RIP1 inhibitory compounds and methods of making and using the same

Abstract

This document discloses kinase inhibitory compounds, such as receptor-interacting protein-1 (RIP1) kinase inhibitors, and pharmaceutical compositions and combinations thereof comprising such inhibitory compounds. The disclosed compounds, pharmaceutical compositions, and / or combinations may be used to treat or prevent kinase-related diseases or conditions, particularly RIP1-related diseases or conditions.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of earlier filed U.S. Provisional Application Nos. 62 / 897,223, filed September 6, 2019; 62 / 932,404, filed November 7, 2019; 63 / 001,016, filed March 27, 2020; 63 / 004,290, filed April 2, 2020; 63 / 004,319, filed April 2, 2020, and 63 / 004,301, filed April 2, 2020. Technical Field

[0003] The present disclosure relates to compounds, and methods of making and using the compounds, such as for inhibiting receptor interacting protein-1 kinase ("RIP1"), and for treating diseases and / or conditions associated with RIP1. Background Art

[0004] Receptor interacting protein-1 kinase (referred to herein as "RIP1") belongs to the tyrosine kinase-like family and is a serine / threonine protein kinase involved in innate immune signaling. RIP1 plays a central role in regulating cell signaling and its role in programmed cell death has been implicated in different inflammatory diseases, such as inflammatory bowel disease, psoriasis, and other diseases and / or disorders associated with inflammatory and / or necrotic cell death.

[0005] Brief description of the invention

[0006] The disclosed compounds according to the present disclosure may have formula I

[0007]

[0008] or a pharmaceutically acceptable salt, N-oxide, solvate, tautomer or stereoisomer thereof. For Formula I, Ring B is a 5-membered or 6-membered heteroaryl group, wherein the heteroaryl group has (a) one, two, or three ring nitrogen atoms and the remaining ring atoms are carbon; or (b) one or two nitrogen atoms and one oxygen atom, provided that R 1 is a heterocyclic group, -C CH or -linker-R 6 , wherein the linker is an alkynyl group; L is a bond, a heteroatom, or R a , the condition is that R a Not H or D; Y is CH2; Z is C 1-10 an aliphatic group or an aromatic group; each R 1 are independently halogen, -C CH, or -linker-R 6 A group wherein the linking group is a bond or R a , the condition is that R a Not H or D, and R 6 is a heterocyclic group, R b ,-C(R f )3, or -C(R f )=C(R f )2; R 2 YesR a ; R 3 YesR a , each R 4 Independently R e ; R a is independently H or D at each occurrence (where L is R a C 1-10 Aliphatic groups, C 1-10 Halogenated aliphatic group, C 5-10 Aromatic groups, C 3-6 Heterocyclic or C 3-10 Spiroheterocycle; R b is independently -OH, -SH, -OR at each occurrence c 、-SR c 、-NR d R d 、-Si(R a )3, -C(O)OH, -C(O)OR c 、-C(O)NR d R d 、-OC(O)NR d R d 、-OC(O)C 1-10 Alkyl, the -OC(O)C 1-10 The alkyl group is replaced by one or two NR d R d , carboxyl or a combination thereof, and optionally further substituted with an aromatic moiety, -SH, -O-acyl, or -C(O)NH2; R c Each occurrence can be independently represented by 1, 2, or 3 R e Substituted C 1-10 Alkyl, may be 1, 2 or 3 R e Substituted C 2-10 Alkenyl, may be 1, 2 or 3 R e Substituted C 2-10 Alkynyl, may be substituted with 1, 2 or 3 R e Substituted C 3-6 Cycloalkyl, or may be substituted by 1, 2 or 3 R e Substituted C 5-10Aromatic group; R d Each occurrence is independently H; may be replaced by 1, 2, or 3 R e or C 3-9 Heterocyclic substituted C 1-6 Alkyl; may be 1, 2 or 3 R e Substituted C 3-6 Cycloalkyl; may be replaced by 1, 2 or 3 R e Substituted C 3-6 Heterocyclic ring; may be 1, 2 or 3 R b Substituted C 5-10 Aryl; may be 1, 2 or 3 R e Substituted C 5-10 heteroaryl; or two R d The group together with the nitrogen to which it is attached provides a e Substituted C 3-9 heterocyclic ring, or may be replaced by one or more R e Substituted C 5-10 Heteroaryl; R e is independently, at each occurrence, a halogen, C 1-6 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 5-10 Heteroaryl, or -OR a ; and R f is independently at each occurrence -alkyl-phosphate, R a , R b , or R e , or two R f The group together with the carbon atom to which it is attached provides C 2-6 Alkenyl, may be one or more R e Substituted C 3-6 Cycloalkyl, or may be replaced by one or more R e or acyl-substituted C 3-10 heterocycle; m is 1, 2, 3 or 4; and n is 0, 1 or 2.

[0009] For certain embodiments, ring B is pyrazolyl, pyridyl, pyrimidinyl or triazolyl. For example, when ring B is pyrazolyl, pyridyl, pyrimidinyl or triazolyl, L can be a heteroatom or C 1-10 Aliphatic group; Z can be C 1-10 an aliphatic group or an aromatic group; each R 1 It can be a heterocyclic group or C 1-10 Aliphatic group; R 2 Can be H or C 1-10 Aliphatic group; R 3Can be H or C 1-10 aliphatic group; each R 4 independently may be halogen or C 1-10 aliphatic group; m can be 1, 2, 3, or 4; and n can be 0, 1, or 2. One of ordinary skill in the art will appreciate that all stereoisomers of the compound are included in Formula I, including, but not limited to, compounds having the formula

[0010] .

[0011] In yet other embodiments, the compound may have a structure satisfying Formula IA

[0012]

[0013] or a pharmaceutically acceptable salt, N-oxide, solvate, tautomer or stereoisomer thereof. For Formula IA, Ring B is a 5-membered or 6-membered heteroaryl group, wherein the heteroaryl group has one, two, or three ring nitrogen atoms and the remaining ring atoms are carbon; L is a bond, a heteroatom, or R a , the condition is that R a Not H or D; Z is C 1-10 an aliphatic group or an aromatic group; each R 1 are independently halogen, -C CH, or -linker-R 6 A group wherein the linking group is a bond or R a , the condition is that R a Not H or D, and R 6 is a heterocyclic group, R b ,-C(R f )3, or -C(R f )=C(R f )2; R 2 YesR a ; R 3 YesR a ; Each R 4 Independently R e ; R a is independently H or D at each occurrence (where L is R a C 1-10 Aliphatic groups, C 1-10 Halogenated aliphatic group, C 5-10 Aromatic groups, C 3-6 Heterocyclic or C 3-10 Spiroheterocycle; R b is independently at each occurrence -OH, -SH, -OR c 、-SR c 、-NR d Rd 、-Si(R a )3, -C(O)OH, -C(O)OR c 、-C(O)NR d R d 、-OC(O)NR d R d 、-OC(O)C 1-10 Alkyl, the -OC(O)C 1-10 The alkyl group is replaced by one or two NR d R d , carboxyl or a combination thereof, and optionally further substituted with an aromatic moiety, -SH, -O-acyl, or -C(O)NH2; R c Each occurrence can be independently represented by 1, 2, or 3 R e Substituted C 1-10 Alkyl, may be 1, 2 or 3 R e Substituted C 2-10 Alkenyl, may be 1, 2 or 3 R e Substituted C 2-10 Alkynyl, may be substituted with 1, 2 or 3 R e Substituted C 3-6 Cycloalkyl, or may be substituted by 1, 2 or 3 R e Substituted C 5-10 Aromatic group; R d Each occurrence is independently H; may be replaced by 1, 2, or 3 R e or C 3-9 Heterocyclic substituted C 1-6 Alkyl; may be 1, 2 or 3 R e Substituted C 3-6 Cycloalkyl; may be replaced by 1, 2 or 3 R e Substituted C 3-6 Heterocyclic ring; may be 1, 2 or 3 R b Substituted C 5-10 Aryl; may be 1, 2 or 3 R e Substituted C 5-10 heteroaryl; or two R d The group together with the nitrogen to which it is attached provides a e Substituted C 3-9 Heterocyclic ring, or C which may be substituted by one or more Re 5-10 Heteroaryl; R e is independently, at each occurrence, a halogen, C 1-6 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 5-10Heteroaryl, or -OR a ; and R f is independently at each occurrence -alkyl-phosphate, R a , R b , or R e , or two R f The group together with the carbon atom to which it is attached provides C 2-6 Alkenyl, may be one or more R e Substituted C 3-6 Cycloalkyl, or may be replaced by one or more R e or acyl-substituted C 3-10 heterocycle; m is 1, 2, 3 or 4; and n is 0, 1 or 2.

[0014] One of ordinary skill in the art will appreciate that all stereoisomers of the compound are included in Formula I A, including, but not limited to, compounds having the formula shown below:

[0015] .

[0016] With respect to specific exemplary embodiments of the disclosed pyridine-, pyrimidine-, triazole-, and pyrazole-type compounds, such compounds may have the chemical formula shown below, including any and all stereoisomers thereof:

[0017]

[0018] .

[0019] For each of the foregoing formulae, a particular compound has R 2 and / or R 3 As H or C 1-6 Alkyl, such as methyl; each R 4 independently as halogen or C 1-6 alkyl, such as chlorine, fluorine or methyl; n is 0, 1 or 2; L is a heteroatom (such as oxygen) or C 1-10 Alkyl or C 1-6 alkyl, such as -CH2-; and Z is aryl or C 3-6 Cycloalkyl.

[0020] For a particular compound, Z is , where each R 5 Independently R e and p is 0, 1, 2, 3, 4, or 5. For example, each R 5 independently may be halogen or C 1-6 Alkyl, such as fluorine or methyl. Z can also be C 1-6Alkyl, such as methyl; or cycloalkyl, such as cyclobutyl or cyclopentyl. For certain embodiments, the -LZ moiety is phenoxy, 4-fluorophenoxy, 3-fluorophenoxy, 2-fluorophenoxy, 2,4-difluorophenoxy, 2,6-difluorophenoxy, 4-fluorobenzyl, 2,6-dimethylphenoxy, cyclobutyloxy, cyclopentyloxy, methoxy, 4-methylphenoxy, or benzyl.

[0021] For a particular compound, each R 1 are independently heterocyclic, unsubstituted C 1-10 an aliphatic group, or a C 1-10 Aliphatic groups: -OH, halogen, carboxyl, carboxyl ester, heterocyclic, amino, alkoxy, phosphate, cycloalkyl, alkenyl, -OC(O)NH(C 1-4 Alkyl)-amino, -OC(O)R 8 ; or -OC(O)(CHR 9 )2CO2H. -OC(O)-R 8 The substituents may be derived from amino acids, particularly naturally occurring amino acids, wherein -OC(O)-R 8 The -OC(O)- portion corresponds to the acid portion of the amino acid, and R 8 Contains -N(R 10 )2 or a nitrogen-containing non-aromatic heterocyclic group, wherein R 10 is H or carboxyl ester. 1 It can also be C 1-10 Alkyne or substituted alkyne, such as an alkyne substituted with hydroxy, oxetanyl, azetidinyl, pyridinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, or phosphate. 1 It may also be an 8- to 12-membered spiroheterocyclic group.

[0022] Exemplary disclosed compounds include compounds 1-1 to 1-39.

[0023] The disclosed embodiments also include pharmaceutical compositions comprising the disclosed compounds. Such compositions may further comprise excipients, additional therapeutic agents, or combinations thereof.

[0024] The method may comprise administering to a subject one or more disclosed compounds, or a composition comprising one or more disclosed compounds. Specific embodiments relate to contacting a receptor interacting protein-1 (RIP1) kinase with one or more disclosed compounds, or a composition comprising one or more disclosed compounds.

[0025] A specific method implementation includes:

[0026] Provide a compound or a composition comprising the compound, wherein the compound has formula I

[0027]

[0028] or a pharmaceutically acceptable salt thereof, wherein: Ring B is a 5-membered or 6-membered heteroaryl; L is a bond, a heteroatom, or R a , the condition is that R a Not H or D; Y is CH2; Z is C 1-10 Aliphatic groups (such as C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, or C 3-6 cycloalkyl); or aryl, such as ; R 1 It is halogen, -C CH, or -linker-R 6 Group, wherein the linker is R a , the condition is that R a Not H or D, and R 6 YesR b ,-C(R f )3, or -C(R f )=C(R f )2; R 2 and R 3 YesR a ; R 4 and R 5 Independently R e ; R a is independently H or D at each occurrence (where L is R a Implementation plan), C 1-10 Aliphatic groups (such as C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, or C 3-6 Cycloalkyl), C 1-10 Halogenated aliphatic group, C 5-10 Aromatic groups, or C 3-6 Heterocyclic ring; R b is independently at each occurrence -OH, -SH, -OR c 、-SR c 、-NR d R d 、-Si(R a )3, -C(O)OH, -C(O)OR c , or -C(O)NR d R d ; R c C independently at each occurrence1-10 Alkyl (which may be 1, 2 or 3 R e Replace), C 2-10 Alkenyl (which may be replaced by 1, 2 or 3 R e Replace), C 2-10 Alkynyl (which may be replaced by 1, 2 or 3 R e Replace), C 3-6 Cycloalkyl (which may be replaced by 1, 2 or 3 R e Replace), or C 5-10 Aromatic groups (which may be replaced by 1, 2 or 3 R e Replacement); R d H independently at each occurrence; C 1-6 Alkyl (which may be 1, 2 or 3 R e Replacement); C 3-6 Cycloalkyl (which may be replaced by 1, 2 or 3 R e Replacement); C 3-6 Heterocyclic ring (which may be replaced by 1, 2 or 3 R e Replacement); C 5-10 Aryl (which may be replaced by 1, 2 or 3 R b Replacement); C 5-10 Heteroaryl (which may be replaced by 1, 2 or 3 R e Replaced); or two R d The group together with the nitrogen to which it is attached provides C 3-9 Heterocyclic ring (which may be replaced by one or more R e Replace), or C 5-10 Heteroaryl (which may be replaced by one or more R e Replacement); R e is independently, at each occurrence, a halogen, C 1-6 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 5-10 Heteroaryl, or -OR a ; R f R independently at each occurrence a , R b , or R e , or two R f The group together with the carbon atom to which it is attached provides C 3-6 Cycloalkyl groups (which may be replaced by one or more R e Replace), or C 3-10 Heterocyclic ring (which may be replaced by one or more R esubstituted); m is 1 to 4, such as 1, 2, 3, or 4; n is 0, 1 or 2; p is 0, 1, 2, 3, 4, or 5; and administering the compound or composition to a subject having a disease involving receptor interacting protein-1 (RIP1) kinase.

[0029] Examples of diseases that can be treated according to this method embodiment include diseases or disorders associated with inflammation, necroptosis, or both. In certain embodiments, the disease to be treated with the compounds of the invention is an inflammatory or immunomodulatory disorder, including autoimmune and proliferative disorders. In some embodiments, the disease to be treated with the compounds of the invention is selected from amyotrophic lateral sclerosis (ALS), autoimmune syndromes, rheumatoid arthritis, type I diabetes, inflammatory bowel disease, including Crohn's disease and ulcerative colitis, biliary cirrhosis, multiple sclerosis, Wegener's granulomatosis, ichthyosis, asthma, pollen allergy, reversible obstructive airway disease, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, chronic or refractory asthma, late-onset asthma and airway hyperresponsiveness, allergic rhinitis, spondyloarthritis, ankylosing spondylitis, autoimmune hepatitis, autoimmune hepatobiliary disease, cerebrovascular accident, allergic diseases, chronic obstructive pulmonary disease, emphysema, Friedreich's ataxia, Lewy body disease, diabetic neuropathy, polyglutamine (poly-Q) disease, Fahr's disease, Menke's disease, Wilson's disease, prion disease, destructive bone lesions such as bone resorption disease, bone lesions associated with multiple myeloma; benign tumors, proliferative lesions, inflammatory rapidly proliferative skin lesions, epidermal hyperproliferation, psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis, seborrheic dermatitis, pustular psoriasis, bullous dermatitis, dermatitis multiforme, linear IgA bullous dermatitis, cement dermatitis, gingivitis, periodontitis, gingiva, alveolar bone, cementum (substantia ossea dentis), sepsis, pancreatitis, lichen planus, pemphigus, bullous pemphigoid, bullous epidermolysis, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia, obesity, eosinophilic fasciitis, acne, alopecia areata, male pattern baldness, senile alopecia, keratoconjunctivitis, vernal conjunctivitis, corneal alkali burns, Behcet's disease, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, keratoconus, corneal epithelial dystrophy, corneal leukoplakia, ocular pemphigus, phagocytic corneal ulcer, scleritis, Vogt-Koyanagi-Harada syndrome, hematologic lesions, hematologic malignancies, lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, breast cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, ABC diffuse large B -cell lymphoma (DLBCL), Waldenström's macroglobulinemia, primary cutaneous T-cell lymphoma, smoldering or indolent multiple myeloma, leukemia, acute myeloid leukemia (AML), DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia,Lymphoplasmacytic lymphoma, myelodysplastic syndrome (MDS), myelofibrosis, polycythemia vera, Kaposi's sarcoma, splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, intravascular large B-cell lymphoma, IL-1 driven lesions, MyD88 driven lesions, drug resistant malignancies, such as JAK inhibitor resistant malignancies and ibrutinib resistant malignancies, such as ibrutinib resistant hematological malignancies, ibrutinib resistant CLL and ibrutinib resistant Waldenström's macroglobulinemia, acute myeloid leukemia, chronic myeloid leukemia; Angiogenic lesions, such as the following angiogenic lesions: solid tumors, ocular neovascularization, hemangiomas, such as infantile hemangiomas; Sepsis, septic shock, shigellosis; Migraine, bronchitis, gastric ulcer, necrotizing enterocolitis, intestinal lesions associated with thermal burns, celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, interleukin-1 converting enzyme-related febrile syndrome, tumor necrosis factor receptor-related periodic syndrome, NEMO-deficiency syndrome, HOIL-1 deficiency, linear ubiquitin chain assembly complex deficiency syndrome, lysosomal storage diseases, Gaucher disease, GM2 gangliosidosis, alpha-mannose storage disease, aspartylglucosaminuria, cholesterol ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Farber disease, fucosidosis, galactosialidosis, GM1 Gangliosidosis, mucolipidosis, infantile free sialic acid storage disease, juvenile hexosaminidase A deficiency, Krabbe disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidosis, multiple sulfatase deficiency, Niemann-Pick disease, neuronal ceroid lipofuscinosis, Pompe disease, pycnodystrophy, Sandhoff disease, Schindler disease, sialic acid storage disease, Tay-Sachs disease, Wolman disease, Huntington disease, Parkinson disease, neurodegenerative diseases, Huntington disease, Parkinson disease, metastatic melanoma, neurodegeneration associated with HIV infection and CMV retinitis, such as associated neurocognitive disorders or dementia, fibrotic disorders such as nonalcoholic steatohepatitis, and cardiac disorders such as ischemia-reperfusion; Allergy, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, erythematosus, chronic thyroiditis, Graves' disease, autoimmune gastritis, autoimmune neutropenia, thrombocytopenia, graft-versus-host disease, endotoxin-induced inflammatory response, tuberculosis, atherosclerosis, muscle degeneration, cachexia, Reiter's syndrome, rubella arthritis, acute synovitis, pancreatic beta-cell disease; diseases characterized by massive neutrophil infiltration; rheumatoid spondylitis, gouty arthritis, psoriatic arthritis, and other arthritic conditions, cerebral malaria,Chronic inflammatory lung disease, silicosis, pulmonary sarcoidosis, fibrotic lung, idiopathic interstitial pneumonia, allograft rejection, bone marrow rejection, fever and myalgia caused by infection, keloid formation, scar tissue formation, heartburn, influenza, chronic myeloid leukemia; angiogenic lesions including solid tumors; viral diseases, including acute hepatitis infection (including hepatitis A, B and C); AIDS, ARC or malignancy, herpes; Stroke, Myocardial infarction, Arteriosclerosis, Atherosclerosis, Aortitis syndrome, Polyarteritis nodosa, Myocardial ischemia, Ischemia during stroke heart attack, Organ hypoxia, Vascular proliferation, Reperfusion injury of the heart and kidneys, Ischemia-reperfusion injury during organ preservation, transplantation or ischemic disease, Cardiac hypertrophy, Thrombin-induced platelet aggregation, Endotoxemia and / or toxic shock syndrome, Conditions associated with prostaglandin endoperoxidase synthase-2, Pemphigus vulgaris, Autoimmune / polymyositis, Dermatomyositis, Vitiligo vulgaris, Photosensitivity, Ischemia-reperfusion injury, Ischemia-reperfusion injury of the heart due to myocardial infarction, Multiple system atrophy, Parkinson's syndrome, Frontotemporal dementia, Intracranial hemorrhage, Cerebral hemorrhage, Progressive muscular atrophy, Pseudobulbar palsy, Progressive bulbar palsy, Spinal muscular atrophy, Hereditary muscular atrophy, Peripheral neuropathy, Progressive supranuclear palsy, Corticobasal degeneration, Demyelinating disease, Systemic juvenile idiopathic arthritis (SoJIA) or Still's disease, systemic lupus erythematosus (SLE), Sjögren's syndrome, antiphospholipid syndrome (APS), primary sclerosing cholangitis (PSC), kidney transplant, surgery, acute kidney injury (AKI), systemic inflammatory response syndrome (SIRS), cytokine release syndrome (CRS), acute respiratory distress syndrome (ARDS), ARDS caused by COVID-19, post-infectious autoimmune disease, rheumatic fever, post-infectious glomerulonephritis, systemic sclerosis, cerebrovascular accident (CVA), chronic obstructive pulmonary disease (COPD), NEMO-deficiency syndrome (F-kappa-B essential regulator gene (also known as IKK gamma or IKKG) deficiency syndrome), Solid organ malignancies, lysosomal storage diseases, glaucoma, retinal degenerative diseases, retinal ischemia / reperfusion injury, renal ischemia-reperfusion injury, cataracts, siderosis, retinitis pigmentosa, retinal degenerative diseases, retinal detachment, age-related macular degeneration, vitreous scarring, septic shock caused by anthrax lethal toxin, LPS-induced cell death, infectious encephalopathy, encephalitis, allergic encephalomyelitis, autoimmune uveoretinitis, giant cell arteritis, regional enteritis, granulomatous enteritis, distal ileitis, regional ileitis, terminal ileitis, insulin-dependent diabetes mellitus, scleroderma, systemic scleroderma, macular edema, diabetic retinopathy, central halo-shaped retinochoroidal dystrophy, BEST disease, adult vitelliform disease,Figure dystrophy, myopic degeneration, central serous retinopathy, Stargardt disease, cone-rod dystrophy, North Carolina dystrophy, infectious retinitis, inflammatory retinitis, uveitis, posterior uveitis, toxic retinitis and phototoxicity, macular edema, central halo-shaped retinochoroidal dystrophy, BEST disease, adult vitelliform disease, figure dystrophy, optic nerve injury, optic neuritis, optic neuropathy, central retinal artery occlusion, ischemic optic neuropathy (e.g., arteritic or nonarteritic anterior ischemic neuropathy and posterior ischemic optic neuropathy), compressive optic neuropathy, infiltrative optic neuropathy, traumatic optic neuropathy, mitochondrial optic neuropathy (e.g., Leber's optic neuropathy), nutritional optic neuropathy, toxic optic neuropathy and hereditary optic neuropathy, dominant optic atrophy, Behr syndrome, Creutzfeldt-Jakob disease disease), progressive supranuclear palsy, hereditary spastic paresis, subarachnoid hemorrhage, perinatal brain injury, subclinical brain injury, spinal cord injury, hypoxic-ischemic brain injury, cerebral ischemia, focal cerebral ischemia, global cerebral ischemia, and hypoxic hypoxia, peritoneal dialysis fluid-induced peritoneal injury (PDF) and PD-related side effects, glomerular disease, tubulointerstitial disease, interstitial nephritis, obstruction, polycystic kidney disease), focal glomerulosclerosis, immune complex nephropathy, diabetic nephropathy, Goodpasture syndrome, hepatocellular carcinoma, Pancreatic cancer, urinary tract cancer, bladder cancer, colorectal cancer, colon cancer, breast cancer, prostate cancer, prostatic hyperplasia, kidney cancer, renal cancer, liver cancer, adrenal cancer, thyroid cancer, gallbladder cancer, peritoneal cancer, ovarian cancer, cervical cancer, gastric cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, neuroendocrine cancer, CNS cancer, brain tumors (e.g., brain cancer, glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma), bone cancer, soft tissue sarcoma, retinoblastoma, neuroblastoma tumors, peritoneal effusions, malignant pleural effusions, mesothelioma, Wilms' tumor, trophoblastic tumors, epithelial neoplasia, gastric cancer, ovarian cancer, colorectal cancer, prostate cancer, pancreatic cancer, lung cancer, vaginal cancer, cervical cancer, testicular cancer, genitourinary tract cancer, esophageal cancer, laryngeal cancer, skin cancer, bone cancer, thyroid cancer, sarcoma, glioblastoma, neuroblastoma, gastrointestinal cancer, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma, colon cancer, colorectal adenoma, hemangiopericytoma, myxoid carcinoma, round cell carcinoma, squamous cell carcinoma, squamous cell carcinoma of the esophagus, oral cancer, vulvar cancer, adrenocortical carcinoma, tumors producing ACTH, and leukemia, respiratory tract infections caused by viruses (e.g. influenza virus, rhinovirus, coronavirus, parainfluenza virus, RS virus, adenovirus, reovirus, etc.), herpes zoster caused by herpes virus,Diarrhea caused by rotavirus, viral hepatitis, AIDS, bacterial infectious diseases, e.g. Bacillus cereus, parahaemolytic Vibrio parahaemolyticus, Enterohemorrhagic Escherichia coli), Staphylococcus aureus, MRS A, Salmonella, Botulinum Botulinus, Candida,Paget's disease, achondroplasia, osteochondritis, hyperparathyroidism, osteogenesis imperfecta, partial hepatectomy, acute hepatic necrosis, toxin-induced necrosis, viral hepatitis-induced necrosis, shock-induced necrosis, hypoxia-induced necrosis, viral hepatitis B, non-A / non-B hepatitis, cirrhosis, alcoholic liver disease, alcoholic cirrhosis, alcoholic steatohepatitis, non-alcoholic steatohepatitis (NASH), acetaminophen toxicity, hepatotoxicity, liver failure, fulminant liver failure, delayed liver failure, "acute- "chronic" liver failure, chronic kidney disease, renal damage / injury, renal damage / injury caused by nephritis, renal damage / injury caused by renal transplantation, renal damage / injury caused by surgery, renal damage / injury caused by nephrotoxic administration, enhanced chemotherapy effects, cytomegalovirus infection, HCMV infection, AIDS, cancer, Alzheimer's disease, trauma, chronic bacterial infection, diseases caused by environmental pollution, aging, hypotension, diseases caused by histamine or leukotriene-C4 release, muscular dystrophy, pyoderma and Sezary syndrome, Addison's disease, pseudomembranous colitis, drug- or radiation-induced colitis, ischemic acute renal insufficiency, chronic renal insufficiency, pulmonary oxygen or drug-induced toxic diseases, congenital hypophosphatasia, fibromatosis, fibrous dysplasia, bone turnover, osteolytic bone disease, treating post-traumatic bone surgery, treating post-prosthetic joint surgery, treating post-plastic bone surgery, treating post-dental surgery), bone chemotherapy or bone radiation therapy, bone cancer, vulnerable plaques, lesions, occlusive lesions, stenosis, coronary artery disease, peripheral artery disease, arterial occlusion, aneurysm formation, post-traumatic aneurysm formation, restenosis, post-operative graft occlusion, Guillain-Barré syndrome, Meniere's disease, polyneuritis, polyneuritis, mononeuritis, radiculopathy, hyperthyroidism, Brazilian disease, autoimmune idiopathic thrombocytopenic purpura (autoimmune ITP), membranous nephritis, autoimmune thyroiditis, Hashimoto's thyroiditis, myasthenia gravis, warm and cold agglutinin diseases, Evan's syndrome, hemolytic uremic syndrome / thrombotic thrombocytopenic purpura (HUS / TTP), autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, agenesis of erythrocytosis, or a combination thereof.

[0030] In some embodiments, the disease is myelodysplastic syndrome. In some embodiments, the disease is atopic dermatitis, rheumatoid arthritis, or ankylosing spondylitis.

[0031] The foregoing and other objects and features of the present disclosure will become more apparent from the following detailed description. DETAILED DESCRIPTION OF THE INVENTION

[0033] I. Overview of Terminology

[0034] The following explanations of terms and methods are provided to better describe the present disclosure and guide those of ordinary skill in the art to implement the present disclosure. The singular forms "a", "an", and "the" refer to one or more than one, unless the context clearly states otherwise. The term "or" refers to a single element or a combination of two or more elements of the alternative element, unless the context clearly states otherwise. As used herein, "comprising" means "including". Therefore, "comprising A or B" means "including A, B, or A and B", without excluding other elements.

[0035] Unless otherwise indicated, all numbers expressing amounts of components, molecular weights, percentages, temperatures, times, etc., used in the specification or claims are to be understood as modified by the term "about". Therefore, unless otherwise implicitly or explicitly indicated, the numerical parameters set forth are approximate values, which may depend on the desired properties sought and / or the limits of detection under standard test conditions / methods. When the embodiment is directly and unambiguously distinguished from the prior art being discussed, the embodiment numbers are not approximate values ​​unless the word "about" is explicitly cited.

[0036] Unless otherwise indicated, all technical and scientific terms used herein have the same meaning as those generally understood by those of ordinary skill in the art to which the present disclosure belongs. Although methods and materials similar or equivalent to the methods and materials described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. The materials, methods, and examples are illustrative only and are not intended to be limiting.

