RIP1 inhibitor compounds and methods for making and using same

Abstract

Disclosed herein are kinase inhibitor compounds, such as receptor-interacting protein-1 (RIP1) kinase inhibitor compounds, as well as pharmaceutical compositions and combinations comprising such inhibitor compounds. The disclosed compounds, pharmaceutical compositions, and / or combinations can be used to treat or prevent kinase-related diseases or conditions, particularly diseases or conditions associated with RIP1.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of previously 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.

[0002] 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 treating diseases and / or conditions associated with RIP1. [Background technology]

[0003] Receptor interacting protein-1 kinase (referred to herein as "RIP1") is a serine / threonine protein kinase that belongs to the tyrosine kinase-like family and is involved in innate immune signaling. RIP1 plays a central role in regulating cell signaling, and its role in programmed cell death is associated with various inflammatory diseases, such as inflammatory bowel disease, psoriasis, and other diseases and / or conditions associated with inflammation and / or necrotic cell death. Summary of the Invention

[0004] The compounds disclosed herein have formula I [ka] or a pharmaceutically acceptable salt, N-oxide, solvate, tautomer, or stereoisomer thereof. Referring to Formula I, Ring B is a 5- or 6-membered heteroaryl, wherein the heteroaryl has (a) 1, 2, or 3 ring nitrogen atoms and the remainder of the ring atoms are carbon, or (b) 1 or 2 nitrogen atoms and 1 oxygen atom, with the proviso that R 1 but heterocyclyl, [ka] , or -linker-R 6 and the linker group is alkynyl and L is a bond, a heteroatom, or R a where R a is not H or D, Y is CH2, and Z is C 1-10 aliphatic or aryl, and each R 1 However, independently, halogen, [ka] , or -linker-R 6 group, and the linker is a bond or R a where R a But not H or D, but R 6 is heterocyclyl, R b , -C(R f )3, or -C(R f )=C(R f )2 and R 2 But R a and R 3 But R a and each R 4 But independently R e and R a However, independently for each occurrence, L is R a H or D, except for embodiments in which 1-10 aliphatic, C 1-10 Haloaliphatic, C 5-10 aromatic, C 3-6 Heterocyclic, or C 3-10 spiro heterocyclic, R b but independently for each occurrence -OH, -SH, -ORc , -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 , one or two NRs d R d , carboxyl, or combinations thereof, optionally further substituted with an aromatic moiety, -SH, -O-acyl, or -C(O)NH 1-10 alkyl, and R c but independently for each occurrence, one, two, or three R e C can be substituted with 1-10 Alkyl, 1, 2, or 3 R e C can be substituted with 2-10 Alkenyl, 1, 2, or 3 R e C can be substituted with 2-10 Alkynyl, 1, 2, or 3 R e C can be substituted with 3-6 cycloalkyl, or one, two, or three R e C can be substituted with 5-10 Aromatic, R d independently for each occurrence, H; 1, 2, or 3 R e C can be substituted with 1-6 Alkyl or C 3-9 Heterocyclyl, 1, 2, or 3 R e C can be substituted with 3-6 Cycloalkyl, 1, 2, or 3 R e C can be substituted with 3-6 Heterocyclic, 1, 2, or 3 R b C can be substituted with 5-10 Aryl, 1, 2, or 3 R e C can be substituted with 5-10 Heteroaryl or two R d A group, together with the nitrogen to which it is attached, can comprise one or more R e C can be substituted with3-9 Heterocyclic or one or more R e C can be substituted with 5-10 heteroaryl, R e But independently for each occurrence, 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 may independently represent 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 forms a C 2-6 alkenyl group, one or more R e C can be substituted with 3-6 Cycloalkyl group or one or more R e or C which can be substituted with acyl 3-10 wherein m is 1, 2, 3, or 4 and n is 0, 1, or 2.

[0005] In certain embodiments, Ring B is pyrazolyl, pyridinyl, pyrimidinyl, or triazolyl. For example, when Ring B is pyrazolyl, pyridinyl, pyrimidinyl, or triazolyl, L is a heteroatom or C 1-10 may be aliphatic, Z may be C 1-10 may be aliphatic or aryl, and each R 1 is heterocyclyl or C 1-10 R may be aliphatic 2 is H or C 1-10 R may be aliphatic 3 is H or C 1-10 may be aliphatic, and each R 4 are independently halogen or C 1-10It may be aliphatic, m may be 1, 2, 3, or 4, and n may be 0, 1, or 2. One of ordinary skill in the art will recognize that Formula I includes all stereoisomeric compounds, including, but not limited to, compounds having the following formula: [ka] .

[0006] In yet further embodiments, the compound has the structure satisfying formula IA. [ka] or a pharmaceutically acceptable salt, N-oxide, solvate, tautomer, or stereoisomer thereof. Referring to Formula IA, Ring B is a 5- or 6-membered heteroaryl, wherein the heteroaryl has 1, 2, or 3 ring nitrogen atoms and the remainder of the ring atoms are carbon, and L is a bond, a heteroatom, or R a where R a But not H or D, but Z, C 1-10 aliphatic or aryl, and each R 1 However, independently, halogen, [ka] , or -linker-R 6 group, and the linker is a bond or R a where R a But not H or D, but R 6 is heterocyclyl, R b , -C(R f )3, or -C(R f )=C(R f )2 and R 2 But R a and R 3 But R a and each R 4 But independently R e and R a However, independently for each occurrence, L is R a H or D, except for embodiments in which 1-10 aliphatic, C1-10 Haloaliphatic, C 5-10 aromatic, C 3-6 Heterocyclic, or C 3-10 spiro heterocyclic, R b but independently for 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 , one or two NRs d R d , carboxyl, or combinations thereof, optionally further substituted with an aromatic moiety, -SH, -O-acyl, or -C(O)NH 1-10 alkyl, and R c but independently for each occurrence, one, two, or three R e C can be substituted with 1-10 Alkyl, 1, 2, or 3 R e C can be substituted with 2-10 Alkenyl, 1, 2, or 3 R e C can be substituted with 2-10 Alkynyl, 1, 2, or 3 R e C can be substituted with 3-6 cycloalkyl, or one, two, or three R e C can be substituted with 5-10 Aromatic, R d independently for each occurrence, H; 1, 2, or 3 R e C can be substituted with 1-6 Alkyl, or C 3-9 Heterocyclyl, 1, 2, or 3 R e C can be substituted with 3-6 Cycloalkyl, 1, 2, or 3 R e C can be substituted with 3-6 Heterocyclic, 1, 2, or 3 R b C can be substituted with 5-10Aryl, 1, 2, or 3 R e C can be substituted with 5-10 Heteroaryl or two R d A group, together with the nitrogen to which it is attached, can comprise one or more R e C can be substituted with 3-9 Heterocyclic or one or more R e C can be substituted with 5-10 heteroaryl, R e But independently for each occurrence, 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 may independently represent 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 forms a C 2-6 alkenyl group, one or more R e C can be substituted with 3-6 Cycloalkyl group or one or more R e or C which can be substituted with acyl 3-10 wherein m is 1, 2, 3, or 4 and n is 0, 1, or 2.

[0007] One of ordinary skill in the art will appreciate that Formula IA includes all stereoisomeric compounds, including, but not limited to, compounds having the formula shown below: [ka] .

[0008] With reference to certain exemplary embodiments of the disclosed pyridine, pyrimidine, triazole, and pyrazole type compounds, such compounds may have the formula shown below, including any and all stereoisomers thereof: [ka] .

[0009] With reference to each of the general formulas above, specific compounds may be selected from the group consisting of H, C, such as methyl, 1-6 R as alkyl 2 and / or R 3 , independently a halogen such as chloro, fluoro, or methyl, or C 1-6 Each R as alkyl 4 wherein n is 0, 1, or 2, and L is a heteroatom such as oxygen, or a C group such as -CH2-. 1-10 Alkyl or C 1-6 alkyl and Z is aryl or C 3-6 It is cycloalkyl.

[0010] In certain compounds, Z is [ka] where each R 5 But independently, R e and p is 0, 1, 2, 3, 4, or 5. For example, each R 5 are independently a halogen such as fluoro or methyl or C 1-6 Z can also be C, such as methyl. 1-6 It can be alkyl, or cycloalkyl, such as cyclobutyl or cyclopentyl. 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.

[0011] In a particular compound, each R 1 are independently heterocyclyl, unsubstituted C 1-10Aliphatic, or -OH, halogen, carboxyl, carboxyl ester, heterocyclyl, amino, alkoxy, phosphate, cycloalkyl, alkenyl, -OC(O)NH(C 1-4 alkyl)-amino, -OC(O)R 8 C substituted with one or two substituents selected from 1-10 Aliphatic; or -OC(O)(CHR 9 )2CO2H. -OC(O)-R 8 The substituents may be derived from amino acids, particularly naturally occurring amino acids, such as -OC(O)-R 8 The -OC(O)- portion of R corresponds to the acid moiety on the amino acid. 8 But -N(R 10 )2 or nitrogen-containing non-aromatic heterocyclyl, R 10 is H or a carboxyl ester. 1 Also, C 1-10 R can be an alkyne or a substituted alkyne, such as an alkyne substituted with hydroxyl, oxetanyl, azetidinyl, pyridinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, or phosphate. 1 can also be an 8- to 12-membered spiroheterocyclyl.

[0012] Exemplary disclosed compounds include compounds I-1 through I-39.

[0013]

[0013] Disclosed embodiments also include pharmaceutical compositions comprising the disclosed compounds. Such compositions may further comprise an excipient, an additional therapeutic agent, or a combination thereof.

[0014] The method can include administering to the subject a disclosed compound or compounds, or a composition comprising a disclosed compound or compounds. Certain embodiments relate to contacting receptor-interacting protein-1 (RIP1) kinase with a disclosed compound or compounds, or a composition comprising a disclosed compound or compounds.

[0015] One particular method embodiment comprises: A compound having formula I, or a compound or [ka] and a pharmaceutically acceptable salt thereof, wherein ring B is a 5- or 6-membered heteroaryl and L is a bond, a heteroatom, or R a where R a is not H or D, Y is CH2, and Z is (C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, or C 3-6 cycloalkyl, etc.)C 1-10 aliphatic, or [ka] and R 1 But halogen, [ka] , or -linker-R 6 group, and the linker is R a where R a But not H or D, but R 6 But R b , -C(R f )3, or -C(R f )=C(R f )2 and R 2 and R 3 But R a and R 4 and R 5 But independently, R e and R a independently for each occurrence (L, R a (Except for embodiments in which 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, or C 3-6 cycloalkyl, etc.)C 1-10 aliphatic, C 1-10 Haloaliphatic, C 5-10Aromatic, or C 3-6 Heterocyclic, R b but independently for 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 and R c independently for each occurrence (1, 2, or 3 R e (can be replaced by)C 1-10 Alkyl, (1, 2, or 3 R e (can be replaced by)C 2-10 alkenyl, (one, two, or three R e (can be replaced by)C 2-10 Alkynyl, (1, 2, or 3 R e (can be replaced by)C 3-6 cycloalkyl, or (one, two, or three R e (can be replaced by)C 5-10 Aromatic, R d independently for each occurrence, H, (one, two, or three R e (can be replaced by)C 1-6 Alkyl, (1, 2, or 3 R e (can be replaced by)C 3-6 Cycloalkyl, (one, two, or three R e (can be replaced by)C 3-6 Heterocyclic, (1, 2, or 3 R b (can be replaced by)C 5-10 Aryl, (1, 2, or 3 R e (can be replaced by)C 5-10 Heteroaryl or two R d The group, together with the nitrogen to which it is attached, can be one or more R e (can be replaced by)C 3-9 Heterocyclic, or (one or more R e (can be replaced by)C 5-10 heteroaryl, R e But independently for each occurrence, halogen, C1-6 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 But for each occurrence, R a , R b , or R e or two R f A group, together with the carbon atom to which it is attached, can be one or more R e (can be replaced by)C 3-6 a cycloalkyl group, or (one or more R e (can be replaced by)C 3-10 providing a heterocyclic compound wherein m is 1 to 4, such as 1, 2, 3, or 4, n is 0, 1, or 2, and 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.

