mg, 0.9 mmol) at rt, and the mixture was allowed to stir at rt for 1 h. Then a THF (1 mL) solution of 6-chloropyrimidine-4-carboxylic acid (Matrix Scientific cat#073471, 50 mg, 0.3 mmol) was added to the mixture, which was allowed to stir at rt for 3 h. The reaction was quenched with water and 1N HCl, the mixture was extracted with DCM/iPrOH. The organic layer was dried and concentrated to afford product which was used in the next step without further purification. LC-MS calculated for C11H10N3O3 (M+H)+: m/z=232.1; found 232.2.
    • Step 2: N-(2-methylbiphenyl-3-yl)-6-(pyridin-3-ylmethoxy)pyrimidine-4-carboxamide
  • Figure US20170174671A1-20170622-C00127
  • This compound was prepared using a similar procedure as described for Example 1, Step 2, with 6-(pyridin-3-ylmethoxy)pyrimidine-4-carboxylic acid replacing 5-(methoxycarbonyl)pyridine-2-carboxylic acid. LC-MS calculated for C24H21N4O2 (M+H)+: m/z=397.2; found 397.1.
    • Example 25: 4-cyano-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00128
  • This compound was prepared using a similar procedure as described for Example 1, Step 2, with 4-cyanopyridine-2-carboxylic acid (Bionet Intermediates, cat#BB-0608) replacing 5-(methoxycarbonyl)pyridine-2-carboxylic acid. The reaction mixture was purified by prep-HPLC (pH=10, acetonitrile/water+NH4OH) to give the desired product. LC-MS calculated for C20H16N3O (M+H)+: m/z=314.1; found 314.1.
    • Example 26: N-(2-methylbiphenyl-3-yl)pyrazine-2-carboxamide
  • Figure US20170174671A1-20170622-C00129
  • This compound was prepared using a similar procedure as described for Example 1, Step 2, with 2-pyrazinecarboxylic acid (Sigma-Aldrich, cat#P56100) replacing 5-(methoxycarbonyl)pyridine-2-carboxylic acid. The reaction mixture was purified by prep-HPLC (pH=10, acetonitrile/water+NH4OH) to give the desired product. LC-MS calculated for C18H16N3O (M+H)+: m/z=290.1; found 290.2.
    • Example 27: N-(2-methylbiphenyl-3-yl)pyrimidine-4-carboxamide
  • Figure US20170174671A1-20170622-C00130
  • This compound was prepared using a similar procedure as described for Example 1, Step 2, with pyrimidine-4-carboxylic acid (VWR International, cat#101390) replacing 5-(methoxycarbonyl)pyridine-2-carboxylic acid. The reaction mixture was purified by prep-HPLC (pH=10, acetonitrile/water+NH4OH) to give the desired product. LC-MS calculated for C18H16N3O (M+H)+: m/z=290.1; found 290.2.
    • Example 28: N-(2-methylbiphenyl-3-yl)pyrimidine-2-carboxamide
  • Figure US20170174671A1-20170622-C00131
  • This compound was prepared using a similar procedure as described for Example 1, Step 2, with pyrimidine-2-carboxylic acid (Ark Pham, cat#AK-24353) replacing 5-(methoxycarbonyl)pyridine-2-carboxylic acid. The reaction mixture was purified by prep-HPLC (pH=10, acetonitrile/water+NH4OH) to give the desired product. LC-MS calculated for C18H16N3O (M+H)+: m/z=290.1; found 290.2.
    • Example 29: N-(2-methylbiphenyl-3-yl)pyridazine-3-carboxamide
  • Figure US20170174671A1-20170622-C00132
  • This compound was prepared using a similar procedure as described for Example 1, Step 2, with pyridazine-3-carboxylic acid (Ark Pham, cat#AK-28139) replacing 5-(methoxycarbonyl)pyridine-2-carboxylic acid. The reaction mixture was purified by prep-HPLC (pH=10, acetonitrile/water+NH4OH) to give the desired product. LC-MS calculated for C18H16N3O (M+H)+: m/z=290.1; found 290.1.
    • Example 30: N-(2-methylbiphenyl-3-yl)-2-(pyridin-3-ylmethoxy)pyrimidine-4-carboxamide
  • Figure US20170174671A1-20170622-C00133
    • Step 1: 2-(pyridin-3-ylmethoxy)pyrimidine-4-carboxylic acid
  • Figure US20170174671A1-20170622-C00134
  • Sodium hydride (20 mg, 0.9 mmol) was added to a tetrahydrofuran (2 mL, 20 mmol) solution of 2-chloropyrimidine-4-carboxylic acid (Ark Pharm, cat#AK-28365, 50 mg, 0.3 mmol) and nicotinyl alcohol (73 μL, 0.76 mmol), which was allowed to stir at 70° C. for 1 h to reach full conversion. The reaction mixture was quenched with water and extracted with DCM/iPrOH, and the organic layer was dried and concentrated to afford the desired product. Then the residue was used in the next step without further purification. LC-MS calculated for C11H10N3O3 (M+H)+: m/z=232.1; found: 232.1.
    • Step 2: N-(2-methylbiphenyl-3-yl)-2-(pyridin-3-ylmethoxy)pyrimidine-4-carboxamide
  • Figure US20170174671A1-20170622-C00135
  • This compound was prepared using a similar procedure as described for Example 1, Step 2, with 2-(pyridin-3-ylmethoxy)pyrimidine-4-carboxylic acid replacing 5-(methoxycarbonyl)pyridine-2-carboxylic acid. The reaction mixture was purified by prep-HPLC (pH=10, acetonitrile/water+NH4OH) to give the desired product. LC-MS calculated for C24H21N4O2 (M+H)+: m/z=397.2; found 397.2.
    • Example 31: 5-{[(2-hydroxyethyl)amino]methyl}-N-(2-methylbiphenyl-3-yl)-4,4′-bipyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00136
    • Step 1: N-(2-methylbiphenyl-3-yl)-5-vinyl-4, 4′-bipyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00137
  • A mixture of 5-bromo-4-chloro-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide (Example 18, Step 1, 50 mg, 0.1 mmol), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (20 L, 0.1 mmol), and [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane (1:1) (6 mg, 0.008 mmol) in 1,4-dioxane (0.9 mL) and water (0.3 mL) was degassed and sealed. It was stirred at 90° C. for 1 h to reach full conversion. The reaction mixture was cooled and concentrated, followed by addition of 4-pyridinylboronic acid (30 mg, 0.2 mmol), cesium carbonate (100 mg, 0.4 mmol) and dichloro[1,1′-bis(dicyclohexylphosphino)ferrocene]palladium(II) (Pd-127: 9 mg, 0.01 mmol), tert-butyl alcohol (1 mL), and water (0.5 mL). The mixture was degassed with N2 and heated at 100° C. for 2 h. After cooling to rt, the mixture was purified by 0 to 40% EtOAc in DCM. LC-MS calculated for C26H22N3O (M+H)+: m/z=392.2; found: 392.1.
    • Step 2: 5-formyl-N-(2-methylbiphenyl-3-yl)-4,4′-bipyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00138
  • This compound was prepared using a similar procedure as described for Example 3, Step 3 with N-(2-methylbiphenyl-3-yl)-5-vinyl-4, 4′-bipyridine-2-carboxamide replacing 3-methyl-N-(2-methylbiphenyl-3-yl)-5-vinylpyridine-2-carboxamide. LC-MS calculated for C25H20N3O2 (M+H)+: m/z=394.2; found 394.1.
    • Step 3: 5-{[(2-hydroxyethyl)amino]methyl}-N-(2-methylbiphenyl-3-yl)-4,4′-bipyridine-2-carboxamide
  • This compound was prepared using a similar procedure as described for Example 4 with 5-formyl-N-(2-methylbiphenyl-3-yl)-4,4′-bipyridine-2-carboxamide (Step 2) replacing 5-formyl-3-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide. The reaction mixture was purified by prep-HPLC (pH=10, acetonitrile/water+NH4OH) to give the desired product, which was concentrated and further purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as its TFA salt. LC-MS calculated for C27H27N4O2 (M+H)+: m/z=439.2; found 439.2.
    • Example 32: (2S)-1-[(4-methyl-6-{[(2-methylbiphenyl-3-yl)amino]carbonyl}pyridin-3-yl)methyl]piperidine-2-carboxylic acid
  • Figure US20170174671A1-20170622-C00139
    • Step 1: 5-bromo-4-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00140
  • This compound was prepared using a similar procedure as described for Example 1, Step 2 with 5-bromo-4-methylpyridine-2-carboxylic acid (Ark Pharm, cat#AK-37510) replacing 5-(methoxycarbonyl)pyridine-2-carboxylic acid. LC-MS calculated for C20H18BrN2O (M+H)+: m/z=381.0; found 381.0.
    • Step 2: 4-methyl-N-(2-methylbiphenyl-3-yl)-5-vinylpyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00141
  • This compound was prepared using a similar procedure as described for Example 3, Step 2 with 5-bromo-4-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide replacing 5-bromo-3-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide. LC-MS calculated for C22H21N2O (M+H)+: m/z=329.2; found 329.1.
    • Step 3: 5-formyl-4-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00142
  • This compound was prepared using a similar procedure as described for Example 3, Step 3 with 4-methyl-N-(2-methylbiphenyl-3-yl)-5-vinylpyridine-2-carboxamide replacing 3-methyl-N-(2-methylbiphenyl-3-yl)-5-vinylpyridine-2-carboxamide. LC-MS calculated for C21H19N2O2 (M+H)+: m/z=331.1; found 331.1.
    • Step 4: (2S)-1-[(4-methyl-6-{[(2-methylbiphenyl-3-yl)amino]carbonyl}pyridin-3-yl)methyl]piperidine-2-carboxylic acid
  • Figure US20170174671A1-20170622-C00143
  • This compound was prepared using a similar procedure as described for Example 1, Step 5 with 5-formyl-4-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide replacing 5-formyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide. The reaction mixture was purified by prep-HPLC (pH=10, acetonitrile/water+NH4OH) to give the desired product. LC-MS calculated for C27H30N3O3 (M+H)+: m/z=444.2; found 444.2.
    • Example 33: 5-{[(2-hydroxyethyl)amino]methyl}-4-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00144
  • This compound was prepared using a similar procedure as described for Example 4 with 5-formyl-4-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide (Example 32, Step 3) replacing 5-formyl-3-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide. The reaction mixture was purified by prep-HPLC (pH=10, acetonitrile/water+NH4OH) to give the desired product. LC-MS calculated for C23H26N3O2 (M+H)+: m/z=376.2; found 376.2.
    • Example 34: 4-(cyclopropylmethoxy)-5-((2-hydroxyethylamino)methyl)-N-(2-methylbiphenyl-3-yl)picolinamide
  • Figure US20170174671A1-20170622-C00145
    • Step 1: 5-bromo-4-(cyclopropylmethoxy)-N-(2-methylbiphenyl-3-yl)picolinamide
  • Figure US20170174671A1-20170622-C00146
  • This compound was prepared using a similar procedure as described for Example 18, Step 2 with cyclopropylmethanol replacing 3-(hydroxymethyl)benzonitrile. LC-MS calculated for C23H22BrN2O2 (M+H)+: m/z=437.1; found 437.1.
    • Step 2: 4-(cyclopropylmethoxy)-N-(2-methylbiphenyl-3-yl)-5-vinylpicolinamide
  • Figure US20170174671A1-20170622-C00147
  • This compound was prepared using a similar procedure as described for Example 3, Step 2 with 5-bromo-4-(cyclopropylmethoxy)-N-(2-methylbiphenyl-3-yl)picolinamide replacing 5-bromo-3-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide. LC-MS calculated for C25H24N2O2 (M+H)+: m/z=385.2; found 385.2.
    • Step 3: 4-(cyclopropylmethoxy)-5-formyl-N-(2-methylbiphenyl-3-yl)picolinamide
  • Figure US20170174671A1-20170622-C00148
  • This compound was prepared using a similar procedure as described for Example 3, Step 3 with 4-(cyclopropylmethoxy)-N-(2-methylbiphenyl-3-yl)-5-vinylpicolinamide replacing 3-methyl-N-(2-methylbiphenyl-3-yl)-5-vinylpyridine-2-carboxamide. LC-MS calculated for C24H23N2O3 (M+H)+: m/z=387.2; found 387.2.
    • Step 4: 4-(cyclopropylmethoxy)-5-((2-hydroxyethylamino)methyl)-N-(2-methylbiphenyl-3-yl)picolinamide
  • Figure US20170174671A1-20170622-C00149
  • This compound was prepared using a similar procedure as described for Example 4 with 4-(cyclopropylmethoxy)-5-formyl-N-(2-methylbiphenyl-3-yl)picolinamide replacing 5-formyl-3-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide. The reaction mixture was purified by prep-HPLC (pH=10, acetonitrile/water+NH4OH) to give the desired product. LC-MS calculated for C26H30N3O3 (M+H)+: m/z=432.2; found 432.2.
    • Example 35: 5-{[(2-hydroxyethyl)amino]methyl}-4-methoxy-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00150
    • Step 1: 5-bromo-4-methoxy-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00151
  • Mixture of sodium methoxide (80 μL, 0.4 mmol) was added to 5-bromo-4-chloro-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide (Example 18, Step 1, 50 mg, 0.1 mmol) at rt. Then the mixture was allowed to stir at rt for 4 h to reach full conversion. The reaction was quenched with water and extracted with EtOAc, and the organic layer was dried and concentrated to afford desired product which was used for next step without further purification. LC-MS calculated for C20H18BrN2O2 (M+H)+: m/z=397.0; found 397.0.
    • Step 2: 4-methoxy-N-(2-methylbiphenyl-3-yl)-5-vinylpyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00152
  • This compound was prepared using a similar procedure as described for Example 3, Step 2 with 5-bromo-4-methoxy-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide replacing 5-bromo-3-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide. LC-MS calculated for C22H21N2O2 (M+H)+: m/z=345.2; found 345.1.
    • Step 3: 5-formyl-4-methoxy-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00153
  • This compound was prepared using a similar procedure as described for Example 3, Step 3 with 4-methoxy-N-(2-methylbiphenyl-3-yl)-5-vinylpyridine-2-carboxamide replacing 3-methyl-N-(2-methylbiphenyl-3-yl)-5-vinylpyridine-2-carboxamide. LC-MS calculated for C21H19N2O3 (M+H)+: m/z=347.1; found 347.1.
    • Step 4: 5-{[(2-hydroxyethyl)amino]methyl}-4-methoxy-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00154
  • This compound was prepared using a similar procedure as described for Example 4 with 5-formyl-4-methoxy-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide replacing 5-formyl-3-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide. The reaction mixture was purified by prep-HPLC (pH=10, acetonitrile/water+NH4OH) to give the desired product. LC-MS calculated for C23H26N3O3 (M+H)+: m/z=392.2; found 392.2.
    • Example 36: (2S)-1-[(5-methyl-2-{[(2-methylbiphenyl-3-yl)amino]carbonyl}pyridin-4-yl)methyl]piperidine-2-carboxylicacid
  • Figure US20170174671A1-20170622-C00155
    • Step 1: 4-bromo-5-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00156
  • This compound was prepared using a similar procedure as described for Example 1, Step 2 with 4-bromo-5-methylpyridine-2-carboxylic acid (Ark Pharm, cat#AK-37510) replacing 5-(methoxycarbonyl)pyridine-2-carboxylic acid. LC-MS calculated for C20H18BrN2O (M+H)+: m/z=381.0; found 381.0.
    • Step 2: 5-methyl-N-(2-methylbiphenyl-3-yl)-4-vinylpyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00157
  • This compound was prepared using a similar procedure as described for Example 3, Step 2 with 4-bromo-5-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide replacing 5-bromo-3-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide. LC-MS calculated for C22H21N2O (M+H)+: m/z=329.1; found 329.2.
    • Step 3: 4-formyl-5-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00158
  • This compound was prepared using a similar procedure as described for Example 3, Step 3 with 5-methyl-N-(2-methylbiphenyl-3-yl)-4-vinylpyridine-2-carboxamide replacing 3-methyl-N-(2-methylbiphenyl-3-yl)-5-vinylpyridine-2-carboxamide. LC-MS calculated for C21H19N2O2 (M+H)+: m/z=331.1; found 331.1.
    • Step 4: (2S)-1-[(5-methyl-2-{[(2-methylbiphenyl-3-yl)amino]carbonyl}pyridin-4-yl)methyl]piperidine-2-carboxylic acid
  • Figure US20170174671A1-20170622-C00159
  • This compound was prepared using a similar procedure as described for Example 1, Step 5 with 4-formyl-5-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide replacing 5-formyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide. The reaction mixture was purified by prep-HPLC (pH=10, acetonitrile/water+NH4OH) to give the desired product. LC-MS calculated for C27H30N3O3 (M+H)+: m/z=444.2; found 444.2.
    • Example 37: 4-{[(2-hydroxyethyl)amino]methyl}-5-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00160
  • This compound was prepared using a similar procedure as described for Example 4 with 4-formyl-5-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide (Example 36, Step 3) replacing 5-formyl-3-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide. The reaction mixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as its TFA salt. LC-MS calculated for C23H26N3O2 (M+H)+: m/z=376.2; found 376.2.
    • Example 38: N-(2-cyano-3-cyclohex-1-en-1-ylphenyl)-5-{[(2-hydroxyethyl)amino]methyl}pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00161
    • Step 1: methyl 5-vinylpyridine-2-carboxylate
  • Figure US20170174671A1-20170622-C00162
  • Sodium carbonate (1200 mg, 12 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with dichloromethane [PdCl2(dppf), 100 mg, 0.1 mmol], 1,4-dioxane (15 mL), water (3 mL), 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (628 μL, 3.70 mmol) were added to 5-bromopyridine-2-carboxylic acid methyl ester (Combi-Blocks, cat#CA-4117, 800 mg, 4 mmol), and degassed with N2. The mixture was heated at 90° C. for 2 h to reach full conversion. The mixture was purified with 0 to 35% EtOAc in Hexanes to afford the desired product as a white solid.
    • Step 2: 5-vinylpyridine-2-carboxylic acid
  • Figure US20170174671A1-20170622-C00163
  • 3 mL 1M NaOH solution (3 mmol) was added to methyl 5-vinylpyridine-2-carboxylate and heated at 45° C. for 2 h to reach full conversion. The mixture was concentrated to afford desired product as a white solid, which was used for next step without further purification.
    • Step 3: N-(3-bromo-2-cyanophenyl)-5-vinylpyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00164
  • 2.0 M oxalyl chloride in DCM (4.7 mL, 9.3 mmol), N,N-dimethylformamide (30 μL, 0.3 mmol) was added to 5-vinylpyridine-2-carboxylic acid (522 mg, 3.50 mmol) under N2 at 0° C. The mixture was allowed to stir at rt for 2 h, then the mixture was concentrated under reduced pressure and the residue was used for next step without further purification. 2-amino-6-bromobenzonitrile (Ark Pharm, AK-36350, 690 mg, 3.5 mmol) and methylene chloride (10 mL) were added to the residue, followed by addition of triethylamine (1000 μL, 10 mmol) at 0° C. drop-wise. The mixture was allowed to stir at rt for 1 h to reach full conversion. The mixture was concentrated and purified by 0 to 50% EtOAc in Hex. LC-MS calculated for C15H11BrN3O (M+H)+: m/z=328.0; found 328.0.
    • Step 4: N-(3-bromo-2-cyanophenyl)-5-formylpyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00165
  • This compound was prepared using a similar procedure as described for Example 3, Step 3 with N-(3-bromo-2-cyanophenyl)-5-vinylpyridine-2-carboxamide replacing 3-methyl-N-(2-methylbiphenyl-3-yl)-5-vinylpyridine-2-carboxamide. LC-MS calculated for C14H9BrN3O2 (M+H)+: m/z=329.0; found 329.0.
    • Step 5: N-(3-bromo-2-cyanophenyl)-5-{[(2-hydroxyethyl)amino]methyl}pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00166
  • This compound was prepared using a similar procedure as described for Example 4 with N-(3-bromo-2-cyanophenyl)-5-formylpyridine-2-carboxamide replacing 5-formyl-3-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide. The reaction mixture was purified by 0 to 12% MeOH in DCM to give the desired product. LC-MS calculated for C16H16BrN4O2 (M+H)+: m/z=375.0; found 375.0.
    • Step 6: N-(2-cyano-3-cyclohex-1-en-1-ylphenyl)-5-{[(2-hydroxyethyl)amino]methyl}pyridine-2-carboxamide
  • A mixture of N-(3-bromo-2-cyanophenyl)-5-{[(2-hydroxyethyl)amino]methyl}pyridine-2-carboxamide (10 mg, 0.03 mmol), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complexed with DCM (1 mg, 0.002 mmol), sodium carbonate (10 mg), and 2-cyclohex-1-en-1-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6.66 mg, 0.0320 mmol) in 1,4-dioxane (0.2 mL) and water (0.07 mL) was degassed with N2 and sealed. It was stirred at 95° C. for 2 h to reach full conversion. The reaction mixture was purified by prep-HPLC (pH=10, acetonitrile/water+NH4OH) to give the desired product. LC-MS calculated for C22H25N4O2 (M+H)+: m/z=377.2; found 377.1.
    • Example 39: N-(2-cyano-3-piperidin-1-ylphenyl)-5-{[(2-hydroxyethyl)amino]methyl}pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00167
  • A stirred mixture of piperidine (10 μL, 0.1 mmol), N-(3-bromo-2-cyanophenyl)-5-{[(2-hydroxyethyl)amino]methyl}pyridine-2-carboxamide (Example 38, Step 5, 11.2 mg, 0.03 mmol), (2′-aminobiphenyl-2-yl)(chloro)[dicyclohexyl(2′,6′-diisopropoxybiphenyl-2-yl)phosphoranyl]palladium (2.28 mg, 0.003 mmol), and sodium tert-butoxide (20 mg, 0.2 mmol) in 1,4-dioxane (0.083 mL) was heated at 110° C. for 2 h to reach full conversion. The volatiles were removed and the residue was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as its TFA salt. LC-MS calculated for C21H26N5O2 (M+H)+: m/z=380.2; found 380.2.
    • Example 40: tert-butyl 5-(2-cyano-3-{[(5-{[(2-hydroxyethyl)amino]methyl}pyridin-2-yl)carbonyl]amino}phenyl)-3,6-dihydropyridine-1(2H)-carboxylate
  • Figure US20170174671A1-20170622-C00168
  • This compound was prepared using a similar procedure as described for Example 38, Step 6 with tert-butyl 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydropyridine-1(2H)-carboxylate (Combi-Blocks, cat# FM-2863) replacing 2-cyclohex-1-en-1-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. The volatiles were removed and the residue was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as its TFA salt. LC-MS calculated for C26H32N5O4 (M+H)+: m/z=478.2; found 478.2.
    • Example 41: N-(2-cyano-3-cyclohexylphenyl)-5-{[(2-hydroxyethyl)amino]methyl}pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00169
    • Step 1: 2-amino-6-cyclohex-1-en-1-ylbenzonitrile
  • Figure US20170174671A1-20170622-C00170
  • This compound was prepared using a similar procedure as described for Example 1, Step 1 with 2-cyclohex-1-en-1-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane replacing phenylboronic acid, and with 2-amino-6-bromobenzonitrile (Astatech, cat#CL8148) replacing 3-bromo-2-methylaniline. LC-MS calculated for C13H15N2 (M+H)+: m/z=199.1; found 199.1.
    • Step 2: 2-amino-6-cyclohexylbenzonitrile
  • Figure US20170174671A1-20170622-C00171
  • A mixture of 2-amino-6-cyclohex-1-en-1-ylbenzonitrile (100 mg, 0.5 mmol) and 10% Pd/C (53 mg, 0.050 mmol) in methanol (5 mL) was stirred under an atmosphere of H2 at room temperature for 3 h to reach full conversion. The mixture was filtered through silica gel and concentrated and used for next step without further purification. LC-MS calculated for C13H17N2 (M+H)+: m/z=201.1; found 201.1.
    • Step 3: 5-(chloromethyl)picolinoyl chloride
  • Figure US20170174671A1-20170622-C00172
  • 1N NaOH solution was added to a THF (1 mL) solution of methyl 5-(bromomethyl) pyridine-2-carboxylate (Ark Pharm, cat#AK153186, 20 mg, 0.08 mmol) and the mixture was allowed to stir at rt for 1 h. The mixture was acidified with 1N HCl solution until pH=4, and then the mixture was extracted with DCM. The organic layers were combined, dried and concentrated. To the residue was added 2.0 M oxalyl chloride in DCM (0.10 mL, 0.20 mmol) and N,N-dimethylformamide (0.6 μL, 0.008 mmol) at 0° C. under N2. The mixture was allowed to stir at rt for 2 h, and then the mixture was concentrated and the residue was used for next step without further purification.
    • Step 4: 5-(chloromethyl)-N-(2-cyano-3-cyclohexylphenyl)pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00173
  • The DCM (1 mL) solution of crude 5-(chloromethyl)picolinoyl chloride was added to a DCM (1 mL) solution of 2-amino-6-cyclohexylbenzonitrile (20 mg, 0.1 mmol) and triethylamine (30 μL, 0.2 mmol) at 0° C. drop-wise. The mixture was allowed to stir at rt for 2 h to reach full conversion. The mixture was concentrated and used for next step without further purification. LC-MS calculated for C20H21ClN3O (M+H)+: m/z=354.1; found 354.1.
    • Step 5: N-(2-cyano-3-cyclohexylphenyl)-5-{[(2-hydroxyethyl)amino]methyl}pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00174
  • A mixture of 5-(chloromethyl)-N-(2-cyano-3-cyclohexylphenyl)pyridine-2-carboxamide (40 mg, 0.1 mmol), ethanolamine (10 μL, 0.2 mmol) and potassium carbonate (41 mg, 0.30 mmol) in N,N-dimethylformamide (0.3 mL, 4 mmol) was stirred at rt for overnight. The mixture was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as its TFA salt. LC-MS calculated for C22H27N4O2 (M+H)+: m/z=379.2; found 379.2.
    • Example 42: (S)-1-((6-(3-methyl-2-phenylpyridin-4-ylcarbamoyl)pyridin-3-yl)methyl)piperidine-2-carboxylic acid
  • Figure US20170174671A1-20170622-C00175
    • Step 1: methyl 6-(chlorocarbonyl)nicotinate
  • Figure US20170174671A1-20170622-C00176
  • This compound was prepared using a similar procedure as described for Example 41, Step 3 with 5-(methoxycarbonyl)pyridine-2-carboxylic acid (Oakwood Chemical, cat#017196) replacing methyl 5-(bromomethyl) pyridine-2-carboxylate.