[0037] When drawing or describing chemical structures, unless explicitly stated otherwise, it is assumed that all carbons contain hydrogen so that each carbon meets the valence of four. For example, in the structure on the left hand side of the representation below, nine hydrogen atoms are implied. Nine hydrogen atoms are depicted in the right hand structure.

[0038]

[0039] Sometimes, specific atoms in a structure are described in the formula herein as having one or more hydrogen atoms, such as -CH2CH2-. One of ordinary skill in the art will appreciate that the foregoing description techniques are common in the chemical arts to provide brevity and simplicity in the description of organic structures.

[0040] If the R group is described as "floating" on the ring system, such as in the following group R 1:

[0041]

[0042] Then, unless otherwise defined, a substituent R (e.g., R 1 ) may be present on any atom in a fused bicyclic ring system, excluding the atom with the " " symbol of the bonds between atoms as long as a stable structure is formed.

[0043] When the group R is described as being present on a ring system containing a saturated carbon, for example in the following formula:

[0044]

[0045] Wherein, in this example, y can be greater than 1, assuming that each hydrogen currently depicted, implied or explicitly defined on the ring is replaced; then, unless otherwise defined, two R can reside on the same carbon. A simple example is when R is methyl. The depicted structure can exist as a geminal dimethyl on a carbon (a "cyclic" carbon) of the depicted ring. In another example, two R on the same carbon, including the carbon, can be contained in a ring, thereby generating a spirocyclic ("spirocyclyl" group) structure.

[0046] As used herein, the term "substituted" refers to all subsequent modifying components in the term, for example, in the term "substituted aryl C 1-8 In the "alkyl" group, substitution can occur on the aromatic C 1-8 The "C" of the alkyl 1-8 on the "alkyl" portion, the "aryl" portion, or both.

[0047] "Substituted", when used to modify a specified group or part, means that at least one and possibly two or more hydrogen atoms of the specified group or part are independently substituted by the same or different substituents defined below. In a specific embodiment, a group, part or substituent can be substituted or unsubstituted, unless explicitly defined as "unsubstituted" or "substituted". Therefore, any group specified herein can be unsubstituted or substituted, unless the context otherwise indicates or a specific structural formula excludes substitution. In a specific embodiment, a substituent may or may not be explicitly defined as substituted, but is still considered to be optionally substituted. For example, an "aliphatic" or "cyclic" part can be unsubstituted or substituted, but an "unsubstituted aliphatic group" or "unsubstituted ring" is not substituted.

[0048] Unless otherwise indicated, a "substituent" or "substituent group" used to replace one or more hydrogen atoms on a saturated carbon atom in a specified group or moiety may be: -R 60 , halogenated, =O, -OR 70, -SR 70 , -N(R 80 )2, haloalkyl, perhaloalkyl, -CN, -NO2, =N2, -N3, -SO2R 70 , -SO3 – M + , -SO3R 70 , -OSO2R 70 ,

[0049] -OSO3 – M + , -OSO3R 70 , -P(O)(O – )2(M + )2, -P(O)(O – )2M 2+ ,

[0050] -P(O)(OR 70 )O – M + , -P(O)(OR 70 )2, -C(O)R 70 , -C(S)R 70 , -C(NR 70 )R 70 ,

[0051] -CO2 – M + , -CO2R 70 , -C(S)OR 70 , -C(O)N(R 80 )2, -C(NR 70 )(R 80 )2, -OC(O)R 70 , -OC(S)R 70 ,

[0052] -OCO2 - M + , -OCO2R 70 , -OC(S)OR 70 , -NR 70 C(O)R 70 , -NR 70 C(S)R 70 ,

[0053] -NR 70 CO2 – M + , -NR 70 CO2R 70 , -NR 70 C(S)OR 70、-NR 70 C(O)N(R 80 )2.-NR 70 C(NR 70 )R 70 and-NR 70 C(NR 70 )N(R 80 )2, where R 60 It is C 1-10 An aliphatic group, a heteroaliphatic group, or an alicyclic group, typically C 1-6 The aliphatic group, more typically C 1-6 Alkyl, where R 60 Optionally substituted; each R 70 is independently hydrogen or R 60 ; Each R 80 R independently at each occurrence 70 Or alternatively, two R 80 The groups, together with the nitrogen atom to which they are attached, form a 3- to 7-membered heteroalicyclic group which optionally includes 1 to 4 identical or different further heteroatoms selected from O, N and S, wherein N optionally has R 70 substituted, such as H or C1-C3 alkyl; and each M + is a counterion with a single net positive charge. Each M + is independently at each occurrence, for example, an alkali metal ion such as K + 、Na + , Li + ; ammonium ions, such as + N(R 60 )4; protonated amino acid ions, such as lysine ions or arginine ions; or alkaline earth metal ions, such as [Ca 2+ ] 0.5 , [Mg 2+ ] 0.5 , or [Ba 2 + ] 0.5 (The subscript "0.5" means, for example, that one of the counterions of such divalent alkaline earth metal ions can be an ionized form of the compound of the present disclosure and other typical counterions such as chloride, or two ionized compounds can be used as counterions of such divalent alkaline earth metal ions, or doubly ionized compounds can be used as counterions of such divalent alkaline earth metal ions). As a specific example, -N(R 80 )2 includes -NH2, -NH-alkyl, -NH-pyrrolidin-3-yl, N -pyrrolidinyl, N -piperazinyl, 4 N -methyl-piperazine-1-yl,N -morpholinyl, etc. Any two hydrogen atoms on a single carbon can also be replaced by, for example, =O, =NR 70 、=N-OR 70 , = N2 or =S.

[0054] Unless otherwise specified, the substituents used to replace the hydrogen atoms on the unsaturated carbon atoms in the groups containing unsaturated carbon are, -R 60 , halogenated, -O - M + 、-OR 70 、-SR 70 , -S – M + 、-N(R 80 )2, perhaloalkyl, -CN, -OCN, -SCN, -NO, -NO2, -N3, -SO2R 70 、-SO3 – M + 、-SO3R 70 、-OSO2R 70 ,

[0055] -OSO3 – M + 、-OSO3R 70 、-PO3 -2 (M + )2.-PO3 -2 M 2+ 、-P(O)(OR 70 ) – M + 、-P(O)(OR 70 )2.

[0056] -C(O)R 70 、-C(S)R 70 、-C(NR 70 )R 70 、-CO2 – M + 、-CO2R 70 、-C(S)OR 70 、-C(O)NR 80 R 80 ,

[0057] -C(NR 70 )N(R 80 )2. -OC(O)R 70 、-OC(S)R 70 , -OCO2 – M + 、-OCO2R 70 、-OC(S)OR70 ,

[0058] -NR 70 C(O)R 70 、-NR 70 C(S)R 70 、-NR 70 CO2 – M + 、-NR 70 CO2R 70 、-NR 70 C(S)OR 70 ,

[0059] -NR 70 C(O)N(R 80 )2.-NR 70 C(NR 70 )R 70 and-NR 70 C(NR 70 )N(R 80 )2, where R 60 , R 70 , R 80 and M + As defined above. In independent embodiments, the substituent is not -O - M + 、-OR 70 、-SR 70 , or -S – M + .

[0060] Unless otherwise specified, the substituents used to replace the hydrogen atoms on nitrogen atoms in groups containing such nitrogen atoms are: -R 60 , -O - M + 、-OR 70 、-SR 70 , -S - M + 、-N(R 80 )2, perhaloalkyl, -CN, -NO, -NO2, -S(O)2R 70 、-SO3 - M + 、-SO3R 70 、-OS(O)2R 70 、-OSO3 - M + 、-OSO3R 70 、-PO3 2- (M + )2.-PO3 2- M 2+、-P(O)(OR 70 ) - M + 、-P(O)(OR 70 )(OR 70 )、-C(O)R 70 、-C(S)R 70 、-C(NR 70 )R 70 、-CO2R 70 、-C(S)OR 70 、-C(O)NR 80 R 80 、-C(NR 70 )NR 80 R 80 、-OC(O)R 70 、-OC(S)R 70 、-OCO2R 70 、-OC(S)OR 70 、-NR 70 C(O)R 70 、-NR 70 C(S)R 70 、-NR 70 CO2R 70 、-NR 70 C(S)OR 70 、-NR 70 C(O)N(R 80 )2.-NR 70 C(NR 70 )R 70 and-NR 70 C(NR 70 )N(R 80 )2, where R 60 , R 70 , R 80 and M + Same as defined before.

[0061] In one embodiment, a substituted group has at least one substituent, up to the number of substituents possible for the particular moiety, such as 1 substituent, 2 substituents, 3 substituents, or 4 substituents.

[0062] In addition, in the embodiment where the substituted substituent of the group or part is substituted, the nesting of the substituent of this type of substitution is limited to three, thereby preventing the formation of polymer. Therefore, in the group or part comprising the first group as the substituent on the second group, the second group itself is the substituent on the third group connected with the parent structure, the first (outermost) group can only be substituted by unsubstituted substituent. For example, in the group comprising-(aryl-1)-(aryl-2)-(aryl-3), aryl-3 can only be substituted by the unsubstituted substituent itself.

[0063] As will be understood by one of ordinary skill in the art, any group or moiety defined herein may be linked to any other part of the disclosed structure, such as a parent or core structure, such as by consideration of valence rules, comparison with exemplary species, and / or consideration of functionality, unless the context clearly states or implies the connectivity of the group or moiety to the rest of the structure.

[0064] "Acyl" refers to the group -C(O)R, where R is H, an aliphatic group, a heteroaliphatic group, or an aromatic group (including both aryl and heteroaryl groups). Exemplary acyl moieties include, but are not limited to, -C(O)H, -C(O)alkyl, -C(O)C1-C6alkyl, -C(O)C1-C6haloalkyl, -C(O)cycloalkyl, -C(O)alkenyl, -C(O)cycloalkenyl, -C(O)aryl, -C(O)heteroaryl, or -C(O)heterocyclyl. Specific examples include, -C(O)H, -C(O)Me, -C(O)Et, or -C(O)cyclopropyl.

[0065] "Aliphatic group" refers to a substantially hydrocarbon-based group or moiety. An aliphatic group or moiety may be acyclic, including alkyl, alkenyl or alkynyl (as well as alkylene, alkenylene or alkynylene), cyclic forms thereof, such as alicyclic groups or moieties, including cycloalkyl, cycloalkenyl or cycloalkynyl, and further including straight chain and branched arrangements, as well as all stereo and positional isomers. Unless otherwise expressly stated, an aliphatic group contains from one to twenty-five carbon atoms (C 1-25 ); for example, for aliphatic groups, one to fifteen (C 1-15 ), one to ten (C 1-10 ) one to six (C 1-6 ) or one to four carbon atoms (C 1-4 ), or for alicyclic groups or moieties, three to fifteen (C 3-15 ), three to ten (C 3-10 ), three to six (C 3-6 ), or three to four (C 3-4) carbon atoms. Aliphatic groups may be substituted or unsubstituted unless specifically referred to as "unsubstituted aliphatic groups" or "substituted aliphatic groups". Aliphatic groups may be substituted with one or more substituents (up to two substituents per methylene carbon in the aliphatic group chain, or up to one substituent per carbon of a C=C double bond in the aliphatic group chain, or up to one substituent for the carbon of a terminal methine group).

[0066] A "lower aliphatic group" refers to a group containing one to ten carbon atoms (C 1-10 ), such as one to six (C 1-6 ), or one to four (C 1-4 ) carbon atoms; or for a lower alicyclic group, three to ten (C 3-10 ), such as three to six (C 3-6 ) carbon atom.

[0067] "Alkoxy" refers to a group -OR, where R is a substituted or unsubstituted alkyl or a substituted or unsubstituted cycloalkyl. In certain instances, R is C 1-6 Alkyl or C 3-6 Cycloalkyl. Methoxy (-OCH3) and ethoxy (-OCH2CH3) are exemplary alkoxy groups. In substituted alkoxy groups, R is substituted alkyl or substituted cycloalkyl, examples of which in the compounds disclosed herein include haloalkoxy groups, such as -OCF2H.

[0068] "Alkoxyalkyl" refers to the group -alkyl-OR, where R is substituted or unsubstituted alkyl or substituted or unsubstituted cycloalkyl; -CH2CH2-O-CH2CH3 is an exemplary alkoxyalkyl.

[0069] "Alkyl" refers to a group having 1 to at least 25 (C 1-25 ) carbon atoms, more typically 1 to 10 (C 1-10 ) carbon atoms, such as 1 to 6 (C 1-6 ) carbon atoms. The alkyl moiety may be substituted or unsubstituted. For example, the term includes straight and branched hydrocarbon groups such as methyl (CH3), ethyl (-CH2CH3), n-propyl (-CH2CH2CH3), isopropyl (-CH(CH3)2), n-butyl (-CH2CH2CH2CH3), isobutyl (-CH2CH2(CH3)2), sec-butyl (-CH(CH3)(CH2CH3), tert-butyl (-C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), and neopentyl (-CH2C(CH3)3).

[0070] "Amino" refers to the group -NH2, -NHR, or -NRR, wherein each R is independently selected from H, an aliphatic group, a heteroaliphatic group, an aromatic group (including both aryl and heteroaryl groups), or a heteroalicyclic group, or two R groups together with the nitrogen to which they are attached form a heterocyclic ring. Examples of such heterocyclic rings include those in which the two R groups together with the nitrogen to which they are attached form -(CH2) 2-5 -rings, which are optionally interrupted by one or two heteroatom groups, such as -O- or -N(R g ) (as in the group and ), where R g YesR 70 、-C(O)R 70 、-C(O)OR 60 or -C(O)N(R 80 )2.

[0071] "Amide" refers to the group -N(R)acyl, where R is hydrogen, a heteroaliphatic group, or an aliphatic group such as an alkyl group, particularly C 1-6 alkyl.

[0072] Unless otherwise indicated, an "aromatic group" refers to a cyclic conjugated group or moiety of 5 to 15 ring atoms having a single ring (e.g., phenyl, pyridyl, or pyrazolyl) or multiple fused rings, wherein at least one ring is aromatic (e.g., naphthyl, indolyl, or pyrazolopyridinyl), i.e., at least one ring and optionally multiple fused rings, have a continuous, delocalized π-electron system. Typically, the number of out-of-plane π electrons corresponds to Huckel's rule (4n + 2). The point of attachment to the parent structure is usually through the aromatic portion of the fused ring system. For example, However, in some instances, the context or explicit disclosure may indicate that the point of attachment is through the non-aromatic portion of the fused ring system. For example, An aromatic group or moiety may contain only ring carbon atoms, as in an aryl group or moiety, or it may contain one or more ring carbon atoms and one or more ring heteroatoms containing a lone pair of electrons (e.g., S, O, N, P, or Si), as in a heteroaryl group or moiety. Unless otherwise indicated, an aryl group may be substituted or unsubstituted.

[0073] Unless otherwise indicated, "aryl" refers to an aromatic carbocyclic group having 6 to 15 carbon atoms, having a single ring (e.g., phenyl) or multiple condensed rings, at least one of which is aromatic (e.g., 1,2,3,4-tetrahydroquinoline, benzodioxolane, etc.). If any aromatic ring portion contains heteroatoms, the group is a heteroaryl rather than an aryl. An aryl group can be, for example, monocyclic, bicyclic, tricyclic, or tetracyclic. Unless otherwise indicated, an aryl group can be substituted or unsubstituted.

[0074] "Araliphatic" refers to an aromatic group attached to the parent moiety through an aliphatic portion. Araliphatic groups include aralkyl or arylalkyl groups such as benzyl and phenethyl.

[0075] "Carboxyl" refers to -CO2H.

[0076] "Carboxamide" refers to a -C(O)amino group.

[0077] "Carboxyl ester" or "carboxylate" refers to the group -C(O)OR, where R is an aliphatic, heteroaliphatic, or aromatic (including both aryl and heteroaryl).

[0078] "Carboxylate" refers to -C(O)O - or a salt thereof.

[0079] "Cyano" refers to the radical -CN.

[0080] "Alicyclic group" refers to a cyclic aliphatic group having a single ring (e.g., cyclohexyl) or multiple rings, such as in a fused, bridged, or spirocyclic system, wherein at least one ring in the ring or system is aliphatic. Typically, the point of attachment to the parent structure is through the aliphatic portion of the polycyclic system. Alicyclic groups include saturated and unsaturated systems, including cycloalkyl, cycloalkenyl, and cycloalkynyl. Alicyclic groups may contain three to twenty-five carbon atoms; For example, three to fifteen, three to ten, or three to six carbon atoms. Unless otherwise indicated, alicyclic groups may be substituted or unsubstituted. Exemplary alicyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, or cyclohexenyl.

[0081] "Halo," "halide," or "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0082] "Haloalkyl" refers to an alkyl moiety substituted with one or more halogens. Exemplary haloalkyl moieties include CH2F, -CHF2, and -CF3.

[0083] "Heteroaliphatic group" refers to an aliphatic compound or group having at least one heteroatom and at least one carbon atom, i.e., at least one carbon atom from an aliphatic compound or group containing at least two carbon atoms has been replaced by an atom having at least one lone pair of electrons, typically nitrogen, oxygen, phosphorus, silicon or sulfur. The heteroaliphatic compound or group may be substituted or unsubstituted, branched or unbranched, chiral or achiral, and / or acyclic or cyclic, such as a heterocycloaliphatic group.

[0084] Unless otherwise indicated, "heteroaryl" refers to an aromatic group or moiety having 5 to 15 ring atoms, including at least one carbon atom and at least one heteroatom, such as N, S, O, P or Si. A heteroaryl group or moiety may contain a single ring (e.g., pyridyl, pyrimidinyl or pyrazolyl) or multiple fused rings (e.g., indolyl, benzopyrazolyl or pyrazolopyridinyl). A heteroaryl group or moiety may be, for example, monocyclic, bicyclic, tricyclic or tetracyclic. Unless otherwise indicated, a heteroaryl group or moiety may be substituted or unsubstituted.

[0085] "Heterocyclyl", "heterocyclo" and "heterocycle" refer to both aromatic and non-aromatic ring systems, and more specifically to stable three to fifteen membered ring moieties containing at least one carbon atom, and typically multiple carbon atoms, and at least one, such as one to five heteroatoms. The one or more heteroatoms may be nitrogen, phosphorus, oxygen, silicon or sulfur atoms. The heterocyclyl moiety may be a monocyclic moiety, or may contain multiple rings, such as in a bicyclic or tricyclic ring system, provided that at least one ring contains heteroatoms. Such polycyclic moieties may include fused or bridged ring systems as well as spirocyclic systems; and any nitrogen, phosphorus, carbon, silicon or sulfur atom in the heterocyclyl moiety may be optionally oxidized to various oxidation states. For convenience, nitrogens, particularly, but not limited to, those defined as cyclic aromatics, are intended to include their corresponding N-oxide forms, although not expressly defined as such in a particular embodiment. Thus, for compounds having, for example, a pyridyl ring, the corresponding pyridyl-N-oxide is included as another compound of the present disclosure unless expressly excluded or excluded by context. In addition, the cyclic nitrogen atom can be optionally quaternized. The heterocycle includes a heteroaryl moiety and a heteroalicyclic or heterocycloaliphatic moiety, which are partially or completely saturated heterocyclic rings. Examples of heterocyclic groups include, but are not limited to, azetidinyl, oxetanyl, acridinyl, benzodioxolanyl, benzodioxane, benzofuranyl, carbazolyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolyl, isoquinolyl, tetrazolyl, tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinetrienyl, azacycloheptatrienyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidine, isothiazolidinyl, indole 1-Hydroxy-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1-Methyl-1

[0086] "Hydroxyl" refers to the group -OH.

[0087] "Nitro" refers to the radical -NO2.

[0088] "Phosphate" refers to the group -OP(O)(OR')2, where each -OR' is independently -OH; an -O-aliphatic group, such as -O-alkyl or -O-cycloalkyl; an -O-aromatic group, including both -O-aryl and -O-heteroaryl; -O-aralkyl; or -OR' is -O - M + , where M + is a counterion with a single positive charge. Each M + Can be an alkali metal ion such as K + 、Na + , Li + ; ammonium ions, such as + N(R")4, wherein R" is H, an aliphatic group, a heteroaliphatic group, or an aromatic group (including both aromatic and heteroaromatic groups); or an alkaline earth metal ion, such as [Ca 2+ ] 0.5 , [Mg 2+ ] 0.5 or[Ba 2+ ] 0.5 Phosphonooxyalkyl refers to the group -alkyl-phosphate, such as, for example, -CH2OP(O)(OH)2, or a salt thereof, such as -CH2OP(O)(OH)2. - Na + )2, and (((dialkoxyphosphoryl)oxy)alkyl) refers to a dialkyl ester of a phosphonooxyalkyl group, such as, for example, -CH2OP(O)(O-tert-butyl)2.

[0089] "Phosphonate" refers to the group -P(O)(OR')2, wherein each -OR' is independently -OH; an -O-aliphatic group such as -O-alkyl or -O-cycloalkyl; an -O-aromatic group, including both -O-aryl and -O-heteroaryl; or -O-aralkyl; or -OR' is -O - M + , and M + is a counterion with a single positive charge. Each M + is a positively charged counterion and may be, for example, an alkali metal ion such as K + 、Na + , Li + ; ammonium ions, such as + N(R")4 wherein R" is H, an aliphatic group, a heteroaliphatic group, or an aromatic group (including both aromatic and heteroaromatic groups); or an alkaline earth metal ion such as [Ca 2+ ] 0.5 , [Mg 2+ ] 0.5, or [Ba 2+ ] 0.5 Phosphonoalkyl refers to the group -alkyl-phosphonate, such as, for example, -CH2P(O)(OH)2, or -CH2P(O)(O - Na + )2, and ((dialkoxyphosphoryl)alkyl) refers to a dialkyl ester of a phosphonoalkyl group, for example, -CH2P(O)(O-tert-butyl)2.

[0090] "Patient" or "subject" can refer broadly to any organism, but more generally refers to mammals and other animals, particularly humans. The disclosed methods are therefore applicable to both human treatment and veterinary applications.

[0091] "Pharmaceutically acceptable excipient" refers to a substance other than an active ingredient that is included in a composition comprising an active ingredient. As used herein, an excipient can be incorporated into the particles of a pharmaceutical composition, or it can be physically mixed with the particles of a pharmaceutical composition. An excipient can be used, for example, to dilute the active agent and / or to change the properties of a pharmaceutical composition. An excipient can include, but is not limited to, an antiadhesive, a binder, a coating, an enteric coating, a disintegrant, a flavoring agent, a sweetener, a colorant, a lubricant, a glidant, an adsorbent, a preservative, a carrier or a vehicle. An excipient can be starch and modified starches, cellulose and cellulose derivatives, sugars and their derivatives such as disaccharides, polysaccharides and sugar alcohols, proteins, synthetic polymers, cross-linked polymers, antioxidants, amino acids or preservatives. Exemplary excipients include, but are not limited to, magnesium stearate, stearic acid, vegetable stearin, sucrose, lactose, starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, xylitol, sorbitol, maltitol, gelatin, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), tocopheryl polyethylene glycol 1000 succinate (also known as vitamin E TPGS, or TPGS), carboxymethylcellulose, dipalmitoylphosphatidylcholine (DPPC), vitamin A, vitamin E, vitamin C, retinyl palmitate, selenium, cysteine, methionine, citric acid, sodium citrate, methylparaben, propylparaben, sugar, silicon dioxide, talc, magnesium carbonate, sodium starch glycolate, tartrate, aspartame, benzalkonium chloride, sesame oil, propyl gallate, sodium metabisulfite, or lanolin.

[0092] An "adjuvant" is a component that modifies the effect of other agents (usually active ingredients). Adjuvants are typically pharmacological and / or immunological agents. Adjuvants can modify the effect of active ingredients by increasing the immune response. Adjuvants can also be used as stabilizers for formulations. Exemplary adjuvants include, but are not limited to, aluminum hydroxide, alum, aluminum phosphate, inactivated bacteria, squalene, detergents, cytokines, paraffin oil, and combination adjuvants such as Freund's complete adjuvant or Freund's incomplete adjuvant.

[0093] "Pharmaceutically acceptable carrier" refers to an excipient that serves as a carrier or vehicle, such as a suspending aid, solubilizing agent, or a nebulizing aid. Remington: The Science and Practice of Pharmacy , The University of the Sciences in Philadelphia, Editor, Lippincott, Williams, & Wilkins, Philadelphia, PA, 21st ed. (2005), incorporated herein by reference, describes exemplary compositions and formulations suitable for drug delivery of one or more therapeutic compositions and additional agents.

[0094] In general, the nature of the carrier will depend on the specific mode of administration adopted. For example, parenteral preparations generally contain injectable fluids, which include pharmaceutically and physiologically acceptable fluids, such as water, saline, balanced salt solutions, aqueous glucose solutions, glycerol, etc. as carriers. In certain embodiments, pharmaceutically acceptable carriers can be sterile to be suitable for application to a subject (e.g., by parenteral, intramuscular or subcutaneous injection). In addition to biological neutral carriers, the pharmaceutical composition to be administered can contain a small amount of non-toxic auxiliary substances, such as wetting agents or emulsifiers, preservatives and pH buffers, such as sodium acetate or sorbitan monolaurate.

[0095] "Pharmaceutically acceptable salt" refers to pharmaceutically acceptable salts of compounds derived from a variety of organic and inorganic counterions known to those of ordinary skill in the art, and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functional group, salts of organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, methanesulfonate, acetate, maleate, oxalate, and the like. "Pharmaceutically acceptable acid addition salts" are a subset of "pharmaceutically acceptable salts" that retain the biological effectiveness of the free bases when formed from acidic partners. In particular, the disclosed compounds form salts with a variety of pharmaceutically acceptable acids, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and organic acids such as amino acids, formic acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, benzenesulfonic acid, isethionic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, 1-hydroxy-2-naphthoic acid, and the like. "Pharmaceutically acceptable base addition salts" are a subset of "pharmaceutically acceptable salts" that are derived from inorganic bases, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, and the like. Exemplary salts are ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, tris(hydroxymethyl)aminomethane (Tris), ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Exemplary organic bases are isopropylamine, diethylamine, tris(hydroxymethyl)aminomethane (Tris), ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. (See, e.g., SM Berge et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66: 1-19, which is incorporated herein by reference.) In specific disclosed embodiments, the compound can be a formate salt, a trifluoroacetate salt, a hydrochloride salt, or a sodium salt.

[0096] An "effective amount" with respect to a compound or pharmaceutical composition refers to an amount of the compound or pharmaceutical composition sufficient to achieve a specific desired result (e.g., inhibition of a protein or enzyme). In specific embodiments, an "effective amount" is an amount that is sufficient to: inhibit RIP1; induce a desired biological or medical response in a tissue, the whole body, a subject, or a patient; treat a specific lesion or disease; improve or eliminate one or more of its symptoms; and / or prevent the occurrence of a disease or lesion. The amount of compound that constitutes an "effective amount" may vary depending on the compound, the desired result, the disease state and its severity, the size, age, and sex of the patient to be treated, etc., as will be understood by those of ordinary skill in the art.

[0097] "Prodrug" means In vivo A compound that is converted to produce a biologically active compound or a compound that is more biologically active than the parent compound. The in vivo conversion may occur, for example, by hydrolysis or enzymatic conversion. 。 Common examples of prodrug moieties include, but are not limited to, ester and amide forms of compounds having an active form with a carboxylic acid moiety. Examples of pharmaceutically acceptable esters of the disclosed compounds include, but are not limited to, esters of a phosphate group and a carboxylic acid, such as aliphatic esters, particularly alkyl esters (e.g., C 1-6 Other prodrug moieties include phosphate esters, such as -CH2-OP(O)(OR')2 or salts thereof, wherein R' is H or C 1-6 Alkyl. Acceptable esters also include cycloalkyl esters and arylalkyl esters, such as, but not limited to benzyl. Examples of pharmaceutically acceptable amides of compounds of the present disclosure include, but are not limited to, primary amides and secondary and tertiary alkyl amides (e.g., having about 1 to about 6 carbons). Amides and esters according to the disclosed exemplary embodiments of compounds of the present disclosure can be prepared according to conventional methods. A full discussion of prodrugs is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems", Volume 14 of the ACSSymposium Series and in Bioreversible Carriers in Drug Design, edited by Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference for all purposes.

[0098] "Solvate" refers to a complex formed by the combination of solvent molecules and molecules or ions of a solute. The solvent can be an organic solvent, an inorganic solvent, or a mixture of the two. Exemplary solvents include, but are not limited to, alcohols such as methanol, ethanol, propanol; amides such as N,N-dialiphatic amides such as N,N-dimethylformamide; tetrahydrofuran; alkyl sulfoxides such as dimethyl sulfoxide; water; and combinations thereof. When combined with pharmaceutically acceptable or non-pharmaceutically acceptable solvents such as water, ethanol, and the like, the compounds described herein may exist in unsolvated forms as well as solvated forms. The solvated forms of the presently disclosed compounds are within the scope of the embodiments disclosed herein.

[0099] "Sulfonamide" refers to the group or moiety -SO2amino or -N(R)sulfonyl, where R is H, aliphatic, heteroaliphatic, or aromatic (including both aryl and heteroaryl).

[0100] "Sulfanyl" refers to a group or -SH, an -S-aliphatic group, an -S-heteroaliphatic group, an -S-aromatic group (including both -S-aryl and -S-heteroaryl groups).

[0101] "Sulfinyl" refers to the group or moiety -S(O)H, -S(O)aliphatic, -S(O)heteroaliphatic, or -S(O)aromatic (including both -S(O)aryl and -S(O)heteroaryl).

[0102] "Sulfonyl" refers to the radical: -SO2H, -SO2aliphatic, -SO2heteroaliphatic, -SO2aromatic (including both -SO2aryl and -SO2heteroaryl).