[0016] Examples of diseases that can be treated according to embodiments of the present method include diseases or disorders associated with inflammation, necroptosis, or both. In certain embodiments, the disease treated with the present compounds is an inflammatory or immunoregulatory disorder, including autoimmune and proliferative disorders. In some embodiments, the disease treated with the compounds is amyotrophic lateral sclerosis (ALS), autoimmune syndromes, rheumatoid arthritis, type 1 diabetes, inflammatory bowel disease including Crohn's disease and ulcerative colitis, biliary cirrhosis, multiple sclerosis, Wegener's granulomatosis, ichthyosis, asthma, pollen allergy, persistent obstructive airways 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 hepatitis-related diseases, cerebrovascular accidents, allergic diseases, chronic obstructive pulmonary disease, emphysema, Friedreich's ataxia, Lewy body diseases, diabetic neuropathy, polyglutamine (polyQ) diseases, Fahr's disease, Menkes disease, Wilson's disease, prion disorders, bone resorption diseases, and the like. Destructive bone disorders such as rheumatoid arthritis (rheumatoid arthritis), bone disorders associated with multiple myeloma; benign tumors, proliferative disorders, inflammatory and hyperproliferative skin disorders, epidermal hyperproliferation, psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis, seborrheic dermatitis, pustular psoriasis, bullous dermatitis, dermatitis erythema multiforme, linear IgA bullous dermatosis, cementum dermatitis, gingivitis, periodontitis, lesions of the gingiva, alveolar bone, and dental cementum, sepsis, pancreatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia, hyperlipidemia, eosinophilic fasciitis, acne, alopecia areata, male pattern baldness, senile alopecia, keratoconjunctivitis, vernal keratoconjunctivitis, corneal alopecia ulcerative burns, Behcet's disease, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, keratoconus, corneal epithelial dystrophy, corneal leukoplakia, ocular pemphigoid, Mooren's ulcer, scleritis, Falk-Koyanagi-Harada disease, hematologic disorders, hematologic malignancies, lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, breast carcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma,ABC diffuse large B-cell lymphoma (DLBCL), Waldenstrom's macroglobulinemia, primary cutaneous T-cell lymphoma, smoldering or asymptomatic 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 syndromes (MDS), myelofibrosis, polycythemia vera, Kaposi's sarcoma, splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, intravascular large B-cell lymphoma, IL-1-mediated disorders, MyD88-mediated disorders, JAK inhibitor-resistant malignancies and ibrutinib-resistant malignancies Drug-resistant malignancies, such as ibrutinib-resistant hematologic malignancies, ibrutinib-resistant CLL, and ibrutinib-resistant Waldenström's macroglobulinemia, acute myeloid leukemia, and chronic myeloid leukemia; angiogenic disorders, such as solid tumors, ocular angiogenesis, and hemangiomas, including infantile hemangiomas; sepsis, septic shock, and shigellosis; migraine, bronchitis, gastric ulcers, necrotizing enterocolitis, intestinal lesions associated with thermal burns, celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, interleukin-1 converting enzyme-associated fever syndromes, tumor necrosis factor receptor-associated periodic syndromes, NEMO deficiency syndrome, HOIL-1 deficiency, and linear ubiquitin chain assembly complex (LINEA) syndrome. complex) deficiency syndrome, lysosomal storage disease, Gaucher disease, GM2 gangliosidosis, alpha-mannosidosis, aspartylglucosaminuria, cholesteryl 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, pyknodysostosis, Sandhoff disease, Schindler disease, sialic acid storage disease, Tay-Sachs disease, Wolman disease, Huntington's disease, Parkinson's disease, neurodegenerative disorders, Huntington's disease, Parkinson's disease,Metastatic melanoma, fibrotic conditions such as CMV retinitis, non-alcoholic steatohepatitis, and cardiac conditions such as metastatic melanoma, HIV-infection-related neurodegeneration, associated neurocognitive disorders or dementia, and ischemia-reperfusion; allergies, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, erythroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, autoimmune neutropenia, thrombocytopenia, graft-versus-host disease, endotoxin-induced inflammatory responses, tuberculosis, atherosclerosis, muscle degeneration, cachexia, Reiter's syndrome, rubella-associated arthritis, acute synovitis, and pancreatic beta-cell disease; Diseases characterized by a large amount of neutrophil infiltration; ankylosing spondylitis, gouty arthritis, psoriatic arthritis, and other arthritic conditions, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, fibrotic lung, idiopathic interstitial pneumonia, allograft rejection, bone marrow rejection, fever and myalgia due to infection, keloid formation, scar tissue formation, fever, influenza, chronic myeloid leukemia; angiogenic disorders including solid tumors; acute hepatitis infection (including hepatitis A, B, and C), AIDS, ARC or malignant tumors, viral diseases including herpes; stroke, myocardial infarction, arteriosclerosis, atheroma Atherosclerosis, aortitis syndrome, polyarteritis nodosa, myocardial ischemia, ischemia in heart attack, organ hypoxia, vascular hyperplasia, cardiac and renal reperfusion injury, organ ischemia-reperfusion injury occurring during preservation, transplantation, or ischemic disease, cardiac hypertrophy, thrombin-induced platelet aggregation, endotoxemia and / or toxic shock syndrome, prostaglandin endoperoxide synthase 2-related conditions, pemphigus vulgaris, autoimmune / polymyositis, dermatomyositis, vitiligo, photoallergic sensitivity, ischemia-reperfusion injury, cardiac ischemia-reperfusion injury resulting from myocardial infarction, multiple system atrophy, Parkinson's disease Plus 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 resulting from COVID-19, post-infectious autoimmune diseases, rheumatic fever, post-infectious glomerulonephritis, systemic sclerosis, cerebrovascular accident (CVA), chronic obstructive pulmonary disease (COPD), NEMO deficiency syndrome (F-kappa-B essential modulator 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 disease, retinal degeneration, retinal detachment, age-related macular degeneration, vitreous scarring, anthrax lethal toxin-induced septic shock, 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 sclerosis, macular edema, diabetic retinopathy, central areolar choroidal dystrophy, BEST disease, adult vitelliform disease vitelliform), 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 light-induced toxicity, macular edema, central areolar 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., arterial or non-arterial 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 neuropathies, toxic optic neuropathies and hereditary optic neuropathies, dominant optic neuropathies, Beer syndrome, Creutzfeldt-Jakob disease), progressive supranuclear palsy, hereditary spastic paraplegia, subarachnoid hemorrhage, perinatal brain injury, subclinical brain injury, spinal cord injury, anoxic-ischemic brain injury, cerebral ischemia, focal cerebral ischemia, global cerebral ischemia, and hypoxic hypoxia, peritoneal damage caused by peritoneal dialysis fluid (PDF) and PD-related side effects, glomerular disease, tubulointerstitial disease, interstitial nephritis, obstruction, polycystic kidney disease), focal glomerulosclerosis, immune complex nephropathy, diabetic nephropathy, Goodpasture's syndrome, hepatocellular carcinoma, pancreatic cancer, urinary cancer, bladder cancer, colorectal cancer, colon cancer, breast cancer, prostate cancer,Prostatic hyperplasia, kidney cancer, renal carcinoma, liver carcinoma, adrenal carcinoma, thyroid cancer, gallbladder cancer, peritoneal cancer, ovarian cancer, cervical cancer, stomach cancer, endometrial cancer, esophageal cancer, stomach cancer, head and neck cancer, neuroendocrine cancer, CNS cancer, brain tumors (e.g., brain carcinoma, glioma, anaplastic oligodendroglioma, adult glioblastoma, and adult anaplastic astrocytoma), bone cancer, soft tissue sarcoma, retinoblastoma, neuroblastoma, peritoneal effusion, malignant pleural effusion, mesothelioma, Wilms' tumor, trophoblastic neoplasm, epithelial neoplasm, gastric carcinoma, ovarian carcinoma, rectal carcinoma, prostate carcinoma, pancreatic carcinoma, lung carcinoma, vaginal carcinoma, cervical carcinoma, testicular carcinoma, genitourinary carcinoma, esophageal carcinoma, laryngeal carcinoma, skin carcinoma, bone carcinoma, thyroid carcinoma Cancer, sarcoma, glioblastoma, neuroblastoma, gastrointestinal cancer, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung carcinoma, lymphoma, colon carcinoma, colorectal adenoma, hemangiopericytoma, mucinous carcinoma, round cell carcinoma, squamous cell carcinoma, esophageal squamous cell carcinoma, oral carcinoma, vulvar cancer, carcinoma of the adrenal cortex, ACTH-producing tumors, and leukemia, respiratory infectious viruses such as influenza virus, rhinovirus, coronavirus, parainfluenza virus, respiratory syncytial virus, adenovirus, and reovirus, herpes zoster caused by herpes virus, diarrhea caused by rotavirus, viral hepatitis, AIDS, Bacillus Bacterial infections such as Escherichia coli, Staphylococcus aureus, MRS A, Salmonella, botulinum, and Candida, Paget's disease, achondroplasia, osteoporosis, hyperparathyroidism, osteogenesis imperfecta, partial liver resection, acute liver necrosis, necrosis caused by toxins, necrosis caused by viral hepatitis, necrosis caused by shock, necrosis caused by anoxia, 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 hepatic failure, delayed onset liver failure, acute exacerbation of chronic liver failure, chronic kidney disease, kidney damage / injury,Kidney damage / injury caused by nephritis, kidney damage / injury caused by kidney transplantation, kidney damage / injury caused by surgery, kidney damage / injury caused by administration of nephrotoxic drugs, kidney damage / injury caused by enhanced chemotherapy effects, cytomegalovirus infection, HCMV infection, AIDS, cancer, senile dementia, trauma, chronic bacterial infection, environmental pollution, diseases caused by the inflammatory bowel disease, aging, altitude sickness, diseases caused by histamine or leukotriene-C4 release, muscular dystrophy, pyoderma and Sézary syndrome, Addison's disease, pseudomembranous colitis, drug- or radiation-induced colitis, ischemic acute renal failure, chronic renal failure, pulmonary oxygen- or drug-induced toxicosis, congenital hypophosphatasia, fibromatous lesions, fibrous dysplasia, bone metabolism, osteolytic bone disease, treatment of post-traumatic bone surgery, treatment after prosthetic joint surgery, treatment after orthopedic bone surgery, treatment after dental surgery, bone chemotherapy or bone radiotherapy treatment, bone cancer, atherosclerotic plaque, disorders, occlusive disorders, stenosis, coronary artery disorders, peripheral arterial disorders, arterial occlusion, aneurysm formation, post-traumatic aneurysm formation, restenosis, occlusion after graft surgery, Guillain-Barré syndrome, Meniere's disease, polyneuritis, multiple neuritis, mononeuritis, radiculopathy, hyperthyroidism, Graves' disease, autoimmune idiopathic thrombocytopenic purpura (autoimmune ITP), membranous nephritis, autoimmune thyroiditis, Hashimoito thyroiditis, myasthenia gravis, cold and warm agglutinin disease, Evan's syndrome, hemolytic uremic syndrome / thrombotic thrombocytopenic purpura (HUS / TTP), autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, anerythroplasia, or a combination thereof.

[0017] In some embodiments, the disease is myelodysplastic syndrome, hi some embodiments, the disease is atopic dermatitis, rheumatoid arthritis, or ankylosing spondylitis.

[0018] 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

[0019] I. Terminology Overview The following explanations of terms and methods are provided to better describe the present disclosure and to guide those skilled in the art in practicing the disclosure. The singular forms "a," "an," and "the" refer to one or more, unless the context clearly dictates otherwise. The term "or" refers to a single element of the described alternative elements or a combination of two or more elements, unless the context clearly dictates otherwise. As used herein, "comprises" means "includes." Thus, "comprising A or B" means "including A, B, or A and B," without excluding additional elements.

[0020] Unless otherwise indicated, all numbers expressing amounts of components, molecular weights, percentages, temperatures, times, and the like used in the specification or claims are understood to be modified by the term "about." Thus, unless otherwise indicated, implicitly or explicitly, the numerical parameters recited are approximations that may depend on the desired properties sought and / or the limits of detection under standard testing conditions / methods. The numerical values ​​of the embodiments are not approximations unless the word "about" is explicitly recited to directly and explicitly distinguish the embodiments from the prior art discussed.

[0021] Unless otherwise explained, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used to practice or test this disclosure, suitable methods and materials are described below. These materials, methods, and examples are illustrative only and are not intended to be limiting.

[0022] When chemical structures are shown or described, unless expressly stated otherwise, all carbons are assumed to contain hydrogen, so that each carbon corresponds to a valence of 4. For example, in the structure on the left of the schematic below, the presence of 9 hydrogen atoms is implied. 9 hydrogen atoms are shown in the structure on the right. [ka]

[0023] In some cases, certain atoms within a structure are described in textual form as having a hydrogen or hydrogen atom, e.g., -CHCH-. It will be appreciated by those skilled in the art that the foregoing descriptive technique is common in the chemical arts to provide brevity and simplicity in describing organic structures.

[0024] For example, R in the group 1 So, if the R group is shown "floating" on the ring system, [ka] Unless otherwise defined, the substituent R (e.g., R above) 1 ) as long as a stable structure is formed, [ka] It may be present on any atom of the fused bicyclic ring system except the atom bearing the bond to the symbol.

[0025] When the group R is present in a ring system containing saturated carbons, for example as shown in the formula: [ka] In this example, it is assumed that y can be two or more, each replacing a currently shown, implied, or explicitly defined hydrogen on the ring; then, unless otherwise defined, two Rs can be present on the same carbon. A simple example is when R is a methyl group. The depicted structure can exist as a pair of dimethyls on the depicted ring carbons ("annular" carbons). In another example, two Rs on the same carbon, including the same carbon, can be included in the ring, thus creating a spirocyclic ring ("spirocyclyl" group) structure.

[0026] As used herein, for example, "substituted aryl C 1-8 The term "substituted" in the term "alkyl" refers to all subsequent modifiers, and substitution is 1-8 The alkyl group, "C 1-8 It may occur in the "alkyl" portion, the "aryl" portion, or both portions.

[0027] "Substituted," when used to modify a specified group or moiety, means that at least one, and possibly two or more, hydrogen atoms of the specified group or moiety are independently replaced with the same or different substituents as defined below. In certain embodiments, a group, moiety, or substituent may be substituted or unsubstituted unless expressly defined otherwise as either "unsubstituted" or "substituted." Thus, any of the groups specified herein may be unsubstituted or substituted unless the context indicates otherwise or a particular structural formula precludes substitution. In certain embodiments, a substituent may or may not be expressly defined as substituted, but is still intended to be optionally substituted. For example, an "aliphatic" or "cyclic" moiety may be unsubstituted or substituted, but an "unsubstituted aliphatic" or "unsubstituted cyclic" is not substituted.