    • Step 2: methyl 6-{[(2-chloro-3-methylpyridin-4-yl)amino]carbonyl}nicotinate
  • Figure US20170174671A1-20170622-C00177
  • This compound was prepared using a similar procedure as described for Example 41, Step 4 with 2-chloro-3-methylpyridin-4-amine (Astatech, cat#25664) replacing 2-amino-6-cyclohexylbenzonitrile, and with methyl 6-(chlorocarbonyl)nicotinate replacing 5-(chloromethyl)picolinoyl chloride. LC-MS calculated for C14H13ClN3O3 (M+H)+: m/z=306.1; found 306.1.
    • Step 3: methyl 6-{[(3-methyl-2-phenylpyridin-4-yl)amino]carbonyl}nicotinate
  • Figure US20170174671A1-20170622-C00178
  • Pd-127 (40 mg, 0.06 mmol) was added to the mixture of methyl 6-{[(2-chloro-3-methylpyridin-4-yl)amino]carbonyl}nicotinate (200 mg, 0.6 mmol), phenylboronic acid (132 mg, 1.08 mmol) and cesium carbonate (400 mg, 1 mmol) in 1,4-dioxane (3.69 mL) and water (216 μL). The mixture was stirred at 90° C. for 1 h. After concentration, the mixture was purified by 0 to 50% EtOAc in hexanes to afford the desired product. LC-MS calculated for C20H18N3O3 (M+H)+: m/z=348.1; found 348.1.
    • Step 4: 5-(hydroxymethyl)-N-(3-methyl-2-phenylpyridin-4-yl)pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00179
  • This compound was prepared using a similar procedure as described for Example 1, Step 3 with methyl 6-{[(3-methyl-2-phenylpyridin-4-yl)amino]carbonyl}nicotinate replacing methyl 6-{[(2-methylbiphenyl-3-yl)amino]carbonyl}nicotinate. LC-MS calculated for C19H18N3O2 (M+H)+: m/z=320.1; found 320.1.
    • Step 5: 5-formyl-N-(3-methyl-2-phenylpyridin-4-yl)pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00180
  • This compound was prepared using a similar procedure as described for Example 1, Step 4 with 5-(hydroxymethyl)-N-(3-methyl-2-phenylpyridin-4-yl)pyridine-2-carboxamide replacing 5-(hydroxymethyl)-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide. LC-MS calculated for C19H16N3O2 (M+H)+: m/z=318.1; found 318.1.
    • Step 6: (S)-1-((6-(3-methyl-2-phenylpyridin-4-ylcarbamoyl)pyridin-3-yl)methyl)piperidine-2-carboxylic acid
  • This compound was prepared using a similar procedure as described for Example 1, Step 5 with 5-formyl-N-(3-methyl-2-phenylpyridin-4-yl)pyridine-2-carboxamide replacing 5-formyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide. The reaction mixture was purified by prep-HPLC (pH=10, acetonitrile/water+NH4OH) to give the desired product. LC-MS calculated for C25H27N4O3 (M+H)+: m/z=431.2; found 431.2.
    • Example 43: 5-{[(2-hydroxyethyl)amino]methyl}-N-(3-methyl-2-phenylpyridin-4-yl)pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00181
  • This compound was prepared using a similar procedure as described for Example 4 with 5-formyl-N-(3-methyl-2-phenylpyridin-4-yl)pyridine-2-carboxamide (Example 42, Step 5) replacing 5-formyl-3-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide. The reaction mixture was purified by prep-HPLC (pH=10, acetonitrile/water+NH4OH) to give the desired product. LC-MS calculated for C21H23N4O2 (M+H)+: m/z=363.1; found 363.2.
    • Example 44: N-[2-cyano-3-(3,4-dihydro-2H-pyran-5-yl)phenyl]-5-{[(2-hydroxyethyl)amino]methyl}pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00182
  • This compound was prepared using a similar procedure as described for Example 38, Step 6 with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-pyran (Combi-Blocks, cat# PN-6040) replacing 2-cyclohex-1-en-1-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. The volatiles were removed, and the residue was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as its TFA salt. LC-MS calculated for C21H23N4O3 (M+H)+: m/z=379.2; found 379.2.
    • Example 45: N-[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-5-fluoro-2-methylphenyl]-5-{[(2-hydroxyethyl)amino]methyl}pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00183
    • Step 1: N-(3-bromo-5-fluoro-2-methylphenyl)-5-(chloromethyl)pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00184
  • This compound was prepared using a similar procedure as described for Example 41, Step 4 with 3-bromo-5-fluoro-2-methylaniline (Combi-Blocks, cat# ST-8934) replacing 2-amino-6-cyclohexylbenzonitrile.
    • Step 2: N-(3-bromo-5-fluoro-2-methylphenyl)-5-{[(2-hydroxyethyl)amino]methyl}pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00185
  • This compound was prepared using a similar procedure as described for Example 41, Step 5 with N-(3-bromo-5-fluoro-2-methylphenyl)-5-(chloromethyl)pyridine-2-carboxamide replacing 5-(chloromethyl)-N-(2-cyano-3-cyclohexylphenyl)pyridine-2-carboxamide. LC-MS calculated for C16H18BrFN3O2 (M+H)+: m/z=382.1; found 382.0.
    • Step 3: N-[3-(2, 3-dihydro-1, 4-benzodioxin-6-yl)-5-fluoro-2-methylphenyl]-5-{[(2-hydroxyethyl)amino]methyl}pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00186
  • This compound was prepared using a similar procedure as described for Example 38, Step 6 with 2,3-dihydro-1,4-benzodioxin-6-ylboronic acid (Sigma-Aldrich, cat#635995) replacing 2-cyclohex-1-en-1-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, and with N-(3-bromo-5-fluoro-2-methylphenyl)-5-{[(2-hydroxyethyl)amino]methyl}pyridine-2-carboxamide replacing N-(3-bromo-2-cyanophenyl)-5-{[(2-hydroxyethyl)amino]methyl}pyridine-2-carboxamide. The volatiles were removed, and the residue was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as its TFA salt. LC-MS calculated for C24H25FN3O4 (M+H)+: m/z=438.2; found 438.1.
    • Example 46: N-[2-cyano-3-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)phenyl]-5-{[(2-hydroxyethyl)amino]methyl}pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00187
  • This compound was prepared using a similar procedure as described for Example 38, Step 6 with 4-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-1,4-benzoxazine (Maybridge Building Blocks, cat# CC13539) replacing 2-cyclohex-1-en-1-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. The volatiles were removed and the residue was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as its TFA salt. LC-MS calculated for C25H26N5O3 (M+H)+: m/z=444.2; found 444.2.
    • Example 47: N-[2-cyano-3-(2,3-dihydro-1-benzofuran-6-yl)phenyl]-5-{[(2-hydroxyethyl)amino]methyl}pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00188
  • This compound was prepared using a similar procedure as described for Example 38, Step 6 with (2,3-dihydrobenzofuran-6-yl)boronic acid (Ark Pharm, cat# AK143637) replacing 2-cyclohex-1-en-1-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. The volatiles were removed and the residue was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as its TFA salt. LC-MS calculated for C24H23N4O3 (M+H)+: m/z=415.2; found 415.2.
    • Example 48: N-[2-cyano-3-(2-methyl-2H-indazol-6-yl)phenyl]-5-{[(2-hydroxyethyl)amino]methyl}pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00189
  • This compound was prepared using a similar procedure as described for Example 38, Step 6 with 2-methylindazole-6-boronic acid pinacol ester (Combi-Blocks, cat# PN-9131) replacing 2-cyclohex-1-en-1-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. The volatiles were removed and the residue was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as its TFA salt. LC-MS calculated for C24H23N6O2 (M+H)+: m/z=427.2; found 427.2.
    • Example 49: N-[2-cyano-3-(1-methyl-1H-indazol-4-yl)phenyl]-5-{[(2-hydroxyethyl)amino]methyl}pyridine-2-carboxamide
  • Figure US20170174671A1-20170622-C00190
  • This compound was prepared using a similar procedure as described for Example 38, Step 6 with 1-methyl-1H-indazole-4-boronic acid pinacol ester (Aldrich, cat#725323) replacing 2-cyclohex-1-en-1-yl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. The volatiles were removed, and the residue was purified by prep-HPLC (pH=2, acetonitrile/water+TFA) to give the desired product as its TFA salt. LC-MS calculated for C24H23N6O2 (M+H)+: m/z=427.2; found 427.2.
    • Example A. PD-1/PD-L1 Homogeneous Time-Resolved Fluorescence (HTRF) Binding Assay
  • The assays were conducted in a standard black 384-well polystyrene plate with a final volume of 20 μL. Inhibitors were first serially diluted in DMSO and then added to the plate wells before the addition of other reaction components. The final concentration of DMSO in the assay was 1%. The assays were carried out at 25° C. in the PBS buffer (pH 7.4) with 0.05% Tween-20 and 0.1% BSA. Recombinant human PD-L1 protein (19-238) with a His-tag at the C-terminus was purchased from AcroBiosystems (PD1-H5229). Recombinant human PD-1 protein (25-167) with Fc tag at the C-terminus was also purchased from AcroBiosystems (PD1-H5257). PD-L1 and PD-1 proteins were diluted in the assay buffer and 10 μL was added to the plate well. Plates were centrifuged and proteins were preincubated with inhibitors for 40 minutes. The incubation was followed by the addition of 10 μL of HTRF detection buffer supplemented with Europium cryptate-labeled anti-human IgG (PerkinElmer-AD0212) specific for Fc and anti-His antibody conjugated to SureLight®-Allophycocyanin (APC, PerkinElmer-AD0059H). After centrifugation, the plate was incubated at 25° C. for 60 min. before reading on a PHERAstar FS plate reader (665 nm/620 nm ratio). Final concentrations in the assay were −3 nM PD1, 10 nM PD-L1, 1 nM europium anti-human IgG and 20 nM anti-His-Allophycocyanin. IC50 determination was performed by fitting the curve of percent control activity versus the log of the inhibitor concentration using the GraphPad Prism 5.0 software.
  • Compounds of the present disclosure, as exemplified in the Examples, showed IC50 values in the following ranges: +=IC50≦10 nM; ++=10 nM<IC50≦100 nM; +++=100 nM<IC50≦1000 nM; ++++=IC50>1000 nM
  • Data obtained for the Example compounds using the PD-1/PD-L1 homogenous time-resolved fluorescence (HTRF) binding assay described in Example A is provided in Table 1.
  • TABLE 1
    PD-1/PD-L1 HTRF
    Example IC50 (nM)
    1 ++
    2 ++
    3 +++
    4 ++
    5 +++
    6 ++
    7 ++
    8 +
    9 ++
    10 +
    11 ++
    12 ++
    13 +++
    14 ++
    15 +++
    16 ++
    17 ++
    18 ++
    19 ++
    20 ++
    21 +++
    23 ++
    24 +++
    25 ++
    26 ++
    27 ++
    28 +++
    29 +++
    30 +++
    31 ++
    32 +
    33 +
    34 ++
    35 +
    36 ++
    37 ++
    38 +
    39 ++++
    40 +++
    41 ++
    42 ++++
    43 +++
    44 ++
    45 +
    46 +++
    47 ++
    48 ++
    49 +
  • Various modifications of the invention, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference, including without limitation all patent, patent applications, and publications, cited in the present application is incorporated herein by reference in its entirety.

Claims (35)

What is claimed is:
1. A compound of Formula (I′):
Figure US20170174671A1-20170622-C00191
or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:
X1 is N or CR1;
X2 is N or CR2;
X3 is N or CR3;
X4 is N or CR4;
wherein no more than two of X1, X2, X3 and X4 are simultaneously N;
X5 is N or CR6a;
X6 is N or CR6b;
ring B is C6-10 aryl, C3-10 cycloalkyl, 5- to 14-membered heteroaryl, or 4- to 10-membered heterocycloalkyl, provided ring B is other than 9-H-carbazol-4-yl, 2,3,4,9-tetrahydro-1H-carbazol-5-yl or 1H-tetrazolyl;
R1, R2, R3, R4 and R7 are each independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, CN, NO2, ORa, SRa, NHORa, C(O)Ra, C(O)NRaRa, C(O)ORa, OC(O)Ra, OC(O)NRaRa, NHRa, NRaRa, NRaC(O)Ra, NRaC(O)ORa, NRaC(O)NRaRa, C(═NRa)Ra, C(═NRa)NRaRa, NRaC(═NRa)NRaRa, NRaS(O)Ra, NRaS(O)2Ra, NRaS(O)2NRaRa, S(O)Ra, S(O)NRaRa, S(O)2Ra, and S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of R1, R2, R3, R4 and R7 are each optionally substituted with 1, 2, 3, or 4 Rb substituents;
R5 is halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, CN, NO2, OR11, SR11, NH2, —NHR11, —NR11R11, NHOR11, C(O)R11, C(O)NR11R11, C(O)OR11, OC(O)R11, OC(O)NR11R11, NR11C(O)R11, NR11C(O)OR11, NR11C(O)NR11R11, C(═NR11)R11, C(═NR11)NR11R11, NR11C(═NR11)NR11R11, NR11S(O)R11, NR11S(O)2R11, NR11S(O)2NR11R11, S(O)R11, S(O)NR11R11, S(O)2R11, and S(O)2NR11R11, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of R5 are each optionally substituted with 1, 2 or 3 Rb substituents; wherein R5 is other than F when ring B is C3-10 cycloalkyl, 5- to 14-membered heteroaryl or 4- to 10-membered heterocycloalkyl;
each R11 is independently selected from H, CN, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of R11 are each optionally substituted with 1, 2 or 3 Rb substituents;
R6a, R6b and R6c are each independently selected from H, C1-4 alkyl, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl-, C6-10 aryl, C6-10 aryl-C1-4 alkyl-, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, C2-4 alkenyl, C2-4 alkynyl, halo, CN, OR10, C1-4 haloalkyl, C1-4 haloalkoxy, NH2, —NHR10, —NR10R10, NHOR10, C(O)R10, C(O)NR10R10, C(O)OR10, OC(O)R10, OC(O)NR10R10, NR10C(O)R10, NR10C(O)OR10, NR10C(O)NR10R10, C(═NR10)R10, C(═NR10)NR10R10, NR10C(═NR10)NR10R10, NR10S(O)R10, NR10S(O)2R10, NR10S(O)2NR10R10, S(O)R10, S(O)NR10R10, S(O)2R10, and S(O)2NR10R10, wherein each R10 is independently selected from H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl-, C6-10 aryl, C6-10 aryl-C1-4 alkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 alkoxy, C3-10 cycloalkyl, C3-10 cycloalkyl-C1-4 alkyl-, C6-10 aryl, C6-10 aryl-C1-4 alkyl-, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of R6a, R6b, R6c and R10 are each optionally substituted with 1, 2 or 3 independently selected Rd substituents;
or two adjacent R7 substituents, taken together with the atoms to which they are attached, form a fused phenyl ring, a fused 4- to 7-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C3-10 cycloalkyl ring, wherein the fused 4- to 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- to 7-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C3-10 cycloalkyl ring are each optionally substituted with 1, 2 or 3 independently selected Rb substituents, provided
Figure US20170174671A1-20170622-C00192
is other than 9-H-carbazol-4-yl or 2,3,4,9-tetrahydro-1H-carbazol-5-yl, each of which is optionally substituted by 1, 2 or 3 independently selected Rb substituents;
or two R7 substituents attached to the same ring carbon atom of ring B, together with the carbon atom to which they are attached, form a 4- to 7-membered heterocycloalkyl ring having 1-4 heteroatoms as ring members selected from N, O and S or a C3-6 cycloalkyl ring, wherein the 4- to 7-membered heterocycloalkyl ring and C3-6 cycloalkyl ring are each optionally substituted with 1, 2 or 3 independently selected Rb substituents;
or R1 and X2 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C5-6 cycloalkyl ring are each optionally substituted with 1, 2 or 3 independently selected Rb substituents;
or R2 and X1 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C5-6 cycloalkyl ring are each optionally substituted with 1, 2 or 3 independently selected Rb substituents;
or R2 and X3 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C5-6 cycloalkyl ring are each optionally substituted with 1, 2 or 3 independently selected Rb substituents;
or R3 and X2 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C5-6 cycloalkyl ring are each optionally substituted with 1, 2 or 3 independently selected Rb substituents;
or R3 and X4 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C5-6 cycloalkyl ring are each optionally substituted with 1, 2 or 3 independently selected Rb substituents;
or R4 and X3 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C5-6 cycloalkyl ring are each optionally substituted with 1, 2 or 3 independently selected Rb substituents;
each Ra is independently selected from H, CN, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Ra are each optionally substituted with 1, 2, 3, 4, or 5 Rd substituents;
each Rd is independently selected from C1-6 alkyl, C1-6 haloalkyl, halo, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, CN, NH2, NHORe, ORe, SRe, C(O)Re, C(O)NReRe, C(O)ORe, OC(O)Re, OC(O)NReRe, NHRe, NReRe, NReC(O)Re, NReC(O)NReRe, NReC(O)ORe, C(═NRe)NReRe, NReC(═NRe)NReRe, NReC(═NOH)NReRe, NReC(═NCN)NReRe, S(O)Re, S(O)NReRe, S(O)2Re, NReS(O)2Re, NReS(O)2NReRe, and S(O)2NReRe, wherein the C1-6 alkyl, C1-6 haloalkyl, C6-10 aryl, 5-10 membered heteroaryl, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Rd are each optionally substituted with 1-3 independently selected Rf substituents;
each Rb substituent is independently selected from halo, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, CN, OH, NH2, NO2, NHORc, ORc, SRc, C(O)Rc, C(O)NRcRc, C(O)ORc, OC(O)Rc, OC(O)NRcRc, C(═NRc)NRcRc, NRcC(═NRc)NRcRc, NHRc, NRcRc, NRcC(O)Rc, NRcC(O)ORc, NRcC(O)NRcRc, NRcS(O)Rc, NRcS(O)2Rc, NRcS(O)2NRcRc, S(O)Rc, S(O)NRcRc, S(O)2Rc and S(O)2NRcRc; wherein the C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-4 haloalkyl, C1-4 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Rb are each further optionally substituted with 1-3 independently selected Rd substituents;
each Rc is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Rc are each optionally substituted with 1, 2, 3, 4, or 5 Rf substituents independently selected from C1-4 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, halo, CN, NHORg, ORg, SRg, C(O)Rg, C(O)NRgRg, C(O)ORg, OC(O)Rg, OC(O)NRgRg, NHRg, NRgRg, NRgC(O)Rg, NRgC(O)NRgRg, NRgC(O)ORg, C(═NRg)NRgRg, NRgC(═NRg)NRgRg, S(O)Rg, S(O)NRgRg, S(O)2Rg, NRgS(O)2Rg, NRgS(O)2NRgRg, and S(O)2NRgRg; wherein the C1-4 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Rf are each optionally substituted with 1, 2, 3, 4, or 5 Rn substituents independently selected from C1-4 alkyl, C3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl-, (4-7 membered heterocycloalkyl)-C1-4 alkyl-, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, halo, CN, Ro, NHORo, ORo, SRo, C(O)Ro, C(O)NRoRo, C(O)ORo, OC(O)Ro, OC(O)NRoRo, NHRo, NRoRo, NRoC(O)Ro, NRoC(O)NRoRo, NRoC(O)ORo, C(═NR)NRoRo, NRoC(═NRo)NRoRo, S(O)Ro, S(O)NRoRo, S(O)2Ro, NRoS(O)2Ro, NRoS(O)2NRoRo, and S(O)2NRoRo, wherein the C1-4 alkyl, C3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl-, (4-7 membered heterocycloalkyl)-C1-4 alkyl-, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl and C1-4 haloalkyl of Rn are each optionally substituted with 1, 2 or 3 Rq substituents;
each Rg is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Rg are each optionally substituted with 1-3 Rp substituents independently selected from C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, halo, CN, NHORr, ORr, SRr, C(O)Rr, C(O)NRrRr, C(O)ORr, OC(O)Rr, OC(O)NRrRr, NHRr, NRrRr, NRrC(O)Rr, NRrC(O)NRrRr, NRrC(O)ORr, C(═NRr)NRrRr, NRrC(═NRr)NRrRr, NRrC(═NOH)NRrRr, NRrC(═NCN)NRrRr, S(O)Rr, S(O)NRrRr, S(O)2Rr, NRrS(O)2Rr, NRrS(O)2NRrRr and S(O)2NRrRr, wherein the C1-6 alkyl, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Rp are each optionally substituted with 1, 2 or 3 Rq substituents;
or any two Ra substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 Rh substituents independently selected from C1-6 alkyl, C3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl-, (4-7 membered heterocycloalkyl)-C1-4 alkyl-, C1-6 haloalkyl, C1-6 haloalkoxy, C2-6 alkenyl, C2-6 alkynyl, halo, CN, ORi, SRi, NHORi, C(O)Ri, C(O)NRiRi, C(O)ORi, OC(O)Ri, OC(O)NRiRi, NHRi, NRiRi, NRiC(O)Ri, NRiC(O)NRiRi, NRiC(O)ORi, C(═NRi)NRiRi, NRiC(═NRi)NRiRi, S(O)Ri, S(O)NRiRi, S(O)2Ri, NRiS(O)2Ri, NRiS(O)2NRiRi, and S(O)2NRiRi, wherein the C1-6 alkyl, C3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl-, and (4-7 membered heterocycloalkyl)-C1-4 alkyl- of Rh are each further optionally substituted by 1, 2, or 3 Rj substituents independently selected from C3-6 cycloalkyl, C6-10 aryl, 5 or 6-membered heteroaryl, 4-7 membered heterocycloalkyl, C2-4 alkenyl, C2-4 alkynyl, halo, C1-4 alkyl, C1-4 haloalkyl, C1-4haloalkoxy, CN, NHORk, ORk, SRk, C(O)Rk, C(O)NRkRk, C(O)ORk, OC(O)Rk, OC(O)NRkRk, NHRk, NRkRk, NRkC(O)Rk, NRkC(O)NRkRk, NRkC(O)ORk, C(═NRk)NRkRk, NRkC(═NRk)NRkRk, S(O)Rk, S(O)NRkRk, S(O)2Rk, NRkS(O)2Rk, NRkS(O)2NRkRk, and S(O)2NRkRk, wherein the C1-4 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5- or 6-membered heteroaryl, 4-7 membered heterocycloalkyl, C2-4 alkenyl, C2-6 alkynyl, C1-4 haloalkyl, and C1-4haloalkoxy of Rj are each optionally substituted with 1, 2 or 3 independently selected Rq substituents; or two Rh groups attached to the same carbon atom of the 4- to 10-membered heterocycloalkyl taken together with the carbon atom to which they are attached form a C3-6 cycloalkyl or 4- to 6-membered heterocycloalkyl having 1-2 heteroatoms as ring members selected from O, N or S;
or any two Rc substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;
or any two Re substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;
or any two Rg substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;
or any two Ri substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;
or any two Rk substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;
or any two Ro substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents; and
each Re, Ri, Rk, Ro or Rr is independently selected from H, C1-4 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5 or 6-membered heteroaryl, 4-6 membered heterocycloalkyl, C1-4 haloalkyl, C2-4 alkenyl, and C2-4 alkynyl, wherein the C1-4 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5 or 6-membered heteroaryl, 4-6 membered heterocycloalkyl, C2-4 alkenyl, and C2-4 alkynyl of Re, Ri, Rk, Ro or Rr are each optionally substituted with 1, 2 or 3 Rq substituents;
each Rq is independently selected from OH, CN, —COOH, NH2, halo, C1-6 haloalkyl, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C3-6 cycloalkyl, NHR8, NR8R8, and C1-4 haloalkoxy, wherein the C1-6 alkyl, phenyl, C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl of Rq are each optionally substituted with halo, OH, CN, —COOH, NH2, C1-4 alkyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, phenyl, C3-10 cycloalkyl, 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl and each R8 is independently C1-6 alkyl;
Figure US20170174671A1-20170622-P00001
is a single bond or a double bond, wherein ring A includes at least one double bond;
the subscript n is an integer of 1, 2, 3, 4 or 5; and
with the proviso (i) when
Figure US20170174671A1-20170622-C00193
is 2,6-dioxohexahydropyrimidin-1-yl, 2-oxopyrrolidin-1-yl, benzo[d]thiazol-2-yl, 2-amino-4-methyl-5,6-dihydro-1,3-thiazin-4-yl, 4-methyl-6-[4-(morpholine-4-carbonyl)anilino]-5-oxo-pyrazin-2-yl, 5,7-dimethylbenzo[d]oxazol-2-yl, 6-[4-(morpholine-4-carbonyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl, 8-[4-(morpholine-4-carbonyl)anilino]imidazo[1,2-a]pyrazin-6-yl, oxazolo[4,5-b]pyridine-2-yl, or 1-methyl-2-oxo-1,6-naphthridin-3-yl, ring A in Formula (I′) is not 2-pyridyl or 2-pyridyl optionally substituted with halo, methylcarboxy, 1,2,4-triazol-4-yl, 1-piperidinyl, or cyclopropyl;
(ii) when ring B is thiazolo[5,4-b]pyridin-2-yl or 6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl, ring A in Formula (I′) is other than 2-quinolyl;
(iii) when ring B is 1-piperazinyl, ring A in Formula (I′) is not 3-(4-benzyloxyphenyl)pyrazolo[1,5-a]pyrimidin-5-yl;
(iv) when
Figure US20170174671A1-20170622-C00194
is 6-[1-(dimethylcarbamoyl)-3,6-dihydro-2H-pyridin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl, ring A in Formula (I′) is not 1-methylpyrrolo[2,3-b]pyridine-6-yl;
(v) when ring B is 2-oxo-1,2-dihydropyridin-5-yl, 2-oxo-1,2-dihydropyrazin-5-yl or 6-oxo-1H-pyridazin-3-yl, R2 is other than t-butyl;
(vi) when
Figure US20170174671A1-20170622-C00195
is 3,5-dimethylphenyl, R5 is other than 4-amino-1-piperidinyl; and
(vii) the compound is other than 6-((2R,6S)-2,6-dimethylmorpholino)-N-(2-methyl-4′-(trifluoromethoxy)biphenyl-3-yl)pyridazine-3-carboxamide or N-(3-(3-acetyl-2-oxoimidazolidin-1-yl)-2-methylphenyl)-5,6,7,8-tetrahydroquinoline-2-carboxamide.