[0103] As used herein, "Treating" or "treatment" refers to treating a disease or condition of interest in a patient or subject, particularly a human suffering from the disease or condition of interest, and illustratively includes, but is not limited to:

[0104] (i) preventing a disease or condition from occurring in a patient or subject, particularly where the patient or subject is susceptible to the condition but has not yet been diagnosed as having the condition;

[0105] (ii) inhibiting a disease or condition, for example, arresting or slowing its progression;

[0106] (iii) ameliorating a disease or condition, e.g., causing the disease or condition or its symptoms to be lessened or resolved; or

[0107] (iv) Stabilizing the disease or condition.

[0108] As used herein, the terms "disease" and "disorder" may be used interchangeably or may be different in that a particular disease or disorder may have no known pathogen (and thus a cause has not yet been determined) and is therefore not yet considered a disease, but merely an undesirable condition or symptom for which a clinician has identified a set of more or less specific symptoms.

[0109] The above definition and the following formula are not intended to include impermissible substitution patterns (e.g., a methyl group substituted with 5 fluoro groups). Such impermissible substitution patterns are readily recognized by one of ordinary skill in the art.

[0110] Those of ordinary skill in the art will appreciate that compounds may exhibit tautomerism, conformational isomerism, geometric isomerism and / or optical isomerism. For example, certain disclosed compounds may include one or more chiral centers and / or double bonds, and therefore may exist as stereoisomers, such as double bond isomers (i.e., geometric isomers), enantiomers, diastereomers, and mixtures thereof (e.g., racemic mixtures). As another example, certain disclosed compounds may exist in several tautomeric forms, including enol forms, keto forms, and mixtures thereof. Since the various compound names and chemical formulas in this specification and claims may represent only one of possible tautomers, conformational isomers, optical isomers, or geometric isomer forms, those of ordinary skill in the art will appreciate that disclosed compounds include any tautomerism, conformational isomerism, optical isomerism, and / or geometric isomer forms of compounds described herein, as well as mixtures of these various different isomeric forms. Using techniques known to those of ordinary skill in the art, particularly with the benefit of this disclosure, mixtures of different isomeric forms, including mixtures of enantiomers and / or stereoisomers, can be separated to provide each individual enantiomer and / or stereoisomer. In cases of limited rotation, for example around an amide bond or between two directly connected rings such as a pyridine ring, biphenyl, etc., atropisomers are also possible and are also specifically included in the compounds of the present disclosure.

[0111] In any embodiment, any or all hydrogens present in a compound or in a particular group or moiety within a compound may be replaced by deuterium or tritium. Thus, reference to an alkyl group includes deuterated alkyl groups in which one to a maximum number of the hydrogens present may be replaced by deuterium. For example, ethyl refers to both C2H5 or C2H5 in which 1 to 5 hydrogens are replaced by deuterium, as in C2D x H 5-x middle.

[0112] II. RIP1-active compounds and pharmaceutical compositions containing RIP1-active compounds

[0113] A. Compounds

[0114] Disclosed herein are compounds that can be used to inhibit RIP1 and / or for treating diseases and / or conditions associated with RIP1 and pharmaceutical compositions comprising such compounds. In some embodiments, the compounds are selective kinase inhibitors. For example, exemplary compounds can selectively inhibit RIP1 relative to RIP2, RIP3, or both RIP2 and RIP3.

[0115] In some embodiments, the compounds of the present disclosure have a structure according to Formula I

[0116]

[0117] Or a pharmaceutically acceptable salt thereof. It will be understood by those skilled in the art that, unless otherwise indicated, compounds within the scope of Formula I also include stereoisomers, N-oxides, tautomers, hydrates, solvates, isotopes and / or prodrugs thereof. In other embodiments, the compound may have a structure according to Formula IA.

[0118]

[0119] For Formula I and IA, Ring B is a heteroaryl, and may be a monocyclic heteroaryl. In some embodiments, Ring B is a 5-membered or 6-membered heteroaryl. In some embodiments, Ring B is a 5-membered or 6-membered heteroaryl, wherein the heteroaryl has one, two, or three ring nitrogen atoms, and the remaining ring atoms are carbon. In some embodiments, Ring B is a 5-membered or 6-membered heteroaryl, wherein the heteroaryl has one or two nitrogen atoms and one oxygen atom, provided that R 1 is a heterocyclic group, -C CH or -linker-R 6 , wherein the linking group is an alkynyl group. In an independent embodiment, ring B is not a triazole, a triazine, or a heteroaryl group containing oxygen or sulfur ring atoms, such as oxazole, thiazole, or isoxazole. In another independent embodiment, ring B is not a triazine, or a heteroaryl group containing oxygen or sulfur ring atoms, such as oxazole, thiazole, or isoxazole. In certain embodiments, ring B is pyrazolyl or triazole, and in other specific embodiments, ring B is pyridyl or pyrimidyl. In particular for formula I, Y is CH2.

[0120] Each R 1 independently may be halogen, -C CH, or -linker-R 6 A group wherein the linking group is a bond or R a , the condition is that R a Not H or D, and R 6 is a heterocyclic group, R b ,-C(R f )3, or -C(Rf )=C(R f )2.

[0121] R 2 YesR a . and R 3 YesR a .

[0122] If present, each R 4 Independently R e .

[0123] L is a bond, a heteroatom, or R a , the condition is that R a Not H or D.

[0124] Z is for C 1-10 an aliphatic group or an aromatic group.

[0125] m is 1, 2, 3, or 4, and n is 0, 1, or 2.

[0126] R a is independently H or D at each occurrence (where L is R a C 1-10 Aliphatic groups, C 1-10 Halogenated aliphatic group, C 5-10 Aromatic groups, C 3-6 Heterocyclic or C 3-10 Spiro heterocycle.

[0127] R b is independently at each occurrence -OH, -SH, -OR c 、-SR c 、-NR d R d 、-Si(R a )3, -C(O)OH, -C(O)OR c 、-C(O)NR d R d 、-OC(O)NR d R d 、-OC(O)C 1-10 Alkyl, the -OC(O)C 1-10 The alkyl group is replaced by one or two NR d R d , carboxyl, or a combination thereof, and is optionally further substituted with an aromatic moiety, -SH, -O-acyl, or -C(O)NH2.

[0128] R c Each occurrence can be independently represented by 1, 2, or 3 R e Substituted C 1-10Alkyl, may be 1, 2 or 3 R e Substituted C 2-10 Alkenyl, may be 1, 2 or 3 R e Substituted C 2-10 Alkynyl, may be substituted with 1, 2 or 3 R e Substituted C 3-6 Cycloalkyl, or may be substituted by 1, 2 or 3 R e Substituted C 5-10 Aromatic groups.

[0129] R d Each occurrence is independently H; may be replaced by 1, 2, or 3 R e or C 3-9 Heterocyclic substituted C 1-6 Alkyl; may be 1, 2 or 3 R e Substituted C 3-6 Cycloalkyl; may be replaced by 1, 2 or 3 R e Substituted C 3-6 Heterocyclic ring; may be 1, 2 or 3 R b Substituted C 5-10 Aryl; may be 1, 2 or 3 R e Substituted C 5-10 heteroaryl; or two R d The group together with the nitrogen to which it is attached provides a e Substituted C 3-9 heterocyclic ring, or may be replaced by one or more R e Substituted C 5-10 Heteroaryl.

[0130] R e is independently, at each occurrence, a halogen, C 1-6 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 5-10 Heteroaryl, or -OR a .

[0131] and R f is independently at each occurrence -alkyl-phosphate, R a , R b , or R e , or two R f The group together with the carbon atom to which it is attached provides C 2-6 Alkenyl, may be one or more R e Substituted C 3-6 Cycloalkyl, or may be replaced by one or more R e or acyl-substituted C 3-10Heterocyclic ring.

[0132] In certain embodiments of Formula I and / or Formula IA, Ring B is pyrazolyl, pyridinyl, pyrimidinyl, or triazolyl; L is a heteroatom or C 1-10 aliphatic group; Z is C 1-10 an aliphatic group or an aromatic group; each R 1 is a heterocyclic group or C 1-10 Aliphatic group; R 2 Is H or C 1-10 Aliphatic group; R 3 is H; each R 4 are independently halogen or C 1-10 an aliphatic group; m is 1, 2, 3 or 4; and n is 0, 1 or 2.

[0133] In some embodiments, each R 1 are independently heterocyclic, unsubstituted C 1-10 an aliphatic group, or a C 1-10 Aliphatic groups: -OH, halogen, carboxyl, carboxyl ester, heterocyclic, amino, alkoxy, phosphate, cycloalkyl, alkenyl, -OC(O)NH(C 1-4 Alkyl)-amino, -OC(O)R 8 , or -OC(O)(CHR 9 )2CO2H. -OC(O)-R 8 Partially derived from amino acids, where -OC(O)-R 8 The -OC(O)- portion corresponds to the acid portion of the amino acid, and R 8 Contains -N(R 10 )2 or a nitrogen-containing non-aromatic heterocyclic group, wherein R 10 is H or a carboxyl ester. And each R 9 is independently H or -O-acyl.

[0134] For OC(O)-R 8Part, the nitrogen-containing non-aromatic heterocyclic group can be a 5- or 6-membered unsaturated nitrogen-containing heterocyclic group, such as a pyrrolidinyl group. The amino acid can be any amino acid, such as a naturally occurring amino acid, and can be selected from the following amino acids: glycine, valine, alanine, leucine, isoleucine, methionine, phenylalanine, tryptophan, tyrosine, serine, threonine, asparagine, glutamine, arginine, histidine, lysine, aspartic acid, glutamic acid, cysteine ​​or proline. Those of ordinary skill in the art will understand that in the case where an amino acid contains one or more chiral centers, all enantiomers, diastereomers and / or mixtures thereof are considered. For example, an amino acid can be an L-amino acid, a D-amino acid or a mixture thereof. In some embodiments, an amino acid is an L-amino acid. And in certain embodiments, -OC(O)-R 8 Yes -OC(O)CH(NH2)R 11 , , or -OC(O)-(CH2) 1-2 C(NH2)CO2H, where R 11 is an amino acid side chain, and / or may be H, -CH3, isopropyl, -CH2CH(CH3)2, -CH(CH3)Et, -CH2CH2SCH3, , , 、-CH2OH、-CH(OH)CH3、

[0135] -CH2C(O)NH2, -CH2CH2C(O)NH2, -CH2SH, -CH2CH2CH2NHC(O)(NH)NH2, , -CH2CH2CH2CH2NH2, -CH2CO2H, or CH2CH2CO2H.

[0136] In addition, for R 1 , at least one R 1 It may be an 8- to 12-membered spiroheterocyclic group or a C 1-10 Alkyne. 1-10 The alkyne may have one or two substituents. One substituent may be OH. In some embodiments, one substituent is oxetane, azetidinyl, pyridinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, or phosphate, and / or in some embodiments, one substituent is -OC(O)-R 8 .

[0137] In some embodiments, m is 1, 2, or 3, and can be 1 or 2, and in certain embodiments, m is 1.

[0138] R 2 Can be H or C1-6 Alkyl groups, such as methyl.

[0139] R 3 Can be H or C 1-6 alkyl, and in certain embodiments, R 3 It's H.

[0140] Each R 4 independently may be halogen (such as F, Br, Cl or I), or C 1-10 Aliphatic groups (such as C 1-6 In some embodiments, each R 4 is independently chloro, fluoro or methyl.

[0141] In certain embodiments, n is 0, while in other specific embodiments, n is 1.

[0142] In addition, for Formula I and / or Formula IA or IB, L is a bond, a heteroatom, or R a , the condition is that R a Not H or D. L can be oxygen or C 1-10 Alkyl (such as C 1-6 alkyl), more particularly methylene (-CH2-) or .Z is C 1-10 In some embodiments, Z is C 3-6 Cycloalkyl (such as cyclobutyl or cyclopentyl), or C 1-6 In other embodiments, Z is , where each R 5 Independently R e , and p is 0, 1, 2, 3, 4 or 5. In such embodiments, each R 5 independently may be halogen or C 1-6 Alkyl, such as methyl or fluoro. In some embodiments, p is 1 or 2, but in other embodiments, p is 0. And in certain embodiments, the -LZ moiety is phenoxy, 4-fluorophenoxy, 3-fluorophenoxy, 2-fluorophenoxy, 2,4-difluorophenoxy, 2,6-difluorophenoxy, 4-fluorobenzyl, 2,6-dimethylphenoxy, cyclobutyloxy, cyclopentyloxy, methoxy, 4-methylphenoxy, or benzyl.

[0143] In some embodiments of Formula I and / or Formula IA, the compound may have a structure according to Formula IA-1 or IA-2 below.

[0144]

[0145] In some embodiments, the compound may have a structure according to one or more of the following formulas:

[0146]

[0147]

[0148]

[0149] .

[0150] For Formulas IA-1 to IA-29, Ring B, L, Z, R 1 , R 2 , R 3 , R 4 , m and n, if present, are as defined herein for Formula I and / or Formula IA.

[0151] In any of the above embodiments regarding Formula I, Formula IA, and / or IA-1 through IA-29, R 1 Can be selected from any of the following:

[0152]

[0153]

[0154]

[0155]

[0156]

[0157] And in certain embodiments, in Formula I, Formula IA, and / or Formulas IA-1 to IA-29, R 1 Can be selected from any of the following:

[0158]

[0159]

[0160] .

[0161] In other embodiments of Formula I

[0162]

[0163] Ring B is a 5-membered or 6-membered heteroaryl group;

[0164] L is a bond, a heteroatom, or R a , the condition is that R a Not H or D;

[0165] Y is CH2;

[0166] Z is for C 1-10 Aliphatic groups (such as C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, or C 3-6 cycloalkyl); or ;

[0167] R 1 It is halogen, -C CH, or -linker-R 6 Group, wherein the linker is R a , the condition is that R a Not H or D, and R 6 YesR b ,-C(R f )3, or -C(R f )=C(R f )2;

[0168] R 2 and R 3 Independently R a ;

[0169] R 4 and R 5 Independently R e ;

[0170] R a is independently H or D at each occurrence (where L is R a Implementation plan), C 1-10 Aliphatic groups (such as C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, or C 3-6 Cycloalkyl), C 1-10 Halogenated aliphatic group, C 5-10 Aromatic groups, or C 3-6 Heterocyclic ring;

[0171] R b is independently at each occurrence -OH, -SH, -OR c 、-SR c 、-NR d R d 、-Si(R a )3, -C(O)OH, -C(O)OR c , or -C(O)NR d R d ;

[0172] R c C independently at each occurrence 1-10Alkyl (which may be 1, 2 or 3 R e Replace), C 2-10 Alkenyl (which may be replaced by 1, 2 or 3 R e Replace), C 2-10 Alkynyl (which may be replaced by 1, 2 or 3 R e Replace), C 3-6 Cycloalkyl (which may be replaced by 1, 2 or 3 R e Replace), or C 5-10 Aromatic groups (which may be replaced by 1, 2 or 3 R e replace);

[0173] R d H independently at each occurrence; C 1-6 Alkyl (which may be 1, 2 or 3 R e Replacement); C 3-6 Cycloalkyl (which may be replaced by 1, 2 or 3 R e Replacement); C 3-6 Heterocyclic ring (which may be replaced by 1, 2 or 3 R e Replacement); C 5-10 Aryl (which may be replaced by 1, 2 or 3 R b Replacement); C 5-10 Heteroaryl (which may be replaced by 1, 2 or 3 R e or two R d The group together with the nitrogen to which it is attached provides C 3-9 Heterocyclic ring (which may be replaced by one or more R e Replace), or C 5-10 Heteroaryl (which may be replaced by one or more R e replace);

[0174] R e is independently, at each occurrence, a halogen, C 1-6 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 5-10 Heteroaryl, or -OR a ; and

[0175] R f R independently at each occurrence a , R b , or R e , or two R f The group together with the carbon atom to which it is attached provides C 3-6 Cycloalkyl groups (which may be replaced by one or more R e Replace), or C 3-10Heterocyclic ring (which may be replaced by one or more R e replace);

[0176] m is 1 to 4, such as 1, 2, 3, or 4, wherein specific embodiments are 1 or 2;

[0177] n is 0, 1, or 2; and

[0178] p is 0, 1, 2, 3, 4, or 5.

[0179] In some embodiments, the compounds of the present disclosure may have a structure satisfying Formula IIA

[0180]

[0181] Or a pharmaceutically acceptable salt thereof. Those of ordinary skill in the art will understand that the disclosed formulae include within their scope all stereoisomers, N-oxides, tautomers, hydrates, solvates, isotopes and / or prodrugs of the compounds that otherwise have the required structural features of such formulae.

[0182] For Formula IIA:

[0183] Ring B is a 5-membered or 6-membered heteroaryl group;

[0184] L is a bond, a heteroatom, or R a , the condition is that R a Not H or D;

[0185] R 1 It is halogen, -C CH, or -linker-R 6 Group, wherein the linker is R a , the condition is that R a Not H or D, and R 6 YesR b ,-C(R f )3, or -C(R f )=C(R f )2;

[0186] R 2 and R 3 Independently R a ;

[0187] R 4 and R 5 Independently R e ;

[0188] R a is independently H or D at each occurrence (where L is R a Implementation plan), C 1-10Aliphatic groups (such as C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, or C 3-6 Cycloalkyl), C 1-10 Halogenated aliphatic group, C 5-10 Aromatic groups, or C 3-6 Heterocyclic ring;

[0189] R b is independently -OH, -SH, -OR at each occurrence c 、-SR c 、-NR d R d 、-Si(R a )3, -C(O)OH, -C(O)OR c , or -C(O)NR d R d ;

[0190] R c C independently at each occurrence 1-10 Alkyl (which may be 1, 2 or 3 R e Replace), C 2-10 Alkenyl (which may be replaced by 1, 2 or 3 R e Replace), C 2-10 Alkynyl (which may be replaced by 1, 2 or 3 R e Replace), C 3-6 Cycloalkyl (which may be replaced by 1, 2 or 3 R e Replace), or C 5-10 Aromatic groups (which may be replaced by 1, 2 or 3 R e replace);

[0191] R d H independently at each occurrence; C 1-6 Alkyl (which may be 1, 2 or 3 R e Replacement); C 3-6 Cycloalkyl (which may be replaced by 1, 2 or 3 R e Replacement); C 3-6 Heterocyclic ring (which may be replaced by 1, 2 or 3 R e Replacement); C 5-10 Aryl (which may be replaced by 1, 2 or 3 R b Replacement); C 5-10 Heteroaryl (which may be replaced by 1, 2 or 3 R e or two R d The group together with the nitrogen to which it is attached provides C 3-9 Heterocyclic ring (which may be replaced by one or more R e Replace), or C5-10 Heteroaryl (which may be replaced by one or more R e replace);

[0192] R e is independently, at each occurrence, a halogen, C 1-6 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-6 Haloalkyl, C 3-6 Cycloalkyl, C 5-10 Heteroaryl, or -OR a ; and

[0193] R f R independently at each occurrence a , R b , or R e , or two R f The group together with the carbon atom to which it is attached provides C 3-6 Cycloalkyl groups (and in some embodiments, C 3-6 The cycloalkyl group is replaced by one or more R e Replace), or C 3-10 Heterocyclic (and in some embodiments, C 3-10 The heterocyclic group is replaced by one or more R e replace);

[0194] m is 1 to 4, such as 1, 2, 3, or 4, wherein specific embodiments are 1 or 2;

[0195] n is 0, 1, or 2; and

[0196] p is 0, 1, 2, 3, 4, or 5.

[0197] In certain embodiments of Formula I, IA, or IIA, the 5-membered heteroaryl group of Ring B may have a The structure of wherein at least one W is nitrogen, and each remaining W is independently selected from carbon, CH, oxygen, sulfur, nitrogen or NH. In some embodiments, the 5-membered heteroaryl is diazole, triazole, oxadiazole or oxazole. Exemplary triazoles include any of the following:

[0198]

[0199] .

[0200] Exemplary oxadiazoles are selected from any of the following:

[0201] .

[0202] Exemplary oxazoles are selected from any of the following:

[0203] .

[0204] Exemplary oxadiazoles are selected from any of the following:

[0205] .

[0206] In certain embodiments of Formula I, IA, or IIA, L is oxygen or R a , where R a It is C 1- C4 alkyl, such as -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-. In some embodiments, L is a bond (and is therefore directly attached to Z), or -CH2-, or oxygen.

[0207] Where R 1 is the linker-R 6 R 1 The linker of the group is a C1, C2, C3 or C4 aliphatic group, such as a C2 alkyl, alkenyl or alkynyl group, or a C1, C2, C3 or C4 halogenated aliphatic group, such as a C2 haloalkyl or haloalkenyl group. 1 The linker is R a , where R a It is C 1- C4 alkyl, such as -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-; or the linking group is C 2- C4 alkenyl, such as -CH=CH-, -CH=CHCH2-, -CH2CH=CH-, or -CH2CH=CHCH2-; or the linking group is C 2- C4 alkynyl, such as -C C-、-C CCH2-、-CH2C C-, or -CHC In some embodiments, the linker is C 2- C4 haloalkenyl, such as -CF=CH-, -CCl=CH-, -CH=CCl-, -CH=CF-, -CCl=CCl-, -CF=CF-, or -CCl=CF-, -CF=CCl-. In some embodiments, the linker is -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH=CH-, -CCl=CH-, -CH=CCl-, or -C C-.

[0208] In some embodiments, R 1 R 6 The group is C(R f )3, one of the R f YesR e , where R e Yes-OR a (eg, hydroxyl or OMe) and each additional R f Independently R a , where R a It is C 1-4 aliphatic group and preferably each additional R f YesR a , where R a C independently at each occurrence 1-4 In certain embodiments, each additional R f YesR a , where R a is methyl or CD3. In yet other embodiments, R 6 Yes-C(R f )3, where each R f YesR a , where R a is methyl or H or, where each R f YesR a , where R a is methyl or R b , where R b Yes -C(O)OR c In some other embodiments, one R f YesR e Yes-OR a (e.g., hydroxyl or OMe) and the other two R f The groups are linked together to provide an alicyclic group (e.g., cyclopropane, cyclobutane, cyclopentane or cyclohexane) or a heterocyclic group (e.g., epoxide, oxetane, tetrahydrofuran, tetrahydropyran or hexahydrofuran) having the carbon atom to which they are attached. b In some such embodiments, the alicyclic and / or heterocyclic groups may be substituted, with some specific embodiments being substituted with one or more hydroxyl groups or benzyl-carbonyl groups.

[0209] Some compound embodiments have C 2-4 In a specific embodiment, R 1 Yes-Linker-R 6 group and the linking group is R a , where R ais -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH=CH-, or -C C-, or -CH2C C-, and R 6 YesR b , where R b Is -C(O)OEt or -C(O)NR d R d or -NR d R d , where each R d Each occurrence is independently hydrogen, C 5-10 Heteroaryl, C 3-6 Cycloalkyl, or two R d The groups are linked together to provide a heterocyclic group with the nitrogen atom to which they are attached, which may further contain one or more in addition to R d In some embodiments, one R d is hydrogen and the other R d It is C 5-10 Heteroaryl, which may be replaced by one or more R e Replace with one of the following:

[0210] .

[0211] R 6 It can also be R b , where R b Is -OH or -OR c (where R c It is C 1-6 Alkyl and in some embodiments C 1-6 Alkyl is C 5-10 Heteroaryl (such as pyridyl) substituted; or wherein R c It is C 5-10 heteroaryl, such as quinolyl), or R b Can be -NR d R d , where R d In each occurrence, it is independently H, C 5-10 Heteroaryl (and in some embodiments, the C 5-10 Heteroaryl is represented by one or more R e group substitution), or two R d The group together with the nitrogen to which it is attached provides C 3-9 Heterocyclic (and in some embodiments, the C 3-9 The heterocyclic ring is replaced by one or more R e Group substitution) or C 5-10Heteroaryl (and in some embodiments, the C 5-10 Heteroaryl is represented by one or more R e In the case of R e In the substituted embodiment, R e C independently at each occurrence 5-10 Heteroaryl or -OR a , where R a It is C 1-10 alkyl.

[0212] Some compounds contain a linker as a C1 group and a b R 6 Group, where R b Yes - NR d R d , one of which R d It's H and another R d is pyridyl, or two of them are d The group together with the nitrogen to which it is attached provides C 5-10 heteroaryl; or R b Yes OR c , where R c is a C substituted with a pyridyl group 1-4 In some embodiments, R b yes

[0213] .

[0214] In some embodiments, R 1 Can be selected from any of the following:

[0215]

[0216]

[0217] .

[0218] In some embodiments, R 2 and R 3 Each independently is R a , where R a is independently hydrogen, methyl, ethyl, propyl, butyl, pentyl or hexyl at each occurrence. In certain embodiments, R 2 and R 3 Each is independently R a , which is independently hydrogen, methyl or ethyl at each occurrence. In an exemplary embodiment, R 2 is methyl and R 3 It's hydrogen.

[0219] In some embodiments, each R 4 Independently and / or each R 5 Independently R e , where R e is alkyl, alkenyl, alkynyl, chlorine, bromine, iodine or fluorine. In certain embodiments, each R 4 and / or each R 5 Independently R e , where R e is a lower aliphatic group (eg methyl), fluorine or chlorine.

[0220] In some embodiments, m is 1; n is 0 or 1; p is 0, 1 or 2. In specific embodiments, m is 1, n is 0 and p is 0, 1 or 2.

[0221] Compounds of Formula I, IA, or IIA may also have a structure satisfying any one or more of Formula IIIA or IIIA1 to IIIA5.

[0222]

[0223] For Formulae IIIA and IIIA1 to IIIA5, R 1 and R 5 Each is as described above for Formula I, IA and IIA. In certain embodiments, there are 0, 1 or 2 R 5 Group. R 5 It can be R e , where R e is fluorine or chlorine. In other specific embodiments, R 5 For Formulae IIIA1 to IIIA5, each W is independently nitrogen or oxygen, and in particular nitrogen.

[0224] Certain disclosed embodiments have Formula IIIA6.

[0225]

[0226] For Formula IIIA6, R 1 , R 2 and R 3 As above. 10 is an alkyl group, a cyclic alkyl group or an aryl group. More particularly, R 10 is a lower alkyl group, such as C 1-10 Alkyl, more particularly C 1-5 Alkyl, including methyl, ethyl, propyl, butyl and pentyl. Cyclic alkyl groups are typically selected from cyclobutyl, cyclopentyl, or cyclohexyl, in particular cyclobutyl or cyclopentyl. In some embodiments, compounds according to the present disclosure have formula IIIA7.

[0227]

[0228] For many disclosed embodiments, R 10 is phenyl. Accordingly, certain disclosed embodiments of the present disclosure have Formula IIIA8.

[0229]

[0230] For Formula IIIA7 or IIIA8, R 1 and R 5 Each is as described above for Formula I, IA and / or IIA. 5 YesR e In certain embodiments, there are 0, 1 or 2 R 5 In certain embodiments, R 5 is absent or is a halogen (such as fluorine or chlorine, especially fluorine), or C 1-6 Alkyl (such as methyl).

[0231] In some embodiments, the compound of Formula I, IA and / or IIA may also have a structure satisfying any one or more of Formulas IVA to VIIA:

[0232]

[0233]

[0234] For Formulas IVA to VIIA, each R 5 Independently, it can be as described above and in some specific embodiments, it is a lower aliphatic group (such as methyl) or a halogen, such as chlorine or fluorine. In addition, ring B is as described above and in some embodiments is selected from

[0235] .

[0236] As shown in Formulas IVA to VIIA, R 6 As described above and in some embodiments selected from one of the following:

[0237]

[0238]

[0239]

[0240] .

[0241] Certain disclosed exemplary compounds within the scope of one or more of Formulas I, IA, IA-1 to IA-32, IIA, IIIA, IIIA1-IIIA8, and IVA to VIIA include:

[0242]

[0243]

[0244]

[0245] .

[0246] Exemplary compounds within one or more of Formulas I, IA, IA-1 to IA-32, IIA, IIIA, IIIA1-IIIA8, and IVA to VIIA include those named and / or shown below.