[0028] A "substituent" or "substituent group" to replace one or more hydrogen atoms on a saturated carbon atom of a specified group or moiety is represented by the radical -R, unless otherwise specified. 60、ハロ、=O、-OR 70 、-SR 70 、-N(R 80 )2、ハロアルキル、ペルハロアルキル、-CN、-NO2、 =N2、-N3、-SO2R 70 、-SO3 - M + 、-SO3R 70 、-OSO2R 70 、-OSO3 - M + 、-OSO3R 70 、-P(O)(O - )2(M + )2、 -P(O)(O - )2M 2+ 、-P(O)(OR 70 )O - M + 、-P(O)(OR 70 )2、-C(O)R 70 、-C(S)R 70 、-C(NR 70 )R 70 、-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 、-OCO2 - M + 、-OCO2R 70 、-OC(S)OR 70 、-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 、-NR 70 C(O)N(R 80 )2、-NR 70 C(NR70 )R 70 , and -NR 70 C(NR 70 )N(R 80 )2, where R 60 But C 1-10 Aliphatic, heteroaliphatic, or alicyclic, typically C 1-6 Aliphatic, more typically C 1-6 alkyl, and R 60 may be optionally substituted, and each R 70 may be independently hydrogen or R 60 and each R 80 But for each occurrence, R 70 or alternatively two R 80 The groups, together with the nitrogen atom to which they are attached, optionally form a 3- to 7-membered heteroalicyclic ring system containing 1 to 4 of the same or different additional heteroatoms selected from O, N, S, wherein N is optionally H or an R group such as a C1-C3 alkyl substituted group. 70 substitutions, and each M + is a counterion with a net single positive charge. + is calculated independently for each occurrence, e.g., K + , Na + , Li + Alkali metal ions such as + N(R 60 ) 4, protonated amino acid ions such as lysine or arginine, or [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 ions may be the ionized form of a compound of the present disclosure, and that other typical counterions, such as chloride, or a two-ionized compound may serve as the counterion of such divalent alkaline earth ion, or a doubly-ionized compound may serve as the counterion of such divalent alkaline earth ion.) Specific examples include -N(R80 )2 includes -NH2, -NH-alkyl, -NH-pyrrolidin-3-yl, N-pyrrolidinyl, N-piperazinyl, N-methyl-piperazin-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.

[0029] Substituents for replacing a hydrogen atom on an unsaturated carbon atom of a group containing an unsaturated carbon are -R, unless otherwise specified. 60 , halo, -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 , -OSO3 - M + , -OSO3R 70 , -PO3 -2 (M + )2, -PO3 -2 M 2+ , -P(O)(OR 70 )O - M + , -P(O)(OR 70 )2, -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 , -C(NR 70 )N(R 80 )2, -OC(O)R 70 , -OC(S)R 70 , -OCO2- M + , -OCO2R 70 , -OC(S)OR 70 , -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 , -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 + is as previously defined. In an independent embodiment, the substituent is -O - M + , -OR 70 , -SR 70 , or -S - M + isn't it.

[0030] Substituents for replacing a hydrogen atom on a nitrogen atom of such nitrogen-containing groups are, unless otherwise specified, -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 , -PO32- (M + )2, -PO3 2- M 2+ , -P(O)(OR 70 )O - 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 + is as previously defined.

[0031] In one embodiment, a substituted group has at least one substituent, such as one substituent, two substituents, three substituents, or four substituents, up to the maximum number of substituents possible for a particular moiety.

[0032] In addition, in embodiments in which groups or moieties are substituted with substituted substituents, the nesting of such substituted substituents is limited to three, thereby preventing the formation of polymers. Thus, in a group or moiety containing a first group that is a substituent of a second group attached to a parent structure, which is itself a substituent of a third group, the first (outermost) group can only be substituted with unsubstituted substituents. For example, in a group containing -(aryl-1)-(aryl-2)-(aryl-3), aryl-3 can only be substituted with substituents that are themselves unsubstituted.

[0033] Any group or moiety defined herein may be connected to any other portion of the disclosed structures, such as a parent or core structure, as would be understood by one of ordinary skill in the art, such as by considering valence rules and / or considering functionality, relative to exemplary species, unless the connectivity of the group or moiety to other portions of the structure is explicitly stated or implied by context.

[0034] "Acyl" refers to the group -C(O)R, where R is H, aliphatic, heteroaliphatic, or aromatic (including both aryl and heteroaryl). Exemplary acyl moieties include, but are not limited to, -C(O)H, -C(O)alkyl, -C(O)Ci-C6 alkyl, -C(O)Ci-C6 haloalkyl, -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.

[0035] "Aliphatic" refers to a substantially hydrocarbon-based group or moiety. Aliphatic groups or moieties can be acyclic, including alkyl, alkenyl, or alkynyl groups (as well as alkylene, alkenylene, or alkynylene groups), cycloalkyl, cycloalkenyl, or cycloalkynyl, including straight-chain and branched-chain configurations, and all stereoisomers and positional isomers as well, and cyclic versions thereof, such as alicyclic groups or moieties, further including 1 to 25 carbon atoms (C 1-25 ), for example, 1 to 15 (C 1-15 ), 1 to 10 (C 1-10 ), 1~6(C 1-6 ), or 1 to 4 carbon atoms (C 1-4 ), or in alicyclic groups or moieties, 3 to 15 (C 3-15 ), 3~10(C 3-10 ), 3~6(C 3~6 ), or 3-4 (C 3-4 ) carbon atoms. An aliphatic group can be substituted or unsubstituted, unless expressly referred to as "unsubstituted aliphatic" or "substituted aliphatic." An aliphatic group can be substituted with one or more substituents (up to two substituents for each methylene carbon of the aliphatic chain, or up to one substituent for each carbon of the -C=C- double bond of the aliphatic chain, or up to one substituent for the carbon of the terminal methine group).

[0036] "Lower aliphatic" refers to 1-6(C 1-6 ), or 1-4 (C 1-4 1 to 10 carbon atoms (C 1-10 ), or in the case of a lower alicyclic group, 3 to 6 ( 3-6 ) carbon atoms, such as 3 to 10 (C 3-10 ) refers to an aliphatic group containing

[0037] "Alkoxy" refers to the group -OR, where R is a substituted or unsubstituted alkyl, or a substituted or unsubstituted cycloalkyl group. In certain instances, R is C 1-6 Alkyl group or C 3-6is a cycloalkyl group. Methoxy (-OCH3) and ethoxy (-OCH2CH3) are exemplary alkoxy groups. In substituted alkoxy, R is substituted alkyl or substituted cycloalkyl, examples of which in compounds of the present disclosure include haloalkoxy groups such as -OCF2H.

[0038] "Alkoxyalkyl" refers to the group -alkyl-OR where R is a substituted or unsubstituted alkyl, or a substituted or unsubstituted cycloalkyl group, where -CH2CH2-O-CH2CH3 is an exemplary alkoxyalkyl group.

[0039] "Alkyl" is a group consisting of 1 to at least 25 (C 1-25 ) carbon atoms, more typically 1 to 6 (C 1-6 ) carbon atoms, such as 1 to 10 (C 1-10 ) carbon atoms. The alkyl portion can be substituted or unsubstituted. By way of example, this term includes linear or branched hydrocarbyl groups such as (CH), ethyl (-CHCH), n-propyl (-CHCHCH), isopropyl (-CH(CH)), n-butyl (-CHCHCHCHCH), isobutyl (-CHCH(CH)), sec-butyl (-CH(CH)(CHCH), t-butyl (-C(CH)), n-pentyl (-CHCHCHCHCHCH), and neopentyl (-CHC(CH)).

[0040] "Amino" refers to the groups -NH, -NHR, or -NRR, where each R is independently selected from H, aliphatic, heteroaliphatic, aromatic, including both aryl and heteroaryl, or heteroalicyclic, or two R groups taken together with the nitrogen to which they are attached form a heterocyclic ring. Examples of such heterocyclic rings include two R groups taken together with the nitrogen to which they are attached, optionally forming the group [ka] -O- or -N( g), interrupted by one or two heteroatom groups such as (CH2) 2-5 - forms a ring, R g But R 70 , -C(O)R 70 , -C(O)OR 60 , or -C(O)N(R 80 )2.

[0041] "Amido" refers to an amide where R is hydrogen, heteroaliphatic, or alkyl, especially C 1-6 It refers to the group -N(R) acyl, which is an aliphatic group such as alkyl.

[0042] "Aromatic," unless otherwise specified, refers to a cyclic conjugated group or moiety of 5 to 15 ring atoms having a single ring (e.g., phenyl, pyridinyl, or pyrazolyl) or multiple fused rings (e.g., naphthyl, indolyl, or pyrazolopyridinyl) in which at least one ring is aromatic, i.e., at least one ring, and optionally multiple fused rings, have a contiguous delocalized π-electron system. Typically, the number of out-of-plane π-electrons corresponds to Hückel's rule (4n+2). The point of attachment to the parent structure is typically through the aromatic portion of the fused ring system. For example, [ka] . However, in certain instances, the context or explicit disclosure may dictate that the point of attachment is through the non-aromatic portion of the fused ring system. For example, [ka] . An aromatic group or moiety can contain only carbon atoms in the ring, such as an aryl group or moiety, or it can contain one or more ring carbon atoms and one or more ring heteroatoms (e.g., O, N, P, or Si) containing lone pairs of electrons, such as a heteroaryl group or moiety. Unless otherwise stated, an aromatic group can be substituted or unsubstituted.

[0043] "Aryl," unless otherwise specified, refers to an aromatic carbocyclic group of 6 to 15 carbon atoms having a single ring (e.g., phenyl) or multiple condensed rings in which at least one ring is aromatic (e.g., 1,2,3,4-tetrahydroquinoline, benzodioxole, etc.). If any aromatic ring moiety contains a heteroatom, the group is heteroaryl and not aryl. Aryl groups can be, for example, monocyclic, bicyclic, tricyclic, or tetracyclic. Unless otherwise specified, aryl groups can be substituted or unsubstituted.

[0044] "Aliphatic" refers to an aryl group attached to the parent through an aliphatic moiety. Aliphatic groups include aralkyl or arylalkyl groups such as benzyl and phenylethyl.

[0045] "Carboxyl" refers to -CO2H.

[0046] "Carboxamido" refers to --C(O)amino.

[0047] "Carboxyl ester" or "carboxy ester" refers to the group --C(O)OR, where R is aliphatic, heteroaliphatic, or aromatic (including both aryl and heteroaryl).

[0048] "Carboxylate" is -C(O)O - Or its salt.

[0049] "Cyano" refers to the group --CN.

[0050] "Alicyclic" 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, where a ring or at least one ring of the system is aliphatic. Typically, the point of attachment to the parent structure is through the aliphatic portion of the polycyclic system. Alicyclics include saturated and unsaturated systems, including cycloalkyl, cycloalkenyl, and cycloalkynyl. Alicyclic groups can contain 3 to 25 carbon atoms, e.g., 3 to 15, 3 to 10, or 3 to 6 carbon atoms. Unless otherwise stated, alicyclic groups can be substituted or unsubstituted. Exemplary alicyclic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, or cyclohexenyl.

[0051] "Halo," "halide," or "halogen" refers to fluoro, chloro, bromo, or iodo.

[0052] "Haloalkyl" refers to an alkyl moiety substituted with one or more halogens. Exemplary haloalkyl moieties include -CHF, -CHF, and -CF.

[0053] "Heteroaliphatic" 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 with an atom having at least one lone pair of electrons, typically nitrogen, oxygen, phosphorus, silicon, or sulfur. Heteroaliphatic compounds or groups, such as heteroalicyclic groups, can be substituted or unsubstituted, branched or unbranched, chiral or achiral, and / or acyclic or cyclic.

[0054] "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, unless otherwise specified. A heteroaryl group or moiety can contain a single ring (e.g., pyridinyl, pyrimidinyl, or pyrazolyl) or multiple condensed rings (e.g., indolyl, benzopyrazolyl, or pyrazolopyridinyl). A heteroaryl group or moiety can be, for example, monocyclic, bicyclic, tricyclic, or tetracyclic. Unless otherwise specified, a heteroaryl group or moiety can be substituted or unsubstituted.

[0055] "Heterocyclyl," "heterocyclo," and "heterocycle" refer to both aromatic and non-aromatic ring systems, and more specifically to stable 3- to 15-membered ring moieties containing at least one carbon atom, typically multiple carbon atoms, and at least one heteroatom, such as 1 to 5. The heteroatom(s) can be nitrogen, phosphorus, oxygen, silicon, or sulfur atom(s). A heterocyclyl moiety can be a monocyclic moiety or can contain multiple rings, such as in a bicyclic or tricyclic ring system, provided that at least one of the rings contains a heteroatom. Such polycyclic moieties can include fused or bridged ring systems, as well as spirocyclic systems, and any nitrogen, phosphorus, carbon, silicon, or sulfur atom of the heterocyclyl moiety can be optionally oxidized to various oxidation states. For convenience, nitrogens, specifically, but not limited to, those defined as cyclic aromatic nitrogens, are meant to include their corresponding N-oxide forms, even if not expressly defined as such in specific instances. Thus, for example, for a compound having a pyridinyl ring, the corresponding pyridinyl-N-oxide is included as another disclosed compound unless expressly excluded or excluded by context. In addition, the ring nitrogen atom can be optionally quaternized. Heterocycles include heteroaryl moieties and heteroalicyclyl or heteroalicyclic moieties, which are partially or fully saturated heterocyclyl rings.Examples of heterocyclyl groups include, but are not limited to, azetidinyl, oxetanyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazoyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, naphthalazinyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, Quinolinyl, isoquinolinyl, tetrazoyl, tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, pyridinyl, pyrazinyl , pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, diazebicycloheptane, diazepane, diazepine, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothieyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphosphoranyl, and oxadiazolyl.