2. The compound of claim 1, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:
X1 is N or CR1;
X2 is N or CR2;
X3 is N or CR3;
X4 is N or CR4;
wherein no more than two of X1, X2, X3 and X4 are simultaneously N;
X5 is N or CR6a;
X6 is N or CR6b;
ring B is C6-10 aryl, C3-10 cycloalkyl, 5- to 14-membered heteroaryl, or 4- to 10-membered heterocycloalkyl, provided ring B is other than 9-H-carbazol-4-yl, 2,3,4,9-tetrahydro-1H-carbazol-5-yl or 1H-tetrazolyl;
R1, R2, R3, R4 and R7 are each independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, CN, NO2, ORa, SRa, NHORa, C(O)Ra, C(O)NRaRa, C(O)ORa, OC(O)Ra, OC(O)NRaRa, NHRa, NRaRa, NRaC(O)Ra, NRaC(O)ORa, NRaC(O)NRaRa, C(═NRa)Ra, C(═NRa)NRaRa, NRaC(═NRa)NRaRa, NRaS(O)Ra, NRaS(O)2Ra, NRaS(O)2NRaRa, S(O)Ra, S(O)NRaRa, S(O)2Ra, and S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of R1, R2, R3, R4 and R7 are each optionally substituted with 1, 2, 3, or 4 Rb substituents;
R5 is halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, CN, NO2, OR11, SR11, NH2, —NH—C1-4 alkyl, —N(C1-4 alkyl)2, NHOR11, C(O)R11, C(O)NR11R11, C(O)OR11, OC(O)R11, OC(O)NR11R11, NR11C(O)R11, NR11C(O)OR11, NR11C(O)NR11R11, C(═NR11)R11, C(═NR11)NR11R11, NR11C(═NR11)NR11R11, NR11S(O)R11, NR11S(O)2R11, NR11S(O)2NR11R11, S(O)R11, S(O)NR11R11, S(O)2R11, and S(O)2NR11R11, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of R5 are each optionally substituted with 1, 2 or 3 Rb substituents; wherein R5 is other than F when ring B is C3-10 cycloalkyl, 5- to 14-membered heteroaryl or 4- to 10-membered heterocycloalkyl;
each R11 is independently selected from H, CN, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of R11 are each optionally substituted with 1, 2 or 3 Rb substituents;
R6a, R6b and R6c are each independently selected from H, C1-4 alkyl, C3-6 cycloalkyl, C2-4 alkenyl, C2-4 alkynyl, halo, CN, OH, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, NH2, —NH—C1-4 alkyl, —N(C1-4 alkyl)2, NHOR10, C(O)R10, C(O)NR10R10, C(O)OR10, OC(O)R10, OC(O)NR10R10, NR10C(O)R10, NR10C(O)OR10, NR10C(O)NR10R10, C(═NR10)R10, C(═NR10)NR10R10, NR10C(═NR10)NR10R10, NR10S(O)R10, NR10S(O)2R10, NR10S(O)2NR10R10, S(O)R10, S(O)NR10R10, S(O)2R10, and S(O)2NR10R10, wherein each R10 is independently H or C1-4 alkyl optionally substituted with 1 or 2 groups independently selected from halo, OH, CN and C1-4 alkoxy, and wherein the C1-4 alkyl, C3-6 cycloalkyl, C2-4 alkenyl and C2-4 alkynyl of R6a, R6b, and R6c are each optionally substituted with 1 or 2 substituents independently selected from halo, OH, CN, C1-4 alkyl and C1-4 alkoxy;
or two adjacent R7 substituents, taken together with the atoms to which they are attached, form a fused phenyl ring, a fused 4- to 7-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C3-10 cycloalkyl ring, wherein the fused 4- to 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- to 7-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C3-10 cycloalkyl ring are each optionally substituted with 1 or 2 independently selected Rb substituents, provided
Figure US20170174671A1-20170622-C00196
is other than 9-H-carbazol-4-yl or 2,3,4,9-tetrahydro-1H-carbazol-5-yl, each of which is optionally substituted by 1 or 2 independently selected Rb substituents;
or two R7 substituents attached to the same ring carbon atom of ring B, together with the carbon atom to which they are attached, form a 4- to 7-membered heterocycloalkyl ring having 1-4 heteroatoms as ring members selected from N, O and S or a C3-6 cycloalkyl ring, wherein the 4- to 7-membered heterocycloalkyl ring and C3-6 cycloalkyl ring are each optionally substituted with 1 or 2 independently selected Rb substituents;
or R1 and X2 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C5-6 cycloalkyl ring are each optionally substituted with 1 or 2 independently selected Rb substituents;
or R2 and X1 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C5-6 cycloalkyl ring are each optionally substituted with 1 or 2 independently selected Rb substituents;
or R2 and X3 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C5-6 cycloalkyl ring are each optionally substituted with 1 or 2 independently selected Rb substituents;
or R3 and X2 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C5-6 cycloalkyl ring are each optionally substituted with 1 or 2 independently selected Rb substituents;
or R3 and X4 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C5-6 cycloalkyl ring are each optionally substituted with 1 or 2 independently selected Rb substituents;
or R4 and X3 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C5-6 cycloalkyl ring are each optionally substituted with 1 or 2 independently selected Rb substituents;
each Ra is independently selected from H, CN, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Ra are each optionally substituted with 1, 2, 3, 4, or 5 Rd substituents;
each Rd is independently selected from C1-4 alkyl, C1-4 haloalkyl, halo, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, CN, NH2, NHORe, ORe, SRe, C(O)Re, C(O)NReRe, C(O)ORe, OC(O)Re, OC(O)NReRe, NHRe, NReRe, NReC(O)Re, NReC(O)NReRe, NReC(O)ORe, C(═NRe)NReRe, NReC(═NRe)NReRe, S(O)Re, S(O)NReRe, S(O)2Re, NReS(O)2Re, NReS(O)2NReRe, and S(O)2NReRe, wherein the C1-4 alkyl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl of Rd are each further optionally substituted with 1-3 independently selected Rf substituents;
each Rb substituent is independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, CN, OH, NH2, NO2, NHORc, ORc, SRc, C(O)Rc, C(O)NRcRc, C(O)ORc, OC(O)Rc, OC(O)NRcRc, C(═NRc)NRcRc, NRcC(═NRc)NRcRc, NHRc, NRcRc, NRcC(O)Rc, NRcC(O)ORc, NRcC(O)NRcRc, NRcS(O)Rc, NRcS(O)2Rc, NRcS(O)2NRcRc, S(O)Rc, S(O)NRcRc, S(O)2Rc and S(O)2NRcRc; wherein the C1-4 alkyl, C1-4 haloalkyl, C1-4 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Rb are each further optionally substituted with 1-3 independently selected Rd substituents;
each Rc is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Rc are each optionally substituted with 1, 2, 3, 4, or 5 Rf substituents independently selected from C1-4 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, halo, CN, NHORg, ORg, SRg, C(O)Rg, C(O)NRgRg, C(O)ORg, OC(O)Rg, OC(O)NRgRg, NHRg, NRgRg, NRgC(O)Rg, NRgC(O)NRgRg, NRgC(O)ORg, C(═NRg)NRgRg, NRgC(═NRg)NRgRg, S(O)Rg, S(O)NRgRg, S(O)2Rg, NRgS(O)2Rg, NRgS(O)2NRgRg, and S(O)2NRgRg; wherein the C1-4 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Rf are each optionally substituted with 1, 2, 3, 4, or 5 Rn substituents independently selected from C1-4 alkyl, C1-4 haloalkyl, halo, CN, Ro, NHORo, ORo, SRo, C(O)Ro, C(O)NRoRo, C(O)ORo, OC(O)Ro, OC(O)NRoRo, NHRo, NRoRo, NRoC(O)Ro, NRoC(O)NRoRo, NRoC(O)ORo, C(═NR)NRoRo, NRoC(═NR)NRoRo, S(O)Ro, S(O)NRoRo, S(O)2Ro, NRoS(O)2Ro, NRoS(O)2NRoRo, and S(O)2NRoRo;
each Rg is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Rg are each optionally substituted with 1-3 independently selected Rp substituents;
or any two Ra substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 Rh substituents independently selected from C1-6 alkyl, C3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl-, (4-7 membered heterocycloalkyl)-C1-4 alkyl-, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, halo, CN, ORi, SRi, NHORi, C(O)Ri, C(O)NRiRi, C(O)ORi, OC(O)Ri, OC(O)NRiRi, NHRi, NRiRi, NRiC(O)Ri, NRi(O)NRiRi, NRiC(O)ORi, C(═NRi)NRiRi, NRiC(═NRi)NRiRi, S(O)Ri, S(O)NRiRi, S(O)2Ri, NRiS(O)2Ri, NRiS(O)2NRiRi, and S(O)2NRiRi, wherein the C1-6 alkyl, C3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl-, and (4-7 membered heterocycloalkyl)-C1-4 alkyl- of Rh are each further optionally substituted by 1, 2, or 3 Rj substituents independently selected from C3-6 cycloalkyl, C6-10 aryl, 5 or 6-membered heteroaryl, C2-4 alkenyl, C2-4 alkynyl, halo, C1-4 alkyl, C1-4 haloalkyl, CN, NHORk, ORk, SRk, C(O)Rk, C(O)NRkRk, C(O)ORk, OC(O)Rk, OC(O)NRkRk, NHRk, NRkRk, NRkC(O)Rk, NRkC(O)NRkRk, NRkC(O)ORk, C(═NRk)NRkRk, NRkC(═NRk)NRkRk, S(O)Rk, S(O)NRkRk, S(O)2Rk, NRkS(O)2Rk, NRkS(O)2NRkRk, and S(O)2NRkRk; or two Rh groups attached to the same carbon atom of the 4- to 10-membered heterocycloalkyl taken together with the carbon atom to which they are attached form a C3-6 cycloalkyl or 4- to 6-membered heterocycloalkyl having 1-2 heteroatoms as ring members selected from O, N or S;
or any two Rc substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;
or any two Re substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;
or any two Rg substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;
or any two Ri substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;
or any two Rk substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;
or any two Ro substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents; and
each Re, Ri, Rk, Ro or Rp is independently selected from H, C1-4 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5 or 6-membered heteroaryl, C1-4 haloalkyl, C2-4 alkenyl, and C2-4 alkynyl, wherein the C1-4 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5 or 6-membered heteroaryl, C2-4 alkenyl, and C2-4 alkynyl of Re, Ri, Rk, Ro or Rp are each optionally substituted with 1, 2 or 3 Rq substituents;
each Rq is independently selected from OH, CN, —COOH, NH2, halo, C1-6 haloalkyl, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, phenyl, 5-6 membered heteroaryl, 4-6 membered heterocycloalkyl, C3-6 cycloalkyl, NHR8, NR8R8, and C1-4 haloalkoxy, wherein the C1-6 alkyl, phenyl, C3-6 cycloalkyl, 4-6 membered heterocycloalkyl, and 5-6 membered heteroaryl of Rq are each optionally substituted with halo, OH, CN, —COOH, NH2, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, phenyl, C3-10 cycloalkyl and 4-6 membered heterocycloalkyl and each R8 is independently C1-6 alkyl;
Figure US20170174671A1-20170622-P00001
is a single bond or a double bond, wherein ring A includes at least one double bond;
the subscript n is an integer of 1, 2, 3, 4 or 5; and
with the proviso (i) when
Figure US20170174671A1-20170622-C00197
is 2,6-dioxohexahydropyrimidin-1-yl, 2-oxopyrrolidin-1-yl, benzo[d]thiazol-2-yl, 2-amino-4-methyl-5,6-dihydro-1,3-thiazin-4-yl, 4-methyl-6-[4-(morpholine-4-carbonyl)anilino]-5-oxo-pyrazin-2-yl, 5,7-dimethylbenzo[d]oxazol-2-yl, 6-[4-(morpholine-4-carbonyl)phenyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl, 8-[4-(morpholine-4-carbonyl)anilino]imidazo[1,2-a]pyrazin-6-yl, oxazolo[4,5-b]pyridine-2-yl, or 1-methyl-2-oxo-1,6-naphthridin-3-yl, ring A in Formula (I′) is not 2-pyridyl or 2-pyridyl optionally substituted with halo, methylcarboxy, 1,2,4-triazol-4-yl, 1-piperidinyl, or cyclopropyl;
(ii) when ring B is thiazolo[5,4-b]pyridin-2-yl or 6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-a]azepin-3-yl, ring A in Formula (I′) is other than 2-quinolyl;
(iii) when ring B is 1-piperazinyl, ring A in Formula (I′) is not 3-(4-benzyloxyphenyl)pyrazolo[1,5-a]pyrimidin-5-yl;
(iv) when
Figure US20170174671A1-20170622-C00198
is 6-[1-(dimethylcarbamoyl)-3,6-dihydro-2H-pyridin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl, ring A in Formula (I′) is not 1-methylpyrrolo[2,3-b]pyridine-6-yl;
(v) when ring B is 2-oxo-1,2-dihydropyridin-5-yl, 2-oxo-1,2-dihydropyrazin-5-yl or 6-oxo-1H-pyridazin-3-yl, R2 is other than t-butyl;
(vi) when
Figure US20170174671A1-20170622-C00199
is 3,5-dimethylphenyl, R5 is other than 4-amino-1-piperidinyl; and
(vii) the compound is other than 6-((2R,6S)-2,6-dimethylmorpholino)-N-(2-methyl-4′-(trifluoromethoxy)biphenyl-3-yl)pyridazine-3-carboxamide or N-(3-(3-acetyl-2-oxoimidazolidin-1-yl)-2-methylphenyl)-5,6,7,8-tetrahydroquinoline-2-carboxamide.
3. The compound of claim 1 or 2 having Formula (I):
Figure US20170174671A1-20170622-C00200
or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:
X1 is N or CR1;
X2 is N or CR2;
X3 is N or CR3;
X4 is N or CR4;
wherein no more than two of X1, X2, X3 and X4 are simultaneously N;
R1, R2, R3, R4 and R7 are each independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, CN, NO2, ORa, SRa, NHORa, C(O)Ra, C(O)NRaRa, C(O)ORa, OC(O)Ra, OC(O)NRaRa, NHRa, NRaRa, NRaC(O)Ra, NRaC(O)ORa, NRaC(O)NRaRa, C(═NRa)Ra, C(═NRa)NRaRa, NRaC(═NRa)NRaRa, NRaS(O)Ra, NRaS(O)2Ra, NRaS(O)2NRaRa, S(O)Ra, S(O)NRaRa, S(O)2Ra, and S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of R1, R2, R3, R4 and R7 are each optionally substituted with 1, 2, 3, or 4 Rb substituents;
R5 is C1-4 alkyl, halo, CN, OH, cyclopropyl, C2-4 alkynyl, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, NH2, —NH—C1-4 alkyl, —N(C1-4 alkyl)2, NHOR11, C(O)R11, C(O)NR11R11, C(O)OR11, OC(O)R11, OC(O)NR11R11, NR11C(O)R11, NR11C(O)OR11, NR11C(O)NR11R11, C(═NR11)R11, C(═NR11)NR11R11, NR11C(═NR11)NR11R11, NR11S(O)R11, NR11S(O)2R11, NR11S(O)2NR11R11, S(O)R11, S(O)NR11R11, S(O)2R11, and S(O)2NR11R11, wherein each R11 is independently selected from H and C1-4 alkyl optionally substituted with 1 or 2 halo, OH, CN or OCH3;
each R6 is independently selected from H, C1-4 alkyl, C3-6 cycloalkyl, C2-4 alkenyl, C2-4 alkynyl, halo, CN, OH, C1-4 alkoxy, C1-4 haloalkyl, C1-4 haloalkoxy, NH2, —NH—C1-4 alkyl, —N(C1-4 alkyl)2, NHOR10, C(O)R10, C(O)NR10R10, C(O)OR10, OC(O)R10, OC(O)NR10R10, NR10C(O)R10, NR10C(O)OR10, NR10C(O)NR10R10, C(═NR10)R10, C(═NR10)NR10R10, NR10C(═NR10)NR10R10, NR10S(O)R10, NR10S(O)2R10, NR10S(O)2NR10R10, S(O)R10S(O)NR10R10, S(O)2R10, and S(O)2NR10R10, wherein each R10 is independently H or C1-4 alkyl optionally substituted with 1 or 2 groups independently selected from halo, OH, CN and C1-4 alkoxy, and wherein the C1-4 alkyl, C3-4 cycloalkyl, C2-4 alkenyl and C2-4 alkynyl of R6 are each optionally substituted with 1 or 2 substituents independently selected from halo, OH, CN, C1-4 alkyl and C1-4 alkoxy;
or two adjacent R7 substituents, taken together with the carbon atoms to which they are attached, form a fused phenyl ring, a fused 5- to 7-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C5-6 cycloalkyl ring, wherein the fused 5- to 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- to 7-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C3-10 cycloalkyl ring are each optionally substituted with 1 or 2 independently selected Rq substituents;
or R1 and X2 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C5-6 cycloalkyl ring are each optionally substituted with 1 or 2 independently selected Rb substituents;
or R2 and X1 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C5-6 cycloalkyl ring are each optionally substituted with 1 or 2 independently selected Rb substituents;
or R2 and X3 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C5-6 cycloalkyl ring are each optionally substituted with 1 or 2 independently selected Rb substituents;
or R3 and X2 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C5-6 cycloalkyl ring are each optionally substituted with 1 or 2 independently selected Rb substituents;
or R3 and X4 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C5-6 cycloalkyl ring are each optionally substituted with 1 or 2 independently selected Rb substituents;
or R4 and X3 taken together form a fused phenyl ring, a fused 4- to 10-membered heterocycloalkyl ring, a fused 5- or 6-membered heteroaryl ring or a fused C3-10 cycloalkyl ring, wherein the fused 4- to 10-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N, O and S and wherein the fused phenyl ring, fused 5- or 6-membered heterocycloalkyl ring, fused 5- or 6-membered heteroaryl ring and fused C5-6 cycloalkyl ring are each optionally substituted with 1 or 2 independently selected Rb substituents;
each Ra is independently selected from H, CN, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Ra are each optionally substituted with 1, 2, 3, 4, or 5 Rd substituents;
each Rd is independently selected from C1-4 alkyl, C1-4 haloalkyl, halo, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, CN, NH2, NHORe, ORe, SRe, C(O)Re, C(O)NReRe, C(O)ORe, OC(O)Re, OC(O)NReRe, NHRe, NReRe, NReC(O)Re, NReC(O)NReRe, NReC(O)ORe, C(═NRe)NReRe, NReC(═NRe)NReRe, S(O)Re, S(O)NReRe, S(O)2Re, NReS(O)2Re, NReS(O)2NReRe, and S(O)2NReRe, wherein the C1-4 alkyl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl of Rd are each further optionally substituted with 1-3 independently selected Rq substituents;
each Rb substituent is independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, CN, OH, NH2, NO2, NHORc, ORc, SRc, C(O)Rc, C(O)NRcRc, C(O)ORc, OC(O)Rc, OC(O)NRcRc, C(═NRc)NRcRc, NRcC(═NRc)NRcRc, NHRc, NRcRc, NRcC(O)Rc, NRcC(O)ORc, NRcC(O)NRcRc, NRcS(O)Rc, NRcS(O)2Rc, NRcS(O)2NRcRc, S(O)Rc, S(O)NRcRc, S(O)2Rc and S(O)2NRcRc; wherein the C1-4 alkyl, C1-4 haloalkyl, C1-4 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Rb are each further optionally substituted with 1-3 independently selected Rd substituents;
each Rc is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Rc are each optionally substituted with 1, 2, 3, 4, or 5 Rf substituents independently selected from C1-4 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, halo, CN, NHORg, ORg, SRg, C(O)Rg, C(O)NRgRg, C(O)ORg, OC(O)Rg, OC(O)NRgRg, NHRg, NRgRg, NRgC(O)Rg, NRgC(O)NRgRg, NRgC(O)ORg, C(═NRg)NRgRg, NRgC(═NRg)NRgRg, S(O)Rg, S(O)NRgRg, S(O)2Rg, NRgS(O)2Rg, NRgS(O)2NRgRg, and S(O)2NRgRg; wherein the C1-4 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Rf are each optionally substituted with 1, 2, 3, 4, or 5 Rn substituents independently selected from C1-4 alkyl, C1-4 haloalkyl, halo, CN, Ro, NHORo, ORo, SRo, C(O)Ro, C(O)NRoRo, C(O)ORo, OC(O)Ro, OC(O)NRoRo, NHRo, NRoRo, NRoC(O)Ro, NRoC(O)NRoRo, NRoC(O)ORo, C(═NR)NRoRo, NRoC(═NR)NRoRo, S(O)Ro, S(O)NRoRo, S(O)2Ro, NRoS(O)2Ro, NRoS(O)2NRoRo, and S(O)2NRoRo;
each Rg is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Rg are each optionally substituted with 1-3 independently selected Rp substituents;
or any two Ra substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, 7-, 8-, 9- or 10-membered heterocycloalkyl group optionally substituted with 1, 2 or 3 Rh substituents independently selected from C1-6 alkyl, C3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl-, (4-7 membered heterocycloalkyl)-C1-4 alkyl-, C1-6 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, halo, CN, ORi, SRi, NHORi, C(O)Ri, C(O)NRiRi, C(O)ORi, OC(O)Ri, OC(O)NRiRi, NHRi, NRiRi, NRiC(O)Ri, NRiC(O)NRiRi, NRiC(O)ORi, C(═NRi)NRiRi, NRiC(═NRi)NRiRi, S(O)Ri, S(O)NRiRi, S(O)2Ri, NRiS(O)2Ri, NRiS(O)2NRiRi, and S(O)2NRiRi, wherein the C1-6 alkyl, C3-10 cycloalkyl, 4-7 membered heterocycloalkyl, C6-10 aryl, 5-6 membered heteroaryl, C3-10 cycloalkyl-C1-4 alkyl-, (5-6 membered heteroaryl)-C1-4 alkyl-, and (4-7 membered heterocycloalkyl)-C1-4 alkyl- of Rh are each further optionally substituted by 1, 2, or 3 Rj substituents independently selected from C3-6 cycloalkyl, C6-10 aryl, 5 or 6-membered heteroaryl, C2-4 alkenyl, C2-4 alkynyl, halo, C1-4 alkyl, C1-4 haloalkyl, CN, NHORk, ORk, SRk, C(O)Rk, C(O)NRkRk, C(O)ORk, OC(O)Rk, OC(O)NRkRk, NHRk, NRkRk, NRkC(O)Rk, NRkC(O)NRkRk, NRkC(O)ORk, C(═NRk)NRkRk, NRkC(═NRk)NRkRk, S(O)Rk, S(O)NRkRk, S(O)2Rk, NRkS(O)2Rk, NRkS(O)2NRkRk, and S(O)2NRkRk; or two Rh groups attached to the same carbon atom of the 4- to 10-membered heterocycloalkyl taken together with the carbon atom to which they are attached form a C3-6 cycloalkyl or 4- to 6-membered heterocycloalkyl having 1-2 heteroatoms as ring members selected from O, N or S;
or any two Rc substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;
or any two Re substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;
or any two Rg substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;
or any two Ri substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;
or any two Rk substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents;
or any two Ro substituents together with the nitrogen atom to which they are attached form a 4-, 5-, 6-, or 7-membered heterocycloalkyl group optionally substituted with 1, 2, or 3 independently selected Rh substituents; and
each Re, Ri, Rk, Ro or Rp is independently selected from H, C1-4 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5 or 6-membered heteroaryl, C1-4 haloalkyl, C2-4 alkenyl, and C2-4 alkynyl, wherein the C1-4 alkyl, C3-6 cycloalkyl, C6-10 aryl, 5 or 6-membered heteroaryl, C2-4 alkenyl, and C2-4 alkynyl of Re, Ri, Rk, Ro or Rp are each optionally substituted with 1, 2 or 3 Rq substituents;
each Rq is independently selected from OH, CN, —COOH, NH2, halo, C1-4 alkyl, C1-4 alkoxy, C1-4 alkylthio, phenyl, 5-6 membered heteroaryl, C3-6 cycloalkyl, NHR8, NR8R8, and C1-4 haloalkoxy, wherein the C1-4 alkyl, phenyl and 5-6 membered heteroaryl of Rq are each optionally substituted with OH, CN, —COOH, NH2, C1-4 alkoxy, C3-10 cycloalkyl and 4-, 5-, or 6-membered heterocycloalkyl and each R8 is independently C1-6 alkyl;
the subscript n is an integer of 1, 2, 3, 4 or 5;
the subscript m is an integer of 1, 2 or 3; and
Figure US20170174671A1-20170622-P00001
is a single bond or a double bond, wherein ring A includes at least one double bond;
with the proviso that the compound is other than 6-((2R,6S)-2,6-dimethylmorpholino)-N-(2-methyl-4′-(trifluoromethoxy)biphenyl-3-yl)pyridazine-3-carboxamide.
4. The compound of any one of claims 1-3, wherein ring A is aromatic.
5. The compound of any one of claims 1-4, having Formula (II):
Figure US20170174671A1-20170622-C00201
wherein R2 is halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, CN, NO2, ORa, SRa, NHORa, C(O)Ra, C(O)NRaRa, C(O)ORa, OC(O)Ra, OC(O)NRaRa, NHRa, NRaRa, NRaC(O)Ra, NRaC(O)ORa, NRaC(O)NRaRa, C(═NRa)Ra, C(═NRa)NRaRa, NRaC(═NRa)NRaRa, NRaS(O)Ra, NRaS(O)2Ra, NRaS(O)2NRaRa, S(O)Ra, S(O)NRaRa, S(O)2Ra, and S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of R2 are each optionally substituted with 1, 2, 3, or 4 Rb substituents, or a pharmaceutically acceptable salt or a stereoisomer thereof.
6. The compound of any one of claims 1-5, having Formula (III):
Figure US20170174671A1-20170622-C00202
or a pharmaceutically acceptable salt or a stereoisomer thereof.
7. The compound of any one of claims 1-6, having Formula (IV):
Figure US20170174671A1-20170622-C00203
or a pharmaceutically acceptable salt or a stereoisomer thereof.
8. The compound of any one of claims 1-5, having Formula (V):
Figure US20170174671A1-20170622-C00204
or a pharmaceutically acceptable salt or a stereoisomer thereof.
9. The compound of any one of claims 1-5 and 8, having Formula (VI):
Figure US20170174671A1-20170622-C00205
or a pharmaceutically acceptable salt or a stereoisomer thereof.