[0247] I-1: (S)-4-(4-fluorobenzyl)-N-(8-((3-hydroxyoxetane-3-yl)ethynyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-pyrazole-1-carboxamide;

[0248] I-2: (S)-N-(8-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-4-phenoxypyridine-2-carboxamide;

[0249] I-3: (±)-1-(2,6-dichlorobenzyl)- N -(1-methyl-2-oxo-8-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-1 H -1,2,4-triazole-3-carboxamide;

[0250] I-4: (±)-5-Benzyl- N -(1-methyl-2-oxo-8-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-1 H -1,2,4-triazole-3-carboxamide;

[0251] I-5: (±)-1-(2,6-dichlorobenzyl)- N -(2-oxo-8-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-1 H -Benzo[b]azepine-3-yl)-1H -1,2,4-triazole-3-carboxamide;

[0252] I-6: (±)-5-Benzyl-N-(2-oxo-8-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-1 H -1,2,4-triazole-3-carboxamide;

[0253] I-7: (±)-5-Benzyl- N -(2-oxo-8-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-1 H -1,2,4-triazole-3-carboxamide;

[0254] I-8: (±)-5-Benzyl-N-(8-((5,6-dihydro-[1,2,4]triazolo[1,5- a ]Pyrazine-7(8 H )-1-methyl-2-oxo-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-1 H -1,2,4-triazole-3-carboxamide;

[0255] I-9: (±)-5-Benzyl- N -(2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-1 H -1,2,4-triazole-3-carboxamide;

[0256] I-10: (S)-5-benzyl-N-(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0257] I-11:(±)- N -(8-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-5-benzyl-1H-1,2,4-triazole-3-carboxamide;

[0258] I-12: (±)-5-Benzyl- N -(1-methyl-2-oxo-8-(2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1 H -Benzo[b]azepine-3-yl)-1 H -1,2,4-triazole-3-carboxamide;

[0259] I-13: (±)-5-Benzyl- N -(1-methyl-2-oxo-8-(3-oxa-9-azaspiro[5.5]undec-9-yl)-2,3,4,5-tetrahydro-1 H -Benzo[b]azepine-3-yl)-1 H -1,2,4-triazole-3-carboxamide;

[0260] I-14: (±)-5-Benzyl- N -(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-1-(methyl- d 3 )-2-oxo-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-1 H -1,2,4-triazole-3-carboxamide;

[0261] I-15: (±)-5-Benzyl- N -(1-(methyl- d 3 )-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-1 H -1,2,4-triazole-3-carboxamide;

[0262] I-16: (±)-5-Benzyl- N -(8-((3-hydroxyoxetane-3-yl)ethynyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-1 H -1,2,4-triazole-3-carboxamide;

[0263] I-17: (S)-5-Benzyl- N-(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1 H -1,2,4-triazole-3-carboxamide;

[0264] I-18: (S)-5-Benzyl- N -(1-methyl-2-oxo-8-(pyridin-3-ylethynyl)-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-1 H -1,2,4-triazole-3-carboxamide;

[0265] I-19: (±)-5-Benzyl- N -(1-methyl-2-oxo-8-(pyridin-4-ylethynyl)-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-1 H -1,2,4-triazole-3-carboxamide;

[0266] I-20: (±)-5-Benzyl- N -(1-methyl-2-oxo-8-(pyridin-2-ylethynyl)-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-1 H -1,2,4-triazole-3-carboxamide;

[0267] I-21: (S)-5-Benzyl- N -(8-(3,3-dimethylbut-1-yn-1-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-1 H -1,2,4-triazole-3-carboxamide;

[0268] I-22:( S )- N -(8-((3-hydroxyoxetane-3-yl)ethynyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-4-phenoxypyridine-2-carboxamide;

[0269] I-23: (±)-4-Benzyl- N-(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-1H-pyrazole-1-carboxamide;

[0270] I-24: (±)- N -(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-4-phenoxypyridine-2-carboxamide;

[0271] I-25:(±)- N -(1-methyl-2-oxo-8-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-4-phenoxypyridine-2-carboxamide;

[0272] I-26: (±)-N-(2-oxo-8-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-4-phenoxypyridine-2-carboxamide;

[0273] I-27: (±) - N -(1-methyl-2-oxo-8-(3-oxa-9-azaspiro[5.5]undec-9-yl)-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-4-phenoxypyridine-2-carboxamide;

[0274] I-28:(±)- N -(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-1-(methyl- d 3 )-2-oxo-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-4-phenoxypyridine-2-carboxamide;

[0275] I-29: (±)- N -(1-(methyl- d 3)-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-4-phenoxypyridine-2-carboxamide;

[0276] I-30:(±)- N -(1-methyl-2-oxo-8-(2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-4-phenoxypyridine-2-carboxamide;

[0277] I-31:(±)- N -(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-4-phenoxypyridine-2-carboxamide;

[0278] I-32: (S)-1-Benzyl- N -(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-1 H -pyrazole-3-carboxamide;

[0279] I-33: (S)-1-Benzyl- N -(8-(3,3-dimethylbut-1-yn-1-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-1 H -pyrazole-3-carboxamide;

[0280] I-34:( S )-4-(4-fluorobenzyl)- N -(8-((4-Hydroxytetrahydro-2 H -pyran-4-yl)ethynyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-1 H -pyrazole-1-carboxamide;

[0281] I-35:( S )-4-(4-fluorophenoxy)-N -(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-2-oxo-2,3,4,5-tetrahydro-1 H -Benzo[ b ] azepine-3-yl)pyridine-2-carboxamide;

[0282] I-36:4-(4-Fluorobenzyl)- N -(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-1-(methyl- d 3 )-2-oxo-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-1 H -pyrazole-1-carboxamide;

[0283] I-37:( S )- N -(1-methyl-8-(3-methyl-3-(4-methylpiperazin-1-yl)but-1-yn-1-yl)-2-oxo-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-4-phenoxypyridine-2-carboxamide;

[0284] I-38:(±)- N -(1-methyl-2-oxo-8-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-1 H -Benzo[ b ]azepine-3-yl)-4-phenylpyrimidine-2-carboxamide; or

[0285] I-39: (±)- N -(8-((5,6-dihydro-[1,2,4]triazolo[1,5- a ]Pyrazine-7(8 H )-1-methyl-2-oxo-2,3,4,5-tetrahydro-1 H -Benzo[ b ]azepine-3-yl)-4-phenylpyrimidine-2-carboxamide.

[0286]

[0287]

[0288]

[0289]

[0290]

[0291] .

[0292] In some embodiments, one or more compounds may be included in a pharmaceutical composition or medicament, and in some embodiments, one or more compounds may be in the form of a parent compound or a pharmaceutically acceptable salt, stereoisomer, N-oxide, tautomer, hydrate, solvate, isotope or prodrug thereof. Pharmaceutical compositions typically include at least one additional component in addition to the disclosed one or more compounds, such as a pharmaceutically acceptable excipient, adjuvant, additional therapeutic agent (described in the following section) or any combination thereof.

[0293] Pharmaceutically acceptable excipients may be included in pharmaceutical compositions for a variety of purposes, such as diluting the pharmaceutical composition for delivery to a subject, facilitating processing of the formulation, providing favorable material properties to the formulation, facilitating dispersion from a delivery device, stabilizing the formulation (e.g., antioxidants or buffers), providing a pleasant or palatable taste or viscosity to the formulation, etc. Pharmaceutically acceptable excipients may include pharmaceutically acceptable carriers. Exemplary excipients include, but are not limited to, monosaccharides, disaccharides, and polysaccharides, sugar alcohols and other polyols, such as lactose, glucose, raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol, starch, or combinations thereof; surfactants, such as sorbitol, diphosphatidylcholine, and lecithin; fillers; buffers, such as phosphate and citrate buffers; antiadherents, such as magnesium stearate; binders, such as carbohydrates (including disaccharides, such as sucrose and lactose), polysaccharides (such as starch, cellulose, microcrystalline cellulose, cellulose ethers (such as hydroxypropyl cellulose), gelatin, synthetic polymers (such as polyvinyl pyrrolidone, polyalkylene glycols); coatings (such as cellulose ethers, including hydroxypropyl methylcellulose, shellac, zein zein, and gelatin); release aids (such as enteric coatings); disintegrants (such as cross-linked polyvinylpyrrolidone, cross-linked carboxymethyl cellulose, and polyvinylpyrrolidone). fillers (such as calcium hydrogen phosphate, vegetable fats and oils, lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate and magnesium stearate); flavoring and sweetening agents (such as mint, cherry, anise, peach, apricot or licorice, raspberry and vanilla); lubricants (such as minerals, exemplified by talc or silicon dioxide; fats, exemplified by vegetable stearin, magnesium stearate or stearic acid); preservatives (such as antioxidants, exemplified by vitamin A, vitamin E, vitamin C, retinyl palmitate and selenium; amino acids, exemplified by cysteine ​​and methionine; citric acid and sodium citrate; parabens, exemplified by methylparaben and propylparaben); colorants; compression aids; emulsifiers; encapsulation agents; gums; granulating agents; and combinations thereof.

[0294] B. Combinations of Therapeutic Agents

[0295] The compounds described herein can be used alone, in combination with each other, in separate pharmaceutical compositions, together in a single pharmaceutical composition, or as an adjuvant to other established therapies or in combination with other established therapies. The one or more compounds or compositions comprising the one or more compounds can be administered once or multiple times. In some embodiments, the compounds of the present disclosure can be used in combination with other therapeutic agents that can be used for the lesions or conditions being treated. These other therapeutic agents can be administered simultaneously, in any order, by the same route of administration as the compounds of the present disclosure or by different routes. For sequential administration, one or more compounds and one or more therapeutic agents can be administered so that the effective time period of at least one compound and therapeutic agent overlaps with the effective time period of at least one other compound and / or therapeutic agent. In an exemplary embodiment of a combination comprising four components, the effective time period of the first component administered can overlap with the effective time period of the second, third, and fourth components, but the effective time periods of the second, third, and fourth components independently may or may not overlap with each other. In another exemplary embodiment of a combination comprising four components, the effective time period of the first component administered overlaps with the effective time period of the second component, but does not overlap with the effective time period of the third or fourth component; the effective time period of the second component overlaps with the effective time period of the first component and the third component; the effective time period of the fourth component overlaps only with the effective time period of the third component. In some embodiments, the effective time periods of all compounds and / or therapeutic agents overlap with each other.

[0296] In some embodiments, the compound is administered with another therapeutic agent, such as an analgesic, an antibiotic, an anticoagulant, an antibody, an anti-inflammatory agent, an immunosuppressant, a guanylyl cyclase-C agonist, an intestinal secretagogue, an antiviral agent, an anticancer agent, an antifungal agent, or a combination thereof. The anti-inflammatory agent may be a steroid or a nonsteroidal anti-inflammatory agent. In certain embodiments, the nonsteroidal anti-inflammatory agent is selected from aminosalicylate, a cyclooxygenase inhibitor, diclofenac, etodolac, famotidine, fenoprofen, flurbiprofen, ketoprofen, ketorolac, ibuprofen, indomethacin, meclofenamic acid, mefenamic acid, meloxicam, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin, or a combination thereof. In some embodiments, the immunosuppressant is a mercaptopurine, a corticosteroid, an alkylating agent, a calcineurin inhibitor, an inosine monophosphate dehydrogenase inhibitor, an antilymphocyte globulin, an antithymocyte globulin, an anti-T cell antibody, or a combination thereof. In one embodiment, the antibody is infliximab.

[0297] In some embodiments, the compounds of the present invention can be used together with anticancer agents or cytotoxic agents. Various classes of anticancer and antitumor compounds include, but are not limited to, alkylating agents, antimetabolites, BCL-2 inhibitors, vinca alkaloids, taxanes, antibiotics, enzymes, cytokines, platinum coordination complexes, proteasome inhibitors, substituted ureas, kinase inhibitors, hormones and hormone antagonists, and demethylating agents, such as DNMT inhibitors, such as azacitidine and decitabine. Exemplary alkylating agents include, but are not limited to, nitrogen mustard, cyclophosphamide, ifosfamide, melphalan, chlorambucil, ethyleneimines, methylmelamines, alkyl sulfonates (e.g., busulfan) and carmustine. Exemplary antimetabolites include, for example, but not limited to, folic acid analog methotrexate; pyrimidine analogs fluorouracil, cytosine arabinoside; purine analogs mercaptopurine, thioguanine and thioazapurine. Exemplary vinca alkaloid compounds include, for example, but not limited to, vinblastine, vincristine, paclitaxel, and colchicine. Exemplary antibiotics include, but are not limited to, actinomycin D, daunorubicin, and bleomycin. Exemplary enzymes effective as antitumor agents include L-asparaginase. Exemplary coordination compounds include, for example, but not limited to, cisplatin and carboplatin. Exemplary hormones and hormone-related compounds include, for example, but not limited to, the adrenocortical hormone analogs prednisone and dexamethasone; the aromatase inhibitors amino glutethimide, formestane, and anastrozole; the progesterone compounds hydroxyprogesterone caproate, medroxyprogesterone; and the anti-estrogen compound tamoxifen.

[0298] These and other useful anticancer compounds are described in the Merck Index, 13th Edition (O'Neil MJ et al., eds.) Merck Publishing Group (2001) and in Goodman and Gilman, The Pharmacological Basis of Therapeutics, 12th Edition, Brunton LL ed., Chapters 60-63, McGraw Hill, (2011), both of which are incorporated herein by reference.

[0299] Ipilimumab is one of the CTLA 4 antibodies that can be used in combination with the inhibitors disclosed herein and is marketed by Bristol-Myers Squibb as YERVOY ® Sale.

[0300] Other chemotherapeutic agents for combination include tumor immunoncology agents, such as checkpoint pathway inhibitors, for example, PD-1 inhibitors, such as nivolumab and lambrolizumab, and PD-L1 inhibitors, such as pembrolizumab, MEDI-4736 and MPDL3280A / RG7446. Other checkpoint inhibitors for combination with the compounds disclosed herein include anti-LAG-3 agents, such as BMS-986016 (MDX-1408).

[0301] Other chemotherapeutic agents for use in combination with the inhibitors of the present disclosure include anti-SLAMF7 agents, such as the humanized monoclonal antibody elotuzumab (BMS-901608); anti-KIR agents, such as the anti-KIR monoclonal antibody lirilumab (BMS-986015); and anti-CD137 agents, such as the fully human monoclonal antibody urelumab (BMS-663513).

[0302] The compounds of the present disclosure may also be advantageously used with CAR-T therapy. Examples of currently available CAR-T therapies are axicabtagene ciloleucel and tisagenlecleucel.

[0303] Other anti-proliferative compounds that can be used in combination with the compounds of the present disclosure include, for example, but not limited to, antibodies against growth factor receptors (eg, anti-Her2); and cytokines, such as interferon-α and -γ, interleukin-2, and GM-CSF.

[0304] Other chemotherapeutic agents that may be used in combination with the compounds of the present invention include proteasome inhibitors such as bortezomib, carfilzomib, marizomib, and the like.

[0305] Examples of kinase inhibitors that can be used in combination with the compounds disclosed herein, particularly in the treatment of malignancies, include: Btk inhibitors such as ibrutinib; CDK inhibitors such as palbociclib; EGFR inhibitors, afatinib, erlotinib, gefitinib, lapatinib, osimertinib, and vandetinib; Mek inhibitors such as trametinib; Raf inhibitors such as dabrafenib, sorafenib, and vemurafenib; VEGFR inhibitors such as axitinib, lenvatinib, nintedanib, pazopanib; BCR-Abl inhibitors such as bosutinib, dasatinib, imatinib, and nilotinib; FLT-3 inhibitors such as gilteritinib and quizartinib, PI3-kinase inhibitors such as idelalisib, Syk inhibitors such as fostamatinib; and JAK inhibitors such as ruxolitinib and fedratinib.

[0306] In other embodiments, the second therapeutic agent may be selected from any of the following:

[0307] pain medications - morphine, fentanyl, hydromorphone, oxycodone, codeine, acetaminophen, hydrocodone, buprenorphine, tramadol, venlafaxine, flupirtine, meperidine, pentazocine, dexmechlorethamine, dipyrone;

[0308] Antibiotics - aminoglycosides (such as amikacin, gentamicin, kanamycin, neomycin, netilmicin, tobramycin, and paromycin), carbapenems (such as ertapenem, doripenem, imipenem, cilastatin, and meropenem), cephalosporins (such as cefadroxil, cefazolin, cephalothin, cephalexin, cefaclor, cefadroxil, cefoxitin, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, cephalosporins) ceftriaxone, cefepime, and cefobiprole), glycopeptides (e.g., teicoplanin, vancomycin, and telavancin), lincosamides (e.g., clindamycin and lincomycin), lipopeptides (e.g., daptomycin), macrolides (azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, oxadiazine, telithromycin, and spectinomycin), monobactams (e.g., aztreonam), nitrofurans (e.g., e.g., furazolidone and nitrofurantoin), penicillins (e.g., amoxicillin, ampicillin, azlocillin, carbenicillin, cloxacillin, dicloxacillin, flucloxacillin, mezlocillin, methicillin, nafcillin, oxacillin, penicillin G, penicillin V, piperacillin, temocillin, and ticarcillin), penicillin combinations (e.g., amoxicillin / clavulanic acid, ampicillin / sulbactam, piperacillin / tazobactam, and ticarcillin / clavulanic acid), peptides (e.g., bacitracin, polymyxin, and polymyxin B), and quinolones (e.g., ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, trovafloxacin, grepafloxacin, sparfloxacin, and temafloxacin), sulfonamides (e.g., mafenide, sulfonamidochrysoidine, sulfacetamide, sulfadiazine, silver sulfadiazine, sulfamethoxazole, sulfamethoxazole, sulfanilimide ), sulfasalazine, sulfisoxazole, trimethoprim, and trimethoprim-sulfamethoxazole), tetracyclines (e.g., demeclocycline, doxycycline, minocycline, oxytetracycline, and tetracycline), antimycobacterial compounds (e.g., clofazimine, dapsone, capreomycin, cycloserine, ethambutol, ethionamide, isoniazid, pyrazinamide, rifampicin, rifampin, rifabutin, rifapentine, and streptomycin), and others, such as arsphenamine, chloramphenicol, fosfomycin, fusidic acid, linezolid, metronidazole, mupirocin, platelet mycin, quinuprine / dalfopristin, rifaximin, thiamphenicol, tigecycline, and tinidazole;

[0309] Antibodies - anti-TNF-α antibodies, such as infliximab (Remicade™), adalimumab, golimumab, certolizumab; anti-B cell antibodies, such as rituximab; anti-IL-6 antibodies, such as tocilizumab; anti-IL-1 antibodies, such as anakinra; anti-PD-1 and / or anti-PD-L1 antibodies, such as nivolumab, pembrolizumab, pidilizumab, BMS-936559, MPDL3280A, AMP-224, MEDI4736; ixekizumab, Brodalumab, ofatumumab, sirukumab, clicximab, clazakiumab, fezakinumab, fletikumab, mavrilimumab, ocrelizumab, sarilumab, secukinumab, toralizumab, zalumab;

[0310] Anticoagulants - warfarin (Coumadin™), acenaphthenocoumarol, phenprocoumon, schizotin, phenindione, heparin, fondaparinux, idraparinux, rivaroxaban, apixaban, hirudin, lepirudin, bivalirudin, argatrobam, dabigatran, ximelagatran, batroxobin, fibrase;

[0311] anti-inflammatory agents - steroids such as budesonide, nonsteroidal anti-inflammatory agents such as aminosalicylates (e.g., sulfasalazine, mesalazine, olsalazine, and balsalazide), cyclooxygenase inhibitors (COX-2 inhibitors such as rofecoxib, celecoxib), diclofenac, etodolac, famotidine, fenoprofen, flurbiprofen, ketoprofen, ketorolac, ibuprofen, indomethacin, meclofenamate, mefenamic acid, meloxicam, naproxen, naproxen, oxaprozin, piroxicam, salicylic acid, sulindac, tolmetin;

[0312] Immunosuppressants - mercaptopurines, corticosteroids such as dexamethasone, hydrocortisone, prednisone, methylprednisolone, and prednisolone, alkylating agents such as cyclophosphamide, calcineurin inhibitors such as cyclosporine, sirolimus, and tacrolimus, inosine monophosphate dehydrogenase (IMPDH) inhibitors such as mycophenolate mofetil, mycophenolate mofetil, and azathioprine, and agents used to suppress cellular immunity while leaving the recipient's humoral immune response intact, including various antibodies (e.g., antilymphocyte globulin (ALG), antithymocyte globulin (ATG), monoclonal anti-T-cell antibodies (OKT3)) and radiation. Azathioprine is currently available from Salix Pharmaceuticals, Inc. under the trade name Azasan; mercaptopurine is currently available from Gate Pharmaceuticals, Inc. under the trade name Purinethol; prednisone and prednisolone are currently available from Roxane Laboratories, Inc.; methylprednisolone is currently available from Pfizer; sirolimus (rapamycin) is currently available from Wyeth-Ayerst under the trade name Rapamune; tacrolimus is currently available from Fujisawa under the trade name Prograf; cyclosporine is currently available from Novartis under the trade name Sandimmune and Abbott under the trade name Gengraf; IMPDH inhibitors such as mycophenolate mofetil and mycophenolic acid are currently available from Roche under the trade name Cellcept and from Novartis under the trade name Myfortic; azathioprine is currently available from Glaxo Smith Kline under the trade name Imuran; and antibodies are currently available from Ortho Biotech available under the trade name Orthoclone, from Novartis under the trade name Simulect (basiliximab), and from Roche under the trade name Zenapax (daclizumab); and

[0313] Guanylate cyclase-C receptor agonists or intestinal secretagogues, such as linaclotide, are sold under the name Linzess.

[0314] These various agents may be used in their standard or customary dosages as specified in the prescribing information accompanying the commercially available pharmaceutical forms (see also prescribing information in the 2006 edition of The Physician's Desk Reference), the disclosure of which is incorporated herein by reference.

[0315] III. Methods of preparing compounds

[0316] Disclosed embodiments of the compounds of the present invention can be prepared by any suitable method as would be appreciated by one of ordinary skill in the art. An exemplary suitable method is provided below with reference to specific compounds in the Examples, and may include the following first reaction step according to Scheme 1.

[0317]

[0318] According to Scheme 1, a metal-mediated cross-coupling reaction can be used to couple the protected amine precursor 100 with R 1 Group 102 coupling, R 1 Group 102 comprises "R 6 -linker" group to provide a cross-coupling product 104. In some embodiments, the metal-mediated cross-coupling reaction can be carried out using a transition metal catalyst such as a palladium catalyst. Exemplary palladium catalysts include, but are not limited to, Pd(0) catalysts (e.g., Pd2(dba)3, Pd(dba)2, Pd(PPh3)4, etc.) or Pd(II) catalysts (e.g., XPhos Pd 2nd or 3rd generation In some embodiments, the palladium catalyst can be used in combination with another co-catalyst (such as CuI) to promote the cross-coupling reaction, such as in the Sonogoshira reaction. The metal-mediated cross-coupling can also include the use of a base, such as an amine base (e.g., Et3N), or an inorganic base (e.g., Cs2CO3, Na2CO3, K2CO3, etc.) and a solvent (e.g., dimethylformamide). According to Scheme 1, X is a suitable group for metal-mediated cross-coupling, such as a halogen or triflate group, and PG is an amine protecting group, which can be selected from, but not limited to, a 9-fluorenylmethyloxycarbonyl ("Fmoc") group, a tert-butyloxycarbonyl ("Boc") group, a trityl ("Tr") group, an allyloxycarbonyl ("Alloc") group, a benzyloxycarbonyl ("Cbz") group, and the like.

[0319] Representative examples of the process steps shown in Scheme 1 are provided below in Schemes 2A-2F. Methods similar to those shown in Scheme 2A can be used to prepare other compound embodiments disclosed herein (by replacing the propargyl alcohol in Scheme 2A with the corresponding alkynyl groups that produce such compounds); further modifications that can be used to obtain the final structures of such compounds are discussed below.

[0320]

[0321]

[0322] Once the cross-coupling product 104 is prepared, it can be subjected to an optional linker group reduction step, wherein a linker group containing one or more unsaturated sites can be reduced to a saturated linker and / or a linker with less unsaturation. If a linker reducing group is used, a deprotection step can then be performed, followed by an amide formation step, as shown in Scheme 3. Alternatively, if a linker reduction step is not used, the cross-coupling product 104 can be deprotected and converted to an amide compound 302.

[0323]

[0324] According to Scheme 3, an optional linker reduction step can be performed. For example, if the linker contains an unsaturated site (e.g., a double bond or a triple bond), the unsaturated site can be reduced so that it becomes fully saturated (e.g., such as reducing a double bond and / or a triple bond to a single bond) or it has little unsaturation (e.g., reducing a triple bond to a double bond). One of ordinary skill in the art with the benefit of this disclosure understands suitable reagents for performing such optional linker reduction steps; however, one set of exemplary conditions includes exposing the cross-coupling product 104 to H2 in the presence of palladium on carbon. Because these steps are optional, they do not need to be performed in all embodiments. Instead, in some embodiments, the cross-coupling product 104 can be deprotected to provide an amine, which is then converted to an amide compound 302 by reacting the amine with a suitable acid coupling partner 300, as shown in Scheme 3.

[0325] Representative examples of the process steps shown in Scheme 3 are provided in Schemes 4A-4D below. Methods similar to those described in Scheme 4A can be used to prepare other compounds disclosed herein. Certain compounds can be further functionalized as described below.

[0326]

[0327]

[0328]

[0329]

[0330] In some embodiments, the method can further include performing one or more additional modifications on amide compound 302 to provide amide compound 500, such as modifying R 6 Groups to form different R 6 Group, as shown in Scheme 5.

[0331]

[0332] According to Scheme 5, R6 For example, if R 6 is an ester group, which can be converted to a carboxylic acid or a primary alcohol. One of ordinary skill in the art with the benefit of this disclosure will appreciate suitable reagents for carrying out such optional modification steps; however, one exemplary set of conditions includes converting R 6 The ester group is exposed to LiOH to provide the corresponding acid. By using suitable amide coupling conditions (such as those described above) in combination with an amine coupling partner, the resulting acid can even be further modified to provide an amide-containing product. Similar methods can be used to prepare compound embodiments disclosed herein (wherein the double bond of the linker is not first reduced prior to coupling). In yet other embodiments, compound embodiments comprising an alkyne with a terminal OH group can be prepared by converting the terminal alcohol obtained in the above method into a functionalized alcohol.

[0333] Many exemplary disclosed compounds are alkynyl substituted analogs. These compounds can be prepared using metal-mediated coupling strategies as discussed above in accordance with Scheme 1. Scheme 6 illustrates a more detailed general method for preparing alkynyl substituted analogs according to the present disclosure.

[0334]

[0335] According to Scheme 6, nitrogen is bubbled through a stirred solution of an aryl halide (1 eq.), compound 700, CuI (0.1-0.2 eq.), and Pd(PPh3)4 (0.05-0.1 eq.) in dry DMF (3-4 mL / mmol) in a vial for 3 minutes. Subsequently, NEt3 (10 eq.) is added to the dark reaction solution, followed by the corresponding alkyne (1.5-3 eq.), compound 702 in rapid succession. Nitrogen is bubbled through the reaction mixture for 2 minutes and the vial is capped. The reaction mixture is stirred at an effective reaction temperature, such as 70-90°C, for an effective reaction time, such as 3-6 hours. Alternatively, the reaction mixture can be heated in a microwave reactor (30-45 minutes) until the aryl halide 700 is consumed. The dark reaction solution was treated by one of the following methods: a) post-treatment with dilution with ice-water / organic solvent; b) concentration to dryness followed by post-treatment with dilution with ice-water / organic solvent; or c) the crude residue was diluted with ice-water, sonicated and the slurry was allowed to warm to room temperature. The resulting grey / black solid was collected by filtration, drained, dissolved in THF (20 mL), filtered through a celite® / silica gel pad, and the pad was washed with THF. The crude material was then purified by reverse phase column chromatography or by normal phase silica gel flash column chromatography to provide the corresponding alkynyl substituted analog (yield: 25-69%), compound 704.

[0336] IV. Methods of Using the Compounds

[0337] A. Disease / lesion

[0338] The disclosed compounds and combinations and / or pharmaceutical compositions can be used to In vivo or In vitro Contact with one or more compounds of the present disclosure or a composition comprising one or more compounds of the present disclosure to inhibit RIP1 kinase. One or more compounds disclosed, or a composition comprising one or more compounds disclosed, can also be used to improve, treat or prevent a variety of diseases and / or lesions. In certain embodiments, the disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof can be used to treat conditions in which inhibition of RIP1 or pathways involving RIP1 is therapeutically useful. In some embodiments, the compounds directly inhibit RIP1 kinase activity. In certain embodiments, the disclosed compounds can be used to treat autoimmune diseases, inflammatory lesions, cardiovascular diseases, neuropathy, neurodegenerative lesions, allergic lesions, respiratory diseases, kidney diseases, cancers, ischemic conditions, red blood cell defects, lung and brain injuries (e.g., caused by ischemia-reperfusion or cisplatin and / or cerebrovascular accidents), and bacterial and viral infections.

[0339] In some embodiments, the disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof can be used to treat or prevent allergic diseases, amyotrophic lateral sclerosis (ALS), spinal muscular atrophy, systemic lupus erythematosus, rheumatoid arthritis, type I diabetes, inflammatory bowel disease including Crohn's disease and ulcerative colitis, biliary cirrhosis, uveitis, multiple sclerosis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmune myositis, Wegener's granulomatosis, ichthyosis, Graves' ophthalmopathy, or asthma.

[0340] The disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof may also be used to treat immunomodulatory lesions associated with bone marrow or organ transplant rejection or graft-versus-host disease. Examples of inflammatory and immunomodulatory lesions that may be treated with the compounds (or pharmaceutical compositions or combinations thereof) include, but are not limited to, organ or tissue transplantation, graft-versus-host disease caused by transplantation, autoimmune syndromes including rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, systemic sclerosis, systemic inflammatory response syndrome, myasthenia gravis, type I diabetes, uveitis, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, post-infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis, inflammatory and hyperproliferative skin diseases. , such as psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, bullous epidermolysis, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia, lupus erythematosus, acne, alopecia areata, keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, keratoconus, corneal epithelial dystrophy, corneal leukoplakia, ocular pemphigus, phagocytic corneal ulcer, scleritis, Graves' ophthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, pollen allergy, reversible inhibitory Obstructive airway disease, bronchial asthma, allergic asthma, intrinsic asthma, exogenous asthma, dust asthma, chronic or refractory asthma, late-onset asthma and airway hyperresponsiveness, bronchitis, gastric ulcer, vascular damage and thrombosis caused by ischemic disease, ischemic bowel disease, ischemia-reperfusion injury, inflammatory bowel disease, necrotizing enterocolitis, intestinal lesions associated with thermal burns, celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, migraine, rhinitis, eczema, interstitial nephritis, Goodpasture syndrome, hemolytic urine septic syndrome, diabetic nephropathy, polymyositis, Guillain-Barré syndrome, Meniere's disease, polyneuritis, polyneuritis, mononeuritis, radiculopathy, hyperthyroidism, Brazilian disease, pure red cell aplasia, aplastic anemia, aplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, erythropoiesis, osteoporosis, sarcoidosis, fibrotic lung, idiopathic interstitial pneumonia, dermatomyositis, vitiligo vulgaris, ichthyosis vulgaris, photosensitivity, cutaneous T-cell lymphoma, chronic lymphocytic leukemia, arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, cardiomyopathy or myocardial infarction, scleroderma (including systemic scleroderma), antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, obesity, eosinophilic fasciitis;Lesions of gums, periodontal tissues, alveolar bone, cementum, glomerulonephritis, male pattern baldness or senile alopecia by preventing hair loss or providing hair germination and / or promoting hair generation and hair growth, muscular dystrophy, pyoderma and Sezary syndrome, Addison's disease; ischemia-reperfusion injury during organ preservation, transplantation or ischemic disease, endotoxin shock, pseudomembranous colitis, colitis caused by drugs or radiation, ischemic acute renal failure, chronic renal failure, toxic diseases caused by pulmonary oxygen or drugs, lung cancer, emphysema, cataracts, siderosis, pigmented retinitis, retinal degeneration, retinal detachment, age-related macular degeneration, vitreous scar, corneal alkali burns, dermatitis multiforme erythema, linear IgA Bullous dermatitis and cement dermatitis, gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by environmental pollution, aging, carcinogenesis, metastasis and hypotension, diseases caused by histamine or leukotriene-C4 release, Behcet's disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, partial hepatectomy, acute liver necrosis, necrosis caused by toxins, viral hepatitis, shock, or hypoxia, hepatitis B, non-A / non-B hepatitis, cirrhosis, alcoholic liver disease, including alcoholic cirrhosis, alcoholic fatty liver hepatitis, nonalcoholic steatohepatitis (NASH), autoimmune hepatobiliary disease, acetaminophen toxicity, hepatotoxicity, liver failure, fulminant liver failure, delayed liver failure, "acute-on-chronic" liver failure, chronic kidney disease, kidney damage / injury (caused by, for example, nephritis, kidney transplantation, surgery, administration of nephrotoxic drugs, acute kidney injury), enhanced chemotherapy effects, cytomegalovirus infection, HCMV infection, AIDS, cancer, Alzheimer's disease, Parkinson's disease, trauma, or chronic bacterial infection.;

[0341] In certain embodiments, the compounds of the invention are useful for treating neurological pain, including neuropathic pain and pain resulting from inflammation.