[0056] "Hydroxyl" refers to the group --OH.

[0057] "Nitro" refers to the group -NO2.

[0058] A "phosphate" is a group in which each -OR' is independently -OH; -O-aliphatic, such as -O-alkyl or -O-cycloalkyl; -O-aromatic, including both -O-aryl and -O-heteroaryl; -O-aralkyl; or -OR' is M + is a single positively charged counterion -O - M + Each M + is K + , Na + , Li + Alkaline ions such as + ammonium ions such as N(R")4 (where R" is H, aliphatic, heteroaliphatic, or aromatic (including both aryl and heteroaryl), or [Ca 2+ ] 0.5 , [Mg 2+ ] 0.5 , or [Ba 2+ ] 0.5 The phosphonooxyalkyl may be, for example, —CH2OP(O)(O - Na + (((dialkoxyphosphoryl)oxy)alkyl) refers to a dialkyl ester of a phosphonooxyalkyl group such as, for example, —CH2OP(O)(O-tert-butyl)2.

[0059] A "phosphonate" is a group in which each -OR' is independently -OH; -O-aliphatic, such as -O-alkyl or -O-cycloalkyl; -O-aromatic, including both -O-aryl and -O-heteroaryl; or -O-aralkyl; or -OR' is -O - M + and M + refers to the group -P(O)(OR')2, a counterion with a single positive charge. + is a positively charged counterion, e.g., K + , Na + , Li + Alkali metal ions such as +ammonium ions such as N(R")4 (where R" is H, aliphatic, heteroaliphatic, or aromatic (including both aryl and heteroaryl), or [Ca 2+ ] 0.5 , [Mg 2+ ] 0.5 , or [Ba 2+ ] 0.5 The phosphonoalkyl may be, for example, —CHP(O)(OH) or —CHP(O)(O - Na + ((dialkoxyphosphoryl)alkyl) refers to a dialkyl ester of a phosphonoalkyl group such as, for example, —CH 2 P(O)(O-tert-butyl) 2 .

[0060] "Patient" or "subject" may generally refer to any organism, but more typically refers to mammals and other animals, particularly humans. Thus, the disclosed methods are applicable to both human therapy and veterinary applications.

[0061] A "pharmaceutically acceptable excipient" refers to a substance, other than an active ingredient, contained in a composition containing an active ingredient. As used herein, an excipient may be incorporated within or physically mixed with particles of a pharmaceutical composition. An excipient may be used, for example, to dilute an active agent and / or modify the properties of a pharmaceutical composition. Excipients may include, but are not limited to, antiadherents, binders, coatings, enteric coatings, disintegrants, flavors, sweeteners, colorants, lubricants, glidants, adsorbents, preservatives, carriers, or vehicles. An excipient may be starch and modified starch, cellulose and cellulose derivatives, sugars and sugar 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, hydroxypropyl cellulose, 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, silica, talc, magnesium carbonate, sodium starch glycolate, tartrazine, aspartame, benzalkonium chloride, sesame oil, propyl gallate, sodium metabisulfite, or lanolin.

[0062] An "adjuvant" is a component that modifies the effect of another agent, typically an active ingredient. Adjuvants are often pharmacological and / or immunological agents. Adjuvants can modify the effect of an active ingredient by increasing the immune response. Adjuvants can also act as stabilizers for the formulation. Exemplary adjuvants include, but are not limited to, aluminum hydroxide, alum, aluminum phosphate, killed bacteria, squalene, detergents, cytokines, paraffin oil, and combination adjuvants such as Freund's complete or incomplete adjuvant.

[0063] "Pharmaceutically acceptable carrier" refers to an excipient that is a carrier or vehicle, such as a suspending aid, solubilizing aid, or aerosolizing aid. See Remington: The Science and Practice of Pharmacy, The University of the Sciences in Philadelphia, Editor, Lippincott, Williams, & Wilkins, Philadelphia, PA, 21, incorporated herein by reference. st Edition (2005) describes exemplary compositions and formulations suitable for pharmaceutical delivery of one or more therapeutic compositions and additional pharmaceutical agents.

[0064] Generally, the nature of the carrier will depend on the particular mode of administration used. For example, parenteral formulations usually contain an injectable fluid as a vehicle, including pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solution, aqueous dextrose, glycerol, etc. In some instances, the pharmaceutically acceptable carrier can be sterilized so as to be suitable for administration to a subject (e.g., by parenteral, intramuscular, or subcutaneous injection). In addition to biologically neutral carriers, the pharmaceutical compositions to be administered may contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, preservatives, and pH buffering agents, for example, sodium acetate or sorbitan monolaurate.

[0065] "Pharmaceutically acceptable salts," as would be known to one skilled in the art, refer to pharmaceutically acceptable salts of compounds derived from a variety of organic and inorganic counterions, including, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, etc., and, where the molecule contains a basic functional group, salts of organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, etc. "Pharmaceutically acceptable acid addition salts" are a subset of "pharmaceutically acceptable salts" that are formed with acid partners while retaining the biological effectiveness of the free base. 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, and phosphoric acid, as well as 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, and xinafoic acid. "Pharmaceutically acceptable base addition salts" are a subset of "pharmaceutically acceptable salts" derived from inorganic bases, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. 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, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Exemplary organic bases are isopropylamine, diethylamine, tris(hydroxymethyl)aminomethane (Tris), ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. (See, e.g., S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977;66:1-19, incorporated herein by reference.) In particularly disclosed embodiments, the compound may be a formate, trifluoroactate, hydrochloride, or sodium salt.

[0066] An "effective amount" of a compound or pharmaceutical composition refers to the amount of the compound or pharmaceutical composition sufficient to achieve a specific desired result, such as inhibiting a protein or enzyme. In certain embodiments, an "effective amount" is an amount sufficient to inhibit RIP1, elicit a desired biological or medical response in a tissue, system, subject, or patient, treat a specified disorder or disease, improve or eradicate one or more of its symptoms, and / or prevent the occurrence of a disease or disorder. The amount of a compound that constitutes an "effective amount" can vary depending on the compound, the desired result, the condition and its severity, the size, age, and sex of the patient being treated, etc., as will be understood by those skilled in the art.

[0067] "Prodrug" refers to a compound that is biologically active or that is converted in vivo to yield a compound that is more biologically active than the parent compound. In vivo conversion can occur, for example, by hydrolysis or enzymatic conversion. Common examples of prodrug moieties include, but are not limited to, ester and amide forms of a compound having an active form bearing a carboxylic acid moiety. Examples of pharmaceutically acceptable esters of the compounds of the present disclosure include, but are not limited to, aliphatic esters, particularly alkyl esters (e.g., C 1-6 Other prodrug moieties include phosphate ester groups and carboxylic acid esters, such as alkyl esters (e.g., alkyl esters). Other prodrug moieties include those where R' is H or C 1-6 Examples of phosphate esters or salts thereof include alkyl esters such as -CH2-OP(O)(OR')2. Acceptable esters also include, but are not limited to, cycloalkyl esters and arylalkyl esters such as benzyl. Examples of pharmaceutically acceptable amides of the 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 of the disclosed exemplary embodiments of the compounds according to the present disclosure can be prepared according to conventional methods. A thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, "Prodrugs as Novel Delivery Systems," Vol. 14 of the ACS Symposium Series, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated by reference for all purposes.

[0068] "Solvate" refers to a complex formed by the combination of solvent molecules with solute molecules or ions. The solvent can be an organic solvent, an inorganic solvent, or a mixture of both. Exemplary solvents include, but are not limited to, alcohols such as methanol, ethanol, and propanol; amides such as N,N-dialiphatic amides such as N,N-dimethylformamide; tetrahydrofuran; alkyl sulfoxides such as dimethyl sulfoxide; water; and combinations thereof. The compounds described herein can exist in unsolvated and solvated forms when combined with pharmaceutically acceptable or non-acceptable solvents such as water, ethanol, and the like. Solvated forms of the compounds of the present disclosure are within the scope of the embodiments disclosed herein.

[0069] "Sulfonamido" refers to the group or moiety -SO2 amino, or -N(R)sulfonyl, where R is H, aliphatic, heteroaliphatic, or aromatic (including both aryl and heteroaryl).

[0070] "Sulfanyl" refers to the group or -SH, -S-aliphatic, -S-heteroaliphatic, -S-aromatic (including both -S-aryl and -S-heteroaryl).

[0071] "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).

[0072] "Sulfonyl" refers to the groups: -SO2H, -SO2aliphatic, -SO2heteroaliphatic, -SO2aromatic (including both -SO2aryl and -SO2heteroaryl).

[0073] As used herein, "treating" or "treatment" relates to the treatment of a disease or condition of interest in a patient or subject, particularly a human having the disease or condition of interest, including, by way of example and not limitation, the following: (i) specifically, to prevent a disease or condition from occurring in a patient or subject, where such patient or subject is susceptible to the condition but has not yet been diagnosed as having the disease or condition; (ii) inhibiting the disease or condition, e.g., preventing or delaying its onset; (iii) alleviating the disease or condition, e.g., reducing the symptoms thereof or causing regression of the disease or condition or its symptoms; or (iv) stabilizing the disease or condition;

[0074] As used herein, the terms "disease" and "condition" may be used interchangeably or may differ in that a particular disease or condition may not have a known causative agent (and thus the etiology has not yet been determined) and therefore is not yet recognized as a disease, but is recognized only as an undesirable state or syndrome in which a more or less specific set of symptoms has been identified by clinicians.

[0075] The above definitions and the following general formula are not intended to include impermissible substitution patterns (e.g., methyl substituted with five fluoro groups), which would be readily recognized by one of ordinary skill in the art.

[0076] Those skilled in the art will understand that compounds may exhibit the phenomena of tautomerism, conformational isomerism, geometric isomerism, and / or optical isomerism. For example, certain disclosed compounds may contain one or more chiral centers and / or double bonds and, as a result, may exist as double bond isomers (i.e., geometric isomers), stereoisomers such as enantiomers, diastereomers, and mixtures thereof, such as racemic mixtures. As another example, certain disclosed compounds may exist in several tautomeric forms, including enol forms, keto forms, and mixtures thereof. Because the various compound names, formulas, and compound diagrams in the specification and claims may represent only one of the possible tautomeric, conformational, optical, or geometric isomeric forms, those skilled in the art will understand that the disclosed compounds encompass any tautomeric, conformational, optical, and / or geometric isomeric forms of the compounds described herein, as well as mixtures of these various different isomeric forms. Techniques known to those skilled in the art can be used to separate mixtures of different isomeric forms, including mixtures of enantiomers and / or stereoisomers, to provide each individual enantiomer and / or stereoisomer with particular benefit of the present disclosure. In cases of restricted rotation, for example, about an amide bond or between two directly bonded rings such as a pyridinyl ring, a biphenyl group, etc., atropisomers are also possible and are also specifically included in the disclosed compounds.

[0077] In any embodiment, any or all hydrogens present in a compound, or in a particular group or moiety within a compound, can be replaced with deuterium or tritium. Thus, the recitation of alkyl includes deuterated alkyls where one to a maximum number of hydrogens present can be replaced with deuterium. For example, C2D x H 5-x When one to five hydrogens in, etc. are replaced with deuterium, ethyl refers to both C2H5 or C2H5.

[0078] II. RIP1-ACTIVE COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS COMPRISING RIP1-ACTIVE COMPOUNDS A. Compound Disclosed herein are compounds and pharmaceutical compositions comprising such compounds that are useful for inhibiting RIP1 and / or treating diseases and / or conditions associated with RIP1.In some embodiments, the compounds are selective kinase inhibitors.For example, exemplary compounds can selectively inhibit RIP1 over RIP2, RIP3, or both RIP2 and RIP3.

[0079] In some embodiments, compounds of the present disclosure have the structure according to Formula I [ka] or a pharmaceutically acceptable salt thereof. One of ordinary skill in the art will understand that unless otherwise specified, compounds within the scope of Formula I also include stereoisomers, N-oxides, tautomers, hydrates, solvates, isotopes, and / or prodrugs thereof. In yet further embodiments, compounds may have a structure according to Formula IA [ka] ,

[0080] With respect to Formulas I and IA, Ring B is heteroaryl and may be a monocyclic heteroaryl. In some embodiments, Ring B is a 5- or 6-membered heteroaryl. In some embodiments, Ring B is a 5- or 6-membered heteroaryl, where the heteroaryl has 1, 2, or 3 ring nitrogen atoms and the remaining ring atoms are carbon. In some embodiments, Ring B is a 5- or 6-membered heteroaryl, where the heteroaryl has 1 or 2 nitrogen atoms and 1 oxygen atom, with the proviso that R 1 but heterocyclyl, [ka] or Linker-R 6and the linker group is alkynyl. In an independent embodiment, Ring B is not a triazole, triazine, or heteroaryl containing an oxygen or sulfur ring atom, such as oxazole, thiazole, or isoxazole. In another independent embodiment, Ring B is not a triazine or heteroaryl containing an oxygen or sulfur ring atom, such as oxazole, thiazole, or isoxazole. In certain embodiments, Ring B is pyrazolyl or triazole, and in other particular embodiments, Ring B is pyridinyl or pyrimidinyl. With particular reference to Formula I, Y is CH.