10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein the moiety
Figure US20170174671A1-20170622-C00206
is selected from:
Figure US20170174671A1-20170622-C00207
11. The compound of any one of claims 1-4, having Formula (VII):
Figure US20170174671A1-20170622-C00208
wherein R3 is halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, CN, NO2, ORa, SRa, NHORa, C(O)Ra, C(O)NRaRa, C(O)ORa, OC(O)Ra, OC(O)NRaRa, NHRa, NRaRa, NRaC(O)Ra, NRaC(O)ORa, NRaC(O)NRaRa, C(═NRa)Ra, C(═NRa)NRaRa, NRaC(═NRa)NRaRa, NRaS(O)Ra, NRaS(O)2Ra, NRaS(O)2NRaRa, S(O)Ra, S(O)NRaRa, S(O)2Ra, and S(O)2NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of R1 are each optionally substituted with 1, 2, 3, or 4 Rb substituents, or a pharmaceutically acceptable salt or a stereoisomer thereof.
12. The compound of any one of claims 1-4 and 11, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein the moiety
Figure US20170174671A1-20170622-C00209
is selected from:
Figure US20170174671A1-20170622-C00210
13. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein X1 is CR1, X3 is CR3 and X4 is CR4.
14. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein X1 is CR1, X3 is N and X4 is CR4.
15. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein X1 is N, X3 is CR3 and X4 is CR4.
16. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein X1 is CR1, X3 is CR3 and X4 is N.
17. The compound of any one of claims 1-10 and 13-16, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R1, R3 and R4, when applicable, are each independently selected from H, C1-6 alkyl and halo.
18. The compound of claim 11 or 12, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R1, R2 and R4, when applicable, are each independently selected from H, C1-6 alkyl and halo.
19. The compound of any one of claims 1-10 and 13-17, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R2 is —CH2—Rb.
20. The compound of claim 19, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein Rb is —NRcRc.
21. The compound of any of claims 11, 12 and 18, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R3 is —CH2—Rb.
22. The compound of claim 21, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein Rb is —NRcRc.
23. The compound of any of claims 1-10, and 13-16 or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R2 is 2-hydroxyethylaminomethyl, 2-carboxypiperidin-1-ylmethyl, (S)-2-carboxypiperidin-1-ylmethyl, (R)-2-carboxypiperidin-1-ylmethyl or (3-cyanobenzyl)oxy.
24. The compound of any of claims 1, 2, 11, and 12, or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein R3 is 2-hydroxyethylaminomethyl, 2-carboxypiperidin-1-ylmethyl, (S)-2-carboxypiperidin-1-ylmethyl, (R)-2-carboxypiperidin-1-ylmethyl or (3-cyanobenzyl)oxy.
25. A compound of Formula (I′):
Figure US20170174671A1-20170622-C00211
or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:
X1 is N or CR1;
X2 is N or CR2;
X3 is N or CR3;
X4 is N or CR4;
wherein no more than two of X1, X2, X3 and X4 are simultaneously N;
X5 is N or CR6a;
X6 is CR6b;
ring B is phenyl, cyclohexyl, piperidinyl, or tetrahydropyridinyl;
R1, R2, R3, R4 and R7 are each independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, CN, ORa, NHRa, and NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-14 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of R1, R2, R3, R4 and R7 are each optionally substituted with 1, 2, 3, or 4 Rb substituents;
R5 is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C1-6 haloalkoxy, or CN, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, and C1-6 haloalkoxy of R5 are each optionally substituted with 1, 2 or 3 Rb substituents;
R6a, R6b and R6c are each independently selected from H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, halo, CN, OH, C1-4 alkoxy, C1-4 haloalkyl, NH2, —NH—C1-4 alkyl, and —N(C1-4 alkyl)2, wherein the C1-4 alkyl, C2-4 alkenyl and C2-4 alkynyl of R6a, R6b, and R6c are each optionally substituted with 1 or 2 substituents independently selected from halo, OH, CN, C1-4 alkyl and C1-4 alkoxy;
or two adjacent R7 substituents, taken together with the atoms to which they are attached, form a fused 4- to 7-membered heterocycloalkyl ring or a fused 5- or 6-membered heteroaryl ring, wherein the fused 4- to 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N and O and wherein the fused 5- to 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring are each optionally substituted with 1 or 2 independently selected Rb substituents;
each Ra is independently selected from H, CN, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Ra are each optionally substituted with 1, 2, 3, 4, or 5 Rd substituents;
each Rd is independently selected from C1-4 alkyl, C1-4 haloalkyl, halo, C3-10 cycloalkyl, 4-10 membered heterocycloalkyl, CN, NH2, ORe, SRe, C(O)Re, C(O)NReRe, C(O)ORe, OC(O)Re, OC(O)NReRe, NHRe, NReRe, and NReC(O)Re, and S(O)2NReRe, wherein the C1-4 alkyl, C3-10 cycloalkyl and 4-10 membered heterocycloalkyl of Rd are each further optionally substituted with 1-3 independently selected Rf substituents;
each Rb substituent is independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 haloalkoxy, CN, OH, NH2, NO2, NHORc, ORc, SRc, C(O)Rc, C(O)NRcRc, C(O)ORc, OC(O)Rc, OC(O)NRcRc, NHRc, NRcRc, NRcC(O)Rc, and NRcC(O)ORc; wherein the C1-4 alkyl, C1-4 haloalkyl, and C1-4 haloalkoxy of Rb are each further optionally substituted with 1-3 independently selected Rd substituents;
each Rc is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein the C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl of Rc are each optionally substituted with 1, 2, 3, 4, or 5 Rf substituents independently selected from C1-4 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, halo, CN, NHORg, ORg, SRg, C(O)Rg, C(O)NRgRg, C(O)ORg, OC(O)Rg, OC(O)NRgRg, NHRg, NRgRg, and NRgC(O)Rg;
each Rg is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl;
each Re is independently selected from H, C1-4 alkyl, C1-4 haloalkyl, C2-4 alkenyl, and C2-4 alkynyl;
Figure US20170174671A1-20170622-P00001
is a single bond or a double bond, wherein ring A includes at least one double bond; and
the subscript n is an integer of 1, 2, 3, 4 or 5.
26. A compound of Formula (I′):
Figure US20170174671A1-20170622-C00212
or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:
X1 is N or CR1;
X2 is N or CR2;
X3 is N or CR3;
X4 is N or CR4;
wherein no more than two of X1, X2, X3 and X4 are simultaneously N;
X5 is N or CR6a;
X6 is CR6b;
ring B is phenyl, cyclohexyl, piperidinyl, or tetrahydropyridinyl;
R1, R2, R3, R4 and R7 are each independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, (5-14 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, CN, ORa, NHRa, and NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, (5-14 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of R1, R2, R3, R4 and R7 are each optionally substituted with 1, 2, 3, or 4 Rb substituents;
R5 is C1-6 alkyl or CN;
R6a, R6b and R6c are each independently selected from H, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, halo, CN, OH, NH2, —NH—C1-4 alkyl, and —N(C1-4 alkyl)2;
or two adjacent R7 substituents, taken together with the atoms to which they are attached, form a fused 4- to 7-membered heterocycloalkyl ring or a fused 5- or 6-membered heteroaryl ring, wherein the fused 4- to 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N and O and wherein the fused 5- to 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring are each optionally substituted with 1 or 2 independently selected Rb substituents;
each Ra is independently selected from H, CN, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Ra are each optionally substituted with 1, 2, 3, 4, or 5 Rd substituents;
each Rd is independently selected from C1-4 alkyl, C1-4 haloalkyl, halo, CN, and NH2;
each Rb substituent is independently selected from halo, C1-4 alkyl, C1-4 haloalkyl, C1-4 haloalkoxy, CN, OH, NH2, C(O)ORc, NHRc, and NRcRc;
each Rc is independently selected from H, C1-6 alkyl, C1-4 haloalkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein the C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl of Rc are each optionally substituted with 1, 2, 3, 4, or 5 Rf substituents independently selected from C1-4 alkyl, C1-4 haloalkyl, C2-6 alkenyl, C2-6 alkynyl, halo, CN, ORg, C(O)Rg, C(O)NRgRg, C(O)ORg, NHRg, NRgRg, and NRgC(O)Rg;
each Rg is independently selected from H, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;
Figure US20170174671A1-20170622-P00001
is a single bond or a double bond, wherein ring A includes at least one double bond; and
the subscript n is an integer of 1, 2, 3, 4 or 5.
27. A compound of Formula (I′):
Figure US20170174671A1-20170622-C00213
or a pharmaceutically acceptable salt or a stereoisomer thereof, wherein:
X1 is N or CR1;
X2 is N or CR2;
X3 is N or CR3;
X4 is N or CR4;
wherein no more than two of X1, X2, X3 and X4 are simultaneously N;
X5 is N or CR6a;
X6 is CR6b;
ring B is phenyl, cyclohexyl, piperidinyl, or tetrahydropyridinyl;
R1, R2, R3, R4 and R7 are each independently selected from H, halo, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, (5-14 membered heteroaryl)-C1-4 alkyl-, (4-10 membered heterocycloalkyl)-C1-4 alkyl-, CN, ORa, NHRa, and NRaRa, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 5-14 membered heteroaryl, 4-10 membered heterocycloalkyl, (5-14 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of R1, R2, R3, R4 and R7 are each optionally substituted with 1 or 2, Rb substituents;
R5 is C1-6 alkyl or CN;
R6a, R6b and R6c are each independently selected from H, C1-4 alkyl and halo;
or two adjacent R7 substituents, taken together with the atoms to which they are attached, form a fused 4- to 7-membered heterocycloalkyl ring or a fused 5- or 6-membered heteroaryl ring, wherein the fused 4- to 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring each have 1-4 heteroatoms as ring members selected from N and O and wherein the fused 5- to 7-membered heterocycloalkyl ring and fused 5- or 6-membered heteroaryl ring are each optionally substituted with 1 or 2 independently selected Rb substituents;
each Ra is independently selected from H, CN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl-, and (4-10 membered heterocycloalkyl)-C1-4 alkyl-, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C6-10 aryl, C3-10 cycloalkyl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, C6-10 aryl-C1-4 alkyl-, C3-10 cycloalkyl-C1-4 alkyl-, (5-10 membered heteroaryl)-C1-4 alkyl- and (4-10 membered heterocycloalkyl)-C1-4 alkyl- of Ra are each optionally substituted with 1 or 2 Rd substituents;
each Rd is independently selected from C1-4 alkyl, halo, CN, and NH2;
each Rb substituent is independently selected from halo, C1-4 alkyl, CN, OH, NH2, C(O)ORc, NHRc, and NRcRc;
each Rc is independently selected from H, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein the C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl of Rc are each optionally substituted with 1, 2 or Rf substituents independently selected from C1-4 alkyl, C2-6 alkenyl, C2-6 alkynyl, halo, CN, and ORg;
each Rg is independently selected from H and C1-6 alkyl;
Figure US20170174671A1-20170622-P00001
is a single bond or a double bond, wherein ring A includes at least one double bond; and
the subscript n is an integer of 1, 2, 3, 4 or 5.
28. The compound of claim 1, wherein the compound is selected from:
(2S)-1-[(6-{[(2-methylbiphenyl-3-yl)amino]carbonyl}pyridin-3-yl)methyl]piperidine-2-carboxylic acid;
5-{[(2-hydroxyethyl)amino]methyl}-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide;
(2S)-1-[(5-methyl-6-{[(2-methylbiphenyl-3-yl)amino]carbonyl}pyridin-3-yl)methyl]piperidine-2-carboxylic acid;
5-{[(2-hydroxyethyl)amino]methyl}-3-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide;
(2S)-1-[(2-{[(2-methylbiphenyl-3-yl)amino]carbonyl}pyrimidin-5-yl)methyl]piperidine-2-carboxylic acid;
5-{[(2-hydroxyethyl)amino]methyl}-N-(2-methylbiphenyl-3-yl)pyrimidine-2-carboxamide;
(2S)-1-[(6-{[(2-cyanobiphenyl-3-yl)amino]carbonyl}pyridin-3-yl)methyl]piperidine-2-carboxylic acid;
N-(2-cyanobiphenyl-3-yl)-5-{[(2-hydroxyethyl)amino]methyl}pyridine-2-carboxamide;
(2S)-1-{[6-({[2-cyano-3-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]amino}carbonyl)pyridin-3-yl]methyl}piperidine-2-carboxylic acid;
N-(2-cyano-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)phenyl)-5-((2-hydroxyethylamino)methyl)picolinamide;
5-{[(2-hydroxyethyl)amino]methyl}-N-(2-methylbiphenyl-3-yl)pyrazine-2-carboxamide;
6-{[(2-hydroxyethyl)amino]methyl}-N-(2-methylbiphenyl-3-yl)pyridazine-3-carboxamide;
(2S)-1-[(2-methyl-6-{[(2-methylbiphenyl-3-yl)amino]carbonyl}pyridin-3-yl)methyl]piperidine-2-carboxylic acid;
5-{[(2-hydroxyethyl)amino]methyl}-6-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide;
(2S)-1-[(5-chloro-6-{[(2-methylbiphenyl-3-yl)amino]carbonyl}pyridin-3-yl)methyl]piperidine-2-carboxylic acid;
3-chloro-5-{[(2-hydroxyethyl)amino]methyl}-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide;
3-fluoro-5-{[(2-hydroxyethyl)amino]methyl}-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide;
4-[(3-cyanobenzyl)oxy]-5-{[(2-hydroxyethyl)amino]methyl}-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide;
5-{[(2-hydroxyethyl)amino]methyl}-N-(2-methylbiphenyl-3-yl)-4-(pyridin-3-ylmethoxy)pyridine-2-carboxamide;
5-{[(2-hydroxyethyl)amino]methyl}-N-(2-methylbiphenyl-3-yl)-4-(pyridin-2-ylmethoxy)pyridine-2-carboxamide;
3-(dimethylamino)-5-{[(2-hydroxyethyl)amino]methyl}-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide;
(2S)-1-[(2-{[(2-methylbiphenyl-3-yl)amino]carbonyl}pyridin-4-yl)methyl]piperidine-2-carboxylic acid;
4-{[(2-hydroxyethyl)amino]methyl}-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide;
N-(2-methylbiphenyl-3-yl)-6-(pyridin-3-ylmethoxy)pyrimidine-4-carboxamide;
4-cyano-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide;
N-(2-methylbiphenyl-3-yl)pyrazine-2-carboxamide;
N-(2-methylbiphenyl-3-yl)pyrimidine-4-carboxamide;
N-(2-methylbiphenyl-3-yl)pyrimidine-2-carboxamide;
N-(2-methylbiphenyl-3-yl)pyridazine-3-carboxamide; and
N-(2-methylbiphenyl-3-yl)-2-(pyridin-3-ylmethoxy)pyrimidine-4-carboxamide; or a pharmaceutically acceptable salt or a stereoisomer thereof.
29. The compound of claim 1, wherein the compound is selected from:
5-{[(2-hydroxyethyl)amino]methyl}-N-(2-methylbiphenyl-3-yl)-4,4′-bipyridine-2-carboxamide;
(2S)-1-[(4-methyl-6-{[(2-methylbiphenyl-3-yl)amino]carbonyl}pyridin-3-yl)methyl]piperidine-2-carboxylic acid;
5-{[(2-hydroxyethyl)amino]methyl}-4-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide;
4-(cyclopropylmethoxy)-5-((2-hydroxyethylamino)methyl)-N-(2-methylbiphenyl-3-yl)picolinamide;
5-{[(2-hydroxyethyl)amino]methyl}-4-methoxy-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide;
(2S)-1-[(5-methyl-2-{[(2-methylbiphenyl-3-yl)amino]carbonyl}pyridin-4-yl)methyl]piperidine-2-carboxylic acid;
4-{[(2-hydroxyethyl)amino]methyl}-5-methyl-N-(2-methylbiphenyl-3-yl)pyridine-2-carboxamide;
N-(2-cyano-3-cyclohex-1-en-1-ylphenyl)-5-{[(2-hydroxyethyl)amino]methyl}pyridine-2-carboxamide;
N-(2-cyano-3-piperidin-1-ylphenyl)-5-{[(2-hydroxyethyl)amino]methyl}pyridine-2-carboxamide;
tert-butyl 5-(2-cyano-3-{[(5-{[(2-hydroxyethyl)amino]methyl}pyridin-2-yl)carbonyl]amino}phenyl)-3,6-dihydropyridine-1 (2H)-carboxylate;
N-(2-cyano-3-cyclohexylphenyl)-5-{[(2-hydroxyethyl)amino]methyl}pyridine-2-carboxamide;
(S)-1-((6-(3-methyl-2-phenylpyridin-4-ylcarbamoyl)pyridin-3-yl)methyl)piperidine-2-carboxylic acid;
5-{[(2-hydroxyethyl)amino]methyl}-N-(3-methyl-2-phenylpyridin-4-yl)pyridine-2-carboxamide;
N-[2-cyano-3-(3,4-dihydro-2H-pyran-5-yl)phenyl]-5-{[(2-hydroxyethyl)amino]methyl}pyridine-2-carboxamide;
N-[3-(2,3-dihydro-1,4-benzodioxin-6-yl)-5-fluoro-2-methylphenyl]-5-{[(2-hydroxyethyl)amino]methyl}pyridine-2-carboxamide;
N-[2-cyano-3-(4-methyl-3,4-dihydro-2H-1,4-benzoxazin-7-yl)phenyl]-5-{[(2-hydroxyethyl)amino]methyl}pyridine-2-carboxamide;
N-[2-cyano-3-(2,3-dihydro-1-benzofuran-6-yl)phenyl]-5-{[(2-hydroxyethyl)amino]methyl}pyridine-2-carboxamide;
N-[2-cyano-3-(2-methyl-2H-indazol-6-yl)phenyl]-5-{[(2-hydroxyethyl)amino]methyl}pyridine-2-carboxamide; and
N-[2-cyano-3-(1-methyl-1H-indazol-4-yl)phenyl]-5-{[(2-hydroxyethyl)amino]methyl}pyridine-2-carboxamide;
or a pharmaceutically acceptable salt or a stereoisomer thereof.
30. A pharmaceutical composition comprising a compound of any one of claims 1-29, or a pharmaceutically acceptable salt or a stereoisomer thereof, and a pharmaceutically acceptable carrier or excipient.
31. A method of inhibiting PD-1/PD-L1 interaction, said method comprising administering to a patient a compound of any one of claims 1-29 or a pharmaceutically acceptable salt or a stereoisomer thereof.
32. A method of treating a disease or disorder associated with PD-1/PD-L1 interaction, said method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1-29, or a pharmaceutically acceptable salt or a stereoisomer thereof, or a composition of claim 30.
33. The method of claim 32, wherein the disease or disorder is a viral infection or cancer.
34. A method of enhancing, stimulating, modulating and/or increasing the immune response in a patient, said method comprising administering to the patient in need thereof a therapeutically effective amount of a compound of any of claims 1-29, or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, or a composition of claim 30.
35. A method of inhibiting growth, proliferation, or metastasis of cancer cells in a patient, said method comprising administering to the patient in need thereof a therapeutically effective amount of a compound of any of claims 1-29, or a pharmaceutically acceptable salt thereof or a stereoisomer thereof, or a composition of claim 30.