[0342] In certain embodiments, the compounds are used to treat interleukin-1 converting enzyme-associated febrile syndrome, tumor necrosis factor receptor-associated periodic syndrome, NEMO-deficiency syndrome, HOIL-1 deficiency, linear ubiquitin chain assembly complex deficiency syndrome, lysosomal storage diseases (e.g., Gaucher disease, GM2 gangliosidosis, α-mannose storage disease, aspartylglucosaminuria, cholesterol ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Farber disease, fucosidosis, galactosialidosis, GM1 Gangliosidosis, mucolipidosis, free sialic acid storage disease of infancy, juvenile hexosamine esterase A deficiency, Krabbe disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidosis, multiple sulfatase deficiency, Niemann-Pick disease, neuronal ceroid lipofuscinosis, Pompe disease, pycnodysostosis, Sandhoff disease, Schindler disease, sialic acid storage diseases, Tay-Sachs disease, and Wolman disease).

[0343] In certain embodiments, the disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof are useful for treating and / or preventing rheumatoid arthritis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, lupus nephritis, ankylosing spondylitis, osteoporosis, systemic sclerosis, multiple sclerosis, psoriasis, particularly pustular psoriasis, type I diabetes, type II diabetes, inflammatory bowel disease (Crohn's disease and ulcerative colitis), hyperimmunoglobulinemia and periodic fever syndromes, cryopyrin-associated periodic syndromes, Schnitzler's syndrome, systemic juvenile idiopathic arthritis, adult 's onset Still's disease, gout, gouty flare, pseudogout, sapho syndrome, Castleman's disease, sepsis, stroke, atherosclerosis, celiac disease, DIRA (IL-1 receptor antagonist deficiency), Alzheimer's disease, Huntington's disease, or Parkinson's disease.

[0344] Proliferative diseases that can be treated by the disclosed compounds include hyperproliferative skin lesions and benign and malignant tumors, solid tumors, brain cancer, kidney cancer, liver cancer, adrenal cancer, bladder cancer, breast cancer, stomach cancer, gastric tumors, ovarian cancer, colon cancer, rectal cancer, prostate cancer, pancreatic cancer, lung cancer, vaginal cancer, cervical cancer, testicular cancer, genitourinary tract cancer, esophageal cancer, laryngeal cancer, skin cancer, bone cancer or thyroid cancer, sarcoma, glioblastoma, neuroblastoma, multiple sclerosis, myeloma ... Myeloma, gastrointestinal cancer, especially colon cancer or colorectal adenoma, head and neck tumors, epidermal hyperplasia, psoriasis, prostatic hyperplasia, neoplasia, epithelial neoplasia, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma, Hodgkin and non-Hodgkin, breast cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, IL-1 driven lesions, MyD88 driven lesions (such as ABC diffuse large B -cell lymphoma (DLBCL) and Waldenström's macroglobulinemia), Hodgkin's lymphoma, primary cutaneous T-cell lymphoma or chronic lymphocytic leukemia), smoldering or indolent multiple myeloma, or hematologic malignancies (including leukemia, acute myeloid leukemia (AML), DLBCL, ABCDLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, myelodysplastic syndrome (MDS), myelofibrosis, polycythemia vera, Kaposi's sarcoma, Waldenström's macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, intravascular large B-cell lymphoma). In particular, the compounds of the present disclosure may be used to treat drug-resistant malignancies, such as those resistant to the JAK inhibitor ibrutinib, including ibrutinib-resistant hematological malignancies, such as ibrutinib-resistant CLL and ibrutinib-resistant Waldenström's macroglobulinemia.

[0345] Examples of allergic pathologies that can be treated using the disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof include, but are not limited to, asthma (e.g., atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, non-atopic asthma, bronchial asthma, non-allergic asthma, essential asthma, true asthma, intrinsic asthma caused by pathophysiological disorders, essential asthma of unknown or unexplained cause, emphysematous asthma, exercise-induced asthma, emotion-induced asthma, extrinsic asthma caused by environmental factors, cold air-induced asthma, occupational asthma, infectious asthma caused by or associated with bacterial, fungal, protozoan, or viral infection, incipient asthma, wheezing infant syndrome, bronchiolitis, cough variant asthma, or drug-induced asthma), allergic bronchopulmonary aspergillosis (ABPA) ), allergic rhinitis, perennial allergic rhinitis, perennial rhinitis, vasomotor rhinitis, postnasal drip, purulent or non-purulent sinusitis, acute or chronic sinusitis, and ethmoid, frontal, maxillary or sphenoid sinusitis.

[0346] As another example, rheumatoid arthritis (RA) generally causes swelling, pain, loss of motion and tenderness of target joints throughout the body. RA is characterized by a chronically inflamed synovium densely packed with lymphocytes. The synovium, usually a thick layer of cells, becomes densely packed with cells and presents a form similar to lymphoid tissue, including dendritic cells, T-, B- and NK cells, macrophages and plasma cell clusters. This process, as well as a variety of immunopathological mechanisms including the formation of antigen-immunoglobulin complexes, ultimately leads to the destruction of joint integrity, resulting in deformities at or near the joints, permanent loss of function and / or bone erosion. The disclosed compounds, combinations of disclosed compounds or pharmaceutical compositions thereof can be used to treat, improve or prevent any one, several or all of these symptoms of RA. Therefore, in the case of RA, when any symptom commonly associated with RA is alleviated or improved, the compound is considered to provide a therapeutic benefit, regardless of whether the treatment leads to a combined treatment of potential RA and / or reduces the amount of circulating rheumatoid factor ("RF").

[0347] The American College of Rheumatology (ACR) has established criteria for defining improvement and clinical remission in RA. Once such parameters are achieved, ACR20 (ACR criteria for 20% clinical improvement), a 20% improvement in tender and swollen joint counts, as well as a 20% improvement in 3 of the following 5 parameters is required: patient global assessment, physician global assessment, patient assessment of pain, degree of disability, and acute phase reactant levels. These criteria have been expanded to 50% and 70% improvement in ACR50 and ACR70, respectively. Other criteria include Paulu criteria and radiographic progression (e.g., Sharp score).

[0348] In some embodiments, a therapeutic benefit is obtained in a patient suffering from RA when the patient exhibits an ACR of 20. In specific embodiments, an ACR improvement of ACR 50 or even ACR 70 may be achieved.

[0349] In one embodiment, the compounds disclosed herein can be used to slow the onset of the consequences of aging. For example, the compounds of the present invention reduce the exacerbated chronic inflammation associated with advanced age ("inflammatory aging"). Numerous symptoms and conditions are associated with inflammatory aging, for example, such conditions that can be treated with the compounds of the present invention include neurodegenerative diseases, such as Parkinson's disease and Alzheimer's disease, hematopoietic tumors, and myeloproliferative diseases. Other conditions that can be treated or improved by the compounds of the present invention include those chronic inflammations (inflammatory aging) described by Franceschi C, Campisi J. and their potential contribution to age-related diseases. J Gerontol A Biol Sci Med Sci . 2014;69 Suppl 1:S4-S9. In another aspect, the compounds of the invention can be used to reduce the effects of aging on the reproductive system. For example, necroptosis induced by RIP1 signaling has been implicated in the aging of reproductive organs (Li et al. eLife 2017;6:e27692 and Chaudhary et al. Journal of Biomedical Science (2019) 26:11), and thus the compounds of the present invention may be used to treat symptoms associated with aging, such as decreased testosterone levels, decreased fertility, and prostate hyperplasia.

[0350] The compounds of the present invention are particularly useful in treating hyperproliferative lesions in combination with other therapies. The compounds of the present invention can be used in combination with standard of care to treat lesions such as cancer, leukemia and lymphoma. For example, myelodysplastic syndrome (MDS) can be treated with the compounds disclosed herein together with standard of care. Therapeutic agents used in combination with the compounds of the present invention include demethylating agents such as azacitidine and decitabine, and other chemotherapeutic agents such as cytarabine, daunorubicin and idarubicin. Immunomodulatory therapies such as lenalidomide and CAR-T therapy can also be used in combination with the compounds of the present invention for the treatment of MDS.

[0351] For specific embodiments, at least one compound according to the invention or a composition comprising at least one compound is administered to a subject suffering from or likely to develop atopic dermatitis. In another specific embodiment, at least one compound according to the invention or a composition comprising at least one compound is administered to a subject suffering from or likely to develop rheumatoid arthritis. In another specific embodiment, at least one compound according to the invention or a composition comprising at least one compound is administered to a subject suffering from or likely to develop ankylosing spondylitis. In another specific embodiment, at least one compound according to the invention or a composition comprising at least one compound is administered to a subject suffering from or likely to develop myelodysplastic syndrome.

[0352] Other diseases or conditions that can be treated and / or prevented using the compounds and compositions of the present invention include amyotrophic lateral sclerosis (ALS), autoimmune syndromes, rheumatoid arthritis, type I diabetes, inflammatory bowel disease, including Crohn's disease and ulcerative colitis, biliary cirrhosis, multiple sclerosis, Wegener's granulomatosis, ichthyosis, asthma, pollen allergy, reversible obstructive airway disease, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, chronic or refractory asthma, late-onset asthma and airway hyperresponsiveness, allergic rhinitis, spondyloarthritis, ankylosing spondylitis, autoimmune hepatitis, autoimmune hepatobiliary disease, cerebrovascular accident, allergic diseases, chronic obstructive pulmonary disease, emphysema, Friedreich's ataxia, Lewy body disease, diabetic neuropathy, polyglutamine (poly-Q) disease, Fahr's disease, Menke's disease, Wilson's disease, prion lesions, destructive bone lesions such as bone resorption disease, bone lesions associated with multiple myeloma; benign tumors, proliferative lesions, inflammatory rapidly proliferative skin lesions, epidermal hyperplasia, psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis, seborrheic dermatitis, pustular psoriasis, bullous dermatitis, dermatitis multiforme erythema, linear IgA bullous dermatitis, cement dermatitis, gingivitis, periodontitis; lesions of the gums, alveolar bone, and cementum, sepsis, pancreatitis, lichen planus, pemphigus, bullous pemphigoid, bullous epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia, obesity, eosinophilic fasciitis, acne, alopecia areata, male pattern baldness, senile alopecia, keratoconjunctivitis, vernal conjunctivitis, corneal alkali burns, Behcet's disease, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, keratoconus, corneal epithelial dystrophy, corneal leukoplakia, ocular pemphigus, erosive corneal ulcer, scleritis, Vogt-Koyanagi-Harada syndrome, blood system lesions, blood system malignancies, lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, breast cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, ABC diffuse large B -cell lymphoma (DLBCL), Waldenström's macroglobulinemia, primary cutaneous T-cell lymphoma, smoldering or indolent multiple myeloma, leukemia, acute myeloid leukemia (AML), DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, myelodysplastic syndrome (MDS), myelofibrosis, polycythemia vera, Kaposi's sarcoma, splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, intravascular large B-cell lymphoma, IL-1 driven lesions, MyD88 driven lesions, drug resistant malignancies, e.g. anti-JAKInhibitor-resistant malignancies and ibrutinib-resistant malignancies. Such as ibrutinib-resistant hematological malignancies, ibrutinib-resistant CLL and ibrutinib-resistant Waldenström's macroglobulinemia, acute myeloid leukemia, chronic myeloid leukemia; angiogenic lesions such as angiogenic lesions including solid tumors, ocular neovascularization; hemangiomas, such as infantile hemangiomas; sepsis, septic shock, shigellosis; migraine, bronchitis, gastric ulcer, necrotizing enterocolitis, intestinal lesions associated with thermal burns, celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, interleukin-1 converting enzyme-related febrile syndrome, tumor necrosis factor receptor-related periodic syndrome, NEMO-deficiency syndrome, HOIL-1 deficiency, linear ubiquitin chain assembly complex deficiency syndrome, lysosomal storage disease, Gaucher disease, GM2 Gangliosidosis, alpha-mannose storage disease, aspartylglucosaminuria, cholesterol ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Farber disease, fucosidosis, galactosialidosis, GM1 gangliosidosis, mucolipidosis, free sialic acid storage disease of infancy, juvenile hexosaminidase A deficiency, Krabbe disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidosis, multiple sulfatase deficiency, Niemann-Pick disease, neuronal ceroid lipofuscinosis, Pompe disease, pycnodysostosis, Sandhoff disease, Schindler disease, sialic acid storage disease, Tay-Sachs disease, Wolman disease, Huntington's disease, Parkinson's disease, neurodegenerative diseases, Huntington's disease, Parkinson's disease, metastatic melanoma, neurodegeneration associated with HIV infection and CMV retinitis, such as associated neurocognitive disorders or dementia, fibrotic conditions such as non-alcoholic steatohepatitis and cardiac conditions such as ischemia-reperfusion; allergies, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, erythematosus, chronic thyroiditis, Graves' disease, autoimmune gastritis, autoimmune neutropenia, thrombocytopenia, graft-versus-host disease, endotoxin-induced inflammatory response, tuberculosis, atherosclerosis, muscle degeneration, cachexia, Reiter's syndrome, rubella arthritis, acute synovitis, pancreatic beta-cell disease; Diseases characterized by heavy neutrophil infiltration; rheumatoid spondylitis, gouty arthritis, psoriatic arthritis, and other arthritic conditions, cerebral malaria, chronic inflammatory lung disease, silicosis, pulmonary sarcoidosis, fibrotic lung, idiopathic interstitial pneumonia, allograft rejection, bone marrow rejection, fever and myalgia caused by infection, keloid formation, scar tissue formation, heartburn, influenza, chronic myeloid leukemia; angiogenic lesions including solid tumors; viral diseases, including acute hepatitis infection(including hepatitis A, B and C), AIDS, ARC or malignant tumors, herpes; Stroke, myocardial infarction, arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, myocardial ischemia, ischemia during stroke heart attack, organ hypoxia, angiogenesis, cardiac and renal reperfusion injury, ischemia reperfusion injury during organ preservation, transplantation or ischemic disease, cardiac hypertrophy, thrombin-induced platelet aggregation, endotoxemia and / or toxic shock syndrome, conditions related to prostaglandin endoperoxidase synthase-2, pemphigus vulgaris, autoimmune / polymyositis, dermatomyositis, vitiligo vulgaris, photosensitivity, ischemia reperfusion injury, cardiac ischemia reperfusion injury caused by myocardial infarction, multiple system atrophy, Parkinson's syndrome, frontotemporal dementia, intracranial hemorrhage, cerebral hemorrhage, progressive muscular atrophy, pseudobulbar palsy, progressive bulbar palsy, spinal muscular atrophy, hereditary muscular atrophy, peripheral neuropathy, progressive supranuclear palsy, corticobasal degeneration, demyelinating disease, Systemic juvenile idiopathic arthritis (SoJIA) or Still's disease, systemic lupus erythematosus (SLE), Sjögren's syndrome, antiphospholipid syndrome (APS), primary sclerosing cholangitis (PSC), kidney transplant, surgery, acute kidney injury (AKI), systemic inflammatory response syndrome (SIRS), cytokine release syndrome (CRS), acute respiratory distress syndrome (ARDS), ARDS caused by COVID-19, post-infectious autoimmune disease, rheumatic fever, post-infectious glomerulonephritis, systemic sclerosis, cerebrovascular accident (CVA), chronic obstructive pulmonary disease (COPD), NEMO-deficiency syndrome (F-kappa-B essential regulator gene (also known as IKK gamma or IKKG) deficiency syndrome), solid organ malignancies, lysosomal storage diseases, glaucoma, retinal degenerative diseases, retinal ischemia / reperfusion injury, renal ischemia-reperfusion injury, cataracts, siderosis, retinitis pigmentosa, retinal degeneration, retinal detachment, age-related macular degeneration, vitreous scarring, septic shock caused by anthrax lethal toxin, LPSCaused by cell death, infectious encephalopathy, encephalitis, allergic encephalomyelitis, autoimmune uveoretinitis, giant cell arteritis, regional enteritis, granulomatous enteritis, distal ileitis, regional ileitis, terminal ileitis, insulin-dependent diabetes mellitus, scleroderma, systemic scleroderma, macular edema, diabetic retinopathy, central halo-shaped retinal choroidal dystrophy, BEST disease, adult yolk disease, pattern dystrophy, myopic degeneration, central serous retinopathy, Stargardt disease, cone-rod dystrophy, North Carolina dystrophy, infectious retinitis, inflammatory retinitis, uveitis, Posterior uveitis, toxic retinitis and phototoxicity, macular edema, central halo choroidal dystrophy, BEST disease, adult vitelliform disease, pattern dystrophy, optic nerve injury, optic neuritis, optic neuropathy, central retinal artery occlusion, ischemic optic neuropathy (e.g., arteritic or nonarteritic anterior ischemic neuropathy and posterior ischemic optic neuropathy), compressive optic neuropathy, infiltrative optic neuropathy, traumatic optic neuropathy, mitochondrial optic neuropathy (e.g., Leber's optic neuropathy), nutritional optic neuropathy, toxic optic neuropathy and hereditary optic neuropathy, dominant optic atrophy, Behr syndrome, Creutzfeldt-Jakob disease), progressive supranuclear palsy, hereditary spastic paresis, subarachnoid hemorrhage, perinatal brain injury, subclinical brain injury, spinal cord injury, hypoxic-ischemic brain injury, cerebral ischemia, focal cerebral ischemia, global cerebral ischemia, and hypoxic hypoxia, peritoneal dialysis fluid-induced peritoneal injury (PDF) and PD-related side effects, glomerular disease, tubulointerstitial disease, interstitial nephritis, obstruction, polycystic kidney disease), focal glomerulosclerosis, immune complex nephropathy, diabetic nephropathy, Goodpasture syndrome, hepatocellular carcinoma,pancreatic cancer, urinary system cancer, bladder cancer, colorectal cancer, colon cancer, breast cancer, prostate cancer, prostatic hyperplasia, kidney cancer, renal cancer, liver cancer, adrenal cancer, thyroid cancer, gallbladder cancer, peritoneal cancer, ovarian cancer, cervical cancer, gastric cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, neuroendocrine cancer, CNS cancer, brain tumors (e.g., brain cancer, glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma), bone cancer, soft tissue sarcoma, retinoblastoma, neuroblastoma, peritoneal effusion, malignant pleural effusion, mesothelioma, Wilms' tumor, trophoblastic tumor, epithelial neoplasia, gastric cancer, ovarian cancer, rectal cancer, prostate cancer, pancreatic cancer, lung cancer, vaginal cancer, cervical cancer, testicular cancer, genitourinary tract cancer, esophageal cancer, Laryngeal cancer, skin cancer, bone cancer, thyroid cancer, sarcoma, glioblastoma, neuroblastoma, gastrointestinal cancer, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma, colon cancer, colorectal adenoma, hemangiopericytoma, myxoid carcinoma, round cell carcinoma, squamous cell carcinoma, esophageal squamous cell carcinoma, oral cancer, vulvar cancer, adrenal cortical carcinoma, ACTH-producing tumors, and leukemia, respiratory tract infection viruses, such as influenza virus, rhinovirus, coronavirus, parainfluenza virus, RS virus, adenovirus, reovirus, etc.), herpes zoster caused by herpes virus, diarrhea caused by rotavirus, viral hepatitis, AIDS, bacterial infectious diseases, such as Bacillus cereus, Vibrio parahaemolyticus, enterohemorrhagic Escherichia coli, Staphylococcus aureus, MRS A, Salmonella, Clostridium botulinum, Candida ；Paget's disease, achondroplasia, osteochondritis, hyperparathyroidism, osteogenesis imperfecta, partial hepatectomy, acute hepatic necrosis, toxin-induced necrosis, viral hepatitis-induced necrosis, shock-induced necrosis, hypoxia-induced necrosis, viral hepatitis B, non-A / non-B hepatitis, cirrhosis, alcoholic liver disease, alcoholic cirrhosis, alcoholic steatohepatitis, non-alcoholic steatohepatitis (NASH), acetaminophen toxicity, hepatotoxicity, liver failure, fulminant liver failure, delayed liver failure, "acute- "Chronic" liver failure, chronic kidney disease, renal damage / injury, renal damage / injury caused by nephritis, renal damage / injury caused by kidney transplantation, renal damage / injury caused by surgery, renal damage / injury caused by nephrotoxic administration, enhanced chemotherapy effect, cytomegalovirus infection, HCMV infection, AIDS, cancer, Alzheimer's disease, trauma, chronic bacterial infection, diseases caused by environmental pollution, aging, hypotension, diseases caused by histamine or leukotriene-C4 release, muscular dystrophy, pyoderma and Sezary syndrome, Addison's disease, pseudomembranous colitis, colitis caused by drugs or radiation, ischemic acute renal insufficiency, chronic renal insufficiency, pulmonary oxygen or drug-induced toxic diseases, congenital hypophosphatasia, fibromatosis, fibrous dysplasia, bone turnover, osteolytic bone disease, treatment of post-traumatic bone surgery, treatment of post-repair joint surgery, treatment of plastic surgery Post-bone surgery, post-dental surgery, bone chemotherapy or bone radiation therapy, bone cancer, vulnerable plaques, lesions, occlusive lesions, stenosis, coronary artery disease, peripheral arterial disease, arterial occlusion, aneurysm formation, post-traumatic aneurysm formation, restenosis, post-operative graft occlusion, Guillain-Barré syndrome, Meniere's disease, polyneuritis, polyneuritis, mononeuritis, radiculopathy, hyperthyroidism, Brazilian disease, autoimmune idiopathic thrombocytopenic purpura (autoimmune ITP), membranous nephritis, autoimmune thyroiditis, Hashimoto's thyroiditis, myasthenia gravis, cold and warm agglutinin diseases, Evan's syndrome, hemolytic uremic syndrome / thrombotic thrombocytopenic purpura (HUS / TTP), autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, erythropoiesis, and combinations thereof.

[0353] B. Formulation and Administration

[0354] Pharmaceutical compositions comprising one or more active compounds of the present disclosure can be prepared by any suitable method, such as mixing, dissolving, granulating, dragee manufacturing, grinding, emulsifying, encapsulating, embedding or lyophilizing processes. Pharmaceutical compositions can be formulated using one or more physiologically acceptable excipients (e.g., diluents, carriers or auxiliary agents), one or more adjuvants or combinations thereof to provide pharmaceutically acceptable preparations.

[0355] The one or more active compounds can be formulated into pharmaceutical compositions by themselves, or in the form of pharmaceutically acceptable salts, stereoisomers, N-oxides, tautomers, hydrates, solvates, isotopes or prodrugs thereof. Generally, such salts are more soluble in aqueous solution than the corresponding free acids and bases, but salts with lower solubility than the corresponding free acids and bases may also be formed.

[0356] The pharmaceutical compositions of the present disclosure may take a form suitable for nearly any mode of administration including, for example, topical, ocular, oral, buccal, systemic, nasal, injectable such as iv or ip, transdermal, rectal, vaginal, etc., or in a form suitable for administration by inhalation or insufflation.

[0357] For topical administration, one or more active compounds, pharmaceutically acceptable salts, stereoisomers, N-oxides, tautomers, hydrates, solvates, isotopes or prodrugs can be formulated into solutions, gels, ointments, creams, suspensions, etc., as known in the art.

[0358] Systemic formulations include those designed for administration by injection, such as subcutaneous, intravenous, intramuscular, intrathecal, or intraperitoneal injection, as well as those designed for transdermal, transmucosal oral, or pulmonary administration.

[0359] Useful injection preparations include sterile suspensions, solutions or emulsions of one or more active compounds in aqueous or oily vehicles. The pharmaceutical composition may also include preparatons, such as suspending agents, stabilizers and / or dispersants. Injection preparations may be present in unit dosage form, such as in ampoules or multidose containers, and may include added preservatives.

[0360] Alternatively, the injection preparation may be provided in powder form for reconstitution with a suitable vehicle prior to use, including but not limited to sterile, pyrogen-free water, buffer, dextrose solution, etc. To this end, one or more active compounds may be dried by any technique known in the art (e.g., lyophilization) and reconstituted prior to use.

[0361] For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are known in the art.

[0362] For oral administration, the pharmaceutical composition can take the form of, for example, lozenges, tablets or capsules, prepared by conventional methods with pharmaceutically acceptable excipients such as: binders (e.g., pregelatinized corn starch, polyvinyl pyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silicon dioxide); disintegrants (e.g., potato starch or sodium starch glycolate); and / or wetting agents (e.g., sodium lauryl sulfate). Tablets can be coated with, for example, sugar, film or enteric coatings by methods well known in the art.

[0363] Liquid preparations for oral administration may take the form of, for example, elixirs, solutions, syrups or suspensions, or they may be presented as dry products for constitution with water or other suitable vehicles before use. Such liquid preparations may be prepared by conventional methods using pharmaceutically acceptable excipients such as: suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifiers (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethanol, cremophore TM or fractionated vegetable oils); and preservatives (e.g., methyl or propyl p-hydroxybenzoate or sorbic acid). The preparations may also contain buffer salts, preservatives, flavoring agents, coloring agents and sweeteners as appropriate.

[0364] Preparations for oral administration may be suitably formulated to give controlled release of the active compound, as is well known.

[0365] For buccal administration, the pharmaceutical compositions may take the form of tablets or lozenges formulated in conventional manner.

[0366] For rectal and vaginal routes of administration, the active compound or compounds may be formulated as solutions (for retention enemas), suppositories, or ointments containing conventional suppository bases such as cocoa butter or other glycerides.

[0367] For nasal administration or administration by inhalation or insufflation, one or more active compounds, pharmaceutically acceptable salts, stereoisomers, N-oxides, tautomers, hydrates, solvates, isotopes or prodrugs can be conveniently delivered in the form of an aerosol spray from a pressurized package or nebulizer using a suitable propellant (e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, fluorocarbons, carbon dioxide or other suitable gases). In the case of a pressurized aerosol, the dosage unit can be determined by providing a valve to deliver a metered amount. Capsules and cartridges for use in an inhaler or insufflator (e.g., capsules and cartridges consisting of gelatin) can be formulated as a powder mix containing the compound and a suitable powder base (e.g., lactose or starch).

[0368] A specific example of an aqueous suspension formulation suitable for nasal administration using a commercially available nasal spray device comprises the following ingredients: active compound (0.5 20 mg / ml); benzalkonium chloride (0.1 0.2 mg / mL); polysorbate 80 (TWEEN ® 80; 0.5 5 mg / ml); sodium carboxymethylcellulose or microcrystalline cellulose (1 15 mg / ml); phenylethyl alcohol (1 4 mg / ml); and glucose (20 50 mg / ml). The pH of the final suspension can be adjusted to a range of about pH 5 to pH 7, with a typical pH of about pH 5.5.

[0369] Another specific example of an aqueous suspension suitable for administration of a compound by inhalation comprises 20 mg / mL of one or more disclosed compounds, 1% (v / v) polysorbate 80 (TWEEN ® 80), 50 mM citrate and / or 0.9% sodium chloride.

[0370] For ocular administration, one or more active compounds can be formulated into solutions, emulsions, suspensions, etc. suitable for administration to the eye. Various vehicles suitable for administering compounds to the eye are known in the art. Specific non-limiting examples are described in U.S. Pat. Nos. 6,261,547; 6,197,934; 6,056,950; 5,800,807; 5,776,445; 5,698,219; 5,521,222; 5,403,841; 5,077,033; 4,882,150; and 4,738,851, which are incorporated herein by reference.

[0371] For long-acting delivery, one or more active compounds can be formulated as reservoir preparations for use by implantation or intramuscular injection. Active ingredient can be formulated with suitable polymerization or hydrophobic material (e.g., as an emulsion in an acceptable oil) or ion exchange resin, or as a slightly soluble derivative, for example, as a slightly soluble salt. Alternatively, a transdermal delivery system manufactured as an adhesive disc (adhesive disc) or a patch for slowly releasing one or more active compounds for percutaneous absorption can be used. For this reason, a penetration enhancer can be used to promote the transdermal penetration of one or more active compounds. Suitable transdermal patches are described, for example, in U.S. Patent Nos. 5,407,713; 5,352,456; 5,332,213; 5,336,168; 5,290,561; 5,254,346; 5,164,189; 5,163,899; 5,088,977; 5,087,240; 5,008,110; and 4,921,475, which are incorporated herein by reference.