[0081] Each R 1 are independently halogen, [ka] , or -linker-R 6 group, and the linker is a bond, or R a where R a But not H or D, but R 6 is heterocyclyl, R b , -C(R f )3, or -C(R f )=C(R f )2.

[0082] R 2 is R a Also, R 3 is R a is.

[0083] If present, each R 4 are independently e is.

[0084] L is a bond, a heteroatom, or R a where R a But not H or D.

[0085] Z is C 1-10 It is aliphatic or aryl.

[0086] m is 1, 2, 3, or 4; and n is 0, 1, or 2.

[0087] R a independently for each occurrence, L is R a H or D, except for embodiments in which 1-10 aliphatic, C 1-10 Haloaliphatic, C 5-10 aromatic, C 3-6 Heterocyclic, or C 3-10 It is a spiro heterocyclic ring.

[0088] R b but independently for 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 , one or two NRs d R d , carboxyl, or combinations thereof, optionally further substituted with an aromatic moiety, -SH, -O-acyl, or -C(O)NH 1-10 It is alkyl.

[0089] R c may be independently one, two, or three R e C can be substituted with 1-10 Alkyl, 1, 2, or 3 R e C can be substituted with 2-10 Alkenyl, 1, 2, or 3 R e C can be substituted with 2-10 Alkynyl, 1, 2, or 3 R e C can be substituted with 3-6 cycloalkyl, or one, two, or three R e C can be substituted with 5-10 It is aromatic.

[0090] R d independently for each occurrence: H; 1, 2, or 3 R e , or C 3-9 C, which may be substituted with heterocyclyl 1-6 alkyl; 1, 2, or 3 R e C can be substituted with 3-6 Cycloalkyl; 1, 2, or 3 R e C can be substituted with 3-6 Heterocyclic; 1, 2, or 3 R b C can be substituted with 5-10 Aryl; 1, 2, or 3 R e C can be substituted with 5-10 Heteroaryl or two R d The group, together with the nitrogen attached thereto, may be one or more R e C can be substituted with 3-9 Heterocyclic, or one or more R e C can be substituted with 5-10 Heteroaryls are provided.

[0091] R e independently for each occurrence, 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 is.

[0092] Also, R f represents independently at each occurrence an -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, is C 2-6 alkenyl group, one or more R e C can be substituted with 3-6 Cycloalkyl group or one or more R e or C which can be substituted with acyl 3-10Heterocyclic compounds are provided.

[0093] In certain embodiments of formula I and / or formula IA, ring B is pyrazolyl, pyridinyl, pyrimidinyl, or triazolyl, and L is a heteroatom or C 1-10 aliphatic, Z is C 1-10 aliphatic or aryl, and each R 1 is heterocyclyl, or C 1-10 It is aliphatic and R 2 is H or C 1-10 It is aliphatic and R 3 is H, and each R 4 are independently halogen or C 1-10 aliphatic, m is 1, 2, 3, or 4, and n is 0, 1, or 2.

[0094] In some embodiments, each R 1 are independently heterocyclyl, unsubstituted C 1-10 Aliphatic, or -OH, halogen, carboxyl, carboxyl ester, heterocyclyl, amino, alkoxy, phosphate, cycloalkyl, alkenyl, -OC(O)NH(C 1-4 alkyl)-amino, -OC(O)R 8 C substituted with one or two substituents selected from 1-10 Aliphatic; or -OC(O)(CHR 9 )2CO2H. -OC(O)-R 8 The moiety is derived from an amino acid and is -OC(O)-R 8 The -OC(O)- portion of R corresponds to the acid moiety on the amino acid. 8 But -N(R 10 )2 or nitrogen-containing non-aromatic heterocyclyl, R 10 is H or a carboxyl ester. 9 is independently H or -O-acyl.

[0095] -OC(O)-R 8With respect to the moiety, the nitrogen-containing non-aromatic heterocyclyl may be a 5- or 6-membered unsaturated nitrogen-containing heterocyclyl, such as pyrrolidinyl. The amino acid may be any amino acid, such as a naturally occurring amino acid, selected from glycine, valine, alanine, leucine, isoleucine, methionine, phenylalanine, tryptophan, tyrosine, serine, threonine, asparagine, glutamine, arginine, histidine, lysine, aspartic acid, glutamic acid, cysteine, or proline. Those skilled in the art will understand that when an amino acid contains one or more chiral centers, all enantiomers, diastereomers, and / or mixtures thereof are contemplated. For example, the amino acid may be an L-amino acid, a D-amino acid, or a mixture thereof. In some embodiments, the amino acid is an L-amino acid. Also, in certain embodiments, -OC(O)-R 8 is -OC(O)CH(NH2)R 11 , [ka] , or -OC(O)-(CH2) 1-2 C(NH2)CO2H, R 11 is an amino acid side chain, and / or H, -CH3, isopropyl, -CH2CH(CH3)2, -CH(CH3)Et, -CH2CH2SCH3, [ka] , -CH2OH, -CH(OH)CH3, -CH2C(O)NH2, -CH2CH2C(O)NH2, -CH2SH, -CH2CH2CH2NHC(O)(NH)NH2, [ka] , -CH2CH2CH2CH2NH2, -CH2CO2H, or CH2CH2CO2H.

[0096] Also, R 1 With respect to at least one R1 is an 8- to 12-membered spiroheterocyclyl or C 1-10 It can be an alkyne. 1-10 The alkyne may have one or two substituents. One substituent may be OH. In some embodiments, one substituent is oxetanyl, azetidinyl, pyridinyl, pyrrolidinyl, piperidinyl, tetrahydropyranyl, or phosphate, and / or in some embodiments, one substituent is -OC(O)-R 8 is.

[0097] In some embodiments, m is 1, 2, or 3, and can be 1 or 2; in certain embodiments, m is 1.

[0098] R 2 is H, or C such as methyl 1-6 It can be alkyl.

[0099] R 3 is H or C 1-6 In certain embodiments, R 3 is H.

[0100] Each R 4 are independently a halogen such as F, Br, Cl, or I, or C 1-6 C such as alkyl 1-10 In some embodiments, each R 4 is independently chloro, fluoro, or methyl.

[0101] In certain embodiments, n is 0, and in other certain embodiments, n is 1.

[0102] Also, with respect to Formula I and / or Formula IA, or IB, L is a bond, a heteroatom, or R a where R a but not H or L. L is hydrogen or C 1-6 C such as alkyl 1-10alkyl, more specifically methylene (-CH2-), or [ka] Z can be C 1-10 In some embodiments, Z is a C alkyl group such as cyclobutyl or cyclopentyl. 3-6 C such as cycloalkyl or methyl 1-6 In another embodiment, Z is [ka] and each R 5 But independently, R e and p is 0, 1, 2, 3, 4, or 5. In such embodiments, each R 5 are independently halogen or C such as methyl or fluoro 1-6 In some embodiments, p is 1 or 2, while in other embodiments, p is 0. Also, 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.

[0103] 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. [ka]

[0104] In some embodiments, the compound may have a structure according to one or more of the following formulas: [ka] [ka] [ka] .

[0105] With respect to formulae IA-1 to IA-29, rings 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.

[0106] In any of the above embodiments relating to Formula I, Formula IA, and / or IA-1 through IA-29, R 1 may be selected from any of the following: [ka] [ka] [ka]

[0107] Also, in certain embodiments of Formula I, Formula IA, and / or Formulas IA-1 through IA-29, R 1 may be selected from any of the following: [ka] [ka] .

[0108] In another embodiment of Formula I, [ka] , Ring B is a 5- or 6-membered heteroaryl; L is a bond, a heteroatom, or R a where R aBut not H or D, Y is CH2, Z is (C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, or C 3-6 cycloalkyl, etc.)C 1-10 aliphatic, or [ka] and Each R 1 is a halogen, [ka] , or -linker-R 6 group, and the linker can be R a where R a But not H or D, but R 6 is R b , -C(R f )3, or -C(R f )=C(R f )2, R 2 and R 3 are independently a and R 4 and R 5 are independently e and R a independently for each occurrence (L, R a (Except for embodiments in which 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, or C 3-6 cycloalkyl, etc.)C 1-10 aliphatic, C 1-10 Haloaliphatic, C 5-10 Aromatic, or C 3-6 is heterocyclic, R b independently for each occurrence: -OH, -SH, -OR c , -SR c , -NR d Rd , -Si(R a )3, -C(O)OH, -C(O)OR c , or -C(O)NR d R d and R c independently for each occurrence (one, two, or three R e (can be replaced by)C 1-10 Alkyl, (1, 2, or 3 R e (can be replaced by)C 2-10 alkenyl, (one, two, or three R e (can be replaced by)C 2-10 Alkynyl, (1, 2, or 3 R e (can be replaced by)C 3-6 cycloalkyl, or (one, two, or three R e (can be replaced by)C 5-10 It is aromatic and R d independently for each occurrence: H; (one, two, or three R e (can be replaced by)C 1-6 alkyl; (one, two, or three R e (can be replaced by)C 3-6 Cycloalkyl; (one, two, or three R e (one, two, or three R b (can be replaced by)C 3-6 Heterocyclic C 5-10 Aryl; (1, 2, or 3 R e (can be replaced by)C 5-10 Heteroaryl or two R d The group, together with the nitrogen attached thereto, can be one or more R e C can be substituted with 3-9 Heterocyclic, or one or more R e C can be substituted with 5-10 providing a heteroaryl, R e independently for each occurrence, halogen, C 1-6 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, C 1-6 Haloalkyl, C3-6 Cycloalkyl, C 5-10 Heteroaryl, or -OR a and R f is calculated independently for each occurrence, a , R b , or R e or two R f A group, together with the carbon atom to which it is attached, can be one or more R e (can be replaced by)C 3-6 a cycloalkyl group, or (one or more R e (can be replaced by)C 3-10 providing a heterocyclic m is 1 to 4, such as 1, 2, 3, or 4, and in certain embodiments, is 1 or 2; n is 0, 1, or 2; p is 0, 1, 2, 3, 4, or 5.

[0109] In some embodiments, compounds of the present disclosure have the structure satisfying formula IIA: [ka] or a pharmaceutically acceptable salt thereof. Those skilled in the art will understand that the disclosed generic formulas include within their scope all stereoisomers, N-oxides, tautomers, hydrates, solvates, isotopes, and / or prodrugs of compounds having the structural features required by such formulas.

[0110] With respect to Formula IIA: Ring B is a 5- or 6-membered heteroaryl; L is a bond, a heteroatom, or R a where R a But not H or D, Each R 1 is a halogen, [ka] , or -linker-R 6 group, and the linker can be Ra where R a But not H or D, but R 6 is R b , -C(R f )3, or -C(R f )=C(R f )2, R 2 and R 3 are independently a and R 4 and R 5 But independently, R e and R a independently for each occurrence (L, R a (Except for embodiments in which 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl, or C 3-6 cycloalkyl, etc.)C 1-10 aliphatic, C 1-10 Haloaliphatic, C 5-10 Aromatic, or C 3-6 is heterocyclic, R b independently for 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 and R c independently for each occurrence (one, two, or three R e (can be replaced by)C 1-10 Alkyl, (1, 2, or 3 R e (can be replaced by)C 2-10 alkenyl, (one, two, or three R e (can be replaced by)C 2-10 Alkynyl, (1, 2, or 3 R e (can be replaced by)C 3-6 cycloalkyl, or (one, two, or three Re (can be replaced by)C 5-10 It is aromatic and R d independently for each occurrence: H; (one, two, or three R e (can be replaced by)C 1-6 alkyl; (one, two, or three R e (can be replaced by)C 3-6 Cycloalkyl; (one, two, or three R e (one, two, or three R b (can be replaced by)C 3-6 Heterocyclic C 5-10 Aryl; (1, 2, or 3 R e (can be replaced by)C 5-10 Heteroaryl or two R d The group, together with the nitrogen attached thereto, can be one or more R e C can be substituted with 3-9 Heterocyclic, or one or more R e C can be substituted with 5-10 providing a heteroaryl, R e independently for each occurrence, 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 calculated independently for each occurrence, a , R b , or R e or two R f The group, together with the carbon atom to which it is attached, is C 3-6 Cycloalkyl groups (in some embodiments, C 3-6 A cycloalkyl group can be formed by one or more R e (which may be replaced by 3-10 Heterocyclic (in some embodiments, C 3-10 A heterocyclic group can be formed by one or more R e and m is 1 to 4, such as 1, 2, 3, or 4, and in certain embodiments, is 1 or 2; n is 0, 1, or 2; p is 0, 1, 2, 3, 4, or 5.

[0111] In certain embodiments of formula I, IA, or IIA, the 5-membered heteroaryl group of ring B is of the formula [ka] 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 group is a diazole, triazole, oxadiazole, or oxazole. Exemplary triazoles include any of the following: [ka] .

[0112] Exemplary diazoles are selected from any of the following: [ka] .

[0113] Exemplary oxazoles are selected from any of the following: [ka] .

[0114] Exemplary oxadiazoles are selected from any of the following: [ka] .