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Cited By (112)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018218100A1 (en) 2017-05-26 2018-11-29 Incyte Corporation Crystalline forms of a fgfr inhibitor and processes for preparing the same
WO2019051265A1 (en) * 2017-09-08 2019-03-14 Fronthera U.S. Pharmaceuticals Llc Apoptosis signal-regulating kinase inhibitors and uses thereof
US10308644B2 (en) 2016-12-22 2019-06-04 Incyte Corporation Heterocyclic compounds as immunomodulators
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US10618916B2 (en) 2018-05-11 2020-04-14 Incyte Corporation Heterocyclic compounds as immunomodulators
US10632126B2 (en) 2015-02-20 2020-04-28 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US10669271B2 (en) 2018-03-30 2020-06-02 Incyte Corporation Heterocyclic compounds as immunomodulators
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US10793565B2 (en) 2016-12-22 2020-10-06 Incyte Corporation Heterocyclic compounds as immunomodulators
US10806785B2 (en) 2016-12-22 2020-10-20 Incyte Corporation Immunomodulator compounds and methods of use
US10813930B2 (en) 2010-12-22 2020-10-27 Incyte Corporation Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3
US10851105B2 (en) 2014-10-22 2020-12-01 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
WO2021007269A1 (en) 2019-07-09 2021-01-14 Incyte Corporation Bicyclic heterocycles as fgfr inhibitors
US10947230B2 (en) 2013-04-19 2021-03-16 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
WO2021063404A1 (en) * 2019-09-30 2021-04-08 南京明德新药研发有限公司 Compound as small molecule inhibitor pd-1/pd-l1 and application thereof
WO2021067374A1 (en) 2019-10-01 2021-04-08 Incyte Corporation Bicyclic heterocycles as fgfr inhibitors
WO2021076691A1 (en) * 2019-10-16 2021-04-22 Chemocentryx, Inc. Heteroaryl-biphenyl amides for the treatment of pd-l1 diseases
WO2021076728A1 (en) 2019-10-16 2021-04-22 Incyte Corporation Bicyclic heterocycles as fgfr inhibitors
WO2021076688A1 (en) * 2019-10-16 2021-04-22 Chemocentryx, Inc. Heteroaryl-biphenyl amines for the treatment of pd-l1 diseases
WO2021076602A1 (en) 2019-10-14 2021-04-22 Incyte Corporation Bicyclic heterocycles as fgfr inhibitors
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US11053246B2 (en) 2012-06-13 2021-07-06 Incyte Corporation Substituted tricyclic compounds as FGFR inhibitors
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US11066404B2 (en) 2018-10-11 2021-07-20 Incyte Corporation Dihydropyrido[2,3-d]pyrimidinone compounds as CDK2 inhibitors
WO2021146424A1 (en) 2020-01-15 2021-07-22 Incyte Corporation Bicyclic heterocycles as fgfr inhibitors
WO2021150613A1 (en) 2020-01-20 2021-07-29 Incyte Corporation Spiro compounds as inhibitors of kras
WO2021158891A1 (en) 2020-02-06 2021-08-12 Incyte Corporation Salts and solid forms and processes of preparing a pi3k inhibitor
WO2021178779A1 (en) 2020-03-06 2021-09-10 Incyte Corporation Combination therapy comprising axl/mer and pd-1/pd-l1 inhibitors
WO2021211864A1 (en) 2020-04-16 2021-10-21 Incyte Corporation Fused tricyclic kras inhibitors
WO2021231526A1 (en) 2020-05-13 2021-11-18 Incyte Corporation Fused pyrimidine compounds as kras inhibitors
WO2021252781A1 (en) 2020-06-12 2021-12-16 Incyte Corporation Imidazopyridazine compounds with activity as alk2 inhibitors
WO2021257857A1 (en) 2020-06-19 2021-12-23 Incyte Corporation Naphthyridinone compounds as jak2 v617f inhibitors
WO2021257863A1 (en) 2020-06-19 2021-12-23 Incyte Corporation Pyrrolotriazine compounds as jak2 v617f inhibitors
WO2022006457A1 (en) 2020-07-02 2022-01-06 Incyte Corporation Tricyclic urea compounds as jak2 v617f inhibitors
WO2022006456A1 (en) 2020-07-02 2022-01-06 Incyte Corporation Tricyclic pyridone compounds as jak2 v617f inhibitors
WO2022033303A1 (en) * 2020-08-11 2022-02-17 中国人民解放军军事科学院军事医学研究院 Benzylamine derivative, preparation method therefor and use thereof
WO2022046989A1 (en) 2020-08-27 2022-03-03 Incyte Corporation Tricyclic urea compounds as jak2 v617f inhibitors
WO2022047093A1 (en) 2020-08-28 2022-03-03 Incyte Corporation Vinyl imidazole compounds as inhibitors of kras
WO2022072783A1 (en) 2020-10-02 2022-04-07 Incyte Corporation Bicyclic dione compounds as inhibitors of kras
US11401279B2 (en) 2019-09-30 2022-08-02 Incyte Corporation Pyrido[3,2-d]pyrimidine compounds as immunomodulators
US11407749B2 (en) 2015-10-19 2022-08-09 Incyte Corporation Heterocyclic compounds as immunomodulators
US11427567B2 (en) 2019-08-14 2022-08-30 Incyte Corporation Imidazolyl pyrimidinylamine compounds as CDK2 inhibitors
WO2022182839A1 (en) 2021-02-25 2022-09-01 Incyte Corporation Spirocyclic lactams as jak2 v617f inhibitors
US11440914B2 (en) 2019-05-01 2022-09-13 Incyte Corporation Tricyclic amine compounds as CDK2 inhibitors
US11447494B2 (en) 2019-05-01 2022-09-20 Incyte Corporation Tricyclic amine compounds as CDK2 inhibitors
WO2022204112A1 (en) 2021-03-22 2022-09-29 Incyte Corporation Imidazole and triazole kras inhibitors
US11465981B2 (en) 2016-12-22 2022-10-11 Incyte Corporation Heterocyclic compounds as immunomodulators
WO2022217276A1 (en) * 2021-04-09 2022-10-13 Nimbus Clio, Inc. Cbl-b modulators and uses thereof
WO2022221170A1 (en) 2021-04-12 2022-10-20 Incyte Corporation Combination therapy comprising an fgfr inhibitor and a nectin-4 targeting agent
CN115417870A (en) * 2022-09-20 2022-12-02 中国药科大学 PD-L1 & NAMPT dual-target inhibitor and application
WO2022261159A1 (en) 2021-06-09 2022-12-15 Incyte Corporation Tricyclic heterocycles as fgfr inhibitors
WO2022261160A1 (en) 2021-06-09 2022-12-15 Incyte Corporation Tricyclic heterocycles as fgfr inhibitors
US11535615B2 (en) 2015-12-22 2022-12-27 Incyte Corporation Heterocyclic compounds as immunomodulators
WO2023283213A1 (en) 2021-07-07 2023-01-12 Incyte Corporation Tricyclic compounds as inhibitors of kras
WO2023287896A1 (en) 2021-07-14 2023-01-19 Incyte Corporation Tricyclic compounds as inhibitors of kras
US11572366B2 (en) 2015-11-19 2023-02-07 Incyte Corporation Heterocyclic compounds as immunomodulators
WO2023034290A1 (en) 2021-08-31 2023-03-09 Incyte Corporation Naphthyridine compounds as inhibitors of kras
US11608337B2 (en) 2016-05-06 2023-03-21 Incyte Corporation Heterocyclic compounds as immunomodulators
US11613536B2 (en) 2016-08-29 2023-03-28 Incyte Corporation Heterocyclic compounds as immunomodulators
WO2023049697A1 (en) 2021-09-21 2023-03-30 Incyte Corporation Hetero-tricyclic compounds as inhibitors of kras
WO2023056421A1 (en) 2021-10-01 2023-04-06 Incyte Corporation Pyrazoloquinoline kras inhibitors
WO2023064857A1 (en) 2021-10-14 2023-04-20 Incyte Corporation Quinoline compounds as inhibitors of kras
WO2023091746A1 (en) 2021-11-22 2023-05-25 Incyte Corporation Combination therapy comprising an fgfr inhibitor and a kras inhibitor
US11673894B2 (en) 2018-02-27 2023-06-13 Incyte Corporation Imidazopyrimidines and triazolopyrimidines as A2A / A2B inhibitors
US11673883B2 (en) 2016-05-26 2023-06-13 Incyte Corporation Heterocyclic compounds as immunomodulators
WO2023122134A1 (en) 2021-12-22 2023-06-29 Incyte Corporation Salts and solid forms of an fgfr inhibitor and processes of preparing thereof
US11718605B2 (en) 2016-07-14 2023-08-08 Incyte Corporation Heterocyclic compounds as immunomodulators
US11753406B2 (en) 2019-08-09 2023-09-12 Incyte Corporation Salts of a PD-1/PD-L1 inhibitor
US11760756B2 (en) 2020-11-06 2023-09-19 Incyte Corporation Crystalline form of a PD-1/PD-L1 inhibitor
WO2023178285A1 (en) 2022-03-17 2023-09-21 Incyte Corporation Tricyclic urea compounds as jak2 v617f inhibitors
US11780836B2 (en) 2020-11-06 2023-10-10 Incyte Corporation Process of preparing a PD-1/PD-L1 inhibitor
WO2023239768A1 (en) 2022-06-08 2023-12-14 Incyte Corporation Tricyclic triazolo compounds as dgk inhibitors
US11851426B2 (en) 2019-10-11 2023-12-26 Incyte Corporation Bicyclic amines as CDK2 inhibitors
US11866451B2 (en) 2019-11-11 2024-01-09 Incyte Corporation Salts and crystalline forms of a PD-1/PD-L1 inhibitor
US11866434B2 (en) 2020-11-06 2024-01-09 Incyte Corporation Process for making a PD-1/PD-L1 inhibitor and salts and crystalline forms thereof
US11873309B2 (en) 2016-06-20 2024-01-16 Incyte Corporation Heterocyclic compounds as immunomodulators
US11873304B2 (en) 2018-05-18 2024-01-16 Incyte Corporation Fused pyrimidine derivatives as A2A/A2B inhibitors
WO2024015731A1 (en) 2022-07-11 2024-01-18 Incyte Corporation Fused tricyclic compounds as inhibitors of kras g12v mutants
US11884665B2 (en) 2019-01-29 2024-01-30 Incyte Corporation Pyrazolopyridines and triazolopyridines as A2A / A2B inhibitors
US11919904B2 (en) 2019-03-29 2024-03-05 Incyte Corporation Sulfonylamide compounds as CDK2 inhibitors
US11919908B2 (en) 2020-12-21 2024-03-05 Incyte Corporation Substituted pyrrolo[2,3-d]pyrimidine compounds as JAK2 V617F inhibitors
WO2024086273A1 (en) 2022-10-21 2024-04-25 Incyte Corporation Tricyclic urea compounds as jak2 v617f inhibitors
US11976073B2 (en) 2021-12-10 2024-05-07 Incyte Corporation Bicyclic amines as CDK2 inhibitors
US11981671B2 (en) 2021-06-21 2024-05-14 Incyte Corporation Bicyclic pyrazolyl amines as CDK2 inhibitors
WO2024108100A1 (en) 2022-11-18 2024-05-23 Incyte Corporation Heteroaryl fluoroalkenes as dgk inhibitors
US11999740B2 (en) 2018-07-05 2024-06-04 Incyte Corporation Fused pyrazine derivatives as A2A / A2B inhibitors
WO2024151346A1 (en) 2023-01-12 2024-07-18 Incyte Corporation Heteroaryl fluoroalkenes as dgk inhibitors
WO2024191996A1 (en) 2023-03-13 2024-09-19 Incyte Corporation Bicyclic ureas as kinase inhibitors
WO2024163382A3 (en) * 2023-01-30 2024-09-19 The Johns Hopkins University 18f-labeled pet radiotracers for imaging macrophage colony stimulating factor 1 receptor
WO2024220532A1 (en) 2023-04-18 2024-10-24 Incyte Corporation Pyrrolidine kras inhibitors
WO2025043151A2 (en) 2023-08-24 2025-02-27 Incyte Corporation Bicyclic dgk inhibitors
US12269812B2 (en) 2018-07-13 2025-04-08 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
WO2025096738A1 (en) 2023-11-01 2025-05-08 Incyte Corporation Kras inhibitors
WO2025122545A1 (en) 2023-12-05 2025-06-12 Incyte Corporation Tricyclic triazolo compounds as dgk inhibitors
US12331320B2 (en) 2018-10-10 2025-06-17 The Research Foundation For The State University Of New York Genome edited cancer cell vaccines
WO2025129002A1 (en) 2023-12-13 2025-06-19 Incyte Corporation Bicyclooctane kras inhibitors
US12338233B2 (en) 2018-02-13 2025-06-24 Gilead Sciences, Inc. PD-1/Pd-L1 inhibitors
RU2848051C1 (en) * 2019-10-16 2025-10-16 Кемосентрикс, Инк. Heteraryl biphenyl amides for the treatment of pd-l1 diseases
US12466822B2 (en) 2016-12-22 2025-11-11 Incyte Corporation Heterocyclic compounds as immunomodulators
US12516044B2 (en) 2015-12-17 2026-01-06 Incyte Corporation Heterocyclic compounds as immunomodulators
WO2026060143A1 (en) 2024-09-11 2026-03-19 Incyte Corporation Kras inhibitors
US12590062B2 (en) 2017-04-20 2026-03-31 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US12600722B2 (en) 2022-07-18 2026-04-14 Incyte Corporation Tetracyclic compounds as DGK inhibitors
US12600723B2 (en) 2022-07-18 2026-04-14 Incyte Corporation Tetracyclic compounds as DGK inhibitors

Families Citing this family (86)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR102401963B1 (en) 2016-06-27 2022-05-25 케모센트릭스, 인크. Immunomodulatory compounds
FI3526323T3 (en) 2016-10-14 2023-06-06 Prec Biosciences Inc Engineered meganucleases specific for recognition sequences in the hepatitis b virus genome
CN110121505B (en) 2016-12-28 2023-08-01 株式会社绿十字细胞治疗 Chimeric antigen receptors and natural killer cells expressing them
US11130740B2 (en) 2017-04-25 2021-09-28 Arbutus Biopharma Corporation Substituted 2,3-dihydro-1H-indene analogs and methods using same
WO2019008154A1 (en) * 2017-07-07 2019-01-10 Rijksuniversiteit Groningen 3-(azolylmethoxy)biphenyl derivatives as inhibitors of the pd-1/pd-l1 protein/protein interaction
MA49701A (en) 2017-07-28 2020-06-03 Chemocentryx Inc IMMUNOMODULATOR COMPOUNDS
CN111225665B (en) 2017-08-08 2023-12-08 凯莫森特里克斯股份有限公司 Macrocyclic immunomodulators
CN109400522B (en) * 2017-08-18 2023-04-28 上海轶诺药业有限公司 Compound with PD-L1 inhibition activity, preparation method and application thereof
SG11202002032SA (en) 2017-09-22 2020-04-29 Jubilant Epipad LLC Heterocyclic compounds as pad inhibitors
CA3076476A1 (en) 2017-10-18 2019-04-25 Jubilant Epipad LLC Imidazo-pyridine compounds as pad inhibitors
CN109678796B (en) * 2017-10-19 2023-01-10 上海长森药业有限公司 PD-1/PD-L1 small molecule inhibitor and its preparation method and use
BR112020008851A2 (en) * 2017-11-06 2020-10-20 Jubilant Prodel LLC compound of formula i, process for preparing compounds of formula i, pharmaceutical composition, method for treating and / or preventing various diseases, use, method for treating cancer, method of treating cancer and method for treating and / or prevention of cancer and infectious diseases
EP3712178A4 (en) 2017-11-14 2021-08-11 Green Cross Lab Cell Corporation ANTI-HER2 ANTIBODIES OR ANTIGEN BINDING FRAGMENT OF THE SAME, AND CHEMERICAL ANTIGENIC RECEPTOR INCLUDING IT
US11649294B2 (en) 2017-11-14 2023-05-16 GC Cell Corporation Anti-HER2 antibody or antigen-binding fragment thereof, and chimeric antigen receptor comprising same
PL3704120T3 (en) 2017-11-24 2024-09-16 Jubilant Episcribe Llc Heterocyclic compounds as prmt5 inhibitors
KR102492187B1 (en) 2017-12-20 2023-01-27 인스티튜트 오브 오가닉 케미스트리 앤드 바이오케미스트리 에이에스 씨알 브이.브이.아이. 3'3' cyclic dinucleotides with phosphonate linkages that activate STING adapter proteins
JP7098748B2 (en) 2017-12-20 2022-07-11 インスティチュート オブ オーガニック ケミストリー アンド バイオケミストリー エーエスシーアール，ヴイ．ヴイ．アイ． 2'3'cyclic dinucleotide with phosphonate binding that activates the STING adapter protein
ES3035608T3 (en) * 2018-02-05 2025-09-05 Abbisko Therapeutics Co Ltd Biaryl derivatives and their pharmaceutical application for the treatment of pd-1/pd-l1 signal pathway-mediated diseases
US10568874B2 (en) 2018-02-22 2020-02-25 Chemocentryx, Inc. Indane-amines as PD-L1 antagonists
KR102526964B1 (en) 2018-02-26 2023-04-28 길리애드 사이언시즈, 인코포레이티드 Substituted pyrrolizine compounds as HBV replication inhibitors
SG11202008950PA (en) * 2018-03-13 2020-10-29 Jubilant Prodel LLC Bicyclic compounds as inhibitors of pd1/pd-l1 interaction/activation
CA3093851A1 (en) 2018-03-29 2019-10-03 Arbutus Biopharma Corporation Substituted 1,1'-biphenyl compounds, analogues thereof, and methods using same
US10870691B2 (en) 2018-04-05 2020-12-22 Gilead Sciences, Inc. Antibodies and fragments thereof that bind hepatitis B virus protein X
TWI818007B (en) 2018-04-06 2023-10-11 捷克科學院有機化學與生物化學研究所 2'3'-cyclic dinucleotides
TW202005654A (en) 2018-04-06 2020-02-01 捷克科學院有機化學與生物化學研究所 2'2'-cyclic dinucleotides
TWI833744B (en) 2018-04-06 2024-03-01 捷克科學院有機化學與生物化學研究所 3'3'-cyclic dinucleotides
TW201945388A (en) 2018-04-12 2019-12-01 美商精密生物科學公司 Optimized engineered meganucleases having specificity for a recognition sequence in the hepatitis B virus genome
EP4600247A3 (en) 2018-04-19 2025-11-19 Gilead Sciences, Inc. Pd-1/pd-l1 inhibitors
US20190359645A1 (en) 2018-05-03 2019-11-28 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 2'3'-cyclic dinucleotides comprising carbocyclic nucleotide
WO2019232319A1 (en) 2018-05-31 2019-12-05 Peloton Therapeutics, Inc. Compositions and methods for inhibiting cd73
JP7388635B2 (en) 2018-05-31 2023-11-29 小野薬品工業株式会社 Biomarkers to determine the effectiveness of immune checkpoint inhibitors
WO2020011209A1 (en) * 2018-07-11 2020-01-16 上海和誉生物医药科技有限公司 Immunosuppressive agent, preparation method therefor and pharmaceutical use thereof
TWI826492B (en) 2018-07-27 2023-12-21 加拿大商愛彼特生物製藥公司 Substituted tetrahydrocyclopenta[c]pyrroles, substituted dihydropyrrolizines, analogues thereof, and methods using same
WO2020028097A1 (en) 2018-08-01 2020-02-06 Gilead Sciences, Inc. Solid forms of (r)-11-(methoxymethyl)-12-(3-methoxypropoxy)-3,3-dimethyl-8-0x0-2,3,8,13b-tetrahydro-1h-pyrido[2,1-a]pyrrolo[1,2-c] phthalazine-7-c arboxylic acid
TWI855000B (en) 2018-10-11 2024-09-11 日商小野藥品工業股份有限公司 Sting agonist compound
US11236085B2 (en) 2018-10-24 2022-02-01 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
PE20211655A1 (en) 2018-10-31 2021-08-24 Gilead Sciences Inc 6-AZABENZIMIDAZOLE COMPOUNDS SUBSTITUTED AS HPK1 INHIBITORS
WO2020092528A1 (en) 2018-10-31 2020-05-07 Gilead Sciences, Inc. Substituted 6-azabenzimidazole compounds having hpk1 inhibitory activity
WO2020088357A1 (en) 2018-11-02 2020-05-07 上海再极医药科技有限公司 Diphenyl-like compound, intermediate thereof, preparation method therefor, pharmaceutical composition thereof and uses thereof
TW202415643A (en) 2018-12-12 2024-04-16 加拿大商愛彼特生物製藥公司 Substituted arylmethylureas and heteroarylmethylureas, analogues thereof, and methods using same
WO2020178770A1 (en) 2019-03-07 2020-09-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 3'3'-cyclic dinucleotides and prodrugs thereof
WO2020178768A1 (en) 2019-03-07 2020-09-10 Institute Of Organic Chemistry And Biochemistry Ascr, V.V.I. 3'3'-cyclic dinucleotide analogue comprising a cyclopentanyl modified nucleotide as sting modulator
CN113543851B (en) 2019-03-07 2025-03-18 捷克共和国有机化学与生物化学研究所 2'3'-Cyclic dinucleotides and prodrugs thereof
AU2020246317A1 (en) 2019-03-22 2021-11-18 Guangzhou Maxinovel Pharmaceuticals Co., Ltd Small-molecule inhibitor of PD-1/PD-L1, pharmaceutical composition thereof with PD-L1 antibody, and application of same
TW202210480A (en) 2019-04-17 2022-03-16 美商基利科學股份有限公司 Solid forms of a toll-like receptor modulator
TW202212339A (en) 2019-04-17 2022-04-01 美商基利科學股份有限公司 Solid forms of a toll-like receptor modulator
US11266643B2 (en) 2019-05-15 2022-03-08 Chemocentryx, Inc. Triaryl compounds for treatment of PD-L1 diseases
TWI826690B (en) 2019-05-23 2023-12-21 美商基利科學股份有限公司 Substituted eneoxindoles and uses thereof
EP3986392A4 (en) 2019-06-20 2023-07-12 ChemoCentryx, Inc. Compounds for treatment of pd-l1 diseases
US11872217B2 (en) 2019-07-10 2024-01-16 Chemocentryx, Inc. Indanes as PD-L1 inhibitors
CN113825751A (en) * 2019-07-18 2021-12-21 上海和誉生物医药科技有限公司 A biphenyl derivative that blocks the interaction of PD-1/PD-L1 and its preparation method and application
WO2021011891A1 (en) 2019-07-18 2021-01-21 Gilead Sciences, Inc. Long-acting formulations of tenofovir alafenamide
CN114206386A (en) 2019-08-05 2022-03-18 小野药品工业株式会社 Determining biomarkers for effectiveness of immune checkpoint inhibitors
WO2021034804A1 (en) 2019-08-19 2021-02-25 Gilead Sciences, Inc. Pharmaceutical formulations of tenofovir alafenamide
EP4458975A3 (en) 2019-09-30 2025-02-12 Gilead Sciences, Inc. Hbv vaccines and methods treating hbv
ES3022990T3 (en) 2019-12-06 2025-05-29 Prec Biosciences Inc Optimized engineered meganucleases having specificity for a recognition sequence in the hepatitis b virus genome
KR20220150281A (en) 2020-01-03 2022-11-10 인사이트 코포레이션 Combination Therapy Comprising A2A/A2B and PD-1/PD-L1 Inhibitors
EP4086253A1 (en) 2020-01-03 2022-11-09 Shanghai Hansoh Biomedical Co., Ltd. Biphenyl derivative inhibitor, preparation method therefor and use thereof
CA3169348A1 (en) 2020-03-20 2021-09-23 Gilead Sciences, Inc. Prodrugs of 4'-c-substituted-2-halo-2'-deoxyadenosine nucleosides and methods of making and using the same
WO2021206158A1 (en) 2020-04-10 2021-10-14 小野薬品工業株式会社 Method of cancer therapy
WO2021205631A1 (en) 2020-04-10 2021-10-14 小野薬品工業株式会社 Sting agonistic compound
BR112022022335A2 (en) 2020-05-05 2023-01-10 Teon Therapeutics Inc TYPE 2 CANNABINOID RECEPTOR MODULATORS AND USES THEREOF
CN113801111B (en) * 2020-06-12 2025-10-17 上海翰森生物医药科技有限公司 Biphenyl derivative inhibitor and preparation method and application thereof
EP4212511A4 (en) 2020-09-09 2024-12-18 Guangzhou Maxinovel Pharmaceuticals Co., Ltd. AROMATIC ETHYLENE COMPOUND AND MANUFACTURING PROCESS THEREOF, AS WELL AS INTERMEDIATE PRODUCT, PHARMACEUTICAL COMPOSITION AND USE THEREOF
TW202241441A (en) 2020-12-29 2022-11-01 美商英塞特公司 Combination therapy comprising a2a/a2b inhibitors, pd-1/pd-l1 inhibitors, and anti-cd73 antibodies
AU2022274607A1 (en) 2021-05-13 2023-11-16 Gilead Sciences, Inc. COMBINATION OF A TLR8 MODULATING COMPOUND AND ANTI-HBV siRNA THERAPEUTICS
TWI910028B (en) 2021-06-11 2025-12-21 美商基利科學股份有限公司 Combination mcl-1 inhibitors with anti-cancer agents
JP7673255B2 (en) 2021-06-11 2025-05-08 ギリアード サイエンシーズ， インコーポレイテッド Combination of MCL-1 inhibitors with antibody drug conjugates
EP4337202A4 (en) 2021-06-18 2025-04-02 Aligos Therapeutics, Inc. Methods and compositions for targeting PD-L1
WO2022271659A1 (en) 2021-06-23 2022-12-29 Gilead Sciences, Inc. Diacylglyercol kinase modulating compounds
WO2022271650A1 (en) 2021-06-23 2022-12-29 Gilead Sciences, Inc. Diacylglyercol kinase modulating compounds
US11932634B2 (en) 2021-06-23 2024-03-19 Gilead Sciences, Inc. Diacylglycerol kinase modulating compounds
EP4359415A1 (en) 2021-06-23 2024-05-01 Gilead Sciences, Inc. Diacylglyercol kinase modulating compounds
TW202325306A (en) 2021-09-02 2023-07-01 美商天恩治療有限公司 Methods of improving growth and function of immune cells
WO2023081730A1 (en) 2021-11-03 2023-05-11 Teon Therapeutics, Inc. 4-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamide derivatives as cannabinoid cb2 receptor modulators for the treatment of cancer
WO2023097211A1 (en) 2021-11-24 2023-06-01 The University Of Southern California Methods for enhancing immune checkpoint inhibitor therapy
CA3240346A1 (en) 2021-12-16 2023-06-22 Aligos Therapeutics, Inc. Methods and compositions for targeting pd-l1
EP4554943A1 (en) 2022-07-14 2025-05-21 Teon Therapeutics, Inc. Adenosine receptor antagonists and uses thereof
EP4578876A1 (en) 2022-08-23 2025-07-02 ONO Pharmaceutical Co., Ltd. Bispecific antibody
WO2025080593A1 (en) 2023-10-09 2025-04-17 Incyte Corporation Combination therapy using a kras g12d inhibitor and pd-1 inhibitor or pd-l1 inhibitor
WO2025122695A1 (en) 2023-12-06 2025-06-12 Incyte Corporation Combination therapy comprising dgk inhibitors and pd-1/pd-l1 inhibitors
WO2025240246A1 (en) 2024-05-13 2025-11-20 Gilead Sciences, Inc. Combination therapies with ribavirin
WO2025240243A1 (en) 2024-05-13 2025-11-20 Gilead Sciences, Inc. Combination therapies with bulevirtide and an inhibitory nucleic acid targeting hepatitis b virus
WO2025240242A1 (en) 2024-05-13 2025-11-20 Gilead Sciences, Inc. Combination therapies with ribavirin
WO2025240244A1 (en) 2024-05-13 2025-11-20 Gilead Sciences, Inc. Combination therapies comprising bulevirtide and lonafarnib for use in the treatment of hepatitis d virus infection
WO2026035860A1 (en) 2024-08-07 2026-02-12 Teon Therapeutics, Inc. Formulations of adenosine receptor antagonist

Family Cites Families (372)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3272781A (en) 1963-08-07 1966-09-13 American Potash & Chem Corp Boroureas of phosphinoborine polymers
FR1425700A (en) 1965-02-22 1966-01-24 Basf Ag Compounds forming metal complexes and method of preparing and using them
US4208328A (en) 1978-04-27 1980-06-17 General Electric Company Alkyl 3,5-dihydroxy-4-(2-benzothiazolyl)benzoates
US4789711A (en) 1986-12-02 1988-12-06 Ciba-Geigy Corporation Multifunctional epoxide resins
DE3828535A1 (en) 1988-08-23 1990-03-08 Basf Ag BENZIMIDAZOLE-2-CARBON-ACIDANILIDE, THEIR USE AS ANTI-LIGHTING AGENT FOR ORGANIC MATERIAL AND ORGANIC MATERIAL STABILIZED THEREOF
US5077164A (en) 1989-06-21 1991-12-31 Minolta Camera Kabushiki Kaisha Photosensitive member containing an azo dye
DE69421982T2 (en) 1993-09-20 2000-03-30 Fuji Photo Film Co., Ltd. Positive working photoresist composition
JP3461397B2 (en) 1995-01-11 2003-10-27 富士写真フイルム株式会社 Positive photoresist composition
WO1998027108A2 (en) 1996-12-16 1998-06-25 Fujisawa Pharmaceutical Co., Ltd. New amide compounds and their use as nitric oxide synthase inhibitors
JPH10316853A (en) 1997-05-15 1998-12-02 Sumitomo Bakelite Co Ltd Resin composition for interlaminar insulating membrane for multilayer interconnection of semiconductor, and production of the insulating membrane
WO1999018096A1 (en) 1997-10-02 1999-04-15 Merck & Co., Inc. Inhibitors of prenyl-protein transferase
WO1999044992A1 (en) 1998-03-05 1999-09-10 Nissan Chemical Industries, Ltd. Anilide compounds and herbicide
JP2000128986A (en) 1998-10-28 2000-05-09 Sumitomo Bakelite Co Ltd Polybenzoxazole precursor and polybenzoxazole
JP2000128987A (en) 1998-10-28 2000-05-09 Sumitomo Bakelite Co Ltd Polybenzoxazole precursor and polybenzoxazole
JP2000128984A (en) 1998-10-28 2000-05-09 Sumitomo Bakelite Co Ltd Polybenzoxazole precursor and resin
US6297351B1 (en) 1998-12-17 2001-10-02 Sumitomo Bakelite Company Limited Polybenzoxazole resin and precursor thereof
EE200100323A (en) 1998-12-18 2002-08-15 Axys Pharmaceuticals, Inc. (Hetero) aryl-bicyclic heteroaryl derivatives, their preparation and their use as protease inhibitors
JP2000212281A (en) 1999-01-27 2000-08-02 Sumitomo Bakelite Co Ltd Polybenzoxazole precursor and polybenzoxazole resin
AU6000900A (en) 1999-07-23 2001-02-13 Astrazeneca Uk Limited Carbazole derivatives and their use as neuropeptide y5 receptor ligands
JP2001114893A (en) 1999-10-15 2001-04-24 Sumitomo Bakelite Co Ltd Polybenzoxazole resin and its precursor
US6372907B1 (en) 1999-11-03 2002-04-16 Apptera Corporation Water-soluble rhodamine dye peptide conjugates
JP2001163975A (en) 1999-12-03 2001-06-19 Sumitomo Bakelite Co Ltd Polybenzoxazole resin and its precursor
EP1162196A4 (en) 1999-12-27 2003-04-16 Japan Tobacco Inc Fused-ring compounds and use thereof as drugs
US7041675B2 (en) 2000-02-01 2006-05-09 Abbott Gmbh & Co. Kg Heterocyclic compounds and their use as PARP inhibitors
US6521618B2 (en) 2000-03-28 2003-02-18 Wyeth 3-cyanoquinolines, 3-cyano-1,6-naphthyridines, and 3-cyano-1,7-naphthyridines as protein kinase inhibitors
EP1268478B1 (en) 2000-03-31 2007-05-02 Ortho-McNeil Pharmaceutical, Inc. Phenyl-substituted imidazopyridines
CA2405170A1 (en) 2000-04-24 2001-11-01 Merck Frosst Canada & Co. Method of treatment using phenyl and biaryl derivatives as prostaglandin e inhibitors and compounds useful therefore
KR100786927B1 (en) 2000-06-28 2007-12-17 스미스클라인비이참피이엘시이 Wet Grinding Method
WO2002014321A1 (en) 2000-08-11 2002-02-21 The Regents Of The University Of California Use of stat-6 inhibitors as therapeutic agents
EP1343785A2 (en) 2000-12-13 2003-09-17 Basf Aktiengesellschaft Use of substituted imidazoazines, novel imidazoazines, methods for the production thereof, and agents containing these compounds
ATE301653T1 (en) 2000-12-15 2005-08-15 Glaxo Group Ltd PYRAZOLOPYRIDINES
SE0100567D0 (en) 2001-02-20 2001-02-20 Astrazeneca Ab Compounds
CA2438586A1 (en) 2001-03-14 2002-09-19 Eli Lilly And Company Retinoid x receptor modulators
EP1372643A1 (en) 2001-03-30 2004-01-02 Smithkline Beecham Corporation Pyrazolopyridines, process for their preparation and use as therapeutic compounds
US7141569B2 (en) 2001-04-10 2006-11-28 Smithkline Beecham Corporation Antiviral pyrazolopyridine compounds
JP2002316966A (en) 2001-04-19 2002-10-31 Ueno Seiyaku Oyo Kenkyusho:Kk Binaphthol derivatives and their preparation
ES2242028T3 (en) 2001-04-27 2005-11-01 Smithkline Beecham Corporation DERIVATIVES OF PIRAZOLO (1,5-A) PIRIDINA.