[0372] Alternatively, other drug delivery systems may be used. Liposomes and emulsions are well-known examples of delivery vehicles that can be used to deliver one or more active compounds. Certain organic solvents, such as dimethyl sulfoxide (DMSO), may also be used, although usually at the expense of greater toxicity.

[0373] If desired, the pharmaceutical composition may be present in a package or dispenser device which may contain one or more unit dosage forms containing the active compound. The package may, for example, comprise metal or plastic foil, such as a blister pack. The package or dispenser device may be accompanied by instructions for use.

[0374] There are several methods for transporting molecules across the blood-brain barrier. These include, but are not limited to, physical methods, lipid-based methods, and receptor and channel-based methods. Physical methods for transporting compounds across the blood-brain barrier include, but are not limited to, circumventing the blood-brain barrier entirely and / or creating openings in the blood-brain barrier. Methods of circumvention include, but are not limited to, direct injection (e.g., Papanastassiou et al., Gene Therapy 9:398-406, 2002), interstitial infusion / convection-enhanced delivery (Bobo et al., Proc. Natl. Acad. Sci. USA 91:2076-2080, 1994), and implantation of a delivery device in the brain (see, e.g., Gill et al., Nature Med. 9:589-595, 2003. Openings in the blood-brain barrier include, but are not limited to, ultrasound, osmotic pressure (e.g., by administration of hypertonic mannitol, and permeabilization by, e.g., bradykinin or opener A-7 (see, e.g., U.S. Pat. Nos. 5,112,596, 5,268,164, 5,506,206, and 5,686,416). The compound may also be encapsulated in liposomes coupled to antibody binding fragments that bind to receptors on the vascular endothelium of the blood-brain barrier.

[0375] For certain embodiments, the compound can be administered continuously by infusion into a fluid reservoir of the CNS or by bolus injection. The compound can be administered using an indwelling catheter and a continuous administration method (such as a pump) or by implanting a slow-release vehicle. For example, the compound can be injected through a long-term implanted cannula or infused for a long time with the aid of an osmotic mini-pump. A subcutaneous pump can deliver the compound to the ventricles of the brain.

[0376] C. Dosage

[0377] The disclosed compounds, pharmaceutical compositions, or combinations of disclosed compounds will generally be used in an amount effective to achieve the desired result, for example, in an amount effective to inhibit RIP1 kinase and / or treat, prevent, or improve a particular condition. The disclosed one or more compounds or pharmaceutical compositions thereof may be administered therapeutically to achieve a therapeutic benefit or prophylactically to achieve a preventive benefit. The therapeutic benefit means the eradication or improvement of the underlying lesion being treated and / or the eradication or improvement of one or more symptoms associated with the underlying lesion, so that although the patient may still be troubled by the underlying lesion, the patient reports that the sensation or condition has improved. For example, administering a compound to a patient with allergies provides a therapeutic benefit not only in eradicating or improving the underlying allergic reaction, but also in reporting a decrease in the severity or duration of symptoms associated with the allergy after the patient is exposed to an allergen. As another example, the therapeutic benefit in the context of asthma includes an improvement in breathing after the onset of an asthma attack or a decrease in the frequency or severity of asthma attacks. Whether or not an improvement is achieved, the therapeutic benefit also includes preventing or slowing the progression of the disease.

[0378] As known to those of ordinary skill in the art, the preferred dosage of the disclosed compounds may depend on various factors, including age, weight, general health, and severity of the condition of the patient or subject being treated. When administered by inhalation, the dosage may also need to be adjusted according to the sex of the individual and / or the individual's lung capacity. The dosage may also be adjusted for individuals with more than one condition or for those with other conditions that affect lung capacity and normal breathing ability (e.g., emphysema, bronchitis, pneumonia, respiratory distress syndrome, chronic obstructive pulmonary disease, and respiratory tract infections). The dosage and frequency of administration of the disclosed one or more compounds or their pharmaceutical compositions will also depend on whether the disclosed one or more compounds are formulated for the treatment of acute attacks of the condition or for the preventive treatment of lesions. One of ordinary skill in the art will be able to determine the optimal dosage for a particular individual.

[0379] For prophylactic administration, the disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof may be administered to a patient or subject at risk of developing one of the aforementioned conditions. For example, if it is not known whether the patient or subject is allergic to a particular drug, the disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof may be administered prior to administration of the drug to avoid or improve allergic reactions to the drug. Alternatively, prophylactic administration may be used to avoid or improve the onset of symptoms in a patient diagnosed with a potential lesion. For example, one or more disclosed compounds or pharmaceutical compositions thereof may be administered to an allergy patient prior to expected exposure to an allergen. The disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof may also be prophylactically administered to healthy individuals who are repeatedly exposed to agents known to be one of the above-mentioned diseases to prevent the onset of lesions. For example, the disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof may be administered to healthy individuals who are repeatedly exposed to allergens known to induce allergies (such as latex) in an effort to prevent the individual from developing allergies. Alternatively, the disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof may be administered to a patient with asthma prior to participating in an activity that triggers an asthma attack to reduce the severity of an asthma attack or to avoid an asthma attack altogether.

[0380] Effective doses can be estimated initially from in vitro assays. For example, an initial dose for a subject can be formulated to achieve a circulating blood or serum concentration of the active compound that is equal to or greater than the IC of the particular compound measured in an in vitro assay. 50 or EC 50 The dose to achieve this circulating blood or serum concentration can be calculated taking into account the bioavailability of a particular compound. Additional guidance on effective doses is provided by Fingl & Woodbury, "General Principles", In: Goodman and Gilman, The Pharmaceutical Basis of Therapeutics, Chapter 1, pp. 1-46, Pergamon Press, and references cited therein.

[0381] In some embodiments, the disclosed compounds have an EC greater than 0 to 20 μM, such as greater than 0 to 10 μM, greater than 0 to 5 μM, greater than 0 to 1 μM, greater than 0 to 0.5 μM, greater than 0 to 0.1 μM, greater than 0 to 0.05 μM. 50 .

[0382] Initial doses can also be estimated from in vivo data, such as animal models. Animal models for testing the efficacy of compounds in treating or preventing the various diseases described above are well known in the art. Suitable animal models for hypersensitivity or allergic reactions are described in Foster, (1995) Allergy 50 (21 Suppl): 6-9, discussion 34-38 and Tumas et al., (2001), J. Allergy Clin. Immunol. 107 (6): 1025-1033. Suitable animal models for allergic rhinitis are described in Szelenyi et al., (2000), Arzneimittelforschung 50 (11): 1037-42; Kawaguchi et al., (1994), Clin. Exp. Allergy 24 (3): 238-244 and Sugimoto et al., (2000), Immunopharmacology 48 (1): 1-7. One of ordinary skill in the art can adjust this information to determine a dose suitable for human administration.

[0383] In some embodiments, an assay suitable for determining RIP1 activity may be used. Such assays may be used to assess the efficacy of the compound embodiments disclosed herein and / or may be used to determine the amount / dose of the compound embodiments that may provide a desired therapeutic effect. In some embodiments, the assay may be an ADP-Glo ​​assay that assesses the ability of the compound embodiments to inhibit RIP1. TM In other embodiments, whole cell assays using mouse and / or human cells, such as U937 and / or L929 cell necroptosis assays, can be performed to determine whether the cell-mediated apoptosis of the cell line can be used in humans. in vivo Using these whole cell assays, the activity of compounds against human and / or murine RIP1 can be assessed in an in vitro setting, which then allows one of ordinary skill in the art to determine the safe and effective doses of compounds for use in the assay. in vivo A safe and effective dose for use. Another assay that can be used to evaluate the activity of the compound embodiments described herein for treating a disease or condition involving RIP1 is an acute hypothermic mouse model that evaluates the ability of a compound to inhibit TNF-α-induced hypothermia. Each of these assays and various results from using these assays are described in detail in the Examples section of this disclosure.

[0384] The dosage of the disclosed compound is generally in the following range: from greater than 0 mg / kg / day, such as 0.0001 mg / kg / day or 0.001 mg / kg / day or 0.01 mg / kg / day, to up to at least about 100 mg / kg / day. More typically, the dosage (or effective amount) can be in the range of about 0.0025 mg / kg to about 1 mg / kg at least once a day, such as 0.01 mg / kg to about 0.5 mg / kg or about 0.05 mg / kg / to about 0.15 mg / kg. The total daily dose is generally about 0.1 mg / kg to about 5 mg / kg or to about 20 mg / kg per day, such as 0.5 mg / kg to about 10 mg / kg per day or about 0.7 mg / kg to about 2.5 mg / kg / day per day. The dosage can be higher or lower, depending on, among other factors, the activity of the disclosed compound, its bioavailability, mode of administration, and various factors discussed above.

[0385] Doses and dosage intervals may be adjusted for an individual to provide plasma levels of the disclosed compounds sufficient to maintain a therapeutic or preventive effect. For example, the compounds may be administered once a day, multiple times a day, once a week, multiple times a week (e.g., every other day), once a month, multiple times a month, or once a year, depending, among other things, on the mode of administration, the specific indication for treatment, and the judgment of the prescribing physician. One of ordinary skill in the art will be able to optimize the effective topical dose without undue experimentation.

[0386] Pharmaceutical compositions comprising one or more disclosed compounds typically contain greater than 0 to as much as 99% of the disclosed one or more compounds and / or other therapeutic agents by total weight percentage. More typically, pharmaceutical compositions comprising one or more disclosed compounds contain about 1 to about 20 total weight percentages of the disclosed compounds and other therapeutic agents, and about 80 to about 99 weight percentages of pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition may further contain an adjuvant.

[0387] Preferably, the disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof will provide therapeutic or preventive benefits without causing significant toxicity. The toxicity of the disclosed compounds can be determined using standard pharmaceutical procedures. The dose ratio between toxicity and therapeutic (or preventive) effect is the therapeutic index. Disclosed compounds with high therapeutic indices are preferred.

[0388] V. Examples

[0389] Example 1

[0390] Scheme 7 provides a method for preparing 4-phenoxypyridine-2-carbonitrile and 4-phenoxypyridine-2-carboxylic acid.

[0391]

[0392] According to Scheme 7, cesium carbonate (20.58 g, 63.1 mmol, 1.1 eq) was added to a solution of 4-fluoropyridine-2-carbonitrile 90 (7.00 g, 57.4 mmol, 1.0 eq) and phenol 92 (5.66 g, 60.2 mmol, 1.05 eq) in dimethylformamide (90 mL). The reaction was heated to 80 °C for 8 hours and cooled. The reaction was poured into ice-water (1 L). A precipitate formed, which was isolated by filtration to give 4-phenoxypyridine-2-carbonitrile 94 (10.7 g, 95%) as a white solid; 1 Hnmr (400 MHz, CDCl3) δ 8.52 (1H, d, J 6.0 Hz, pyH-6), 7.50-7.45 (2H, m, 2H of C6H5), 7.33 (1H, tt, J 7.5, 1.0 Hz, 1H of C6H5), 7.20 (1H, d, J 2.0 Hz, pyH-3), 7.11-7.08 (2H, m, 2H of C6H5), 7.02 (1H, dd, J 5.5, 2.5 Hz, pyH-5); m / z : 197 [M+H] + .

[0393] Example 2

[0394] This example relates to a method for preparing 4-phenoxypyridine-2-carboxylic acid 96 from 4-phenoxypyridine-2-carbonitrile 94. A suspension of pyridine-2-carbonitrile 94 (10.7 g, 54.6 mmol) in hydrochloric acid (6M, 100 mL) was heated to 100 °C for 8 hours. The reaction was cooled to room temperature to form a precipitate which was isolated by filtration. The filtrate was cooled to produce additional solid which was isolated by filtration and added to the first batch. The solid was dried under vacuum to give 4-phenoxypyridine-2-carboxylic acid 96 (12.6 g, 92%) as a white solid; 1 H nmr (400 MHz, D6-DMSO) δ 8.64 (1H, d, J 6.0 Hz, pyH-6), 7.57-7.53 (3H, m, pyH-3, 2H of C6H5), 7.38 (1H, tt, J 7.5, 1.0 Hz, 1H of C6H5), 7.33 (1H, dd, J 6.0 2.5 Hz, pyH-5), 7.28-7.26 (2H, m, 2H of C6H5); m / z : 216 [M+H] + .

[0395] Example 3

[0396] This example relates to a method for preparing 5-(4-fluorophenoxy)pyridine-2-carboxylic acid. N-methylpyrrolidone (5 mL) was added to a mixture of methyl fluoropyridine-2-carboxylate (0.400 g, 2.58 mmol, 1.0 eq), 4-fluorophenol (0.318 g, 2.84 mmol, 1.1 eq) and cesium carbonate (0.925 g, 2.84 mmol, 1.1 eq). The reaction was stirred at 95 °C for 75 minutes. The reaction was cooled and added to ice water (150 mL) to form a precipitate. After stirring for 15 minutes, the precipitate (0.540 g, 85%) was isolated by filtration as a white solid; 1H nmr (400 MHz, CDCl3) δ 8.46 (1H, dd, J 3.0, 0.5 Hz, pyH-6), 8.09 (1H, dd, J 9.0 0.5 Hz, pyH-2), 7.24 (1H, dd, J 9.0, 3.0 Hz, pyH-4), 7.14-7.04 (4H, m, C6H4F), 3.99 (3H, s, OCH3); 19F nmr (380 MHz, CDCl3) δ -117.0; m / z: 248[M+H]+.

[0397] Lithium hydroxide aqueous solution (0.14g in 5mL water, 3.28mmol, 1.5eq) is added to a solution of methyl ester (0.54g, 2.19mmol, 1.0eq) in tetrahydrofuran (12mL). The reaction is stirred at room temperature for 35 minutes and concentrated to remove organic matter. The solution is diluted with water (5mL) and hydrochloric acid (3M, ~1mL) is added to pH~3. A white precipitate is produced, which is separated by filtration. In the filtrate, additional hydrochloric acid (3M, 10 drops) is added to form an additional precipitate, which is separated by filtration. The precipitates were combined and dried under vacuum to give the title compound (0.49 g, 75%) as a white solid; 1H nmr (400 MHz, D6-DMSO) δ8.43 (1H, dd, J 3.0, 0.5 Hz, pyH-6), 8.02 (1H, dd, J 8.5 0.5 Hz, pyH-2), 7.39 (1H, dd, J 8.5, 3.0 Hz, pyH-4), 7.33-7.22 (4H, m, C6H4F); 19F nmr (380 MHz, D6-DMSO) δ -117.7; m / z: 234 [M+H]+.

[0398] Example 4

[0399] This example relates to a method for preparing 4-cyclobutyloxypyridine-2-carboxylic acid, as shown in Scheme 8 below.

[0400]

[0401] A solution of cyclobutanol 102 (0.30 mL, 3.84 mmol, 1.2 eq) in tetrahydrofuran (20 mL) was cooled to 0 ° C. Sodium hydride (0.154 g of 60% suspension, 3.84 mmol, 1.2 eq) was added and the reaction was stirred at 0 ° C for 25 minutes. Fluoropyridine-2-carbonitrile 100 (0.390 g, 3.20 mmol, 1.0 eq) was added and the reaction was stirred at room temperature for 2 hours. The reaction was quenched by adding NH4Cl (5 mL). The reaction was diluted with EtOAc (80 mL) and washed with NaHCO3 (80 mL). The aqueous phase was extracted with EtOAc (30 mL). The combined organic matter was washed with brine (60 mL), dried (Na2SO4) and concentrated under reduced pressure. MPLC (10→60% EtOAc-hexanes) afforded 4-cyclobutyloxypyridine-2-carbonitrile 104 (0.487 g, 88%) as a colorless oil. 1 H nmr (400 MHz, CDCl3) δ 8.46 (1H, d, J 5.5 Hz, pyH-6), 7.10 (1H, d, J 2.5 Hz, pyH-3), 6.88 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 4.72 (1H, quintet, J 7.0 Hz, cBuH-1), 2.53-2.46 (2H, m, 2H of cBuH-2, H-4), 2.26-2.16 (2H, m, 2H of cBuH-2, H-4), 1.98-1.89 (1H, m, 1H of cBuH-3), 1.82-1.71 (1H, m, 1H of cBuH-3).

[0402] Hydrochloric acid (6M, 7 mL) was added to 4-cyclobutyloxypyridine-2-carbonitrile 104 (0.487 g, 2.80 mmol) and the reaction was heated to 100 °C for 18 hours. The reaction was cooled but no precipitation occurred. The solution was concentrated to dryness to give a beige solid 4-cyclobutyloxypyridine-2-carboxylic acid 106, which was used without further purification. 1H nmr (400 MHz, D6-DMSO) δ 8.66 (1H, d, J 6.5 Hz, pyH-6), 7.69 (1H, dd, J 2.5 Hz, pyH-3), 7.50 (1H, dd, J 6.5, 2.5 Hz, pyH-5), 5.12 (1H, quintet, J 7.0 Hz, cBuH-1), 2.53-2.46 (2H, m, 2H of cBuH-2, H-4), 2.19-2.09 (2H, m, 2H of cBuH-2, H-4), 1.88-1.80 (1H, m, 1H of cBuH-3), 1.75-1.65 (1H, m, 1H of cBuH-3); m / z : 194 [M+H] + .

[0403] A. Synthesis of tert-butyl 3-ethynyl-3-hydroxyazetidine-1-carboxylate

[0404]

[0405] A solution of (trimethylsilyl)acetylene 1302 (0.71 g, 1.00 mL, 6.28 mmol, 1.1 eq) in tetrahydrofuran (30 mL) was cooled to -78 °C and butyllithium (2.51 mL of a 2.5M solution in hexane, 6.28 mmol, 1.1 eq) was added dropwise. The reaction was stirred at -78 °C for 1 hour and then Boc-azetidinone 1300 (0.98 g, 5.71 mmol, 1.0 eq) was added. The reaction was stirred at -78 °C to room temperature for 20 hours and then quenched by adding NH4Cl (20 mL). The reaction was partitioned between EtOAc (100 mL) and NH4Cl-water (1:1, 100 mL). The organics were washed with brine (100 mL), dried (Na2SO4) and concentrated under reduced pressure.

[0406] The residue containing 1304 is dissolved in tetrahydrofuran (30 mL) and cooled to 0 ° C, then tetrabutylammonium fluoride trihydrate (1.80 g, 5.71 mmol, 1.0 eq) is added. The reaction is stirred at 0 ° C for 3 hours, and then NH4Cl (20 mL) is added. The reaction is distributed between EtOAc (100 mL) and NH4Cl-water (1: 1, 100 mL). Organic matter is washed with NH4Cl (100 mL) and brine (100 mL), dried (Na2SO4) and concentrated under reduced pressure to obtain 1306 as a light yellow oil. 1H nmr (400 MHz, CDCl3) δ 4.20 (2H, dd, J 9.0, 1.0 Hz, azetidine H-2, 2H of H-4), 4.02 (2H, dd, J 9.0, 1.0 Hz, azetidine H-2, 2H of H-4), 2.68 (1H, s, CCH), 1.44 (9H, s, C(CH3)3).

[0407] Example 5

[0408] This example provides the preparation of N-substituted-4-[(aryl)methyl]- 1H -pyrazole-1-carboxamide method.

[0409]

[0410] To a stirred heterogeneous mixture of 4-[(aryl)methyl]-1H-pyrazole hydrochloride 1400 (1 eq) and triphosgene (1.5 eq) in CH2Cl2 (15 mL / mmol) was added over time (15 min / mmol) under nitrogen at 0°C. i -Pr2NEt (5-9 eq). The red reaction solution was stirred at 0°C for 1 hour, warmed to room temperature (2 hours), analyzed by LC / MS for 4-[(aryl)methyl]-1H-pyrazole consumption and concentrated to dryness to give 1402. The red semi-solid concentrate was added to 1404 or the corresponding amine or its salt (1 eq) and DMAP (0.1 eq) and cooled in an ice bath under nitrogen. CH2Cl2 (15 mL / mmol) was added to the flask, stirred for 15 minutes and precipitated with i -Pr2NEt (5-9 eq) was treated with the stirred red solution over time (15 min / mmol). After 1 hour the ice bath was removed and the reaction solution was allowed to warm to room temperature. After analysis of the progress of the reaction, the reaction solution was concentrated to dryness, diluted with water and subjected to extractive workup with EtOAc or CH2Cl2. Silica gel flash column chromatography purification of the crude concentrate provided the requisite N-substituted-4-[(aryl)methyl]-1H-pyrazole-1-carboxamides 1406 (yields: 20-75%).

[0411] Example 6

[0412] This example provides a method for preparing N-substituted-4-[(aryl)methyl]-1H-pyrazole-1-carboxamides according to Scheme 11 via formation of an intermediate isocyanate.

[0413]

[0414] Under nitrogen, at 0°C, i -Pr2NEt (10-15 eq) was added over time (20 min / mmol) to a stirred heterogeneous mixture of compound 1420 or its corresponding amine or its salt (1 eq) and triphosgene (2.3 eq) in CH2Cl2 (15 mL / mmol). The light yellow reaction solution was stirred at 0°C for 1 hour, warmed to room temperature (2 hours), analyzed by LC / MS for consumption of the corresponding amine and concentrated to dryness. To the red semi-solid concentrate containing compound 1422 was added 4-[(aryl)methyl]-1H-pyrazole hydrochloride 1424 (0.9 eq) and DMAP (0.1 eq) and cooled in an ice bath under nitrogen. CH2Cl2 (15 mL / mmol) was added to the flask, stirred for 15 minutes and eluted with i -Pr2NEt (10-15 eq) was treated with the stirred red solution over time (15 min / mmol). After 1 hour, the ice bath was removed and the reaction solution was allowed to warm to room temperature (6-8 hours). After analytical progress, the reaction solution was concentrated to dryness, diluted with water and subjected to extractive workup using EtOAc or CH2Cl2. Silica gel flash column chromatography of the resulting crude product provided the requisite N-substituted-4-[(aryl)methyl]-1 H -pyrazole-1-carboxamide 1426 (yield: 19-73%).

[0415] Example 7

[0416] This example provides methods for preparing embodiments of the disclosed alkynyl substituted compounds according to Scheme 12.

[0417]

[0418] In a vial, nitrogen was bubbled through a stirred solution of aryl halide 1440 (1 eq) and CuI (0.1-0.2 eq), Pd(PPh3)4 (0.05-0.1 eq) in dry DMF (3-4 mL / mmol) for 3 min. Subsequently, NEt3 (10 eq) was added to the dark reaction solution followed by the corresponding alkyne 1442 (1.5-3 eq) in rapid succession. Nitrogen was bubbled through the reaction mixture for 2 min, the vial was capped, and the reaction mixture was stirred at 70-75 °C for 5-6 h. After the progress of the reaction was analyzed by LC / MS, the dark reaction solution was concentrated to dryness. The crude residue was diluted with ice-water, sonicated, and the slurry was warmed to room temperature. The resulting gray / black solid was collected by filtration, drained, dissolved in THF (20 mL), filtered through a celite® / silica pad, and the pad was washed with THF. After concentration of the filtrate, the crude material was purified by flash chromatography to afford alkynyl substituted analogs 1444 (yields: 25-69%).

[0419] Example 8

[0420] This example provides a method for preparing embodiments of the disclosed 4-[(aryl)methyl]-1H-pyrazole compounds according to Scheme 13.

[0421]

[0422] A stirred mixture of 1-boc-pyrazole-4-boronic acid pinacol ester 1450 (1 mmol), (chloromethyl)arene (1.3 mmol) 1452, XPhos-Pd-G2 (0.05 mmol) and K2CO3 (3-4 mmol) in 1,4-dioxane:H2O (9:1, 10 mL / mmole) was degassed by high vacuum and back-purged with argon in a balloon for three cycles over a period of 5-10 minutes and heated at 70-75°C for 2-6 hours. The reaction mixture was cooled and concentrated to dryness. The crude residue was diluted with EtOAc (or CH2Cl2), water and saturated aqueous Na2CO3 solution (6 mL / mmole). The organic layer was separated and the aqueous layer was extracted with EtOAc (or CH2Cl2). The combined organic layers were washed with aqueous NaCl solution, stirred over anhydrous Na2SO4, and filtered through celite®. After the filtrate was concentrated, the crude product was purified by silica gel chromatography to afford tert-butyl 4-[(aryl)methyl]-1H-pyrazole-1-carboxylate (yield 49-85%) 1454. 4.0 N HCl (5-7 eq) in 1,4-dioxane was added to 4-[(aryl)methyl]-1H-pyrazole-1-carboxylate at room temperature. H-pyrazole (1 eq) in a stirred solution of CH2Cl2 (3-6 mL / mmol). The reaction mixture was stirred until tert-butyl 4-[(aryl)methyl]-1H-pyrazole-1-carboxylate was exhausted and concentrated to dryness. The crude solid was sonicated in EtOAc (6-7 mL / mmol), filtered, washed with EtOAc on a funnel and blotted dry for a short time. Therefore, the collected semi-dried solid was further dried under high vacuum to give 4-[(aryl)methyl]-1H-pyrazole hydrochloride 1456 (80-98%), which was used in the next step without further purification (purity>95%).

[0423] Example 9

[0424] This example provides a general method for preparing (S)-N-(8-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-4-phenoxypyridine-2-amide (I-2) as shown in Scheme 14.

[0425]

[0426] ( S )- N -(8-Bromo-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-4-phenoxypyridine-2-carboxamide (71 mg, 0.152 mmol) – Data see below – 2-Chloropyridine-5-boronic acid pinacol ester (47 mg, 0.196 mmol), Pd(PPh3)4 (13 mg, 0.01 mmol), Cs2CO3 (149 mg, 0.456 mmol) in 1,4-dioxane (3 mL):water (0.3 mL) was heated to 75 °C after three vacuum degassing cycles followed by argon back purge. After 6 hours, the reaction mixture was cooled to room temperature, diluted with THF (10 mL) and filtered through Celite®. After concentration of the filtrate, the crude material was diluted with water (3 mL) and extracted into EtOAc (3 X 15 mL). After washing the combined organic layers with saturated aqueous NaCl solution (10 mL), stirring over anhydrous Na2SO4, purification filtration and concentration to dryness. The resulting crude material was dissolved in CH2Cl2 (2 mL), loaded onto hexane-treated silica gel in a cartridge and purified by flash chromatography [Combiflash ® Teledyne RediSep ®Hexane-conditioned silica gel column (12 G Gold) and eluted with 0-35% EtOAc / hexane solvent] to obtain ( S )- N -(8-(6-chloropyridin-3-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1 H -Benzo[ b ]azepine-3-yl)-4-phenoxypyridine-2-carboxamide (35 mg, 46%) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 8.85 (d, J = 7.8 Hz, 1H), 8.58 (dd, J = 2.6, 0.7 Hz, 1H), 8.43(dd, J = 5.6, 0.5Hz, 1H), 7.81 (dd, J = 8.3, 2.6 Hz, 1H), 7.60 (dd, J = 2.6, 0.5 Hz, 1H), 7.45 – 7.31 (m, 6H), 7.23 (ddt, J = 7.9, 7.0, 1.1 Hz, 1H), 7.10 – 7.02 (m, 2H), 6.93 (dd, J = 5.6, 2.6Hz, 1H), 4.68(dt, J = 11.3, 7.3 Hz, 1H), 3.48 (s, 3H), 3.02 – 2.87 (m, 1H), 2.79 – 2.64 (m, 2H), 2.19 – 2.04 (m, 1H). LCMS: purity 93%, MS (m / e) 500 (M+H) + The reaction conditions were similar to those of the Sonogashira reaction mentioned in the general procedure by using CuI (2.7 mg, 0.014 mmol) and Pd(PPh3)4 (8.1 mg, 0.007 mmol) in DMF (1 mL) at 90 °C in the presence of NEt3 (70 mg, 0.10 mL, 0.70 mmol). S )- N -(8-(6-chloropyridin-3-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1 H -Benzo[ b]azepine-3-yl)-4-phenoxypyridine-2-carboxamide (35 mg, 0.07 mmol) and 2-methyl-3-butyn-2-ol (9 mg, 0.01 mL, 0.11 mmol) were used to prepare ( S )- N -(8-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1 H -Benzo[ b ]azepine-3-yl)-4-phenoxypyridine-2-carboxamide (11 mg, 28%, white solid). 1 H NMR (400 MHz, CD2Cl2) δ 8.80 (dd, J = 2.4, 0.9 Hz, 1H), 8.77 (d, J = 7.6 Hz, 1H), 8.46(d, J = 5.6 Hz, 1H), 7.87 (dd, J = 8.1, 2.4 Hz, 1H), 7.70 – 7.59 (m, 2H), 7.59 – 7.49 (m, 3H), 7.49 – 7.38 (m, 6H), 7.32 – 7.24 (m, 1H), 7.14 – 7.06 (m, 2H), 6.97 (dd, J = 5.6, 2.6 Hz, 1H), 4.59 (dt, J = 11.1, 7.4 Hz, 1H), 3.47 (s, 3H), 3.03 – 2.89 (m, 1H), 2.78 – 2.64 (m, 2H), 2.27 (br s, 1H), 2.11 – 2.04 (m, 1H), 1.63 (s, 6H). LCMS: purity 92%, MS (m / e) 547 (M+H) + .