[0115] In certain embodiments of formula I, IA, or IIA, L is oxygen, or R a and Ra But -CH2-, [ka] C such as -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2- 1- In some embodiments, L is a bond (and thus is directly attached to Z), or —CH—, or oxygen.

[0116] R 1 Linker-R 6 is R 1 The linker group 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 haloaliphatic group, such as a C2 haloalkyl or haloalkenyl group. 1 The linker group in R a and R a is -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-, etc. 1- or the linker group is a C alkyl such as -CH=CH-, -CH=CHCH2-, -CH2CH=CH-, or -CH2CH=CHCH2- 2- C4 alkenyl, or the linker group is [ka] C etc. 2- In some embodiments, the linker group is a C alkynyl, such as -CF=CH-, -CCl=CH-, -CH=CCl-, -CH=CF-, -CCl=CCl-, -CF=CF-, or -CCl=CF-, -CF=CCl-. 2- In some embodiments, the linker group is -CH-, -CHCH-, -CHCHCH-, -CHCHCHCH-, -CH=CH-, -CCl=CH-, -CH=CCl-, or [ka] is.

[0117] In some embodiments, R 1 R 6 The group is C(R f )3 and one R f But R e and R e But, -OR a (e.g., hydroxyl or OMe), and R f are mutually independent, R a and R a But C 1-4 aliphatic, preferably R f are mutually, R a and R a But independently for each occurrence, C 1-4 In certain embodiments, R a is methyl or CD3, R f are mutually exclusive, R a In yet some additional embodiments, R 6 is each R f But R a and R a is methyl or H, or each R f But R a and R a is methyl or R b and R b But -C(O)OR c -C(R f )3. In some additional embodiments, one R f is R e and -OR a (e.g., hydroxyl or OMe), and the other two R fThe groups, together with the carbon atoms to which they are attached, provide an alicyclic (e.g., cyclopropane, cyclobutane, cyclopentane, or cyclohexane) or heterocyclic (e.g., epoxide, oxetane, tetrahydrofuran, tetrahydropyran, or hexahydrofuro[3,2-b]furan) group. In some such embodiments, the alicyclic and / or heterocyclic groups can be substituted, and in some particular embodiments, with one or more hydroxyl or benzyl-carbonyl groups.

[0118] Some compound embodiments may include alkynes. 2-4 In certain embodiments, R 1 -linker-R 6 group, and the linker is R a and R a is -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH=CH-, or [ka] and R 6 But R b and R b is -C(O)OEt or -C(O)NR d R d , or -NR d R d and each R d However, each occurrence independently represents hydrogen, C 5-10 Heteroaryl, C 3-6 cycloalkyl, or both R d The groups, together with the nitrogen atom to which they are attached, form R d Heterocyclic groups are provided that may further include one or more additional heteroatoms apart from the nitrogen atom bonded to the group. In some embodiments, one R d is hydrogen, and other R d is one or more R, such as one of the following: e C5-, which may be substituted with 10 Heteroaryl is: [ka] .

[0119] R 6 Also, R b R b -OH or -OR c (R c But C 1-6 alkyl, and in some embodiments, C 1-6 Alkyl is C such as pyridinyl 5-10 may be substituted with heteroaryl or R c However, C such as quinolinyl 5-10 heteroaryl), or R b But, -NR d R d R d However, for each occurrence, H, C 5-10 Heteroaryl (in some embodiments, C 5-10 A heteroaryl group can be formed by one or more R e substituted with two R groups) or d The group, together with the nitrogen attached to it, forms a C 3-9 Heterocyclic (in some embodiments, C 3-9 A heterocyclic ring may contain one or more R e substituted with a group), or C 5-10 Heteroaryl (in some embodiments, C 5-10 Heteroaryl is a heteroaryl group consisting of one or more R e R e In embodiments with substitutions, R e independently for each occurrence, C 5-10 Heteroaryl, or -OR a and R a But C 1-10 It is alkyl.

[0120] Some compounds have a linker that is a C1 group and an R b is R 6 and R b But, -NR d Rd and one R d is H and other R d is pyridinyl, or both R d The group, together with the nitrogen attached to it, forms a C 5-10 providing a heteroaryl, or b But, OR c and R c C substituted with a pyridinyl group 1-4 In some embodiments, R b teeth, [ka] is.

[0121] In some embodiments, R 1 may be selected from any of the following: [ka] .

[0122] In some embodiments, R 2 and R 3 Each of the groups independently represents R a and R a is independently at each occurrence hydrogen, methyl, ethyl, propyl, butyl, pentyl, or hexyl. 2 and R 3 each independently at each occurrence is hydrogen, methyl, or ethyl; a In an exemplary embodiment, R 2 is methyl and R 3 is hydrogen.

[0123] In some embodiments, each R 4 independently, and / or each R 5 are independent, R e and R e is alkyl, alkenyl, alkynyl, chloro, bromo, iodo, or fluoro. In certain embodiments, each R 4and / or each R 5 is independently R e and R e is a lower aliphatic (eg, methyl), fluoro, or chloro.

[0124] In some embodiments, m is 1, n is 0 or 1, and p is 0, 1, or 2. In certain embodiments, m is 1, n is 0, and p is 0, 1, or 2.

[0125] A compound of formula I, IA, or IIA can also have a structure satisfying formula IIIA, or any one or more of IIIA1-IIIA5. [ka]

[0126] With reference to Formulas IIIA and IIIA1-IIIA5, R 1 and R 5 are as listed above for Formulas I, IA, and IIA. In certain embodiments, 0, 1, or 2 R 5 The group R 5 is R e R e is fluoro or chloro. In other particular embodiments, R 5 is not present. Referring to Formulae IIIA1-IIIA5, each W is independently nitrogen or oxygen, specifically nitrogen.

[0127] One particular disclosed embodiment has formula IIIA6: [ka]

[0128] With respect to Formula IIIA6, R 1 , R 2 and R 3 is as described above. R 10 is alkyl, cyclic alkyl, or aryl. More specifically, R10 is C 1-10 lower alkyl, such as alkyl, more specifically C including methyl, ethyl, propyl, butyl, and pentyl 1-5 The cyclic alkyl group is typically selected from cyclobutyl, cyclopentyl, or cyclohexyl, specifically cyclobutyl or cyclopentyl. In some embodiments, the compound according to the present disclosure has formula IIIA7. [ka]

[0129] In many of the disclosed embodiments, R 10 is phenyl. Thus, certain disclosed embodiments of the present disclosure have formula IIIA8: [ka]

[0130] With respect to formula IIIA7 or IIIA8, R 1 and R 5 Each of R is as listed above for Formula I, IA, and / or IIA. 5 is R e In certain embodiments, 0, 1, or 2 R 5 In certain embodiments, R 5 is absent or is a halogen such as fluoro or chloro, specifically fluoro, or C such as methyl 1-6 It is alkyl.

[0131] In some embodiments, compounds of formula I, IA, and / or IIA can also have a structure satisfying any one or more of formulas IVA-VIIA: [ka]

[0132] Referring to Formulas IVA-VIIA, each R 5can be independently as listed above, and in some particular embodiments, is lower aliphatic (e.g., methyl), or halogen such as chloro or fluoro. Also, Ring B is as listed above, and in some embodiments, is selected from: [ka] .

[0133] R shown in formulas IVA to VIIA 6 are as listed above, and in some embodiments are selected from one of the following: [ka] [ka] .

[0134] Exemplary compounds of certain disclosures within one or more of Formulas I, IA, IA-1 through IA-32, IIA, IIIA, IIIA1 through IIIA8, and IVA through VIIA include the following: [ka] [ka] [ka] .

[0135] Exemplary compounds within one or more of Formulas I, IA, IA-1 through IA-32, IIA, IIIA, IIIA1 through IIIA8, and IVA through VIIA include those named and / or shown below: I-1: (S)-4-(4-fluorobenzyl)-N-(8-((3-hydroxyoxetan-3-yl)ethynyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-1H-pyrazole-1-carboxamide; 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]azepin-3-yl)-4-phenoxypicolinamide; 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]azepin-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]azepin-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]azepin-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]azepin-3-yl)-1H-1,2,4-triazole-3-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]azepin-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]azepin-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]azepin-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]azepin-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]azepin-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]azepin-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]undecan-9-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-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]azepin-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]azepin-3-yl)-1H-1,2,4-triazole-3-carboxamide; I-16: (±)-5-benzyl-N-(8-((3-hydroxyoxetan-3-yl)ethynyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-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]azepin-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]azepin-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]azepin-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]azepin-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]azepin-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]azepin-3-yl)-4-phenoxypicolinamide; 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]azepin-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]azepin-3-yl)-4-phenoxypicolinamide; I-25: (±)-N-(1-methyl-2-oxo-8-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-phenoxypicolinamide; I-26: (±)-N-(2-oxo-8-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-phenoxypicolinamide; I-27: (±)-N-(1-methyl-2-oxo-8-(3-oxa-9-azaspiro[5.5]undecan-9-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-phenoxypicolinamide; 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]azepin-3-yl)-4-phenoxypicolinamide; 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]azepin-3-yl)-4-phenoxypicolinamide; I-30: (±)-N-(1-methyl-2-oxo-8-(2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-phenoxypicolinamide; 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]azepin-3-yl)-4-phenoxypicolinamide; 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]azepin-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]azepin-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]azepin-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]azepin-3-yl)picolinamide; 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]azepin-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]azepin-3-yl)-4-phenoxypicolinamide; I-38: (±)-N-(1-methyl-2-oxo-8-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-phenylpyrimidine-2-carboxamide; 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]azepin-3-yl)-4-phenylpyrimidine-2-carboxamide. [ka] [ka] [ka] [ka]

[0136] In some embodiments, one or more of the compounds may be included in a pharmaceutical composition or medicament, and in some embodiments, the compound or 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 other than the disclosed compound or compounds, such as a pharmaceutically acceptable excipient, an adjuvant, an additional therapeutic agent (described in the following section), or any combination thereof.

[0137] 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 advantageous 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 consistency to the formulation, etc. The pharmaceutically acceptable excipient(s) may comprise pharmaceutically acceptable carrier(s).Exemplary excipients include, but are not limited to, mono-, di-, 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; bulking agents; buffers such as phosphate and citrate buffers; anti-adherents such as magnesium stearate; binders such as sugars (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 polyvinylpyrrolidone, polyalkylene glycols); coatings (such as hydroxypropyl methylcellulose, shellac, corn protein zein, and cellulose ethers including gelatin); release aids (such as enteric coatings); disintegrants (such as dibasic calcium phosphate, vegetable fats and oils, lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, and magnesium stearate); fillers (such as mint, cherry, anise, peach, apricot or licorice, raspberry, and vanilla); lubricants (such as minerals exemplified by talc or silica, vegetable stearin, magnesium stearate, or fats exemplified by 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; encapsulating agents; gums; granulating agents; and combinations thereof.

[0138] B. Therapeutic Combinations The compounds described herein may be used alone, in combination with each other, in separate pharmaceutical compositions, together in a single pharmaceutical composition, or as an adjunct to or in combination with other established therapies. The compound or compounds, or compositions containing the compound (or compounds), may be administered once or multiple times. In some embodiments, the compounds of the present disclosure may be used in combination with other therapeutic agents useful for the disorder or condition being treated. These other therapeutic agents may be administered simultaneously, sequentially in any order, by the same route of administration as the compounds of the present disclosure or by a different route. In sequential administration, the compound(s) and therapeutic agent(s) may be administered such that the effective period of at least one compound and therapeutic agent overlaps with the effective period of at least one other compound and / or therapeutic agent. In an exemplary embodiment of a combination containing four components, the effective period of the first component administered may overlap with the effective periods of the second, third, and fourth components, but the effective periods of the second, third, and fourth components may or may not independently overlap with each other. In another exemplary embodiment of a combination comprising four components, the effective period of the first component administered overlaps with the effective period of the second component but not with the effective period of the third or fourth component; the effective period of the second component overlaps with the effective periods of the first and third components; and the effective period of the fourth component overlaps only with the effective period of the third component. In some embodiments, the effective periods of all compounds and / or therapeutic agents overlap with each other.

[0139] 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 guanylate cyclase-C agonist, an intestinal secretagogue, an antiviral agent, an anticancer agent, an antifungal agent, or a combination thereof. The anti-inflammatory agent can be a steroid or a nonsteroidal anti-inflammatory agent. In certain embodiments, the nonsteroidal anti-inflammatory agent is selected from aminosalicylates, cyclooxygenase inhibitors, diclofenac, etodolac, famotidine, fenoprofen, flurbiprofen, ketoprofen, ketorolac, ibuprofen, indomethacin, meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin, or a combination thereof. In some embodiments, the immunosuppressant is 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.

[0140] In some embodiments, the compounds may be used in combination with anticancer or cytotoxic agents.Various classes of anticancer and anti-neoplastic compounds include, but are not limited to, alkylating agents, antimetabolites, BCL-2 inhibitors, vinca alkyloids, taxanes, antibiotics, enzymes, cytokines, platinum coordination complexes, proteasome inhibitors, substituted ureas, kinase inhibitors, multiple 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, mechlorothamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, ethyleneimine, methylmelamine, alkyl sulfonates (e.g., busulfan), and carmustine. Exemplary antimetabolites include, but are not limited to, the folic acid analog methotrexate; pyrimidine analogs fluorouracil and cytosine albinoside; and purine analogs mercaptopurine, thioguanine, and azathioprine. Exemplary vinca alkyloids include, but are 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 anti-neoplastic agents include L-asparaginase. Exemplary coordination compounds include, but are not limited to, cisplatin and carboplatin. Exemplary hormones and hormone-related compounds include, by way of example and not limitation, the corticosteroids prednisone and dexamethasone; the aromatase inhibitors aminoglutethimide, formestane, and anastrozole; the progestin compounds hydroxyprogesterone caproate, medroxyprogesterone; and the anti-estrogen compound tamoxifen.