AR035543A1 (en) 2001-06-26 2004-06-16 Japan Tobacco Inc THERAPEUTIC AGENT FOR HEPATITIS C THAT INCLUDES A CONDENSED RING COMPOUND, CONDENSED RING COMPOUND, PHARMACEUTICAL COMPOSITION THAT UNDERSTANDS, BENZIMIDAZOL, THIAZOL AND BIFENYL COMPOUNDS USED AS INTERMEDIARY COMPARTMENTS OF COMPARTMENTS
ATE364043T1 (en) 2001-09-07 2007-06-15 Smithkline Beecham Corp PYRAZOLO-PYRIDINE FOR THE TREATMENT OF HERPES INFECTIONS
TWI331526B (en) 2001-09-21 2010-10-11 Bristol Myers Squibb Pharma Co Lactam-containing compounds and derivatives thereof as factor xa inhibitors
US20030143199A1 (en) 2001-10-09 2003-07-31 Carson Dennis A. Use of STAT-6 inhibitors as therapeutic agents
BR0213208A (en) 2001-10-09 2004-08-31 Upjohn Co Substituted arylsulfonyl tetrahydro- and hexahydro-carbazoles compounds, their compositions and uses
CA2466279A1 (en) 2001-11-13 2003-05-22 Dana-Farber Cancer Institute, Inc. Agents that modulate immune cell activation and methods of use thereof
JP4024579B2 (en) 2002-01-22 2007-12-19 住友ベークライト株式会社 Plastic optical waveguide material and optical waveguide
JP2005535574A (en) 2002-04-11 2005-11-24 バーテックス　ファーマシューティカルズ　インコーポレイテッド Inhibitors of serine proteases, particularly HCV NS3-NS4A protease
KR20040097375A (en) * 2002-04-23 2004-11-17 시오노기 앤드 컴파니, 리미티드 Pyrazolo[1, 5-a]pyrimidine derivative and NAD(P)H oxidase inhibitor containing the same
AU2003252478A1 (en) 2002-07-10 2004-02-02 Ono Pharmaceutical Co., Ltd. Ccr4 antagonist and medicinal use thereof
AU2003249244A1 (en) 2002-07-15 2004-02-02 Combinatorx, Incorporated Methods for the treatment of neoplasms
JP2004059761A (en) 2002-07-30 2004-02-26 Sumitomo Bakelite Co Ltd Polybenzoxazole resin, its precursor, and optical waveguide material and optical waveguide using these
US20050260126A1 (en) 2002-08-30 2005-11-24 Yukitsuka Kudo Diagnostic probes and remedies for diseases with accumulation of prion protein, and stains for prion protein
JP2004091369A (en) 2002-08-30 2004-03-25 Sumitomo Pharmaceut Co Ltd New biphenyl compounds
JP2006504728A (en) 2002-10-03 2006-02-09 スミスクライン ビーチャム コーポレーション Pyrazolopyridine derivative therapeutic compounds
AU2003301302A1 (en) 2002-10-15 2004-05-04 Smithkline Beecham Corporation Pyradazine compounds as gsk-3 inhibitors
WO2004056875A1 (en) 2002-12-23 2004-07-08 Wyeth Antibodies against pd-1 and uses therefor
KR100624406B1 (en) 2002-12-30 2006-09-18 삼성에스디아이 주식회사 Biphenyl Derivatives and Organic Electroluminescent Devices Employing the Same
US7320989B2 (en) 2003-02-28 2008-01-22 Encysive Pharmaceuticals, Inc. Pyridine, pyrimidine, quinoline, quinazoline, and naphthalene urotensin-II receptor antagonists
US7078419B2 (en) 2003-03-10 2006-07-18 Boehringer Ingelheim Pharmaceuticals, Inc. Cytokine inhibitors
TW200505902A (en) 2003-03-20 2005-02-16 Schering Corp Cannabinoid receptor ligands
JP4595288B2 (en) 2003-03-25 2010-12-08 住友ベークライト株式会社 Polybenzoxazole resin, precursor thereof, optical waveguide material using the same, and optical waveguide
WO2004089940A1 (en) 2003-04-11 2004-10-21 Glenmark Pharmaceuticals S.A. Novel heterocyclic compounds useful for the treatment of inflammatory and allergic disorders: process for their preparation and pharmaceutical compositions containing them
JP2005002330A (en) 2003-05-19 2005-01-06 Sumitomo Electric Ind Ltd Optical resin material, optical element, optical module, fluorinated polymer precursor and fluorinated polymer
AU2004251146A1 (en) 2003-05-19 2005-01-06 Irm, Llc Immunosuppressant compounds and compositions
US20060183746A1 (en) 2003-06-04 2006-08-17 Currie Kevin S Certain imidazo[1,2-a]pyrazin-8-ylamines and method of inhibition of Bruton's tyrosine kinase by such compounds
WO2005014599A1 (en) 2003-06-04 2005-02-17 Cellular Genomics, Inc. Imidazo[1,2-a]pyrazin-8-ylamines and method of inhibition of bruton’s tyrosine kinase by such compounds
US20070010573A1 (en) 2003-06-23 2007-01-11 Xianqi Kong Methods and compositions for treating amyloid-related diseases
WO2005005429A1 (en) 2003-06-30 2005-01-20 Cellular Genomics, Inc. Certain heterocyclic substituted imidazo[1,2-a]pyrazin-8-ylamines and methods of inhibition of bruton’s tyrosine kinase by such compounds
EP1643991B1 (en) 2003-07-11 2014-03-12 Merck Patent GmbH Benzimidazole carboxamides as raf kinase inhibitors
US7276608B2 (en) 2003-07-11 2007-10-02 Bristol-Myers Squibb Company Tetrahydroquinoline derivatives as cannabinoid receptor modulators
WO2005012221A1 (en) 2003-08-04 2005-02-10 Ono Pharmaceutical Co., Ltd. Diphenyl ether compound, process for producing the same, and use
WO2005014543A1 (en) 2003-08-06 2005-02-17 Japan Tobacco Inc. Condensed ring compound and use thereof as hcv polymerase inhibitor
US7504401B2 (en) 2003-08-29 2009-03-17 Locus Pharmaceuticals, Inc. Anti-cancer agents and uses thereof
MXPA06002853A (en) 2003-09-11 2006-06-14 Kemia Inc Cytokine inhibitors.
JP4758349B2 (en) 2003-10-08 2011-08-24 アイアールエム・リミテッド・ライアビリティ・カンパニー Compounds and compositions as protein kinase inhibitors
JPWO2005040135A1 (en) 2003-10-24 2007-03-08 小野薬品工業株式会社 Anti-stress drugs and their medicinal uses
WO2005047290A2 (en) 2003-11-11 2005-05-26 Cellular Genomics Inc. Imidazo[1,2-a] pyrazin-8-ylamines as kinase inhibitors
EP1699763A1 (en) 2003-12-23 2006-09-13 Basf Aktiengesellschaft 3-trifluoromethyl picolinic acid anilides, and use thereof as fungicides
JP2007524682A (en) 2004-02-12 2007-08-30 メルク　エンド　カムパニー　インコーポレーテッド Bipyridylamide as a regulator of metabotropic glutamate receptor-5
WO2005077948A1 (en) 2004-02-16 2005-08-25 Daiichi Pharmaceutical Co., Ltd. Fungicidal heterocyclic compounds
GB0403864D0 (en) 2004-02-20 2004-03-24 Ucl Ventures Modulator
JP2005248082A (en) 2004-03-05 2005-09-15 Sumitomo Electric Ind Ltd Method for producing polybenzoxazole resin precursor and method for producing polybenzoxazole resin
AU2005220882A1 (en) 2004-03-08 2005-09-22 Georgia State University Research Foundation, Inc Novel dicationic imidazo(1,2-a)pyridines and 5,6,7,8-tetrahydro-imidazo(1,2a)pyridines as antiprotozoal agents
US20050250820A1 (en) 2004-03-08 2005-11-10 Amgen Inc. Therapeutic modulation of PPARgamma activity
CN1972914A (en) 2004-03-31 2007-05-30 詹森药业有限公司 Non-imidazole heterocyclic compounds as histamine H3 receptor ligands
JP2005290301A (en) 2004-04-02 2005-10-20 Sumitomo Electric Ind Ltd Method for producing polybenzoxazole resin precursor and method for producing polybenzoxazole resin
US7331997B2 (en) 2004-04-06 2008-02-19 The Procter & Gamble Company Keratin dyeing compounds, keratin dyeing compositions containing them, and use thereof
MXPA06012130A (en) 2004-04-20 2007-01-31 Transtech Pharma Inc Substituted thiazole and pyrimidine derivatives as melanocortin receptor modulators.
DE102004021716A1 (en) 2004-04-30 2005-12-01 Grünenthal GmbH Substituted imidazo [1,2-a] pyridine compounds and drugs containing substituted imidazo [1,2-a] pyridine compounds
CA2560387C (en) 2004-05-03 2013-09-24 Boehringer Ingelheim Pharmaceuticals, Inc. Cytokine inhibitors
TW200626142A (en) 2004-09-21 2006-08-01 Glaxo Group Ltd Chemical compounds
US7250441B2 (en) 2004-09-23 2007-07-31 Wyeth Carbazole and cyclopentaindole derivatives to treat infection with Hepatitis C virus
DE602005023333D1 (en) 2004-10-15 2010-10-14 Takeda Pharmaceutical KINASE INHIBITORS
EP1812442A2 (en) 2004-11-10 2007-08-01 CGI Pharmaceuticals, Inc. Imidazo[1,2-a]pyrazin-8-ylamines useful as modulators of kinase activity
DE102004054665A1 (en) 2004-11-12 2006-05-18 Bayer Cropscience Gmbh Substituted bicyclic and tricyclic pyrazole derivatives Methods for the preparation and use as herbicides and plant growth regulators
US7998974B2 (en) 2005-03-03 2011-08-16 Sirtris Pharmaceuticals, Inc. Fused heterocyclic compounds and their use as sirtuin modulators
WO2006099075A2 (en) 2005-03-10 2006-09-21 Cgi Pharmaceuticals, Inc. Certain substituted amides, method of making, and method of use thereof
JP2006290883A (en) 2005-03-17 2006-10-26 Nippon Nohyaku Co Ltd Substituted heterocyclic carboxylic acid anilide derivatives, intermediates thereof, agricultural and horticultural agents, and methods of use thereof
NZ536009A (en) 2005-04-18 2007-01-26 Neurotrophincell Pty Ltd Choroid plexus preparation and uses thereof
EP1878727A4 (en) * 2005-04-28 2013-11-13 Kyowa Hakko Kirin Co Ltd 2-aminoquinazoline derivatives
PL2161336T5 (en) 2005-05-09 2017-10-31 Ono Pharmaceutical Co Human monoclonal antibodies to programmed death 1(PD-1) and methods for treating cancer using anti-PD-1 antibodies alone or in combination with other immunotherapeutics
RU2007147382A (en) 2005-05-20 2009-06-27 Эррэй Биофарма Инк. (Us) COMPOUNDS WHICH ARE RAF INHIBITORS AND WAYS OF THEIR APPLICATION
CA2612241C (en) 2005-07-01 2018-11-06 Medarex, Inc. Human monoclonal antibodies to programmed death ligand 1 (pd-l1)
US20080220968A1 (en) 2005-07-05 2008-09-11 Ge Healthcare Bio-Sciences Ab [1, 2, 4] Triazolo [1, 5-A] Pyrimidine Derivatives as Chromatographic Adsorbent for the Selective Adsorption of Igg
WO2007034282A2 (en) 2005-09-19 2007-03-29 Pfizer Products Inc. Diaryl-imidazole compounds condensed with a heterocycle as c3a receptor antagonists
US20070078136A1 (en) 2005-09-22 2007-04-05 Bristol-Myers Squibb Company Fused heterocyclic compounds useful as kinase modulators
US7723336B2 (en) 2005-09-22 2010-05-25 Bristol-Myers Squibb Company Fused heterocyclic compounds useful as kinase modulators
EP2612854B1 (en) * 2005-10-25 2015-04-29 Shionogi&Co., Ltd. Aminothiazolidine and aminotetrahydrothiazepine derivatives as BACE 1 inhibitors
ES2390135T3 (en) 2005-11-22 2012-11-06 Merck Sharp & Dohme Corp. Tricyclic compounds useful as kinase inhibitors
WO2007067711A2 (en) 2005-12-08 2007-06-14 Amphora Discovery Corporation Certain chemical entities, compositions, and methods for modulating trpv1
WO2007069565A1 (en) 2005-12-12 2007-06-21 Ono Pharmaceutical Co., Ltd. Bicyclic heterocyclic compound
US20090281075A1 (en) 2006-02-17 2009-11-12 Pharmacopeia, Inc. Isomeric purinones and 1h-imidazopyridinones as pkc-theta inhibitors
WO2007096764A2 (en) 2006-02-27 2007-08-30 Glenmark Pharmaceuticals S.A. Bicyclic heteroaryl derivatives as cannabinoid receptor modulators
US20090304821A1 (en) 2006-03-08 2009-12-10 Takeda Pharmaceutical Company Limited Pharmaceutical Combination
MX2008012617A (en) 2006-03-31 2008-10-10 Novartis Ag Organic compounds.
US7700616B2 (en) 2006-05-08 2010-04-20 Molecular Neuroimaging, Llc. Compounds and amyloid probes thereof for therapeutic and imaging uses
CA2691214A1 (en) 2006-06-09 2007-12-21 Kemia, Inc. Therapy using cytokine inhibitors
US20080280891A1 (en) 2006-06-27 2008-11-13 Locus Pharmaceuticals, Inc. Anti-cancer agents and uses thereof
CA2658764A1 (en) 2006-07-20 2008-01-24 Mehmet Kahraman Benzothiophene inhibitors of rho kinase
DE102006035018B4 (en) 2006-07-28 2009-07-23 Novaled Ag Oxazole triplet emitter for OLED applications
WO2008021745A2 (en) 2006-08-16 2008-02-21 Itherx Pharmaceuticals, Inc. Hepatitis c virus entry inhibitors
TWI389895B (en) 2006-08-21 2013-03-21 Infinity Discovery Inc Compounds and methods for inhibiting the interaction of bcl proteins with binding partners
US7563797B2 (en) 2006-08-28 2009-07-21 Forest Laboratories Holding Limited Substituted imidazo(1,2-A)pyrimidines and imidazo(1,2-A) pyridines as cannabinoid receptor ligands
RU2009113585A (en) 2006-09-11 2010-10-20 Матрикс Лэборетериз Лтд. (In) DIBENZOFURANAN DERIVATIVES AS PDE-4 AND PDE-10 INHIBITORS
JP2010502751A (en) * 2006-09-11 2010-01-28 シージーアイ ファーマシューティカルズ，インコーポレイティド Kinase inhibitors and methods of using and identifying kinase inhibitors
PE20080839A1 (en) 2006-09-11 2008-08-23 Cgi Pharmaceuticals Inc CERTAIN AMIDAS SUBSTITUTED, METHOD OF PREPARATION AND METHOD OF USE OF THE SAME
US7838523B2 (en) 2006-09-11 2010-11-23 Cgi Pharmaceuticals, Inc. Certain substituted amides, method of making, and method of use thereof
PE20081370A1 (en) * 2006-09-11 2008-11-28 Cgi Pharmaceuticals Inc CERTAIN AMIDAS SUBSTITUTED, METHOD OF PREPARATION AND METHOD OF USE OF THE SAME
FR2906250B1 (en) 2006-09-22 2008-10-31 Sanofi Aventis Sa DERIVATIVES OF 2-ARYL-6PHENYL-IMIDAZO (1,2-A) PYRIDINES, THEIR PREPARATION AND THEIR THERAPEUTIC USE
JP2010507674A (en) 2006-10-27 2010-03-11 ワイス エルエルシー Tricyclic compounds as matrix metalloprotease inhibitors
JP5276005B2 (en) 2006-11-08 2013-08-28 ブリストル−マイヤーズ スクイブ カンパニー Pyridinone compounds
GB0623209D0 (en) 2006-11-21 2007-01-03 F2G Ltd Antifungal agents
WO2008064317A1 (en) 2006-11-22 2008-05-29 University Of Medicine And Dentistry Of New Jersey Lipophilic opioid receptor active compounds
WO2008064318A2 (en) 2006-11-22 2008-05-29 University Of Medicine And Dentistry Of New Jersey Peripheral opioid receptor active compounds
JP2010513253A (en) 2006-12-14 2010-04-30 ベーリンガー インゲルハイム インテルナショナール ゲーエムベーハー Benzoxazoles useful for the treatment of inflammation
ES2415863T3 (en) 2006-12-22 2013-07-29 Incyte Corporation Substituted heterocycles as Janus Kinase inhibitors
US8338437B2 (en) 2007-02-28 2012-12-25 Methylgene Inc. Amines as small molecule inhibitors
EP1964840A1 (en) 2007-02-28 2008-09-03 sanofi-aventis Imidazo[1,2-a]pyridines and their use as pharmaceuticals
EP1964841A1 (en) 2007-02-28 2008-09-03 sanofi-aventis Imidazo[1,2-a]azine and their use as pharmaceuticals
JP2008218327A (en) 2007-03-07 2008-09-18 Hitachi Ltd Electrolyte, electrolyte membrane, membrane electrode assembly using the same, fuel cell power source and fuel cell power source system
JP2010120852A (en) 2007-03-09 2010-06-03 Daiichi Sankyo Co Ltd New diamide derivative
WO2008114002A1 (en) 2007-03-22 2008-09-25 Astrazeneca Ab Quinoline derivatives for the treatment of inflammatory diseases
WO2008133273A1 (en) 2007-04-24 2008-11-06 Shionogi & Co., Ltd. Pharmaceutical composition for treatment of alzheimer's disease
TW200902526A (en) 2007-04-24 2009-01-16 Shionogi & Amp Co Ltd Aminodihydrothiazin derivative substituted with a cyclic group
WO2008134553A1 (en) 2007-04-26 2008-11-06 Xenon Pharmaceuticals Inc. Methods of using bicyclic compounds in treating sodium channel-mediated diseases
PT2155747E (en) 2007-05-10 2012-12-19 Ge Healthcare Ltd Imidazol (1,2-a)pyridines and related compounds with activity at cannabinoid cb2 receptors
KR101586617B1 (en) 2007-06-18 2016-01-20 머크 샤프 앤 도메 비.브이. Antibodies to human programmed death receptor PD-1
WO2009027733A1 (en) 2007-08-24 2009-03-05 Astrazeneca Ab (2-pyridin-3-ylimidazo[1,2-b]pyridazin-6-yl) urea derivatives as antibacterial agents
ES2360929T3 (en) 2007-09-20 2011-06-10 Amgen Inc. ACID DERIVATIVES 1- (4- (4-BENCILBENZAMIDO) -BENCIL) AZETIDIN-3-CARBOXYL AND RELATED COMPOUNDS AS MODULATORS OF THE S1P RECEPTOR FOR THE TREATMENT OF IMMUNE DISORDERS.
CL2008002793A1 (en) 2007-09-20 2009-09-04 Cgi Pharmaceuticals Inc Compounds derived from substituted amides, inhibitors of btk activity; pharmaceutical composition comprising them; Useful in the treatment of cancer, bone disorders, autoimmune diseases, among others
DE102007048716A1 (en) 2007-10-11 2009-04-23 Merck Patent Gmbh Imidazo [1,2-a] pyrimidine derivatives
TW200932219A (en) 2007-10-24 2009-08-01 Astellas Pharma Inc Oxadiazolidinedione compound
JP2011500778A (en) 2007-10-25 2011-01-06 アストラゼネカ・アクチエボラーグ Pyridine and pyrazine derivatives-083
US7868001B2 (en) 2007-11-02 2011-01-11 Hutchison Medipharma Enterprises Limited Cytokine inhibitors
WO2009062059A2 (en) 2007-11-08 2009-05-14 Pharmacopeia, Inc. Isomeric purinones and 1h-imidazopyridinones as pkc-theta inhibitors
CA2707491A1 (en) 2007-12-13 2009-06-18 Merck Sharp & Dohme Corp. Inhibitors of janus kinases
RU2364597C1 (en) 2007-12-14 2009-08-20 Андрей Александрович Иващенко HETEROCYCLIC INHIBITORS OF Hh-SYGNAL CASCADE, BASED ON THEM MEDICINAL COMPOSITIONS AND METHOD OF TREATING DISEASES INDUCED BY ABBARANT ACTIVITY OF Hh-SIGNAL SYSTEM
EA201000949A1 (en) * 2007-12-19 2011-02-28 Зингента Партисипейшнс Аг INSECTICIDE CONNECTIONS
US8642660B2 (en) 2007-12-21 2014-02-04 The University Of Rochester Method for altering the lifespan of eukaryotic organisms
WO2009079683A1 (en) 2007-12-21 2009-07-02 The University Of Sydney Translocator protein ligands
ES2548774T3 (en) 2008-01-18 2015-10-20 Eisai R&D Management Co., Ltd. Condensed aminodihydrotiazine derivative
JP5381718B2 (en) 2008-01-31 2014-01-08 コニカミノルタ株式会社 Halopolycyclic aromatic compound and method for producing the same
BRPI0908529A2 (en) 2008-02-26 2015-09-29 Novartis Ag organic compost
EP2095818A1 (en) 2008-02-29 2009-09-02 AEterna Zentaris GmbH Use of LHRH antagonists at non-castrating doses
US8168757B2 (en) 2008-03-12 2012-05-01 Merck Sharp & Dohme Corp. PD-1 binding proteins
FR2928922B1 (en) 2008-03-21 2010-04-23 Sanofi Aventis DERIVATIVES OF POLYSUBSTITUTED 2-ARYL-6-PHENYL-IMIDAZO-1,2-A! PYRIDINES, THEIR PREPARATION AND THEIR THERAPEUTIC USE
FR2928921B1 (en) 2008-03-21 2010-04-23 Sanofi Aventis POLYSUBSTITUTED DERIVATIVES OF 2-ARYL-6-PHENYL-IMIDAZO-1,2-A! PYRIDINES, THEIR PREPARATION AND THEIR THERAPEUTIC USE
FR2928924B1 (en) 2008-03-21 2010-04-23 Sanofi Aventis POLYSUBSTITUTED DERIVATIVES OF 6-HETEROARYL-IMIDAZO-1,2-A! PYRIDINES, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION
EP2271646A1 (en) 2008-03-31 2011-01-12 Takeda Pharmaceutical Company Limited Apoptosis signal-regulating kinase 1 inhibitors
KR101034351B1 (en) 2008-05-14 2011-05-16 한국화학연구원 Pyridine derivatives or pharmaceutically acceptable salts thereof substituted with novel benzoxazoles, preparation methods thereof, and pharmaceutical compositions for the prevention and treatment of abnormal cell growth diseases containing the same as active ingredients
EP2300470A2 (en) 2008-05-19 2011-03-30 Sepracor Inc. Imidazo[1,2-a]pyridine compounds as gaba-a receptor modulators
AU2009251324A1 (en) 2008-05-29 2009-12-03 Sirtris Pharmaceuticals, Inc. Imidazopyridine and related analogs as sirtuin modulators
JP5502858B2 (en) 2008-06-05 2014-05-28 グラクソ グループ リミテッド 4-Carboxamide indazole derivatives useful as inhibitors of PI3 kinase
CN102164604A (en) * 2008-07-24 2011-08-24 百时美施贵宝公司 Fused heterocyclic compounds useful as kinase modulators
US9643922B2 (en) 2008-08-18 2017-05-09 Yale University MIF modulators
US9540322B2 (en) 2008-08-18 2017-01-10 Yale University MIF modulators
JP2011231017A (en) 2008-09-09 2011-11-17 Nissan Chem Ind Ltd Process for producing optically active epoxy compound and optically active sulfoxide compound, ligand and complex for use in the process, and process for producing the complex
PL2342226T3 (en) 2008-09-26 2017-01-31 Dana-Farber Cancer Institute, Inc. Human anti-pd-1, pd-l1, and pd-l2 antibodies and uses thereof
US8598174B2 (en) 2008-11-12 2013-12-03 Genetech, Inc. Pyridazinones, method of making, and method of use thereof
DK2376490T3 (en) 2008-12-04 2013-04-15 Proximagen Ltd imidazopyridine compounds
EP4209510B1 (en) 2008-12-09 2024-01-31 F. Hoffmann-La Roche AG Anti-pd-l1 antibodies and their use to enhance t-cell function
EP2376491B1 (en) 2008-12-19 2015-03-04 Cephalon, Inc. Pyrrolotriazines as alk and jak2 inhibitors
CN102325752B (en) 2008-12-19 2015-02-04 百时美施贵宝公司 Carbazole and carboline kinase inhibitors
ES2443948T3 (en) 2008-12-19 2014-02-21 Bristol-Myers Squibb Company Carbazole carboxamide compounds useful as kinase inhibitors
JP5624275B2 (en) 2008-12-22 2014-11-12 ユー・ディー・シー アイルランド リミテッド Organic electroluminescence device
WO2010075376A2 (en) 2008-12-23 2010-07-01 Abbott Laboratories Anti-viral compounds
WO2010074284A1 (en) 2008-12-26 2010-07-01 味の素株式会社 Pyrazolopyrimidine compound
EP3192811A1 (en) 2009-02-09 2017-07-19 Université d'Aix-Marseille Pd-1 antibodies and pd-l1 antibodies and uses thereof
JP2010202530A (en) 2009-02-27 2010-09-16 Tokyo Institute Of Technology Heterocycle-containing aromatic compound, and optical material
WO2010104306A2 (en) 2009-03-07 2010-09-16 주식회사 메디젠텍 Pharmaceutical compositions for treating or preventing diseases caused by the translocation of gsk3 from the cell nucleus to the cytoplasm, containing compounds for inhibiting the translocation of gsk3 from the cell nucleus to the cytoplasm
SG174125A1 (en) 2009-04-02 2011-10-28 Merck Serono Sa Dihydroorotate dehydrogenase inhibitors
NZ596185A (en) 2009-04-16 2013-01-25 Ct Nac Investigaciones Oncologicas Cnio Imidazopyrazines for use as kinase inhibitors
US8338441B2 (en) 2009-05-15 2012-12-25 Gilead Sciences, Inc. Inhibitors of human immunodeficiency virus replication
KR20120049852A (en) 2009-06-30 2012-05-17 시가 테크놀로지스, 인크. Treatment and prevention of dengue virus infections
US8993604B2 (en) 2009-06-30 2015-03-31 Siga Technologies, Inc. Treatment and prevention of dengue virus infections
TWI491606B (en) * 2009-07-13 2015-07-11 Gilead Sciences Inc Inhibitor of kinases that regulate apoptosis signaling
JP2011057661A (en) 2009-08-14 2011-03-24 Bayer Cropscience Ag Pesticidal carboxamides
UA108363C2 (en) * 2009-10-08 2015-04-27 IMINOTIADIASIADIOXIDE OXIDES AS BACE INHIBITORS, COMPOSITIONS THEREOF AND THEIR APPLICATIONS
US9095596B2 (en) 2009-10-15 2015-08-04 Southern Research Institute Treatment of neurodegenerative diseases, causation of memory enhancement, and assay for screening compounds for such
JP6267863B2 (en) 2009-10-16 2018-01-24 メリンタ セラピューティクス，インコーポレイテッド Antimicrobial compounds and methods of making and using antimicrobial compounds
WO2011050245A1 (en) 2009-10-23 2011-04-28 Yangbo Feng Bicyclic heteroaryls as kinase inhibitors
US20130017199A1 (en) 2009-11-24 2013-01-17 AMPLIMMUNE ,Inc. a corporation Simultaneous inhibition of pd-l1/pd-l2
JPWO2011078221A1 (en) 2009-12-24 2013-05-09 味の素株式会社 Imidazopyridazine compounds
WO2011082400A2 (en) * 2010-01-04 2011-07-07 President And Fellows Of Harvard College Modulators of immunoinhibitory receptor pd-1, and methods of use thereof
WO2011097607A1 (en) 2010-02-08 2011-08-11 Southern Research Institute Anti-viral treatment and assay to screen for anti-viral agent
AR080433A1 (en) 2010-03-02 2012-04-11 Merck Sharp & Dohme USEFUL BENZOFURANCARBOXAMIDS DERIVATIVES TO TREAT OR PREVENT HCV INFECTIONS AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM.