[0427] (±)-5-Benzyl-N-(8-bromo-1-methyl-2-oxo-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-1 H -1,2,4-triazole-3-carboxamide

[0428]

[0429] 1 H NMR (400 MHz, chloroform- d) δ 8.08 – 7.99 (m, 1H), 7.39 – 7.33 (m, 1H), 7.37 – 7.30 (m, 3H), 7.33 – 7.26 (m, 1H), 7.30 – 7.19 (m, 1H), 7.16 – 7.10 (m, 1H), 4.61 (dt, J = 11.5, 7.6 Hz, 1H), 4.15 (s, 2H), 3.41 (d, J = 0.3 Hz, 3H), 2.89 – 2.76 (m, 1H), 2.72 (dt, J = 12.1, 5.5 Hz, 1H), 2.64 (dt, J = 12.1, 6.2 Hz, 1H), 2.04 (td, J = 11.3, 7.2 Hz, 1H). LCMS: purity 98%, MS (m / e) 456 (M+H) + .

[0430] ( S )- N -(8-bromo-1-methyl-2-oxo-2,3,4,5-tetrahydro-1 H -Benzo[ b Azacycloheptatrien-3-yl)-4-(4-fluorobenzyl)-1 H -Pyrazole-1-carboxamide

[0431]

[0432] Path 2. 1 H NMR (400 MHz, chloroform- d ) δ 7.94 (d, J = 7.6 Hz, 1H), 7.86 (q, J = 0.9 Hz, 1H), 7.43 (d, J = 0.8 Hz, 1H), 7.34(dt, J = 4.4, 2.1 Hz, 2H), 7.17 – 7.08 (m, 3H), 7.02 – 6.92 (m, 2H), 4.46 (dt, J = 11.1, 7.4 Hz, 1H), 3.78 (s, 2H), 3.41 (s, 3H), 2.90 – 2.77 (m, 1H), 2.75 – 2.59 (m, 2H), 2.08 (td, J = 11.4, 7.6 Hz, 1H). 19F NMR (376 MHz, chloroform- d ) δ -116.86 (ddd, J = 14.2, 8.8, 5.5 Hz). LC / MS: purity 98%, MS (m / e) 492 (M+Na) + .

[0433] (±)- N -(3-bromo-9-methyl-8-oxo-6,7,8,9-tetrahydro-5 H -pyrido[2,3- b ]azepine-7-yl)-4-(4-fluorophenoxy)pyridine-2-carboxamide

[0434]

[0435] 1 H NMR (400 MHz, chloroform- d ) δ 8.90 (d, J = 7.4 Hz, 1H), 8.45 – 8.39 (m, 2H), 7.71 (d, J = 2.4 Hz, 1H), 7.56(d, J = 2.5 Hz, 1H), 7.14 – 6.98 (m, 4H), 6.90 (dd, J =5.6, 2.6 Hz, 1H), 4.58 (dt, J = 11.1, 7.1 Hz, 1H), 3.47 (s, 3H), 2.90 – 2.72 (m, 2H), 2.64 (p, J = 5.9, 5.5 Hz, 1H), 2.10(ddd, J = 12.4, 9.4, 5.9 Hz, 1H). 19 F NMR (376 MHz, chloroform- d ) δ -116.69 (ddd, J = 12.7, 8.2, 4.6 Hz). LCMS: purity 98%, MS (m / e) 586 (M+H) + .

[0436] ( S )- N -(8-bromo-2-oxo-2,3,4,5-tetrahydro-1 H -Benzo[ b ]azepine-3-yl)-4-(4-fluorophenoxy)pyridine-2-carboxamide

[0437]

[0438] 1 H NMR (400 MHz, dichloromethane- d 2) δ 8.68 (d, J = 7.5 Hz, 1H), 8.45 (d, J = 5.6 Hz, 1H), 7.56 (d, J = 2.5 Hz, 1H), 7.43 (s, 1H), 7.34 (dd, J = 8.1, 2.0 Hz, 1H), 7.23 –7.03 (m, 6H), 6.96 (dd, J = 5.6, 2.6 Hz, 1H), 4.60(dt, J = 11.2, 7.6 Hz, 1H), 3.02 – 2.89 (m, 1H), 2.84 – 2.66 (m, 2H), 2.16 – 2.02 (m, 1H). 19 F NMR (376 MHz, dichloromethane- d 2) δ -117.55 (ddd, J = 12.4, 8.2, 4.7 Hz). LCMS: purity 97%, MS (m / e) 471 (M+H) + .

[0439] Exemplary embodiments of compounds according to the present disclosure were prepared according to the disclosed synthetic schemes, and characterization data for these compounds are provided below.

[0440] (S)-4-(4-Fluorobenzyl)-N-(8-((3-hydroxyoxetan-3-yl)ethynyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-pyrazole-1-carboxamide (I-1)

[0441]

[0442] Path 3. 1 H NMR (400 MHz, chloroform- d ) δ 7.97 (d, J = 7.2 Hz, 1H), 7.85 (q, J = 0.9 Hz, 1H), 7.46 (d, J= 0.8 Hz, 1H), 7.35 – 7.30 (m, 2H), 7.19 – 7.08 (m, 3H), 7.02 – 6.92 (m, 2H), 4.94 (d, J = 6.9 Hz, 2H), 4.91 – 4.83 (m, 1H), 4.80 (dd, J = 6.6, 0.9 Hz, 2H), 4.70 (dd, J = 9.8, 7.2 Hz, 1H), 4.33 (dd, J = 11.3, 9.8 Hz, 1H), 3.78 (s, 2H), 3.43 (s, 3H), 2.60 (s, 1H). LC / MS: purity 94%, MS (m / e) 491 (M+H) + .

[0443] (±)-1-(2,6-dichlorobenzyl)- N -(1-methyl-2-oxo-8-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-1 H -1,2,4-Triazole-3-carboxamide (I-3)

[0444]

[0445] 1 H NMR (400 MHz, chloroform- d ) δ 8.25 (app d, J = 6.8 Hz, 2H), 8.11 (d, J = 7.4Hz, 1H), 7.95 (s, 1H), 7.42 (dd, J = 8.0, 0.9 Hz, 2H), 7.32 (dd, J = 8.9, 7.2 Hz, 1H), 7.19(d, J = 4.1 Hz, 3H), 6.69 – 6.62 (m, 2H), 5.70 (s, 2H), 4.69 (dt, J = 10.8, 7.4 Hz, 1H), 3.60 – 3.48 (m, 2H), 3.43 (s, 3H), 3.39 – 3.32 (m, 4H), 2.92 – 2.73 (m, 2H), 2.70 –2.59 (m, 3H), 2.58 (d, J= 5.2 Hz, 2H), 2.07 – 1.95 (m, 1H). LCMS: purity 93%, MS (m / e) 620 (M+H) + .

[0446] (±)-5-Benzyl- N -(1-methyl-2-oxo-8-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-1 H -1,2,4-Triazole-3-carboxamide (I-4)

[0447]

[0448] 1 H NMR (400 MHz, chloroform- d ) δ 8.25 (app d, J = 6.8 Hz, 2H), 8.12 (d, J = 7.7 Hz, 1H), 7.31 (d, J = 3.8 Hz, 4H), 7.27 – 7.14 (m, 7H), 6.70 – 6.62 (m, 2H), 4.66 (dt, J = 11.2, 7.6 Hz, 1H), 4.15 (s, 2H), 3.54 (s, 2H), 3.42 (s, 3H), 3.38 (t, J = 5.2 Hz, 4H), 2.86 (td, J = 12.3, 7.7 Hz, 2H), 2.80 – 2.67 (m, 2H), 2.67 – 2.62 (m, 2H), 2.59 (d, J =10.3 Hz, 4H), 2.06 (td, J = 11.4, 7.3 Hz, 1H). LCMS: purity 97%, MS (m / e) 551 (M+H) + .

[0449] (±)-1-(2,6-dichlorobenzyl)- N -(2-oxo-8-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-1 H -Benzo[b]azepine-3-yl)-1 H -1,2,4-Triazole-3-carboxamide (I-5)

[0450]

[0451] 1 H NMR (400 MHz, DMSO- d 6) δ 9.96 (s, 1H), 8.78 (s, 1H), 8.19 (d, J = 7.6 Hz, 1H), 8.13 – 8.07 (m, 2H), 7.53 (dd, J = 8.0, 0.9 Hz, 2H), 7.43 (dd, J = 8.9, 7.2 Hz, 1H), 7.24 (d, J = 7.6 Hz, 1H), 7.07 (dd, J = 7.6, 1.7 Hz, 1H), 6.97 (d, J = 1.6 Hz, 1H), 6.79 –6.73 (m, 2H), 5.65 (s, 2H), 4.26 (dt, J = 11.5, 7.8 Hz, 1H), 3.46 (app q, J = 13.3 Hz, 2H), 3.26 (m, 4H), 2.77 – 2.60 (m, 2H), 2.47 – 2.33 (m, 5H), 2.14 (td, J = 12.2, 7.2 Hz, 1H). LCMS: purity 95%, MS (m / e) 606 (M+H) + .

[0452] (±)-5-Benzyl-N-(2-oxo-8-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-1 H -1,2,4-Triazole-3-carboxamide (I-6)

[0453]

[0454] 1 H NMR (400 MHz, DMSO- d 6) δ 9.96 (s, 1H), 8.27 – 8.21 (m, 1H), 8.15 (d, J =7.1 Hz, 2H), 7.33 – 7.16 (m, 6H), 7.08 (dd, J= 7.7, 1.7 Hz, 1H), 7.00 – 6.92 (m, 3H), 4.30 (dt, J = 11.5, 7.9 Hz, 1H), 4.07 (s, 2H), 3.56 – 3.41 (m, 6H), 2.78 – 2.60 (m, 2H), 2.40 (ddd, J = 12.7, 7.9, 5.0 Hz, 3H), 2.19 (d, J = 8.3 Hz, 1H). LCMS: purity 94%, MS (m / e) 537 (M+H) + .

[0455] (±)-5-Benzyl- N -(2-oxo-8-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-1 H -1,2,4-Triazole-3-carboxamide (I-7)

[0456]

[0457] LCMS: purity 94%, MS (m / e) 629 (M-HCOOH+H) + .

[0458] (±)-5-Benzyl-N-(8-((5,6-dihydro-[1,2,4]triazolo[1,5- a ]Pyrazine-7(8 H )-1-methyl-2-oxo-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-1 H -1,2,4-Triazole-3-carboxamide (I-8)

[0459]

[0460] 1 H NMR (400 MHz, chloroform- d ) δ 11.74 (s, 1H), 8.07 (d, J = 7.6 Hz, 1H), 7.83 (s, 1H), 7.34 – 7.15 (m, 7H), 4.61 (d, J= 10.0 Hz, 1H), 4.19 (s, 2H), 4.13 (s, 2H), 3.80 (s, 2H), 3.74 (s, 2H), 3.39 (s, 3H), 2.99 (s, 2H), 2.83 (t, J = 10.6 Hz, 1H), 2.70 (s, 1H), 2.62 (s, 1H), 2.08 – 2.00 (m, 1H). LCMS: purity 94%, MS (m / e) 512 (M+H) + .

[0461] (±)-5-Benzyl- N -(2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-1 H -1,2,4-Triazole-3-carboxamide (I-9)

[0462]

[0463] LCMS: purity 95%, MS (m / e) 487 (M+H) + .

[0464] (S)-5-Benzyl-N-(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-1,2,4-triazole-3-carboxamide (I-10)

[0465]

[0466] 1 H NMR (400 MHz, methanol- d 4) δ 7.37 (s, 1H), 7.33 – 7.18 (m, 7H), 5.46 (app s, 1H), 4.48 (dd, J = 11.5, 7.8 Hz, 1H), 4.13 (s, 2H), 3.36 (s, 3H), 2.91 – 2.79 (m, 1H), 2.71 (dd, J = 13.7, 7.0 Hz, 1H), 2.50(tt, J = 13.5, 7.5 Hz, 1H), 2.14 (td, J= 12.2, 7.8 Hz, 1H), 1.54 (s, 6H). LCMS: purity 97%, MS (m / e) 440 (M-H2O+H) + .

[0467] (±)- N -(8-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-5-benzyl-1H-1,2,4-triazole-3-carboxamide (I-11)

[0468]

[0469] 1 H NMR (400 MHz, methanol- d 4) δ 7.34 – 7.17 (m, 5H), 7.10 (d, J = 8.4 Hz, 1H), 6.79 – 6.69 (m, 2H), 4.53 (dd, J = 11.4, 7.8 Hz, 1H), 4.13 (s, 2H), 3.62 (t, J = 5.6 Hz, 2H), 3.36 (s, 3H), 3.22 – 3.11 (m, 7H), 2.72 (td, J = 13.3, 7.7 Hz, 1H), 2.57 (dd, J =13.7, 7.0 Hz, 1H), 2.53 – 2.38 (m, 1H), 2.18 (s, 2H), 2.07 (td, J = 11.9, 7.4 Hz, 1H), 1.88(dtt, J = 14.9, 10.1, 4.9 Hz, 2H). LCMS: purity 97%, MS (m / e) 500 (M+H) + .

[0470] (±)-5-Benzyl- N -(1-methyl-2-oxo-8-(2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1 H -Benzo[b]azepine-3-yl)-1 H -1,2,4-Triazole-3-carboxamide (I-12)

[0471]

[0472] 1H NMR (400 MHz, chloroform- d ) δ 8.04 (d, J = 7.7 Hz, 1H), 7.35 – 7.24 (m, 5H), 7.01 (d, J = 8.2 Hz, 1H), 6.27(d, J = 8.2 Hz, 1H), 6.20 (s, 1H), 4.62 (dt, J = 11.0, 7.7Hz, 1H), 4.12(s, 2H), 3.54 (s, 4H), 3.36(s, 3H), 2.73 (dd, J = 12.9, 7.3 Hz, 1H), 2.62(ddd, J = 19.9, 12.9, 7.1Hz, 1H), 2.49 (dd, J = 13.1, 6.5 Hz, 1H), 1.95 (td, J = 11.6, 7.2Hz, 1H), 1.68 (d, J = 6.2 Hz, 4H), 1.46 (s, 4H), 1.40 (s, 2H). LCMS: purity 97%, MS (m / e) 499 (M+H) + .

[0473] (±)-5-Benzyl- N -(1-methyl-2-oxo-8-(3-oxa-9-azaspiro[5.5]undec-9-yl)-2,3,4,5-tetrahydro-1 H -Benzo[b]azepine-3-yl)-1 H -1,2,4-Triazole-3-carboxamide (I-13)

[0474]

[0475] 1 H NMR (400 MHz, chloroform- d ) δ 11.58 (s, 1H), 8.05 (d, J = 7.7 Hz, 1H), 7.33 –7.18 (m, 5H), 7.06 (d, J = 8.4 Hz, 1H), 6.76 (dd, J = 8.4, 2.5 Hz, 1H), 6.70 (s, 1H), 4.62 (dt, J= 11.0, 7.6 Hz, 1H), 4.11 (s, 2H), 3.72 – 3.64 (m, 4H), 3.37 (s, 3H), 3.15 (t, J =5.8 Hz, 4H), 2.82 – 2.69 (m, 1H), 2.62 (ddd, J = 19.6, 12.6, 7.1 Hz, 1H), 2.52 (dd, J =12.9, 6.6 Hz, 1H), 1.97 (td, J = 11.6, 7.3 Hz, 1H), 1.69 (app t, J = 5.8 Hz, 4H), 1.62 –1.53 (m, 4H). LCMS: purity 95%, MS (m / e) 529 (M+H) + .

[0476] (±)-5-Benzyl- N -(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-1-(methyl- d 3 )-2-oxo-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-1 H -1,2,4-Triazole-3-carboxamide (I-14)

[0477]

[0478] 1 H NMR (400 MHz, methanol- d 4) δ 7.37 (t, J = 1.0 Hz, 1H), 7.34 – 7.18 (m, 7H), 4.49 (dd, J = 11.5, 7.8 Hz, 1H), 4.14 (s, 2H), 2.85 (td, J = 13.4, 7.9 Hz, 1H), 2.72 (dd, J = 13.7, 6.8 Hz, 1H), 2.51 (tt, J = 13.0, 7.4 Hz, 1H), 2.21 – 2.09 (m, 1H), 1.54 (s, 6H). LCMS: purity 98%, MS (m / e) 443 (M-H2O+H) + .

[0479] (±)-5-Benzyl-N -(1-(methyl- d 3 )-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-1 H -1,2,4-Triazole-3-carboxamide (I-15)

[0480]

[0481] 1 H NMR (400 MHz, methanol- d 4) δ 7.32 – 7.16 (m, 5H), 7.07 (d, J = 8.1 Hz, 1H), 6.39(d, J = 2.3 Hz, 1H), 6.35 (dd, J = 8.1, 2.3 Hz, 1H), 4.51(dd, J = 11.4, 7.7 Hz, 1H), 4.11 (s, 2H), 3.68 – 3.61 (m, 4H), 3.62 (s, 4H), 2.71 (td, J = 13.4, 7.6 Hz, 1H), 2.55(dd, J = 13.8, 6.9 Hz, 1H), 2.44 (tt, J = 12.8, 7.4 Hz, 1H), 2.12 – 1.99 (m, 1H), 1.84 –1.77 (m, 4H). LCMS: purity 948, MS (m / e) 504 (M+H) + .

[0482] (±)-5-Benzyl- N -(8-((3-hydroxyoxetane-3-yl)ethynyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-1 H -1,2,4-Triazole-3-carboxamide (I-16)

[0483]

[0484] 1 H NMR (400 MHz, methanol- d 4) δ 7.46 (d, J= 1.5 Hz, 1H), 7.38 – 7.18 (m, 7H), 4.86 (dd, J = 6.3, 0.9 Hz, 2H), 4.69 (dd, J = 6.3, 0.8 Hz, 2H), 4.49 (dd, J = 11.5, 7.8Hz, 1H), 4.14 (s, 2H), 3.38 (s, 3H), 2.86 (td, J = 13.3, 7.9 Hz, 1H), 2.74 (dd, J = 13.6, 6.9 Hz, 1H), 2.52 (ddd, J = 20.4, 13.0, 7.5Hz, 1H), 2.16 (td, J = 12.1, 7.7 Hz, 1H). LCMS: purity 95%, MS (m / e) 472 (M+H) + .

[0485] (S)-5-Benzyl- N -(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1 H -1,2,4-Triazole-3-carboxamide (I-17)

[0486]

[0487] 1 H NMR (400 MHz, chloroform- d ) δ 11.79 (s, 1H), 8.07 (d, J = 7.8 Hz, 1H), 7.32 –7.21 (app m, 5H), 7.04 (d, J = 8.2 Hz, 1H), 6.29 (dd, J = 8.2, 2.3 Hz, 1H), 6.22 (d, J =2.3 Hz, 1H), 4.65 (app s, 1H), 4.14 (s, 2H), 3.71 (m, 8H), 3.37 (s, 3H), 2.76 (td, J = 12.9, 7.5 Hz, 1H), 2.62 (ddd, J = 19.8, 12.9, 7.3Hz, 1H), 2.51 (dd, J= 13.1, 6.6 Hz, 1H), 1.98(td, J = 11.6, 7.2 Hz, 1H), 1.89 – 1.82 (m, 4H). LCMS: rt 1.50 min (A), purity 96%, MS (m / e) 501 (MH + ).

[0488] (S)-5-Benzyl- N -(1-methyl-2-oxo-8-(pyridin-3-ylethynyl)-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-1 H -1,2,4-Triazole-3-carboxamide (I-18)

[0489]

[0490] 1 H NMR (400 MHz, chloroform- d ) δ 8.77 (dd, J = 2.1, 0.9 Hz, 1H), 8.56 (dd, J = 4.9, 1.7 Hz, 1H), 8.08 (d, J = 7.5 Hz, 1H), 7.82(dt, J = 7.9, 1.9 Hz, 1H), 7.43 – 7.35 (m, 2H), 7.35 – 7.21 (m, 7H), 4.67 – 4.58 (m, 1H), 4.14 (s, 2H), 3.44 (s, 3H), 2.89 (td, J =12.3, 11.7, 7.7 Hz, 1H), 2.80 – 2.63 (m, 2H), 2.13 – 2.01 (m, 1H). LCMS: purity 95%, MS (m / e) 477 (M+H) + .

[0491] (±)-5-Benzyl- N -(1-methyl-2-oxo-8-(pyridin-4-ylethynyl)-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-1 H -1,2,4-Triazole-3-carboxamide (I-19)

[0492]

[0493] 1 H NMR (400 MHz, methanol- d 4) δ 8.60 – 8.53 (m, 2H), 7.61 (d, J = 1.6 Hz, 1H), 7.57 – 7.52 (m, 2H), 7.48 (dd, J = 7.8, 1.6 Hz, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.35–7.20 (m, 5H), 4.53 (dd, J = 11.5, 7.8 Hz, 1H), 4.16 (s, 2H), 3.43 (s, 3H), 2.91 (td, J =13.3, 7.9 Hz, 1H), 2.78 (dd, J = 13.6, 6.9 Hz, 1H), 2.56 (tt, J = 13.4, 7.0 Hz, 1H), 2.20(td, J = 12.2, 8.0 Hz, 1H). 1 H NMR (400 MHz, chloroform- d ) δ 11.59 (s, 1H), 8.65 – 8.59 (m, 2H), 8.08 (d, J = 7.6 Hz, 1H), 7.45 – 7.21 (m, 10H), 4.63 (s, 1H), 4.15 (s, 2H), 3.44 (s, 3H), 2.96 – 2.84 (m, 1H), 2.75 (s, 1H), 2.70 (td, J = 12.3, 11.8, 6.9 Hz, 2H), 2.14 –2.02 (m, 1H). LCMS: purity 94%, MS (m / e) 477 (M+H) + .

[0494] (±)-5-Benzyl- N -(1-methyl-2-oxo-8-(pyridin-2-ylethynyl)-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-1 H -1,2,4-Triazole-3-carboxamide (I-20)

[0495]

[0496] 1 H NMR (400 MHz, chloroform-d ) δ 11.53 (s, 1H), 8.63 (ddd, J = 4.9, 1.8, 0.9 Hz, 1H), 8.09 (d, J = 7.5 Hz, 1H), 7.71 (td, J = 7.7, 1.8 Hz, 1H), 7.54 (dt, J = 7.9, 1.1 Hz, 1H), 7.45 – 7.22 (app m, 9H), 4.62 (q, J = 8.1 Hz, 1H), 4.15 (s, 2H), 3.43 (s, 3H), 2.89 (td, J = 12.5, 12.0, 7.6Hz, 1H), 2.75 (dd, J = 13.0, 6.9 Hz, 1H), 2.67 (dd, J = 12.4, 6.7Hz, 1H), 2.06 (td, J = 11.3, 7.5 Hz, 1H). LCMS: purity 91%, MS (m / e) 477 (M+H) + .

[0497] (S)-5-Benzyl- N -(8-(3,3-dimethylbut-1-yn-1-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-1 H -1,2,4-Triazole-3-carboxamide (I-21)

[0498]

[0499] 1 H NMR (400 MHz, methanol- d 4) δ 7.36 – 7.18 (m, 8H), 4.50 (dd, J = 11.5, 7.8 Hz, 1H), 4.15 (s, 2H), 3.38 (s, 3H), 2.85 (td, J = 13.3, 7.9 Hz, 1H), 2.71 (dd, J = 13.6, 6.9Hz, 1H), 2.52 (tt, J= 12.8, 7.4 Hz, 1H), 2.22 – 2.09 (m, 1H), 1.32 (s, 9H). LCMS: purity 94%, MS (m / e) 456 (M+H) + .

[0500] ( S )- N -(8-((3-hydroxyoxetane-3-yl)ethynyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-4-phenoxypyridine-2-carboxamide (I-22)

[0501]

[0502] 1 H nmr (400 MHz, CDCl3) δ 8.84 (1H, d, J 7.5 Hz, NH), 8.42 (1H, d, J 5.5 Hz, pyH-6), 7.60 (1H, d, J 2.0 Hz, pyH-3), 7.42-7.38 (2H, m, 2H of C6H5), 7.29-7.20 (4H, m, 1H of C6H5, bzazapine H-6, H-8, H-9), 7.07-7.05 (2H, m, 2H of C6H5), 6.92 (1H, dd, J 5.5, 2.5 Hz, pyH-5), 4.93 (2H, d, J 7.0 Hz, oxetane H-2, 2H of H-4), 4.79 (2H, dd, J 7.0, 1.0 Hz, oxetane H-2, 2H of H-4), 4.60 (1H, td, J 11.0, 7.5 Hz, benzazepine H-3), 3.42 (3H, s, NCH3), 2.95-2.86 (1H, m, 1H of benzazepine H-5), 2.75-2.63 (2H, m, 1H of benzazepine H-5, 1H of benzazepine H-4), 2.12-2.04 (1H, m, 1H of benzazepine H-4); m / z: 484 [M+H] + (Measured value [M+H] + ,484.1867,C 28 H 25 N3O5 requires [M+H] + 484.1867).

[0503] (±)-4-Benzyl- N-(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-1H-pyrazole-1-carboxamide (I-23)

[0504]

[0505] 1 H NMR (400 MHz, methanol- d 4) δ 7.87 (q, J = 0.8 Hz, 1H), 7.51 (s, 1H), 7.31 –7.23 (m, 2H), 7.26 – 7.14 (m, 3H), 7.10 (d, J = 8.1 Hz, 1H), 6.45 – 6.35 (m, 2H), 4.38(dd, J = 11.4, 7.7 Hz, 1H), 3.82 (s, 2H), 3.66 (d, J = 4.3 Hz, 8H), 3.37 (s, 3H), 2.74 (td, J = 13.3, 7.6 Hz, 1H), 2.63 – 2.42 (m, 2H), 2.15 – 1.98 (m, 1H), 1.87 – 1.80 (m, 4H). LC / MS: purity 99%, MS (m / e) 500 (M+H) + .

[0506] (±)- N -(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-4-phenoxypyridine-2-carboxamide (I-24)

[0507]

[0508] 1 H NMR (400 MHz, chloroform- d ) δ 8.83 (d, J = 7.6 Hz, 1H), 8.41 (dd, J = 5.6, 0.5Hz, 1H), 7.60(dd, J= 2.5, 0.5 Hz, 1H), 7.44 – 7.34 (m, 2H), 7.27 – 7.13 (m, 4H), 7.09 –7.01 (m, 2H), 6.91 (dd, J = 5.6, 2.5 Hz, 1H), 4.58(dt, J = 11.2, 7.5 Hz, 1H), 3.40 (s, 3H), 2.94 – 2.81 (m, 1H), 2.75 – 2.63 (m, 1H), 2.67 – 2.58 (m, 1H), 2.11 – 1.98 (m, 1H), 1.61 (s, 6H). LCMS: purity 98%, MS (m / e) 470 (M+H) + .

[0509] (±)- N -(1-methyl-2-oxo-8-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-4-phenoxypyridine-2-carboxamide (I-25)

[0510]

[0511] 1 H NMR (400 MHz, chloroform- d ) δ 8.87 (d, J = 7.6 Hz, 1H), 8.42 (dd, J = 5.6, 0.5Hz, 1H), 8.25(d, J = 5.8 Hz, 2H), 7.60 (dd, J = 2.6, 0.5 Hz, 1H), 7.44 – 7.35 (m, 2H), 7.27 – 7.18 (m, 1H), 7.21 – 7.12 (m, 3H), 7.10 – 7.02 (m, 2H), 6.92 (dd, J = 5.6, 2.6Hz, 1H), 6.67 – 6.61 (m, 2H), 4.63 (dt, J= 11.3, 7.5 Hz, 1H), 3.53 (s, 2H), 3.42 (s, 3H), 3.37 – 3.30 (m, 4H), 2.94 – 2.81 (m, 1H), 2.78 – 2.65 (m, 1H), 2.68 – 2.60 (m, 1H), 2.60 – 2.53 (m, 4H), 2.06 (td, J = 11.2, 10.6, 7.3 Hz, 1H). LCMS: purity 95%, MS (m / e) 563 (M+H) + .

[0512] (±)-N-(2-oxo-8-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-4-phenoxypyridine-2-carboxamide (I-26)

[0513]

[0514] 1 H NMR (400 MHz, chloroform- d ) δ 8.79 (d, J = 7.7 Hz, 1H), 8.42 (dd, J = 5.6, 0.6Hz, 1H), 8.28 – 8.22 (m, 2H), 7.62 (d, J = 2.5 Hz, 1H), 7.45 – 7.35 (m, 3H), 7.28 – 7.19 (m, 2H), 7.14 (dd, J = 7.7, 1.6 Hz, 1H), 7.10 – 7.02 (m, 2H), 7.00 (d, J = 1.6 Hz, 1H), 6.93 (dd, J = 5.6, 2.6 Hz, 1H), 6.66 – 6.60 (m, 2H), 4.70 (dt, J = 11.4, 7.7 Hz, 1H), 3.56 – 3.44 (app m, 2H), 3.33 (dd, J = 6.1, 4.3 Hz, 4H), 2.99 (td, J = 12.9, 7.9 Hz, 1H), 2.80 (tt, J = 12.1, 7.4 Hz, 1H), 2.70 (dd, J= 13.1, 7.0 Hz, 1H), 2.56 (dd, J = 6.2, 4.2 Hz, 4H), 2.11 (td, J = 11.7, 7.6 Hz, 1H). LCMS: purity 99%, MS (m / e) 549 (M+H) + .

[0515] (±)- N -(1-methyl-2-oxo-8-(3-oxa-9-azaspiro[5.5]undec-9-yl)-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-4-phenoxypyridine-2-carboxamide (I-27)

[0516]

[0517] 1 H NMR (400 MHz, chloroform- d ) δ 8.82 (d, J = 7.7 Hz, 1H), 8.41 (dd, J = 5.6, 0.5Hz, 1H), 7.59(dd, J = 2.6, 0.5 Hz, 1H), 7.43 – 7.34 (m, 2H), 7.26 – 7.17 (m, 1H), 7.10 –7.01 (m, 3H), 6.91 (dd, J = 5.6, 2.6 Hz, 1H), 6.75(dd, J = 8.4, 2.5 Hz, 1H), 6.69 (d, J =2.4 Hz, 1H), 4.63(dt, J = 11.2, 7.7 Hz, 1H), 3.71 – 3.64 (m, 4H), 3.39 (s, 3H), 3.18 – 3.10 (m, 4H), 2.79 (td, J = 12.7, 7.6 Hz, 1H), 2.70 – 2.57 (m, 1H), 2.53 (dd, J = 13.0, 6.8 Hz, 1H), 2.07 – 1.94 (m, 1H), 1.73 – 1.65 (m, 4H), 1.57 – 1.50 (m, 4H). LCMS: purity 98%, MS (m / e) 541 (M+H) + .