[0141] These and other useful anti-cancer compounds are described in The Merck Index, 13th Ed. (O'Neil MJ et al., ed.) Merck Publishing Group (2001), and Goodman and Gilman's The Pharmacological Basis of Therapeutics, 12th Edition, Brunton LL ed., Chapters 60-63, McGraw Hill, (2011), both of which are incorporated herein by reference.

[0142] Among the CTLA4 antibodies that may be used in combination with the inhibitors of the present disclosure are YERVOY by Bristol-Myers Squibb (登録商標) The drug is ipilimumab, which is marketed as

[0143] Other chemotherapeutic agents for combination use include immuno-oncology 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. Additional checkpoint inhibitors for combination with the compounds disclosed herein include anti-LAG-3 agents such as BMS-986016 (MDX-1408).

[0144] Additional chemotherapeutic agents for 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).

[0145] The compounds of the present disclosure may also be advantageously used in conjunction with CAR-T therapy. Examples of currently available CAR-T therapies are axicabtagenecilloreucel and tisagenlecleucel.

[0146] Additional anti-proliferative compounds useful in combination with the compounds of the present disclosure include, by way of example and not limitation, antibodies against growth factor receptors (e.g., anti-Her2); cytokines such as interferon-α and interferon-γ, interleukin-2, and GM-CSF.

[0147] Additional chemotherapeutic agents useful in combination with the present compounds include proteasome inhibitors such as bortezomib, carfilzomib, and marizomib.

[0148] Examples of kinase inhibitors that are useful in combination with the compounds of the present disclosure, particularly in the treatment of malignant tumors, include Btk inhibitors such as ibrutinib; CDK inhibitors such as palbociclib; EGFR inhibitors such as 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, and 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.

[0149] In other embodiments, the second therapeutic agent may be selected from any of the following: Analgesics - morphine, fentanyl, hydromorphone, oxycodone, codeine, acetaminophen, hydrocodone, buprenorphine, tramadol, venlafaxine, flupirtine, meperidine, pentazocine, dextromoramide, dipipanone; Antibiotics - aminoglycosides (e.g., amikacin, gentamicin, kanamycin, neomycin, netilmicin, tobramycin, and paromycin), carbapenems (e.g., ertapenem, doripenem, imipenem, cilastatin, and meropenem), cephalosporins (e.g., cefadroxil, cefazolin, cephalothin, cephalexin, cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazolin, cephalosporin ... didim, ceftibuten, ceftizoxime, ceftriaxone, cefepime, and cefobiprole), glycopeptides (e.g., teicoplanin, vancomycin, and telavancitin), lincosamides (e.g., clindamycin and incomysin), lipopeptides (e.g., daptomycin), macrolides (azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, troleandomycin, telithromycin, and spectinomycin), monobactams (e.g., azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, troleandomycin, telithromycin, and spectinomycin), dztreonam), nitrofurans (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 / clavulanate, ampicillin / sulfactam, piperacillin / tazobactam, and ticarcillin / clavulanate) , polypeptides (e.g., bacitracin, colistin, and polymyxin B), quinolones (e.g., ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, trovafloxacin, grepafloxacin, sparfloxacin, and temafloxacin), sulfonamides (e.g., mafenide, sulfonamide chrysoidine, sulfacetamide, sulfadiazine, silver sulfadiazine, sulfamethizole, 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, ethionamine, amide, isoniazid, pyrazinamide, rifampicin (rifampin), rifabutin, rifapentine, and streptomycin), and others such as arsphenamine, chloramphenicol, fosfomycin, fusidic acid, linezolid, metronidazole, mupirocin, platensimycin, quinuplicin / dalfopristin, rifaximin, thiamphenicol, tigecycline, and timidazole; 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, clenoliximab, clazakiumab, fezakinumab, freticumab, mavrilimumab, ocrelizumab, sarilumab, secukinumab, toralizumab, zanolimumab; Anticoagulants—warfarin (Coumadin™), acenocoumarol, phenprocoumon, atromentin, phenindione, heparin, fondaparinux, idraparinux, rivaroxaban, apixaban, hirudin, lepirudin, bivalirudin, argatrobam, dabigatran, ximelagatran, batroxobin, hementin; Anti-inflammatory drugs - steroids, e.g., budesonide, non-steroidal anti-inflammatory drugs, e.g., aminosalicylates (e.g., sulfasalazine, mesalamine, 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, nambumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin; Immunosuppressants - drugs designed to inhibit cellular immunity while leaving the recipient's humoral immune response intact, including corticosteroids such as mercaptopurine, dexamethasone, hydrocortisone, prednisone, methylprednisolone, and prednisone; alkylating agents such as cyclophosphamide; calcineurin inhibitors such as cyclosporine, sirolimus, and tacrolimus; inhibitors of inosine monophosphate dehydrogenase (IMPDH) such as mycophenolic acid, mycophenolate mofetil, and azathioprine; and various antibodies (e.g., antilymphocyte globulin (ALG), antithymocyte globulin (ATG), monoclonal anti-T cell antibody (OKT3)), as well as 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 from 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 GlaxoSmithKline under the trade name Imuran; and antibodies are currently available from Ortho It is available from Biotech under the trade name Orthoclone, from Novartis under the trade name Simulect (basiliximab), and from Roche under the trade name Zenapax (daclizumab), Guanylate cyclase-C receptor agonists or intestinal secretagogues, such as linaclotide, are sold under the name Linzess.

[0150] These various agents may be used according to standard or conventional dosages as specified in the prescribing information accompanying the commercially available drug form (see also the compounding information in the 2006 Edition of The Physician's Desk Reference), the disclosures of which are incorporated herein by reference.

[0151] III. Methods of Making Compounds The disclosed embodiments of the present compounds can be prepared by any suitable method, as would be understood by one skilled in the art. One 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: [ka]

[0152] Referring to Scheme 1, a metal-mediated cross-coupling reaction can be used to prepare the "R" amine shown in Scheme 1, which provides the cross-coupling product 104. 6 - R containing a "linker" group 1The protected amine precursor 100 can be coupled with group 102. 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., second- or third-generation XPhos Pd, PdCl2, Pd(OAc)2, etc.). In some embodiments, a palladium catalyst can be used in combination with another co-catalyst, such as CuI, to facilitate the cross-coupling reaction, such as in a Sonogoshira reaction. Metal-mediated cross-coupling can also include using 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). Referring to Scheme 1, X is a group suitable for metal-mediated cross-coupling, such as a halogen or a triflate group, and PG is an amine protecting group that may be selected from, but is not limited to, a 9-fluorenylmethoxycarbonyl ("Fmoc") group, a t-butyloxycarbonyl ("Boc") group, a trityl ("Tr") group, an allyloxycarbonyl ("Alloc") group, a benzyloxycarbonyl ("Cbz") group, and the like.

[0153] Representative examples of the method steps shown in Scheme 1 are provided below in Schemes 2A-2F. Using methods similar to those shown in Scheme 2A, other compound embodiments disclosed herein may be made by replacing the propargyl alcohol of Scheme 2A with the corresponding alkyne group to yield such compounds, and further modifications that may be used to arrive at the final structure of such compounds are discussed below. [ka] [ka] [ka] [ka] [ka] [ka]

[0154] Once cross-coupling product 104 is produced, it may be subjected to an optional linker group reduction step, which can reduce linker groups containing one or more unsaturated sites to saturated linker groups and / or linker groups with a lower degree of unsaturation. If a linker reducing group is used, this may be followed by a deprotection step, as shown in Scheme 3, followed by an amide formation step. Alternatively, if a linker group reduction step is not used, cross-coupling product 104 may be deprotected and converted to amide compound 302. [ka]

[0155] Referring to Scheme 3, an optional linker reduction step can be performed. For example, if the linker contains an unsaturated site (e.g., a double or triple bond), the unsaturated site can be reduced to full saturation (e.g., reducing a double and / or triple bond to a single bond) or to a lesser degree of unsaturation (e.g., reducing a triple bond to a double bond). Suitable reagents for performing such an optional linker reduction step will be recognized by those of skill in the art with the benefit of this disclosure; however, one exemplary set of conditions involves exposing the cross-coupling product 104 to H in the presence of Pd on carbon. Because these steps are optional, they need not be performed in all embodiments. Alternatively, in some embodiments, the cross-coupling product 104 can be deprotected to provide an amine, which can then be converted to amide compound 302 by reacting with a suitable acid coupling partner 300, as shown in Scheme 3.

[0156] Representative examples of the method steps shown in Scheme 3 are provided below in Schemes 4A-4F. Methods similar to those described in Scheme 4A can be used to make other compounds disclosed herein. Certain compounds may be further functionalized, as discussed below. [ka] [ka] [ka] [ka]

[0157] In some embodiments, the method comprises the step of: 6 Modify the group to create different R 6The method may further include performing one or more additional modifications to amide compound 302, such as forming a group, to provide amide compound 500. [ka]

[0158] Referring to Scheme 5, R 6 One or more modifications to the group may be performed. For example, R 6 If R is an ester group, it can be converted to a carboxylic acid or a primary alcohol. Suitable reagents for carrying out such optional modification steps will be recognized by those of skill in the art with the benefit of this disclosure; however, one exemplary set of conditions is 6 This involves exposing the ester group to LiOH to provide the corresponding acid. The resulting acid may then be further modified to provide an amide-containing product by using suitable amide coupling conditions (such as those described above) in combination with an amine coupling partner. Similar methods can be used to prepare embodiments of the compounds disclosed herein (where the double bond of the linker group is not first reduced prior to coupling). In yet additional embodiments, compound embodiments containing alkynes with terminal OH groups can be prepared by converting the terminal alcohol obtained by the above method into a functionalized alcohol.

[0159] Some exemplary disclosed compounds are alkynyl-substituted analogs. These compounds can be prepared using a metal-mediated coupling strategy, as discussed above with reference to Scheme 1. Scheme 6 shows a more detailed general method for preparing alkynyl-substituted analogs according to the present disclosure. [ka]

[0160] Referring to Scheme 6, nitrogen is bubbled through a stirred solution of either an aryl halide (1 equiv.), compound 700, CuI (0.1–0.2 equiv.), and Pd(PPh3)4 (0.05–0.1 equiv.) in dry DMF (3–4 mL / mmol) in a vial for 3 minutes. Subsequently, NEt3 (10 equiv.) is added to the dark reaction solution, followed by the corresponding alkyne (1.5–3 equiv.), 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 a suitable reaction temperature, such as 70–90 °C, for a suitable reaction period, such as 3–6 hours. Alternatively, the reaction mixture can be heated in a microwave reactor (30–45 min) until the aryl halide 700 is consumed. The dark reaction solution is worked up by one of the following methods: a) dilution with ice water / organic solvent; b) dilution with ice water / organic solvent followed by concentration to dryness, followed by workup; or c) dilution of the crude residue with ice water, sonication, and allowing the slurry to warm to room temperature. The resulting gray / dark solid is collected by filtration, suction dried, dissolved in THF (20 mL), and filtered through a Celite® / silica gel pad, washing the pad with THF. The crude material is then purified by reverse-phase or normal-phase silica gel flash column chromatography to provide the corresponding alkynyl-substituted analogs, compound 704, in 25-69% yields.

[0161] IV. Methods of Using the Compounds A. Disease / Disorder The disclosed compounds, as well as combinations and / or pharmaceutical compositions thereof, can be used to inhibit RIP1 kinase by contacting the kinase either in vivo or ex vivo with a compound or compounds of the present disclosure, or a composition comprising a compound or compounds of the present disclosure. The disclosed compound or compounds, or a composition comprising a compound or compounds of the present disclosure, can also be used to ameliorate, treat, or prevent a variety of diseases and / or disorders. In certain embodiments, the disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof can be useful for treating conditions in which inhibition of RIP1 or a pathway involving RIP1 is therapeutically beneficial. In some embodiments, the compounds directly inhibit RIP1 kinase activity. In certain embodiments, the disclosed compounds are useful for treating autoimmune diseases, inflammatory disorders, cardiovascular diseases, neurological disorders, neurodegenerative disorders, allergic disorders, respiratory diseases, kidney diseases, cancer, ischemic conditions, red blood cell deficiencies, lung and brain injuries (e.g., induced by ischemia-reperfusion, or cisplatin, and / or cerebrovascular accidents), and bacterial and viral infections.

[0162] 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 ophthalmyopathy, or asthma.