CA2789471C (en) 2010-03-04 2018-01-02 Merck Sharp & Dohme Corp. Inhibitors of catechol o-methyl transferase and their use in the treatment of psychotic disorders
ES2572387T3 (en) 2010-03-18 2016-05-31 Pasteur Institut Korea Anti-infectious compounds
US8410117B2 (en) 2010-03-26 2013-04-02 Hoffmann-La Roche Inc. Imidazopyrimidine derivatives
US8685969B2 (en) 2010-06-16 2014-04-01 Bristol-Myers Squibb Company Carboline carboxamide compounds useful as kinase inhibitors
CA2802344C (en) 2010-06-18 2023-06-13 The Brigham And Women's Hospital, Inc. Bi-specific antibodies against tim-3 and pd-1 for immunotherapy in chronic immune conditions
CN102295642B (en) 2010-06-25 2016-04-06 中国人民解放军军事医学科学院毒物药物研究所 2-Aryimidazole is [1,2-a] pyridine-3-acetamide, Preparation Method And The Use also
US8907053B2 (en) 2010-06-25 2014-12-09 Aurigene Discovery Technologies Limited Immunosuppression modulating compounds
EP2402345A1 (en) 2010-06-29 2012-01-04 Basf Se Pyrazole fused bicyclic compounds
CN101891895B (en) 2010-07-28 2011-11-30 南京航空航天大学 Benzothiazole derivatives metal coordination polymer based on bridged bis-salicylaldehyde structure as well as manufacture method and application thereof
WO2012016133A2 (en) 2010-07-29 2012-02-02 President And Fellows Of Harvard College Ros1 kinase inhibitors for the treatment of glioblastoma and other p53-deficient cancers
US8633200B2 (en) 2010-09-08 2014-01-21 Bristol-Myers Squibb Company Inhibitors of human immunodeficiency virus replication
CN101993415B (en) * 2010-09-15 2013-08-14 北京韩美药品有限公司 Compound as Hedgehog path inhibitor, medicine composition containing same and application thereof
CN103889428A (en) 2010-10-04 2014-06-25 肝炎与病毒研究所 Novel inhibitors of secretion of hepatitis b virus antigens
WO2012052745A1 (en) 2010-10-21 2012-04-26 Centro Nacional De Investigaciones Oncológicas (Cnio) Combinations of pi3k inhibitors with a second anti -tumor agent
EP2444084A1 (en) 2010-10-21 2012-04-25 Centro Nacional de Investigaciones Oncológicas (CNIO) Use of PI3K inibitors for the treatment of obesity
WO2012068406A2 (en) 2010-11-18 2012-05-24 Ligand Pharmaceuticals Incorporated Use of hematopoietic growth factor mimetics
DE102010053347A1 (en) 2010-12-03 2012-06-06 Merck Patent Gmbh 3-hetaryl-substituted pyrrolo [2,3-b] pyridine-derivative as PDK1 inhibitors
WO2012080376A1 (en) * 2010-12-17 2012-06-21 Syngenta Participations Ag Insecticidal compounds
TWI617559B (en) 2010-12-22 2018-03-11 江蘇恆瑞醫藥股份有限公司 2-arylimidazo[1,2-b]pyridazine, 2-phenylimidazo[1,2-a]pyridine, and 2-phenylimidazo[1,2-a]pyrazine derivatives
BR112013015891A2 (en) 2010-12-23 2016-10-04 Genentech Inc use of a combination, method of treatment of a plasma and use of a combination
KR20140027090A (en) 2011-01-04 2014-03-06 노파르티스 아게 Indole compounds or analogues thereof useful for the treatment of age-related macular degeneration (amd)
WO2012100342A1 (en) 2011-01-27 2012-08-02 Université de Montréal Pyrazolopyridine and pyrazolopyrimidine derivatives as melanocortin-4 receptor modulators
US8921368B2 (en) 2011-03-17 2014-12-30 Bristol-Myers Squibb Company Pyrrolopyridazine JAK3 inhibitors and their use for the treatment of inflammatory and autoimmune diseases
WO2012129562A2 (en) 2011-03-24 2012-09-27 The Scripps Research Institute Compounds and methods for inducing chondrogenesis
WO2012138938A1 (en) 2011-04-05 2012-10-11 Vertex Pharmaceuticals Incorporated Aminopyrazine compounds useful as inhibitors of tra kinase
MX2013011947A (en) 2011-04-13 2014-01-16 Merck Sharp & Dohme 5-substituted iminothiazines and their mono-and dioxides as bace inhibitors,compositions,and their use.
CN102796103A (en) 2011-05-23 2012-11-28 南京英派药业有限公司 6-(aryl formyl) imidazo [1,2-a] pyrimidine and 6-(aryl formyl) [1,2,4] triazol [4,3-a] pyrimidine serving as Hedgehog inhibitors and application thereof
EP2713722B1 (en) 2011-05-31 2017-03-15 Receptos, LLC Novel glp-1 receptor stabilizers and modulators
GB201109763D0 (en) 2011-06-10 2011-07-27 Ucl Business Plc Compounds
MY165963A (en) 2011-06-20 2018-05-18 Incyte Holdings Corp Azetidinyl phenyl, pyridyl or pyrazinyl carboxamide derivatives as jak inhibitors
WO2012175991A1 (en) 2011-06-24 2012-12-27 Pharminox Limited Fused pentacyclic anti - proliferative compounds
KR20140058543A (en) 2011-07-08 2014-05-14 노파르티스 아게 Novel pyrrolo pyrimidine derivatives
EP2548877A1 (en) 2011-07-19 2013-01-23 MSD Oss B.V. 4-(5-Membered fused pyridinyl)benzamides as BTK-inhibitors
WO2013033901A1 (en) 2011-09-08 2013-03-14 Merck Sharp & Dohme Corp. Heterocyclic-substituted benzofuran derivatives and methods of use thereof for the treatment of viral diseases
WO2013040528A1 (en) 2011-09-16 2013-03-21 Microbiotix, Inc. Antimicrobial compounds
WO2013043521A1 (en) 2011-09-22 2013-03-28 Merck Sharp & Dohme Corp. Pyrazolopyridyl compounds as aldosterone synthase inhibitors
JP6040677B2 (en) 2011-09-29 2016-12-07 東洋インキＳｃホールディングス株式会社 Resin composition for solar cell encapsulant
EA201490774A1 (en) 2011-10-13 2014-08-29 Новартис Аг NEW OXAZINE DERIVATIVES AND THEIR APPLICATION IN THE TREATMENT OF THE DISEASE
JP2014530872A (en) 2011-10-20 2014-11-20 グラクソスミスクライン・リミテッド・ライアビリティ・カンパニーＧｌａｘｏＳｍｉｔｈＫｌｉｎｅ ＬＬＣ Substituted bicyclic azaheterocycles and analogs as sirtuin regulators
EP2768832A1 (en) 2011-10-21 2014-08-27 Torrent Pharmaceuticals Limited Novel substituted imidazopyrimidines as gpbar1 receptor modulators
WO2013120040A1 (en) 2012-02-10 2013-08-15 Children's Medical Center Corporation Targeted pathway inhibition to improve muscle structure, function and activity in muscular dystrophy
US9034882B2 (en) 2012-03-05 2015-05-19 Bristol-Myers Squibb Company Inhibitors of human immunodeficiency virus replication
CN104169260A (en) 2012-03-09 2014-11-26 卡尔那生物科学株式会社 Novel triazone derivative
CA2866857C (en) 2012-03-15 2021-03-09 Celgene Avilomics Research, Inc. Salts of an epidermal growth factor receptor kinase inhibitor
US9096586B2 (en) 2012-04-20 2015-08-04 Gilead Sciences, Inc. Therapeutic compounds
WO2013157021A1 (en) * 2012-04-20 2013-10-24 Advinus Therapeutics Limited Bicyclic compounds, compositions and medicinal applications thereof
US20150105433A1 (en) 2012-04-27 2015-04-16 The Uab Research Foundation TREATING VIRAL INFECTIONS HAVING VIRAL RNAs TRANSLATED BY A NON-IRES MEDIATED MECHANISM
JP6168055B2 (en) 2012-06-18 2017-07-26 住友化学株式会社 Fused heterocyclic compounds
JP6299591B2 (en) * 2012-07-03 2018-03-28 小野薬品工業株式会社 Compound having somatostatin receptor agonist activity and pharmaceutical use thereof
US9309243B2 (en) 2012-07-13 2016-04-12 Ucb Biopharma Sprl Imidazopyridine derivatives as modulators of TNF activity
GB201212513D0 (en) 2012-07-13 2012-08-29 Ucb Pharma Sa Therapeutic agents
JP2015178457A (en) 2012-07-25 2015-10-08 杏林製薬株式会社 Pyrazolopyridine derivative or a pharmacologically acceptable salt thereof
ES2666353T3 (en) 2012-09-06 2018-05-04 Bristol-Myers Squibb Company JAK3 imidazopyridazine inhibitors and their use for the treatment of inflammatory and autoimmune diseases
WO2014048939A1 (en) 2012-09-26 2014-04-03 F. Hoffmann-La Roche Ag Cyclic ether pyrazol-4-yl-heterocyclyl-carboxamide compounds and methods of use
WO2014061693A1 (en) 2012-10-17 2014-04-24 塩野義製薬株式会社 Novel non-aromatic carbocyclic or non-aromatic heterocyclic derivative
EP2922548A4 (en) 2012-11-21 2016-06-01 Stategics Inc Substituted triazolo-pyrimidine compounds for modulating cell proliferation, differentiation and survival
JP6037804B2 (en) 2012-12-03 2016-12-07 富士フイルム株式会社 Gas separation membrane
ME03780B (en) 2013-01-15 2021-04-20 Incyte Holdings Corp THIAZOLE CARBOXAMIDE DERIVATIVES AND PYRIDINE CARBOXAMIDE DERIVATIVES USED AS PIM KINASE INHIBITORS
HK1210609A1 (en) 2013-01-22 2016-04-29 霍夫曼-拉罗奇有限公司 Fluoro-[1,3]oxazines as bace1 inhibitors
CN103933036B (en) 2013-01-23 2017-10-13 中国人民解放军军事医学科学院毒物药物研究所 2 Aryimidazoles simultaneously the acetamide derivative of [1,2 α] pyridine 3 prepare preventing and treating PTSD medicine in purposes
US9657082B2 (en) 2013-01-31 2017-05-23 Thomas Jefferson University PD-L1 and PD-L2-based fusion proteins and uses thereof
HUE043059T2 (en) 2013-02-27 2019-07-29 Mochida Pharm Co Ltd Novel pyrazole derivative
AU2014225604B2 (en) 2013-03-08 2018-05-17 Amgen Inc. Perfluorinated cyclopropyl fused 1,3-oxazin-2-amine compounds as beta-secretase inhibitors and methods of use
CN104045552B (en) 2013-03-13 2019-06-11 江苏先声药业有限公司 Medicinal compound as neuroprotective agent
EP2971007A4 (en) 2013-03-13 2017-03-22 Australian Nuclear Science And Technology Organisation Transgenic non-human organisms with non-functional tspo genes
EA201591610A1 (en) 2013-03-14 2015-12-30 Курадев Фарма Прайвит Лтд. KINURENIN PATH INHIBITORS
WO2014152013A1 (en) 2013-03-14 2014-09-25 The Trustees Of Columbia University In The City Of New York 4-phenylpiperidines, their preparation and use
EP2970274B1 (en) 2013-03-14 2017-03-01 VIIV Healthcare UK (No.5) Limited Inhibitors of human immunodeficiency virus replication
CA2906086A1 (en) 2013-03-14 2014-09-25 Celtaxsys, Inc. Inhibitors of leukotriene a4 hydrolase
US9308236B2 (en) 2013-03-15 2016-04-12 Bristol-Myers Squibb Company Macrocyclic inhibitors of the PD-1/PD-L1 and CD80(B7-1)/PD-L1 protein/protein interactions
HRP20181392T1 (en) 2013-03-15 2018-10-19 Plexxikon Inc. HETEROCYCLIC COMPOUNDS AND THEIR USE
WO2014181287A1 (en) 2013-05-09 2014-11-13 Piramal Enterprises Limited Heterocyclyl compounds and uses thereof
EP3483167A1 (en) 2013-06-26 2019-05-15 AbbVie Inc. Primary carboxamides as btk inhibitors
US10939682B2 (en) 2013-07-02 2021-03-09 Syngenta Participations Ag Pesticidally active bi- or tricyclic heterocycles with sulfur containing substituents
SG11201600108PA (en) 2013-07-17 2016-02-26 Otsuka Pharma Co Ltd Cyanotriazole compounds
WO2015013635A2 (en) 2013-07-25 2015-01-29 Dana-Farber Cancer Institute, Inc. Inhibitors of transcription factors and uses thereof
EP2835375A1 (en) 2013-08-09 2015-02-11 Fundació Institut Català d'Investigació Química Bis-salphen compounds and carbonaceous material composites comprising them
KR101715090B1 (en) 2013-08-28 2017-03-13 한국화학연구원 Novel compound or pharmaceutically acceptable salt thereof and pharmaceutical composition for prevention or treatment of disease caused by influenza virus infection containing the same as an active ingredient
ES2642074T3 (en) 2013-09-04 2017-11-15 Bristol-Myers Squibb Company Useful compounds as immunomodulators
CN105814028B (en) 2013-09-06 2018-02-16 奥瑞基尼探索技术有限公司 1,2,4‑*oxadiazole derivatives as immunomodulators
EP3385257A1 (en) 2013-09-06 2018-10-10 Aurigene Discovery Technologies Limited 1,3,4-oxadiazole and 1,3,4-thiadiazole derivatives as immunomodulators
WO2015036927A1 (en) 2013-09-10 2015-03-19 Aurigene Discovery Technologies Limited Immunomodulating peptidomimetic derivatives
JP6336870B2 (en) 2013-09-30 2018-06-06 日本ポリプロ株式会社 Biphenol compound, olefin polymerization catalyst using the same, and process for producing olefin polymer
FR3012140B1 (en) 2013-10-18 2016-08-26 Arkema France UNIT AND PROCESS FOR THE PURIFICATION OF RAW METHYL METHACRYLATE
GB201321746D0 (en) 2013-12-09 2014-01-22 Ucb Pharma Sa Therapeutic agents
GB201321733D0 (en) 2013-12-09 2014-01-22 Ucb Pharma Sa Therapeutic agents
GB201321736D0 (en) 2013-12-09 2014-01-22 Ucb Pharma Sa Therapeutic agents
GB201321743D0 (en) 2013-12-09 2014-01-22 Ucb Pharma Sa Therapeutic agents
WO2015095337A2 (en) 2013-12-18 2015-06-25 The Rockefeller University PYRAZOLO[1,5-a]PYRIMIDINECARBOXAMIDE DERIVATIVES FOR TREATING COGNITIVE IMPAIRMENT
KR20160104065A (en) * 2014-01-03 2016-09-02 바이엘 애니멀 헬스 게엠베하 Novel pyrazolyl-heteroarylamides as pesticides
US20160356794A1 (en) 2014-02-10 2016-12-08 Merck Sharp & Dohme Corp. Antibodies that bind to human tau and assay for quantifying human tau using the antibodies
KR20160118368A (en) 2014-02-25 2016-10-11 아칠리온 파르마세우티칼스 인코포레이티드 Ether compounds for treatment of complement mediated disorders
US9394365B1 (en) 2014-03-12 2016-07-19 Yeda Research And Development Co., Ltd Reducing systemic regulatory T cell levels or activity for treatment of alzheimer's disease
JP6490464B2 (en) 2014-03-26 2019-03-27 三井化学株式会社 Transition metal compound, catalyst for olefin polymerization, and process for producing olefin polymer
ES2823825T3 (en) 2014-04-04 2021-05-10 Iomet Pharma Ltd Indole derivatives for use in medicine
US9850225B2 (en) 2014-04-14 2017-12-26 Bristol-Myers Squibb Company Compounds useful as immunomodulators
CN106661001A (en) 2014-05-14 2017-05-10 哈佛学院院长等 Organic light-emitting diode materials
WO2015197028A1 (en) 2014-06-28 2015-12-30 Sunshine Lake Pharma Co., Ltd. Compounds as hepatitis c virus (hcv) inhibitors and uses thereof in medicine
CN104211726B (en) 2014-08-11 2017-06-16 中南民族大学 The tooth double-core titanium complex of non-luxuriant class three, Preparation method and use
US20170305922A1 (en) 2014-09-17 2017-10-26 Epizyme, Inc. Carm1 inhibitors and uses thereof
TW201625527A (en) 2014-09-19 2016-07-16 財團法人臺灣基督長老教會馬偕紀念社會事業基金會馬偕紀念醫院 Benzo-heterocyclic compounds and their applications
CN107001362A (en) 2014-10-06 2017-08-01 默克专利有限公司 Heteroaryl compound as BTK inhibitor and application thereof
CA2968884A1 (en) 2014-12-10 2016-06-16 Massachusetts Institute Of Technology Fused 1,3-azole derivatives useful for the treatment of proliferative diseases
JP6853619B2 (en) 2015-01-16 2021-03-31 大塚製薬株式会社 Pharmaceutical use of cyanotriazole compounds
DE112016000383B4 (en) 2015-01-20 2026-05-07 Samsung Display Co., Ltd. Organic molecules, their use in optoelectronic components, optoelectronic components and methods for their manufacture
WO2016118404A1 (en) 2015-01-20 2016-07-28 Merck Sharp & Dohme Corp. Iminothiadiazine dioxides bearing an amine-linked substituent as bace inhibitors, compositions, and their use
WO2016156282A1 (en) 2015-04-02 2016-10-06 Bayer Cropscience Aktiengesellschaft Novel triazole compounds for controlling phytopathogenic harmful fungi
WO2017035405A1 (en) * 2015-08-26 2017-03-02 Achillion Pharmaceuticals, Inc. Amino compounds for treatment of immune and inflammatory disorders
US10745382B2 (en) 2015-10-15 2020-08-18 Bristol-Myers Squibb Company Compounds useful as immunomodulators
ES2928164T3 (en) 2015-10-19 2022-11-15 Incyte Corp Heterocyclic compounds as immunomodulators
WO2017070320A1 (en) 2015-10-21 2017-04-27 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Phenyl indole allosteric inhibitors of p97 atpase
US9603950B1 (en) * 2015-10-25 2017-03-28 Institute Of Nuclear Energy Research Compounds of imaging agent with HDAC inhibitor for treatment of Alzheimer syndrome and method of synthesis thereof
KR101717601B1 (en) 2015-11-10 2017-03-20 한국화학연구원 Novel compound or pharmaceutically acceptable salt thereof and pharmaceutical composition for prevention or treatment of disease caused by influenza virus infection containing the same as an active ingredient
MD3377488T2 (en) 2015-11-19 2023-02-28 Incyte Corp Heterocyclic compounds as immunomodulators
MA44075A (en) 2015-12-17 2021-05-19 Incyte Corp N-PHENYL-PYRIDINE-2-CARBOXAMIDE DERIVATIVES AND THEIR USE AS MODULATORS OF PROTEIN / PROTEIN PD-1 / PD-L1 INTERACTIONS
US10750742B2 (en) 2015-12-22 2020-08-25 Syngenta Participations Ag Pesticidally active pyrazole derivatives
EP3393457A1 (en) 2015-12-22 2018-10-31 Synthon B.V. Pharmaceutical composition comprising amorphous lenalidomide and an antioxidant
MY199705A (en) 2015-12-22 2023-11-20 Incyte Corp Heterocyclic compounds as immunomodulators
WO2017107052A1 (en) 2015-12-22 2017-06-29 Merck Sharp & Dohme Corp. Soluble guanylate cyclase stimulators
HRP20210698T1 (en) 2015-12-22 2021-09-17 Immatics Biotechnologies Gmbh Peptides and combination of peptides for use in immunotherapy against breast cancer and other cancers
KR101653560B1 (en) 2016-02-02 2016-09-12 한국화학연구원 Novel compound or pharmaceutically acceptable salt thereof and pharmaceutical composition for prevention or treatment of disease caused by influenza virus infection containing the same as an active ingredient
US10166221B2 (en) 2016-04-22 2019-01-01 Incyte Corporation Formulations of an LSD1 inhibitor
WO2017192961A1 (en) 2016-05-06 2017-11-09 Incyte Corporation Heterocyclic compounds as immunomodulators
WO2017205464A1 (en) 2016-05-26 2017-11-30 Incyte Corporation Heterocyclic compounds as immunomodulators
IL263429B (en) 2016-06-20 2022-08-01 Novartis Ag Crystalline forms of a triazolopyrimidine compound
US10960080B2 (en) 2016-06-20 2021-03-30 Elanco Us Inc. Pegylated porcine interferon and methods of use thereof
KR102685249B1 (en) 2016-06-20 2024-07-17 인사이트 코포레이션 Heterocyclic Compounds as Immunomodulators
JP7054529B2 (en) 2016-06-21 2022-04-14 エックス４ ファーマシューティカルズ， インコーポレイテッド CXCR4 inhibitor and its use
MA45669A (en) 2016-07-14 2019-05-22 Incyte Corp HETEROCYCLIC COMPOUNDS USED AS IMMUNOMODULATORS
JP2019530732A (en) 2016-08-03 2019-10-24 アライジング・インターナショナル・インコーポレイテッドＡｒｉｓｉｎｇ Ｉｎｔｅｒｎａｔｉｏｎａｌ， Ｉｎｃ． Symmetric or semi-symmetrical compounds useful as immune modulators
WO2018044783A1 (en) 2016-08-29 2018-03-08 Incyte Corporation Heterocyclic compounds as immunomodulators
WO2018045084A1 (en) 2016-08-30 2018-03-08 Tetraphase Pharmaceuticals, Inc. Tetracycline compounds and methods of treatment
TWI795381B (en) 2016-12-21 2023-03-11 比利時商健生藥品公司 Pyrazole derivatives as malt1 inhibitors
MY203083A (en) 2016-12-21 2024-06-07 Acerta Pharma Bv Imidazopyrazine inhibitors of bruton's tyrosine kinase
WO2018119224A1 (en) 2016-12-22 2018-06-28 Incyte Corporation Tetrahydro imidazo[4,5-c]pyridine derivatives as pd-l1 internalization inducers
PE20191532A1 (en) 2016-12-22 2019-10-23 Incyte Corp HETEROCYCLIC COMPOUNDS AS IMMUNOMODULATORS
EP3558973B1 (en) 2016-12-22 2021-09-15 Incyte Corporation Pyridine derivatives as immunomodulators
EP3558989B1 (en) 2016-12-22 2021-04-14 Incyte Corporation Triazolo[1,5-a]pyridine derivatives as immunomodulators
EP3842442B1 (en) 2016-12-22 2023-11-01 Precision Pharmaceuticals, Inc. Compositions and methods for inhibiting arginase activity
US20180177784A1 (en) 2016-12-22 2018-06-28 Incyte Corporation Heterocyclic compounds as immunomodulators
CA3047991A1 (en) 2016-12-22 2018-06-28 Incyte Corporation Bicyclic heteroaromatic compounds as immunomodulators
BR102018007822A2 (en) 2017-04-20 2018-11-06 Gilead Sciences, Inc. compound, methods for inhibiting pd-1, pd-11 and / or interaction of pd-1 / pd-11 and for cancer treatment, pharmaceutical composition, and kit for treating or preventing cancer or a disease or condition
MA49701A (en) 2017-07-28 2020-06-03 Chemocentryx Inc IMMUNOMODULATOR COMPOUNDS
CN111225665B (en) 2017-08-08 2023-12-08 凯莫森特里克斯股份有限公司 Macrocyclic immunomodulators
CN109400522B (en) 2017-08-18 2023-04-28 上海轶诺药业有限公司 Compound with PD-L1 inhibition activity, preparation method and application thereof
CN111655288A (en) 2017-11-16 2020-09-11 诺华股份有限公司 combination therapy
KR102708681B1 (en) 2018-02-13 2024-09-26 길리애드 사이언시즈, 인코포레이티드 Pd-1/pd-l1 inhibitors
RS64055B1 (en) 2018-03-30 2023-04-28 Incyte Corp Heterocyclic compounds as immunomodulators
CN111936475B (en) 2018-04-03 2024-05-10 贝达药业股份有限公司 Immunomodulator, composition and preparation method thereof
EP4600247A3 (en) 2018-04-19 2025-11-19 Gilead Sciences, Inc. Pd-1/pd-l1 inhibitors
CA3098698A1 (en) 2018-05-01 2019-11-07 Revolution Medicines, Inc. C26-linked rapamycin analogs as mtor inhibitors
MD3790877T2 (en) 2018-05-11 2023-08-31 Incyte Corp Tetrahydro-imidazo[4,5-c]pyridine derivatives as pd-l1 immunomodulators
WO2020036491A1 (en) 2018-08-15 2020-02-20 Moonshine Solutions As Method and device for supplying liquid to a liner
US11236085B2 (en) 2018-10-24 2022-02-01 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
WO2020088357A1 (en) 2018-11-02 2020-05-07 上海再极医药科技有限公司 Diphenyl-like compound, intermediate thereof, preparation method therefor, pharmaceutical composition thereof and uses thereof
US11596692B1 (en) 2018-11-21 2023-03-07 Incyte Corporation PD-L1/STING conjugates and methods of use
BR112021015131A2 (en) 2019-01-31 2021-09-28 Betta Pharmaceuticals Co., Ltd IMMUNOMODULATORS, COMPOSITIONS AND METHODS THEREOF
GB201911210D0 (en) 2019-08-06 2019-09-18 Amlo Biosciences Ltd Clinical management of oropharyngeal squamous cell carcinoma
JP7665593B2 (en) 2019-08-09 2025-04-21 インサイト・コーポレイション Salts of PD-1/PD-L1 inhibitors
AU2020350137A1 (en) 2019-09-20 2022-04-28 Merck Patent Gmbh Combination of a poxvirus encoding HPV polypeptides and IL-2 with an anti-PD-L1 antibody
AR120109A1 (en) 2019-09-30 2022-02-02 Incyte Corp PYRIDO[3,2-D]PYRIMIDINE COMPOUNDS AS IMMUNOMODULATORS
PE20230407A1 (en) 2019-11-11 2023-03-07 Incyte Corp SALTS AND CRYSTALLINE FORMS OF A PD-1/PD-L1 INHIBITOR
MX2022013808A (en) 2020-05-04 2023-02-09 Beyondspring Pharmaceuticals Inc Triple combination therapy for enhancing cancer cell killing in cancers with low immunogenicity.