[0518] (±)- N -(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-1-(methyl- d 3 )-2-oxo-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-4-phenoxypyridine-2-carboxamide (I-28)

[0519]

[0520] 1 H NMR (400 MHz, chloroform- d ) δ 8.82 (d, J = 7.6 Hz, 1H), 8.40 (dd, J = 5.6, 0.5Hz, 1H), 7.59(dd, J = 2.5, 0.5 Hz, 1H), 7.45 – 7.33 (m, 2H), 7.28 – 7.18 (m, 3H), 7.16 (d, J = 8.3 Hz, 1H), 7.11 – 7.03 (m, 1H), 7.07 – 7.00 (m, 1H), 6.90 (dd, J = 5.6, 2.6Hz, 1H), 4.57(dt, J = 11.2, 7.5 Hz, 1H), 2.86 (td, J = 12.4, 11.9, 7.8Hz, 1H), 2.75 – 2.57(m, 2H), 2.04 (td, J = 11.5, 8.4 Hz, 1H), 1.60 (s, 6H). LCMS: purity 97%, MS (m / e) 473 (M+H) + .

[0521] (±)- N -(1-(methyl- d 3 )-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-4-phenoxypyridine-2-carboxamide (I-29)

[0522]

[0523] 1H NMR (400 MHz, chloroform- d ) δ 8.80 (d, J = 7.8 Hz, 1H), 8.41 (dd, J = 5.6, 0.5Hz, 1H), 7.59(dd, J = 2.5, 0.5 Hz, 1H), 7.43 – 7.34 (m, 2H), 7.22 (ddt, J = 7.9, 7.0, 1.1Hz, 1H), 7.11 – 6.99 (m, 3H), 6.90 (dd, J = 5.6, 2.6 Hz, 1H), 6.27(dd, J = 8.1, 2.3 Hz, 1H), 6.20 (d, J = 2.3 Hz, 1H), 4.63(dt, J = 11.3, 7.7 Hz, 1H), 3.69 – 3.62 (m, 4H), 3.62 (s, 4H), 2.84 – 2.68 (m, 1H), 2.67 – 2.53 (m, 1H), 2.51 (dd, J = 13.1, 6.9 Hz, 1H), 2.05– 1.93 (m, 1H), 1.87 – 1.79 (m, 4H). LCMS: purity 97%, MS (m / e) 516 (M+H) + .

[0524] (±)- N -(1-methyl-2-oxo-8-(2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-4-phenoxypyridine-2-carboxamide (I-30)

[0525]

[0526] 1 H NMR (400 MHz, chloroform- d ) δ 8.81 (d, J = 7.8 Hz, 1H), 8.41 (d, J = 5.6 Hz, 1H), 7.60 (d, J = 2.5 Hz, 1H), 7.45 – 7.34 (m, 2H), 7.26 – 7.17 (m, 1H), 7.09 – 7.01 (m, 2H), 7.00 (d,J = 8.1 Hz, 1H), 6.91 (dd, J = 5.6, 2.6 Hz, 1H), 6.25 (dd, J = 8.2, 2.3Hz, 1H), 6.19 (d, J = 2.3 Hz, 1H), 4.64(dt, J = 11.2, 7.7 Hz, 1H), 3.52 (s, 4H), 3.37 (s, 3H), 2.77 (td, J = 12.9, 7.5 Hz, 1H), 2.61 (tt, J = 12.3, 7.3 Hz, 1H), 2.50 (dd, J = 13.2, 6.8 Hz, 1H), 2.06 – 1.92 (m, 1H), 1.68 (t, J = 5.7 Hz, 4H), 1.45 (d, J = 5.9 Hz, 4H), 1.45 – 1.35 (m, 2H). LCMS: purity 98%, MS (m / e) 511 (M+H) + .

[0527] (±)- N -(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-4-phenoxypyridine-2-carboxamide (I-31)

[0528]

[0529] 1 H NMR (400 MHz, chloroform- d ) δ 8.81 (d, J = 7.8 Hz, 1H), 8.41 (dd, J = 5.6, 0.5Hz, 1H), 7.60(dd, J = 2.6, 0.5 Hz, 1H), 7.46 – 7.34 (m, 2H), 7.25 – 7.18 (m, 1H), 7.09 –7.00 (m, 3H), 6.91 (dd, J = 5.6, 2.6 Hz, 1H), 6.27(dd, J = 8.1, 2.3 Hz, 1H), 6.21 (d, J=2.3 Hz, 1H), 4.64(dt, J = 11.2, 7.7 Hz, 1H), 3.66 (t, J = 5.2 Hz, 4H), 3.63 (s, 4H). 3.38 (s, 3H), 2.84 – 2.72 (m, 1H), 2.68 – 2.47 (m, 2H), 2.00 (td, J = 11.6, 7.3 Hz, 1H), 1.87– 1.80 (m, 4H). LCMS: purity 96%, MS (m / e) 513 (M+H) + .

[0530] (S)-1-Benzyl- N -(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-1 H -Pyrazole-3-carboxamide (I-32)

[0531]

[0532] 1 H NMR (400 MHz, chloroform- d ) δ 7.80 (d, J = 7.6 Hz, 1H), 7.42 – 7.26 (m, 4H), 7.26 – 7.18 (m, 2H), 7.04 (d, J = 8.1 Hz, 1H), 6.72 (d, J = 2.3 Hz, 1H), 6.29 (dd, J =8.1, 2.3 Hz, 1H), 6.22 (d, J = 2.3 Hz, 1H), 5.31 (s, 2H), 4.68 (dt, J = 11.0, 7.6 Hz, 1H), 3.68 (t, J = 5.2 Hz, 4H), 3.65 (s, 4H), 3.39 (s, 3H), 2.79 – 2.59 (m, 2H), 2.52 (dd, J =13.0, 6.5 Hz, 1H), 2.04 – 1.92 (m, 1H), 1.89 – 1.82 (m, 4H). LCMS: purity 95%, MS (m / e) 500 (M+H) + .

[0533] (S)-1-Benzyl- N -(8-(3,3-dimethylbut-1-yn-1-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-1 H -Pyrazole-3-carboxamide (I-33)

[0534]

[0535] 1 H NMR (400 MHz, chloroform- d ) δ 7.80 (d, J = 7.4 Hz, 1H), 7.40 – 7.28 (m, 4H), 7.26 – 7.18 (m, 4H), 7.15 (d, J = 7.7 Hz, 1H), 6.73 (d, J = 2.3 Hz, 1H), 5.30(d, J = 4.7 Hz, 2H), 4.62 (dt, J = 11.0, 7.5 Hz, 1H), 3.41 (s, 3H), 2.85 (td, J = 12.6, 7.6 Hz, 1H), 2.79 – 2.66 (m, 1H), 2.61 (dd, J = 12.7, 6.6 Hz, 1H), 2.09 – 1.97 (m, 1H), 1.32 (s, 9H). LCMS: purity 97%, MS (m / e) 455 (M+H) + .

[0536] ( S )-4-(4-fluorobenzyl)- N -(8-((4-Hydroxytetrahydro-2 H -pyran-4-yl)ethynyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-1 H -Pyrazole-1-carboxamide (I-34)

[0537]

[0538] 1 H NMR (400 MHz, chloroform- d ) δ 7.94 (d, J= 7.6 Hz, 1H), 7.85 (q, J = 0.9 Hz, 1H), 7.42 (d, J = 0.8 Hz, 1H), 7.30 – 7.26 (m, 2H), 7.21 (d, J = 7.7 Hz, 1H), 7.15 –7.08 (m, 2H), 7.02 – 6.88 (m, 2H), 4.45 (dt, J = 11.5, 7.5Hz, 1H), 3.95 (dt, J = 11.8, 4.5 Hz, 2H), 3.77 (s, 2H), 3.72 (ddd, J = 11.8, 9.0, 2.9Hz, 2H), 3.42 (s, 3H), 2.96 – 2.80 (m, 1H), 2.75 – 2.60 (m, 2H), 2.13 – 1.98 (m, 3H), 1.90 (ddd, J = 13.0, 9.1, 4.0 Hz, 2H). 19 F NMR (376 MHz, chloroform- d ) δ -116.87 (ddd, J = 14.2, 8.8, 5.3 Hz). LC / MS: purity 99%, MS (m / e) 517 (M+H) + .

[0539] ( S )-4-(4-fluorophenoxy)- N -(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-2-oxo-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)pyridine-2-carboxamide (I-35)

[0540]

[0541] 1 H NMR (400 MHz, DMSO- d 6) δ 10.07 (s, 1H), 8.77 (d, J = 7.5 Hz, 1H), 8.53 (d, J = 5.6 Hz, 1H), 7.36 – 7.21 (m, 6H), 7.14 (ddd, J = 9.4, 6.7, 2.2 Hz, 2H), 6.96 (d, J=1.6 Hz, 1H), 5.44 (s, 1H), 4.29 (dt, J = 11.5, 7.8 Hz, 1H), 2.81 – 2.64 (m, 2H), 2.53 –2.49 (m, 1H), 2.14 (td, J = 11.9, 6.3 Hz, 1H), 1.42 (s, 6H). 19 F NMR (376 MHz, DMSO- d 6)δ -116.70 (tt, J = 8.8, 4.7 Hz). LCMS: purity 98%, MS (m / e) 474 (M+H) + .

[0542] 4-(4-Fluorobenzyl)- N -(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-1-(methyl- d 3 )-2-oxo-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-1 H -Pyrazole-1-carboxamide (I-36)

[0543]

[0544] Path 3. 1 H NMR (400 MHz, dichloromethane- d 2) δ 7.94 – 7.80 (app m, 2H), 7.46 (appd, J = 0.9 Hz, 1H), 7.28 (dd, J = 6.1, 1.7 Hz, 2H), 7.23 (d, J = 8.2 Hz, 1H), 7.21 – 7.14 (m, 2H), 7.03 – 6.95 (m, 2H), 4.39 (dt, J = 11.5, 7.4 Hz, 1H), 3.80 (s, 2H), 3.02 – 2.80 (m, 1H), 2.79 – 2.59 (m, 2H), 2.40 (br s, 1H), 2.14 – 1.94 (m, 1H), 1.60 (s, 6H). 19 FNMR (376 MHz, dichloromethane- d 2) δ -117.84 (ddd, J= 14.3, 9.0, 5.4 Hz). LC / MS: purity 98%, MS (m / e) 478 (M+H) + .

[0545] ( S )- N -(1-methyl-8-(3-methyl-3-(4-methylpiperazin-1-yl)but-1-yn-1-yl)-2-oxo-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-4-phenoxypyridine-2-carboxamide (I-37)

[0546]

[0547] 1-Methyl-4-(2-methylbut-3-yn-2-yl)piperazine was prepared as follows: To a stirred light green solution of CuCl (0.10 g, 10 mmol) in anhydrous THF was added 1-methylpiperazine (1.10 g, 1.22 mL, 11 mmol) followed by NEt3 (1.11 g, 1.53 mL11 mmol) under argon at room temperature over a period of 20 minutes. After the blue heterogeneous mixture was stirred for 10 minutes, 2-methylbut-3-yn-2-yl acetate (1.27 g, 10 mmol) in dry THF (5 mL) was slowly added over a period of 20 minutes and a mild exotherm was observed. The reaction mixture was stirred for an additional 30 minutes, heated at 58 °C for 7 hours and cooled. The brown-red reaction mixture was diluted with Et2O (70 mL) and aqueous NaHCO3 (40 mL). After separation of the organic layer, the red heterogeneous aqueous layer was extracted with Et2O (3 × 75 mL). The combined light green organic layer was washed with NaHCO3 aqueous solution (40 mL) and NaCl aqueous solution, stirred over anhydrous Na2SO4 and filtered through celite®. The filtrate was concentrated to give the title compound as a crude yellow solid (1.16 g). The product was purified by silica gel chromatography (Combiflash ® Teledyne RediSep ® 12G gold column. A: CH2Cl2B B: 20% MeOH / CH2Cl2@15% B / A. Detection λ 220 and 230nm) was further purified to give an off-white solid (0.54 g, 33% yield). 1 H NMR (400 MHz, chloroform- d ) δ 2.67 (br s, 4H), 2.46 (brs, 4H), 2.26 (app s, 4H), 1.37 (s, 6H).13 C NMR (101 MHz, chloroform- d ) δ 85.55, 71.50, 55.45, 53.82, 46.64, 45.88, 27.71.

[0548] ( S )- N -(1-methyl-8-(3-methyl-3-(4-methylpiperazin-1-yl)but-1-yn-1-yl)-2-oxo-2,3,4,5-tetrahydro-1 H -Benzo[ b ]azepine-3-yl)-4-phenoxypyridine-2-carboxamide was prepared according to the method of the present disclosure using 1-methyl-4-(2-methylbut-3-yn-2-yl)piperazine.

[0549] 1 H NMR (400 MHz, dichloromethane- d 2) δ 8.73 (d, J = 7.6 Hz, 1H), 8.46 (dd, J = 5.6, 0.6 Hz, 1H), 7.57 (dd, J = 2.6, 0.5 Hz, 1H), 7.50 – 7.40 (m, 2H), 7.33 – 7.23 (m, 3H), 7.22 (d, J = 7.7 Hz, 1H), 7.15 – 7.07 (m, 2H), 6.97 (dd, J = 5.6, 2.6 Hz, 1H), 4.52 (dt, J = 11.4, 7.5 Hz, 1H), 3.41 (s, 3H), 2.97 – 2.82 (m, 1H), 2.76 (s, 4H), 2.74 – 2.60 (m, 2H), 2.51 (s, 4H), 2.28 (s, 3H), 2.09 – 1.97 (m, 1H), 1.45 (s, 6H). LCMS: Purity 93%, MS(m / e) 552 (M+H) + .

[0550] (±)- N -(1-methyl-2-oxo-8-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-4-phenylpyrimidine-2-carboxamide (I-38)

[0551]

[0552] 1 H NMR (400 MHz, chloroform- d ) δ 9.16 (d, J = 7.4 Hz, 1H), 8.91 (d, J = 5.3 Hz, 1H), 8.28 – 8.22 (m, 2H), 8.22 – 8.14 (m, 2H), 7.80 (d, J = 5.3 Hz, 1H), 7.58 – 7.50 (m, 3H), 7.27 – 7.12 (m, 3H), 6.67 – 6.61 (m, 2H), 4.75 (dt, J = 11.3, 7.4 Hz, 1H), 3.61– 3.48 (app m, 2H), 3.46 (s, 3H), 3.38 – 3.31 (m, 4H), 2.97 – 2.82 (m, 2H), 2.74 –2.63 (m, 1H), 2.62 – 2.55 (m, 4H), 2.14 – 2.01 (m, 1H). LCMS: purity 96%, MS (m / e) 548 (M+H) + .

[0553] (±)- N -(8-((5,6-dihydro-[1,2,4]triazolo[1,5- a ]Pyrazine-7(8 H )-1-methyl-2-oxo-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-4-phenylpyrimidine-2-carboxamide (I-39)

[0554]

[0555] 1 H NMR (400 MHz, chloroform- d ) δ 9.15 (d, J = 7.4 Hz, 1H), 8.90 (d, J = 5.3 Hz, 1H), 8.23 ​​– 8.14 (m, 2H), 7.86 (s, 1H), 7.79 (d, J = 5.3 Hz, 1H), 7.60 – 7.50 (m, 3H), 7.28 – 7.17 (m, 3H), 4.74 (qd, J= 7.4, 4.1 Hz, 1H), 4.23 – 4.16 (m, 2H), 3.85 (s, 2H), 3.76 (s, 2H), 3.45 (s, 3H), 3.03 – 2.96 (m, 2H), 2.90 (ddt, J = 7.6, 5.5, 3.1Hz, 2H), 2.74 – 2.63 (m, 1H), 2.06 (ddt, J = 12.5, 6.0, 4.8 Hz, 1H). LCMS: purity 98%, MS (m / e) 509 (M+H) + .

[0556] Example 10

[0557] In this embodiment, ADP-Glo TM Techniques Biochemical assays are used to evaluate the compounds of the present disclosure.

[0558] Thaw ADP-Glo™ (Promega, Madison, WI, USA) reagent at ambient temperature. Prepare kinase assay reagent by mixing kinase assay buffer with lyophilized kinase assay substrate.

[0559] Prepare 500 ml stock solution of 5X reaction kinase buffer by mixing 1000 µl of 1M MgCl2, 500 µl of 1M Tris-HCL pH 7.4, 0.5 mg / ml (25 mg) BSA and 3475 µl of distilled H2 O. Prepare 3 ml of 2X working stock solution of reaction kinase buffer containing final concentrations of 100 µM DTT and 4 mM MnCl2.

[0560] RIPK1 enzyme components (Rigel Pharmaceuticals, South San Francisco, CA, USA) were thawed on ice. Diluted RIPK1 was prepared to 31 ng / well in 1X kinase reaction buffer (diluted from 2X buffer). 166 μM working stock ATP assay solution was prepared in 1X kinase reaction buffer (diluted from 2X buffer).

[0561] Compounds were serially diluted in DMSO in 4-fold dilutions from 250uM and then diluted 1:5 in 2X reaction buffer in a 96-well plate. 1.0ul of diluted compound was added to the 384-well plate in duplicate. 2μl of diluted Active RIPK1 was added to the 384-well plate (not added to column 1), and 2X rxn buffer was added to column 1. 150nM of AKT (Anaspec, Fremont, CA, USA) was combined with an equal volume of ATP working stock and added to the 384-well plate at 2ul / well. The final reaction volume was 5.0μl.

[0562] The plate was centrifuged briefly and the reaction was incubated at 30°C for 30 minutes. 5 µl of ADP-Glo TM The reaction was terminated. The plate was centrifuged quickly and the reaction was incubated at room temperature for 40 minutes. The kinase detection reagent was then added and incubated at room temperature for 30 minutes. The relative light units (RLU) of the kinase reaction were measured by luminescence (Luminescence 0.1s) using a Wallac Victor 2 Luminometer (PerkinElmer, Waltham, MA, USA). Table 1 provides the IC values ​​obtained in this example. 50 value.

[0563]

[0564]

[0565] Embodiment 11

[0566] In this example, U937 and L929 cells were exposed to compounds of the present disclosure and subjected to necroptosis assays to evaluate the activity of the compounds against human RIP1 and mouse RIP1.

[0567] U937 and L929 cells were obtained from the American Type Culture Collection (Manassa, VA, USA). Both cells were maintained in logarithmic growth phase in complete RPMI 1640 medium (Sigma, ST Louis, MO, USA) supplemented with 10% fetal bovine serum (Sigma, ST Louis, MO, USA) at 37°C and 5% CO2. For necroptosis assays, L929 cells were seeded at 10K cells / well in 100 μL / well medium in Costar 96-well black clear bottom plates (Fisher Scientific, Hampton, NH, USA) for 18 hours; on the day of the assay, U937 cells were seeded at 50K cells / well in 50 μL / well medium containing 60uM zVAD-fmk (Lonza, Basel, Switzerland). The medium from the L929 cells was removed from the 96-well plate and replaced with 50 μL / well of new medium containing 40uM zVAD-fmk. Each compound of the present disclosure evaluated in this example was serially diluted in DMSO in 4-fold dilutions from 2.5mM and then diluted 1:125 in complete medium. 50 μL / well 2x of the compound was then added to the cells in the plate. The cells were pre-incubated with the compound at 37°C and 5% CO2 for 1 hour, and then 10 μL / well 11x TNFa (Peprotech, Rocky Hill, NJ, USA) was added to give a final concentration of TNFa of 2ng / mL. The relative amount of necroptotic cells was determined by luminescence using a Wallac Victor2 Luminometer (PerkinElmer, Waltham, MA, USA) and CellTiter-Glo® Luminescent Cell Viability Reagent Assay (Promega, Madison, WI, USA) added after 18 hours of TNFa stimulation at 37°C and 5% CO2 according to the manufacturer's instructions. The results of this example are summarized in Table 2. This example establishes that embodiments of the compounds described herein have unexpectedly potent activity against human RIP1 and mouse RIP1, which allows them to be evaluated in an in vivo mouse disease model. These results can be used to determine safe and effective doses for use in humans.

[0568]

[0569]

[0570] *ND means no activity was detected or the inhibition curve shows an artifact. This value does not necessarily indicate an inactive compound, but indicates that the experiment failed to produce data for some reason. For example, insoluble compounds or other experimental artifacts may result in a "Not Determined" value.

[0571] Example 12

[0572] In this example, an acute hypothermia mouse model assay was used to evaluate the ability of compounds disclosed herein to inhibit TNF-α-induced hypothermia.

[0573] Female C57BL / 6 mice were randomized and weighed on day -1. On the day of the study (day 0), mice were administered vehicle or test article by oral gavage. Fifteen minutes after oral administration of the test agent, each mouse was injected intraperitoneally (IP) with a solution containing recombinant human tumor necrosis factor alpha (TNF-a, 25.0 µg) and zVAD-FMK (200 µg). Body temperature was measured at 0 hours (before IP injection) and every hour via a rectal probe temperature measurement device. Three (3) hours after IP injection of TNF-a and zVAD / FMK, mice were euthanized by CO2 asphyxiation and blood was collected by cardiac puncture. Serum and plasma were collected for determination of cytokine and compound levels, respectively. A separate group of mice (satellite mice) was included for determination of compound levels in plasma upon administration of TNFa / zVAD-FMK.

[0574] (S)-5-Benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4H-1,2,4-triazole-3-carboxamide (WO 2014 / 125444), having the structure shown below, was used as a comparative compound and examined using a similar protocol as described in WO 2014 / 125444. According to WO 2014 / 125444, this comparative compound exhibited 93% inhibition at a dose of 30 mg / kg. In contrast, using a similar assay protocol as described above, the compounds of the present disclosure can achieve greater inhibition, such as greater than 75% or greater than 85% inhibition, at lower doses on a mg / kg basis.

[0575]

[0576] Certain embodiments of the present disclosure provide one or more compounds or compositions thereof that cross the blood-brain barrier. The disclosed compound and composition embodiments exhibit sufficient brain permeability as potential therapeutic agents in neurological diseases. Brain permeability can be assessed by evaluating the free brain / plasma ratio (Bu / Pu) measured in rodent in vivo pharmacokinetic studies. Other methods for assessing brain permeability are known to those of ordinary skill in the art. See, e.g., Liu, X. et al., J. Pharmacol. Exp. Therap., 325:349-56, 2008.

[0577] In view of the many possible embodiments of the principles of the present disclosure that can be applied, it should be recognized that the illustrated embodiments are only preferred embodiments and should not be considered restrictive. Instead, the scope of the present disclosure is defined by the following claims. Therefore, we claim all that fall within the scope and spirit of these claims as our invention.

Claims

1. Compounds having formula I or a pharmaceutically acceptable salt thereof, wherein: Ring B is pyrazolyl, pyridyl, pyrimidinyl or triazolyl; L is a bond, oxygen or CH2; Y is CH2; Z is phenyl substituted by 0, 1 or 2 halogens; Each R 1 Independently R 2 is H or CH3; R 3 It is H; m is 1; and n is 0.

2. The compound according to claim 1, wherein the compound has the formula 3. The compound according to claim 1, wherein the compound has the following formula:

4. The compound according to claim 1, wherein the compound has the following formula:

5. The compound according to claim 1, wherein R 2 It is CH3. The compound according to claim 1 , wherein L is a bond.

7. A compound according to claim 1 or claim 2, wherein L is CH2.

8. A compound according to claim 1 or claim 2, wherein L is oxygen.

9. The compound of claim 1, wherein Z is unsubstituted phenyl.

10. The compound according to claim 1, wherein the compound is selected from I-3: (±)-1-(2,6-dichlorobenzyl)-N-(1-methyl-2-oxo-8-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-1,2,4-triazole-3-carboxamide; I-4: (±)-5-benzyl-N-(1-methyl-2-oxo-8-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-1,2,4-triazole-3-carboxamide; I-5: (±)-1-(2,6-dichlorobenzyl)-N-(2-oxo-8-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-1,2,4-triazole-3-carboxamide; I-6: (±)-5-benzyl-N-(2-oxo-8-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-1,2,4-triazole-3-carboxamide; I-8: (±)-5-benzyl-N-(8-((5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)methyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-1,2,4-triazole-3-carboxamide; I-9: (±)-5-benzyl-N-(2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-1,2,4-triazole-3-carboxamide; I-10: (S)-5-benzyl-N-(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-1,2,4-triazole-3-carboxamide; I-14: (±)-5-benzyl-N-(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-1-(methyl-d3)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-1,2,4-triazole-3-carboxamide; I-15: (±)-5-benzyl-N-(1-(methyl-d3)-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-1,2,4-triazole-3-carboxamide; I-17: (S)-5-benzyl-N-(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-1,2,4-triazole-3-carboxamide; I-21: (S)-5-benzyl-N-(8-(3,3-dimethylbut-1-yn-1-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-1,2,4-triazole-3-carboxamide; I-23: (±)-4-benzyl-N-(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-pyrazole-1-carboxamide; I-24: (±)-N-(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-4-phenoxypyridine-2-carboxamide; I-25: (±)-N-(1-methyl-2-oxo-8-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-4-phenoxypyridine-2-carboxamide; I-26: (±)-N-(2-oxo-8-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-4-phenoxypyridine-2-carboxamide; I-28: (±)-N-(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-1-(methyl-d3)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-4-phenoxypyridine-2-carboxamide; I-29: (±)-N-(1-(methyl-d3)-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-4-phenoxypyridine-2-carboxamide; I-31: (±)-N-(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-4-phenoxypyridine-2-carboxamide; I-32: (S)-1-benzyl-N-(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-pyrazole-3-carboxamide; I-33: (S)-1-benzyl-N-(8-(3,3-dimethylbut-1-yn-1-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-pyrazole-3-carboxamide; I-34: (S)-4-(4-fluorobenzyl)-N-(8-((4-hydroxytetrahydro-2H-pyran-4-yl)ethynyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-pyrazole-1-carboxamide; I-35: (S)-4-(4-fluorophenoxy)-N-(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)pyridine-2-carboxamide; I-36: 4-(4-fluorobenzyl)-N-(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-1-(methyl-d3)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-pyrazole-1-carboxamide; I-37: (S)-N-(1-methyl-8-(3-methyl-3-(4-methylpiperazin-1-yl)but-1-yn-1-yl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-4-phenoxypyridine-2-carboxamide; I-38: (±)-N-(1-methyl-2-oxo-8-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-4-phenylpyrimidine-2-carboxamide; or I-39: (±)-N-(8-((5,6-dihydro-[1,2,4]triazolo[1,5-a]pyrazin-7(8H)-yl)methyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-4-phenylpyrimidine-2-carboxamide.

11. A compound selected from: I-2: (S)-N-(8-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-4-phenoxypyridine-2-carboxamide; I-7: (±)-5-benzyl-N-(2-oxo-8-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-1,2,4-triazole-3-carboxamide; I-11: (±)-N-(8-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-5-benzyl-1H-1,2,4-triazole-3-carboxamide; I-12: (±)-5-benzyl-N-(1-methyl-2-oxo-8-(2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-1,2,4-triazole-3-carboxamide; I-13: (±)-5-benzyl-N-(1-methyl-2-oxo-8-(3-oxa-9-azaspiro[5.5]undec-9-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-1,2,4-triazole-3-carboxamide; I-16: (±)-5-benzyl-N-(8-((3-hydroxyoxetane-3-yl)ethynyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-1,2,4-triazole-3-carboxamide; I-18: (S)-5-benzyl-N-(1-methyl-2-oxo-8-(pyridin-3-ylethynyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-1,2,4-triazole-3-carboxamide; I-19: (±)-5-benzyl-N-(1-methyl-2-oxo-8-(pyridin-4-ylethynyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-1,2,4-triazole-3-carboxamide; I-20: (±)-5-benzyl-N-(1-methyl-2-oxo-8-(pyridin-2-ylethynyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-1,2,4-triazole-3-carboxamide; I-22: (S)-N-(8-((3-hydroxyoxetan-3-yl)ethynyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-4-phenoxypyridine-2-carboxamide; I-27: (±)-N-(1-methyl-2-oxo-8-(3-oxa-9-azaspiro[5.5]undec-9-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-4-phenoxypyridine-2-carboxamide; or I-30: (±)-N-(1-methyl-2-oxo-8-(2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-4-phenoxypyridine-2-carboxamide.

12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11.

13. The pharmaceutical composition of claim 12, comprising an excipient, a therapeutic agent or a combination thereof.

14. Use of a compound according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease in a subject, wherein the subject suffers from, is suspected of suffering from, or is developing a disease involving receptor interacting protein-1 (RIP1) kinase.

15. Use of a compound according to any one of claims 1 to 11 in the preparation of a medicament for treating a disease involving inflammation, necroptosis or both.

16. Use according to claim 15, wherein the disease is an inflammatory or immunoregulatory disorder.

17. The use according to claim 15, wherein the disease is a senile disorder.

18. The use according to claim 15, wherein the disease is amyotrophic lateral sclerosis (ALS), multiple sclerosis, Parkinson's disease or Alzheimer's disease.

19. The use according to claim 15, wherein the disease is myelodysplastic syndrome.

20. The use according to claim 15, wherein the disease is selected from atopic dermatitis, rheumatoid arthritis and ankylosing spondylitis.

Images