WO2022099018A1 (en) 2020-11-06 2022-05-12 Incyte Corporation Process of preparing a pd-1/pd-l1 inhibitor
WO2022099075A1 (en) 2020-11-06 2022-05-12 Incyte Corporation Crystalline form of a pd-1/pd-l1 inhibitor
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TW202241420A (en) 2020-12-18 2022-11-01 美商英塞特公司 Oral formulation for a pd-l1 inhibitor
WO2023049831A1 (en) 2021-09-24 2023-03-30 Incyte Corporation Treatment of human papillomavirus-associated cancers by pd-l1 inhibitors

Cited By (181)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10813930B2 (en) 2010-12-22 2020-10-27 Incyte Corporation Substituted imidazopyridazines and benzimidazoles as inhibitors of FGFR3
US11053246B2 (en) 2012-06-13 2021-07-06 Incyte Corporation Substituted tricyclic compounds as FGFR inhibitors
US12534463B2 (en) 2012-06-13 2026-01-27 Incyte Corporation Substituted tricyclic compounds as FGFR inhibitors
US11840534B2 (en) 2012-06-13 2023-12-12 Incyte Corporation Substituted tricyclic compounds as FGFR inhibitors
US11530214B2 (en) 2013-04-19 2022-12-20 Incyte Holdings Corporation Bicyclic heterocycles as FGFR inhibitors
US10947230B2 (en) 2013-04-19 2021-03-16 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US10851105B2 (en) 2014-10-22 2020-12-01 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US10632126B2 (en) 2015-02-20 2020-04-28 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US11667635B2 (en) 2015-02-20 2023-06-06 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US11014923B2 (en) 2015-02-20 2021-05-25 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US10738048B2 (en) 2015-02-20 2020-08-11 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US11173162B2 (en) 2015-02-20 2021-11-16 Incyte Corporation Bicyclic heterocycles as FGFR4 inhibitors
US11407749B2 (en) 2015-10-19 2022-08-09 Incyte Corporation Heterocyclic compounds as immunomodulators
US11572366B2 (en) 2015-11-19 2023-02-07 Incyte Corporation Heterocyclic compounds as immunomodulators
US12516044B2 (en) 2015-12-17 2026-01-06 Incyte Corporation Heterocyclic compounds as immunomodulators
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US11608337B2 (en) 2016-05-06 2023-03-21 Incyte Corporation Heterocyclic compounds as immunomodulators
US11673883B2 (en) 2016-05-26 2023-06-13 Incyte Corporation Heterocyclic compounds as immunomodulators
US11873309B2 (en) 2016-06-20 2024-01-16 Incyte Corporation Heterocyclic compounds as immunomodulators
US11718605B2 (en) 2016-07-14 2023-08-08 Incyte Corporation Heterocyclic compounds as immunomodulators
US11613536B2 (en) 2016-08-29 2023-03-28 Incyte Corporation Heterocyclic compounds as immunomodulators
US10793565B2 (en) 2016-12-22 2020-10-06 Incyte Corporation Heterocyclic compounds as immunomodulators
US10800768B2 (en) 2016-12-22 2020-10-13 Incyte Corporation Heterocyclic compounds as immunomodulators
US12466822B2 (en) 2016-12-22 2025-11-11 Incyte Corporation Heterocyclic compounds as immunomodulators
US11465981B2 (en) 2016-12-22 2022-10-11 Incyte Corporation Heterocyclic compounds as immunomodulators
US10308644B2 (en) 2016-12-22 2019-06-04 Incyte Corporation Heterocyclic compounds as immunomodulators
US11566026B2 (en) 2016-12-22 2023-01-31 Incyte Corporation Heterocyclic compounds as immunomodulators
US11339149B2 (en) 2016-12-22 2022-05-24 Incyte Corporation Heterocyclic compounds as immunomodulators
US11787793B2 (en) 2016-12-22 2023-10-17 Incyte Corporation Heterocyclic compounds as immunomodulators
US10806785B2 (en) 2016-12-22 2020-10-20 Incyte Corporation Immunomodulator compounds and methods of use
US12590062B2 (en) 2017-04-20 2026-03-31 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11472801B2 (en) 2017-05-26 2022-10-18 Incyte Corporation Crystalline forms of a FGFR inhibitor and processes for preparing the same
US10611762B2 (en) 2017-05-26 2020-04-07 Incyte Corporation Crystalline forms of a FGFR inhibitor and processes for preparing the same
WO2018218100A1 (en) 2017-05-26 2018-11-29 Incyte Corporation Crystalline forms of a fgfr inhibitor and processes for preparing the same
US11034671B2 (en) 2017-09-08 2021-06-15 Sichuan Haisco Pharmaceutical Co., Ltd. Apoptosis signal-regulating kinase inhibitors and uses thereof
WO2019051265A1 (en) * 2017-09-08 2019-03-14 Fronthera U.S. Pharmaceuticals Llc Apoptosis signal-regulating kinase inhibitors and uses thereof
US12338233B2 (en) 2018-02-13 2025-06-24 Gilead Sciences, Inc. PD-1/Pd-L1 inhibitors
US11673894B2 (en) 2018-02-27 2023-06-13 Incyte Corporation Imidazopyrimidines and triazolopyrimidines as A2A / A2B inhibitors
US11124511B2 (en) 2018-03-30 2021-09-21 Incyte Corporation Heterocyclic compounds as immunomodulators
US12247026B2 (en) 2018-03-30 2025-03-11 Incyte Corporation Heterocyclic compounds as immunomodulators
US10669271B2 (en) 2018-03-30 2020-06-02 Incyte Corporation Heterocyclic compounds as immunomodulators
US11466004B2 (en) 2018-05-04 2022-10-11 Incyte Corporation Solid forms of an FGFR inhibitor and processes for preparing the same
WO2019213506A1 (en) 2018-05-04 2019-11-07 Incyte Corporation Salts of an fgfr inhibitor
US12552792B2 (en) 2018-05-04 2026-02-17 Incyte Corporation Solid forms of an FGFR inhibitor and processes for preparing the same
US11174257B2 (en) 2018-05-04 2021-11-16 Incyte Corporation Salts of an FGFR inhibitor
EP4309737A2 (en) 2018-05-04 2024-01-24 Incyte Corporation Solid forms of an fgfr inhibitor and processes for preparing the same
EP4710924A2 (en) 2018-05-04 2026-03-18 Incyte Corporation Salts of an fgfr inhibitor
WO2019213544A2 (en) 2018-05-04 2019-11-07 Incyte Corporation Solid forms of an fgfr inhibitor and processes for preparing the same
US12473286B2 (en) 2018-05-04 2025-11-18 Incyte Corporation Salts of an FGFR inhibitor
US12024517B2 (en) 2018-05-04 2024-07-02 Incyte Corporation Salts of an FGFR inhibitor
US11414433B2 (en) 2018-05-11 2022-08-16 Incyte Corporation Heterocyclic compounds as immunomodulators
US10618916B2 (en) 2018-05-11 2020-04-14 Incyte Corporation Heterocyclic compounds as immunomodulators
US12187743B2 (en) 2018-05-11 2025-01-07 Incyte Corporation Heterocyclic compounds as immunomodulators
US10906920B2 (en) 2018-05-11 2021-02-02 Incyte Corporation Heterocyclic compounds as immunomodulators
US11873304B2 (en) 2018-05-18 2024-01-16 Incyte Corporation Fused pyrimidine derivatives as A2A/A2B inhibitors
US11999740B2 (en) 2018-07-05 2024-06-04 Incyte Corporation Fused pyrazine derivatives as A2A / A2B inhibitors
US12269812B2 (en) 2018-07-13 2025-04-08 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
WO2020068729A1 (en) 2018-09-25 2020-04-02 Incyte Corporation Pyrazolo[4,3-d]pyrimidine compounds as alk2 abd/or fgfr modulators
US11111247B2 (en) 2018-09-25 2021-09-07 Incyte Corporation Pyrazolopyrimidine compounds and uses thereof
US12441731B2 (en) 2018-09-25 2025-10-14 Incyte Corporation Pyrazolopyrimidine compounds and uses thereof
US12331320B2 (en) 2018-10-10 2025-06-17 The Research Foundation For The State University Of New York Genome edited cancer cell vaccines
US11866432B2 (en) 2018-10-11 2024-01-09 Incyte Corporation Dihydropyrido[2,3-d]pyrimidinone compounds as CDK2 inhibitors
US11066404B2 (en) 2018-10-11 2021-07-20 Incyte Corporation Dihydropyrido[2,3-d]pyrimidinone compounds as CDK2 inhibitors
US12030889B2 (en) 2018-12-20 2024-07-09 Incyte Corporation Imidazopyridazine and imidazopyridine compounds and uses thereof
WO2020132197A1 (en) 2018-12-20 2020-06-25 Incyte Corporation Imidazopyridazine and imidazopyridine compounds as inhibitors of activin receptor-like kinase-2
US11459329B2 (en) 2018-12-20 2022-10-04 Incyte Corporation Imidazopyridazine and imidazopyridine compounds and uses thereof
US11884665B2 (en) 2019-01-29 2024-01-30 Incyte Corporation Pyrazolopyridines and triazolopyridines as A2A / A2B inhibitors
WO2020168197A1 (en) 2019-02-15 2020-08-20 Incyte Corporation Pyrrolo[2,3-d]pyrimidinone compounds as cdk2 inhibitors
WO2020168178A1 (en) 2019-02-15 2020-08-20 Incyte Corporation Cyclin-dependent kinase 2 biomarkers and uses thereof
US11384083B2 (en) 2019-02-15 2022-07-12 Incyte Corporation Substituted spiro[cyclopropane-1,5′-pyrrolo[2,3-d]pyrimidin]-6′(7′h)-ones as CDK2 inhibitors
US11472791B2 (en) 2019-03-05 2022-10-18 Incyte Corporation Pyrazolyl pyrimidinylamine compounds as CDK2 inhibitors
WO2020180959A1 (en) 2019-03-05 2020-09-10 Incyte Corporation Pyrazolyl pyrimidinylamine compounds as cdk2 inhibitors
WO2020185532A1 (en) 2019-03-08 2020-09-17 Incyte Corporation Methods of treating cancer with an fgfr inhibitor
US11628162B2 (en) 2019-03-08 2023-04-18 Incyte Corporation Methods of treating cancer with an FGFR inhibitor
US11919904B2 (en) 2019-03-29 2024-03-05 Incyte Corporation Sulfonylamide compounds as CDK2 inhibitors
US11447494B2 (en) 2019-05-01 2022-09-20 Incyte Corporation Tricyclic amine compounds as CDK2 inhibitors
US11440914B2 (en) 2019-05-01 2022-09-13 Incyte Corporation Tricyclic amine compounds as CDK2 inhibitors
US11591329B2 (en) 2019-07-09 2023-02-28 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
WO2021007269A1 (en) 2019-07-09 2021-01-14 Incyte Corporation Bicyclic heterocycles as fgfr inhibitors
US11753406B2 (en) 2019-08-09 2023-09-12 Incyte Corporation Salts of a PD-1/PD-L1 inhibitor
US11427567B2 (en) 2019-08-14 2022-08-30 Incyte Corporation Imidazolyl pyrimidinylamine compounds as CDK2 inhibitors
US12312331B2 (en) 2019-08-14 2025-05-27 Incyte Corporation Imidazolyl pyrimidinylamine compounds as CDK2 inhibitors
US12247038B2 (en) 2019-09-30 2025-03-11 Incyte Corporation Pyrido[3,2-d]pyrimidine compounds as immunomodulators
US11401279B2 (en) 2019-09-30 2022-08-02 Incyte Corporation Pyrido[3,2-d]pyrimidine compounds as immunomodulators
WO2021063404A1 (en) * 2019-09-30 2021-04-08 南京明德新药研发有限公司 Compound as small molecule inhibitor pd-1/pd-l1 and application thereof
WO2021067374A1 (en) 2019-10-01 2021-04-08 Incyte Corporation Bicyclic heterocycles as fgfr inhibitors
US12122767B2 (en) 2019-10-01 2024-10-22 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
US11851426B2 (en) 2019-10-11 2023-12-26 Incyte Corporation Bicyclic amines as CDK2 inhibitors
US12466828B2 (en) 2019-10-11 2025-11-11 Incyte Corporation Bicyclic amines as CDK2 inhibitors
US12083124B2 (en) 2019-10-14 2024-09-10 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
WO2021076602A1 (en) 2019-10-14 2021-04-22 Incyte Corporation Bicyclic heterocycles as fgfr inhibitors
US11607416B2 (en) 2019-10-14 2023-03-21 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
RU2848051C1 (en) * 2019-10-16 2025-10-16 Кемосентрикс, Инк. Heteraryl biphenyl amides for the treatment of pd-l1 diseases
WO2021076728A1 (en) 2019-10-16 2021-04-22 Incyte Corporation Bicyclic heterocycles as fgfr inhibitors
US11566028B2 (en) 2019-10-16 2023-01-31 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
WO2021076691A1 (en) * 2019-10-16 2021-04-22 Chemocentryx, Inc. Heteroaryl-biphenyl amides for the treatment of pd-l1 diseases
US12371433B2 (en) 2019-10-16 2025-07-29 Amgen Inc. Heteroaryl-biphenyl amines for the treatment of PD-L1 diseases
WO2021076688A1 (en) * 2019-10-16 2021-04-22 Chemocentryx, Inc. Heteroaryl-biphenyl amines for the treatment of pd-l1 diseases
US11866429B2 (en) 2019-10-16 2024-01-09 Chemocentryx, Inc. Heteroaryl-biphenyl amines for the treatment of PD-L1 diseases
US11713307B2 (en) 2019-10-16 2023-08-01 Chemocentryx, Inc. Heteroaryl-biphenyl amides for the treatment of PD-L1 diseases
US12497383B2 (en) 2019-10-16 2025-12-16 Chemocentryx, Inc. Heteroaryl-biphenyl amides for the treatment of PD-L1 diseases
US11866451B2 (en) 2019-11-11 2024-01-09 Incyte Corporation Salts and crystalline forms of a PD-1/PD-L1 inhibitor
US11897891B2 (en) 2019-12-04 2024-02-13 Incyte Corporation Tricyclic heterocycles as FGFR inhibitors
WO2021113462A1 (en) 2019-12-04 2021-06-10 Incyte Corporation Derivatives of an fgfr inhibitor
US12168660B2 (en) 2019-12-04 2024-12-17 Incyte Corporation Derivatives of an FGFR inhibitor
WO2021113479A1 (en) 2019-12-04 2021-06-10 Incyte Corporation Tricyclic heterocycles as fgfr inhibitors
US11407750B2 (en) 2019-12-04 2022-08-09 Incyte Corporation Derivatives of an FGFR inhibitor
US12552804B2 (en) 2019-12-04 2026-02-17 Incyte Corporation Tricyclic heterocycles as FGFR inhibitors
WO2021142252A1 (en) 2020-01-10 2021-07-15 Incyte Corporation Tricyclic compounds as inhibitors of kras
EP4548918A2 (en) 2020-01-10 2025-05-07 Incyte Corporation Tricyclic compounds as inhibitors of kras
US12012409B2 (en) 2020-01-15 2024-06-18 Incyte Corporation Bicyclic heterocycles as FGFR inhibitors
WO2021146424A1 (en) 2020-01-15 2021-07-22 Incyte Corporation Bicyclic heterocycles as fgfr inhibitors
WO2021150613A1 (en) 2020-01-20 2021-07-29 Incyte Corporation Spiro compounds as inhibitors of kras
WO2021158891A1 (en) 2020-02-06 2021-08-12 Incyte Corporation Salts and solid forms and processes of preparing a pi3k inhibitor
WO2021178779A1 (en) 2020-03-06 2021-09-10 Incyte Corporation Combination therapy comprising axl/mer and pd-1/pd-l1 inhibitors
WO2021211864A1 (en) 2020-04-16 2021-10-21 Incyte Corporation Fused tricyclic kras inhibitors
WO2021231526A1 (en) 2020-05-13 2021-11-18 Incyte Corporation Fused pyrimidine compounds as kras inhibitors
WO2021252781A1 (en) 2020-06-12 2021-12-16 Incyte Corporation Imidazopyridazine compounds with activity as alk2 inhibitors
US11840546B2 (en) 2020-06-12 2023-12-12 Incyte Corporation Imidazopyridazine compounds and uses thereof
WO2021257863A1 (en) 2020-06-19 2021-12-23 Incyte Corporation Pyrrolotriazine compounds as jak2 v617f inhibitors
US11691971B2 (en) 2020-06-19 2023-07-04 Incyte Corporation Naphthyridinone compounds as JAK2 V617F inhibitors
US11753413B2 (en) 2020-06-19 2023-09-12 Incyte Corporation Substituted pyrrolo[2,1-f][1,2,4]triazine compounds as JAK2 V617F inhibitors
WO2021257857A1 (en) 2020-06-19 2021-12-23 Incyte Corporation Naphthyridinone compounds as jak2 v617f inhibitors
WO2022006457A1 (en) 2020-07-02 2022-01-06 Incyte Corporation Tricyclic urea compounds as jak2 v617f inhibitors
WO2022006456A1 (en) 2020-07-02 2022-01-06 Incyte Corporation Tricyclic pyridone compounds as jak2 v617f inhibitors
EP4620469A2 (en) 2020-07-02 2025-09-24 Incyte Corporation Tricyclic urea compounds as jak2 v617f inhibitors
US11767323B2 (en) 2020-07-02 2023-09-26 Incyte Corporation Tricyclic pyridone compounds as JAK2 V617F inhibitors
US12187725B2 (en) 2020-07-02 2025-01-07 Incyte Corporation Tricyclic urea compounds as JAK2 V617F inhibitors
US11780840B2 (en) 2020-07-02 2023-10-10 Incyte Corporation Tricyclic urea compounds as JAK2 V617F inhibitors
US12583822B2 (en) 2020-08-11 2026-03-24 Academy Of Military Medical Sciences Benzylamine derivative, preparation method therefor and use thereof
WO2022033303A1 (en) * 2020-08-11 2022-02-17 中国人民解放军军事科学院军事医学研究院 Benzylamine derivative, preparation method therefor and use thereof
WO2022046989A1 (en) 2020-08-27 2022-03-03 Incyte Corporation Tricyclic urea compounds as jak2 v617f inhibitors
US11661422B2 (en) 2020-08-27 2023-05-30 Incyte Corporation Tricyclic urea compounds as JAK2 V617F inhibitors
WO2022047093A1 (en) 2020-08-28 2022-03-03 Incyte Corporation Vinyl imidazole compounds as inhibitors of kras
WO2022072783A1 (en) 2020-10-02 2022-04-07 Incyte Corporation Bicyclic dione compounds as inhibitors of kras
US12404272B2 (en) 2020-11-06 2025-09-02 Incyte Corporation Process for making a PD-1/PD-L1 inhibitor and salts and crystalline forms thereof
US12084443B2 (en) 2020-11-06 2024-09-10 Incyte Corporation Process of preparing a PD-1/PD-L1 inhibitor
US11780836B2 (en) 2020-11-06 2023-10-10 Incyte Corporation Process of preparing a PD-1/PD-L1 inhibitor
US11866434B2 (en) 2020-11-06 2024-01-09 Incyte Corporation Process for making a PD-1/PD-L1 inhibitor and salts and crystalline forms thereof
US11760756B2 (en) 2020-11-06 2023-09-19 Incyte Corporation Crystalline form of a PD-1/PD-L1 inhibitor
US11919908B2 (en) 2020-12-21 2024-03-05 Incyte Corporation Substituted pyrrolo[2,3-d]pyrimidine compounds as JAK2 V617F inhibitors
WO2022182839A1 (en) 2021-02-25 2022-09-01 Incyte Corporation Spirocyclic lactams as jak2 v617f inhibitors
US11958861B2 (en) 2021-02-25 2024-04-16 Incyte Corporation Spirocyclic lactams as JAK2 V617F inhibitors
WO2022204112A1 (en) 2021-03-22 2022-09-29 Incyte Corporation Imidazole and triazole kras inhibitors
US12325697B2 (en) 2021-04-09 2025-06-10 Nimbus Clio, Inc. CBL-B modulators and uses thereof
WO2022217276A1 (en) * 2021-04-09 2022-10-13 Nimbus Clio, Inc. Cbl-b modulators and uses thereof
US12065494B2 (en) 2021-04-12 2024-08-20 Incyte Corporation Combination therapy comprising an FGFR inhibitor and a Nectin-4 targeting agent
WO2022221170A1 (en) 2021-04-12 2022-10-20 Incyte Corporation Combination therapy comprising an fgfr inhibitor and a nectin-4 targeting agent
WO2022261159A1 (en) 2021-06-09 2022-12-15 Incyte Corporation Tricyclic heterocycles as fgfr inhibitors
US11939331B2 (en) 2021-06-09 2024-03-26 Incyte Corporation Tricyclic heterocycles as FGFR inhibitors
US12428420B2 (en) 2021-06-09 2025-09-30 Incyte Corporation Tricyclic heterocycles as FGFR inhibitors
WO2022261160A1 (en) 2021-06-09 2022-12-15 Incyte Corporation Tricyclic heterocycles as fgfr inhibitors
US11981671B2 (en) 2021-06-21 2024-05-14 Incyte Corporation Bicyclic pyrazolyl amines as CDK2 inhibitors
WO2023283213A1 (en) 2021-07-07 2023-01-12 Incyte Corporation Tricyclic compounds as inhibitors of kras
WO2023287896A1 (en) 2021-07-14 2023-01-19 Incyte Corporation Tricyclic compounds as inhibitors of kras
WO2023034290A1 (en) 2021-08-31 2023-03-09 Incyte Corporation Naphthyridine compounds as inhibitors of kras
WO2023049697A1 (en) 2021-09-21 2023-03-30 Incyte Corporation Hetero-tricyclic compounds as inhibitors of kras
WO2023056421A1 (en) 2021-10-01 2023-04-06 Incyte Corporation Pyrazoloquinoline kras inhibitors
WO2023064857A1 (en) 2021-10-14 2023-04-20 Incyte Corporation Quinoline compounds as inhibitors of kras
WO2023091746A1 (en) 2021-11-22 2023-05-25 Incyte Corporation Combination therapy comprising an fgfr inhibitor and a kras inhibitor
US11976073B2 (en) 2021-12-10 2024-05-07 Incyte Corporation Bicyclic amines as CDK2 inhibitors
WO2023122134A1 (en) 2021-12-22 2023-06-29 Incyte Corporation Salts and solid forms of an fgfr inhibitor and processes of preparing thereof
WO2023178285A1 (en) 2022-03-17 2023-09-21 Incyte Corporation Tricyclic urea compounds as jak2 v617f inhibitors
US12084430B2 (en) 2022-03-17 2024-09-10 Incyte Corporation Tricyclic urea compounds as JAK2 V617F inhibitors
WO2023239768A1 (en) 2022-06-08 2023-12-14 Incyte Corporation Tricyclic triazolo compounds as dgk inhibitors
WO2024015731A1 (en) 2022-07-11 2024-01-18 Incyte Corporation Fused tricyclic compounds as inhibitors of kras g12v mutants
US12600722B2 (en) 2022-07-18 2026-04-14 Incyte Corporation Tetracyclic compounds as DGK inhibitors
US12600723B2 (en) 2022-07-18 2026-04-14 Incyte Corporation Tetracyclic compounds as DGK inhibitors
CN115417870A (en) * 2022-09-20 2022-12-02 中国药科大学 PD-L1 & NAMPT dual-target inhibitor and application
WO2024086273A1 (en) 2022-10-21 2024-04-25 Incyte Corporation Tricyclic urea compounds as jak2 v617f inhibitors
WO2024108100A1 (en) 2022-11-18 2024-05-23 Incyte Corporation Heteroaryl fluoroalkenes as dgk inhibitors
WO2024151346A1 (en) 2023-01-12 2024-07-18 Incyte Corporation Heteroaryl fluoroalkenes as dgk inhibitors
WO2024163382A3 (en) * 2023-01-30 2024-09-19 The Johns Hopkins University 18f-labeled pet radiotracers for imaging macrophage colony stimulating factor 1 receptor
WO2024191996A1 (en) 2023-03-13 2024-09-19 Incyte Corporation Bicyclic ureas as kinase inhibitors
WO2024220532A1 (en) 2023-04-18 2024-10-24 Incyte Corporation Pyrrolidine kras inhibitors
WO2025043151A2 (en) 2023-08-24 2025-02-27 Incyte Corporation Bicyclic dgk inhibitors
WO2025096738A1 (en) 2023-11-01 2025-05-08 Incyte Corporation Kras inhibitors
WO2025122545A1 (en) 2023-12-05 2025-06-12 Incyte Corporation Tricyclic triazolo compounds as dgk inhibitors
WO2025129002A1 (en) 2023-12-13 2025-06-19 Incyte Corporation Bicyclooctane kras inhibitors
WO2026060143A1 (en) 2024-09-11 2026-03-19 Incyte Corporation Kras inhibitors

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