[0163] The disclosed compounds, combinations of the disclosed compounds, or pharmaceutical compositions thereof may also be useful for treating immune dysregulation associated with bone marrow or organ transplant rejection or graft-versus-host disease. Examples of inflammatory and immune dysregulation disorders that can 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 resulting from transplantation, 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. Autoimmune syndromes including rheumatic fever and post-infectious autoimmune diseases including post-infectious glomerulonephritis, psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia, lupus erythematosus, acne, alopecia areata, keratoconjunctivitis, vernal keratoconjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, keratoconus, dystrophic epithelial cornea , corneal leukemia, ocular pemphigus, inflammatory and hyperproliferative skin diseases such as Mooren's ulcer, scleritis, malignant exophthalmos, Falk-Koyanagi-Harada disease, sarcoidosis, pollen allergy, persistent obstructive airway disease, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, chronic or refractory asthma, late-onset asthma and airway hyperresponsiveness, bronchitis, gastric ulcer, vascular damage caused by ischemic disease and thrombosis, ischemic bowel disease, ischemic 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's syndrome, hemolytic uremic syndrome, diabetic nephropathy, polymyositis, Guillain-Barré syndrome, Meniere's disease, polyneuritis, polyneuropathy, mononeuritis, radiculopathy, hyperthyroidism, Graves' disease, pure red cell aplasia, aplastic anemia, hypoplastic anemiaanemia), idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, red blood cell hypoplasia, osteoporosis, sarcoidosis, fibrotic lung, idiopathic interstitial pneumonia, dermatomyositis, albinism, ichthyosis vulgaris, photoallergic sensitivity, cutaneous T-cell lymphoma, chronic lymphocytic leukemia, arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, cardiomyopathy or cardiomyopathic infection, scleroderma (including systemic sclerosis), antiphospholipid syndrome, Wegener's granulomatosis, Sjögren's syndrome, adiposity, eosinophilic fasciitis, gums, teeth Lesions of periodontal tissue, alveolar bone, dental cementum, glomerulonephritis, male pattern baldness or alopecia by preventing hair loss or providing hair growth and / or promoting hair growth and hair growth, muscular dystrophy, pyoderma and Sézary syndrome, Addison's disease, ischemia-reperfusion injury of organs occurring during preservation, transplantation, or ischemic diseases, endotoxin shock, pseudomembranous colitis, colitis caused by drugs or radiation, ischemic acute renal failure, chronic renal failure, pulmonary oxygen-induced or drug-induced toxicosis, lung cancer, emphysema, cataracts, siderosis, retinitis pigmentosa, retinal degeneration eczema, retinal detachment, age-related macular degeneration, vitreous scarring, corneal alkali burns, erythematous polymorphic dermatitis, linear IgA bullous dermatitis and cement dermatitis, gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by environmental pollution, aging, carcinogenesis, carcinoma metastasis and altitude sickness, diseases caused by histamine or leukotriene-C4 release, Behçet's disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, partial liver resection, acute liver necrosis, necrosis caused by toxins, viral hepatitis, shock, or anoxia, type B viral hepatitis, non-A / Examples of causes of liver damage include non-hepatitis B, cirrhosis, alcoholic cirrhosis, alcoholic steatohepatitis, and alcoholic liver disease including non-alcoholic steatohepatitis (NASH), autoimmune hepatitis, acetaminophen toxicity, hepatotoxicity, liver failure, fulminant liver failure, delayed liver failure, acute exacerbation of chronic liver failure, chronic kidney disease, kidney damage / injury (e.g., caused by nephritis, kidney transplant, surgery, administration of nephrotoxic drugs, or acute kidney injury), enhanced chemotherapy effects, cytomegalovirus infection, HCMV infection, AIDS, cancer, senile dementia, Parkinson's disease, trauma, or chronic bacterial infection.

[0164] In certain embodiments, the compounds are useful for treating neuropathic pain, including inflammation-induced pain.

[0165] In certain embodiments, the compound is used to treat interleukin-1 converting enzyme-associated fever 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, alpha-mannosidosis, aspartylglucosaminuria, cholesteryl ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Farber disease, These compounds are useful in treating sialic acid storage diseases, including 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, pyknodysostosis, Sandhoff disease, Schindler disease, sialic acid storage diseases, Tay-Sachs disease, and Wolman disease.

[0166] In certain embodiments, the disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof are useful for the treatment and / or prevention of 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 syndrome, cryopyrin-associated periodic syndrome, Schnitzler's syndrome, systemic juvenile idiopathic arthritis, adult-onset Still's disease, gout, gout flare, pseudogout, Saffo's syndrome, Castleman's disease, sepsis, stroke, atherosclerosis, celiac disease, DIRA (deficiency of Il-1 receptor antagonist), Alzheimer's disease, Huntington's disease, or Parkinson's disease.

[0167] Proliferative diseases that may be treated by the disclosed compounds include hyperproliferative skin disorders, as well as benign and malignant tumors, solid tumors, carcinomas of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung, vagina, cervix, testis, urogenital tract, esophagus, larynx, skin, bone, or thyroid, sarcoma, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancer, particularly colon carcinoma or colorectal adenoma, tumors of the head and neck, epidermal hyperproliferation, psoriasis, prostatic hyperplasia, neoplasms, epithelial neoplasms, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, macrophage, leukemia ... cell carcinoma, non-small cell lung carcinoma, lymphoma, Hodgkin and non-Hodgkin, breast carcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, IL-1-mediated disorders, MyD88-mediated disorders (ABC diffuse large B-cell lymphoma (DLBCL) and Waldenstrom's macroglobulinemia), Hodgkin lymphoma, primary cutaneous T-cell lymphoma or chronic lymphocytic leukemia), smoldering or asymptomatic multiple myeloma, or hematologic malignancies (leukemia, acute myeloid leukemia (AML), DLBCL, ABC These include 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 syndromes (MDS), myelofibrosis, polycythemia vera, Kaposi's sarcoma, Waldenstrom's macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, and intravascular large B-cell lymphoma. Specifically, the compounds of the present disclosure are useful for treating 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 Waldenstrom's macroglobulinemia.

[0168] Examples of allergic disorders that may 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 a pathophysiological disorder, essential asthma of unknown or undetermined cause, emphysema-like asthma, exercise-induced asthma, emotion-induced asthma, asthma caused by environmental factors, These include extrinsic asthma caused by or associated with bacterial, fungal, protozoan, or viral infections, cold-induced asthma, occupational asthma, infectious asthma caused by or associated with bacterial, fungal, protozoan, or viral infections, incipient asthma, wheezing infant syndrome, bronchitis, cough-variant asthma, or drug-induced asthma), allergic bronchopulmonary aspergillosis (ABPA), allergic rhinitis, perennial allergic rhinitis, perennial rhinitis, vasomotor rhinitis, postnasal drip, suppurative or non-suppurative sinusitis, acute or chronic sinusitis, and ethmoid, frontal, maxillary, or sphenoid sinusitis.

[0169] As another example, rheumatoid arthritis (RA) typically causes generalized swelling, pain, loss of movement, and tenderness in target joints. RA is characterized by a chronically inflamed synovium densely packed with lymphocytes. The synovium, typically one cell layer thick, appears to be cellularly dense and similar in morphology to lymphoid tissue, containing clusters of dendritic cells, T, B, and NK cells, macrophages, and plasma cells. This process, as well as numerous immunopathological mechanisms including the formation of antigen-immunoglobulin complexes, ultimately leads to the destruction of joint integrity, resulting in deformity, permanent loss of function, and / or bone erosion at or near the joint. The disclosed compounds, combinations of the disclosed compounds, or pharmaceutical compositions thereof, can be used to treat, ameliorate, or prevent any one, some, or all of these symptoms of RA. Thus, in the context of RA, a compound is considered to provide a therapeutic benefit if it achieves a reduction or amelioration of any of the symptoms commonly associated with RA, regardless of whether the treatment results in a treatment associated with the underlying RA and / or a reduction in the amount of circulating rheumatoid factor ("RF").

[0170] The American College of Rheumatology (ACR) has developed criteria to define improvement and clinical remission in RA. One such parameter, ACR20 (ACR criteria for 20% clinical improvement), requires a 20% improvement in tender and swollen joint counts, as well as a 20% improvement in three of the following five parameters: patient's global assessment, physician's global assessment, patient's pain assessment, degree of disability, and acute phase reactant levels. These criteria are expanded for ACR50 and ACR70, which are 50% and 70% improvements, respectively. Other criteria include Paulu's criteria and radiographic progression (e.g., Sharp score).

[0171] In some embodiments, therapeutic benefit in a patient with RA is achieved when the patient exhibits an ACR20. In certain embodiments, an ACR improvement of ACR50 or even ACR70 can be achieved.

[0172] In one embodiment, the compounds of the present disclosure can be used to delay the onset of the consequences of aging. For example, the compounds reduce the increased chronic inflammation ("inflammation") associated with aging. Numerous symptoms and conditions are associated with inflammation, and examples of such conditions that can be treated with the compounds include neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease, hematopoietic neoplasms, and myeloproliferative disorders. Additional conditions that can be treated or ameliorated by the compounds include those described by Franceschi C, Campisi J. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. J Gerontol A Biol Sci Med Sci. 2014;69 Suppl 1:S4-S9. In another aspect, the compounds can be used to reduce the effects of aging on the reproductive system. For example, necroptosis induced by RIP1 signaling is involved in reproductive aging according to Li et al. eLife 2017;6:e27692 and Chaudhary et al. Journal of Biomedical Science (2019) 26:11, and therefore the compounds can be used to treat aging-related conditions such as reduced testosterone levels, reduced fertility, and prostate enlargement.

[0173] The use of the compound in combination with other therapies is particularly useful for treating hyperproliferative disorders.The compound can be used in combination with standard therapy to treat disorders such as cancer, leukemia, and lymphoma.For example, myelodysplastic syndrome (MDS) can be treated with the compound disclosed herein in combination with standard therapy.Therapeutic agents for use in combination with the compound include demethylating agents such as azacitidine and decitabine, and other chemotherapeutic agents such as cytarabine, daunorubicin, and idarubicin.Immunomodulatory therapy, such as lenalidomide and CAR-T therapy, can also be used in combination with the compound to treat MDS.

[0174] In a specific embodiment, at least one compound according to the present invention or a composition comprising at least one compound is administered to a subject who has or potentially has atopic dermatitis. In another specific embodiment, at least one compound according to the present invention or a composition comprising at least one compound is administered to a subject who has or potentially has rheumatoid arthritis. In another specific embodiment, at least one compound according to the present invention or a composition comprising at least one compound is administered to a subject who has or potentially has ankylosing spondylitis. In another specific embodiment, at least one compound according to the present invention or a composition comprising at least one compound is administered to a subject who has or potentially has myelodysplastic syndrome.

[0175] Additional diseases or disorders that can be treated and / or prevented using the compounds and compositions of the invention include amyotrophic lateral sclerosis (ALS), autoimmune syndromes, rheumatoid arthritis, type 1 diabetes, inflammatory bowel disease including Crohn's disease and ulcerative colitis, biliary cirrhosis, multiple sclerosis, Wegener's granulomatosis, ichthyosis, asthma, pollen allergy, persistent obstructive airways 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, and autoimmune diseases. Autoimmune hepatitis-related diseases, cerebrovascular accidents, allergic diseases, chronic obstructive pulmonary disease, emphysema, Friedreich's ataxia, Lewy body diseases, diabetic neuropathy, polyglutamine (polyQ) diseases, Fahr's disease, Menkes disease, Wilson's disease, prion disorders, bone-destroying disorders such as bone resorption disorders, bone disorders associated with multiple myeloma; benign tumors, proliferative disorders, inflammatory and hyperproliferative skin disorders, epidermal hyperproliferation, psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis, seborrheic dermatitis, pustular psoriasis, bullous dermatitis, erythematous polymorphic dermatitis, linear IgA bullous dermatitis, semen Dermatitis, gingivitis, periodontitis, lesions of the gingiva, alveolar bone, and dental cementum, sepsis, pancreatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia, hyperlipidemia, eosinophilic fasciitis, acne, alopecia areata, male pattern baldness, senile alopecia, keratoconjunctivitis, vernal conjunctivitis, corneal alkali burns, Behçet's disease, uveitis associated with Behçet's disease, keratitis, herpetic keratitis, keratoconus, corneal epithelial dystrophy, corneal leukoplakia, ocular pemphigoid, Mooren's ulcer, scleritis, Falk-Koyanagi-Harada disease, hematological disorders, hematological malignancies, phosphorus lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, breast carcinoma, follicular carcinoma, anaplastic carcinoma, papillary carcinoma, seminoma, melanoma, ABC diffuse large B-cell lymphoma (DLBCL), Waldenstrom's macroglobulinemia, primary cutaneous T-cell lymphoma, smoldering or asymptomatic 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 syndromes (MDS), myelofibrosis, polycythemia vera, Kaposi's sarcoma, splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, intravascular large B-cell lymphoma, IL-1-mediated disorders, MyD88-mediated disorders, drug-resistant malignancies such as JAK inhibitor-resistant malignancies and ibrutinib-resistant malignancies, e.g., ibrutinib-resistant hematologic malignancies, ibrutinib-resistant CLL, and ibrutinib-resistant Waldenström's macroglobulinemia, acute myeloid leukemia, chronic myeloid leukemia; angiogenic disorders such as solid tumors, ocular angiogenesis, and 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-associated fever syndrome, tumor necrosis factor receptor-associated periodic syndrome, NEMO deficiency syndrome, HOIL-1 deficiency, linear ubiquitin chain assembly complex deficiency syndrome, lysosomal storage diseases, Gaucher disease, GM2 gangliosidosis, alpha-mannosidosis, aspartylglucosaminuria, cholesteryl 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, pyknodysostosis, Sandhoff disease, Schindler disease, sialic acid storage disease, Tay-Sachs disease, Wolman disease, Huntington's disease, Parkinson's disease, neurodegenerative disorders fibrotic conditions such as CMV retinitis, non-alcoholic steatohepatitis, and cardiac conditions such as ischemia-reperfusion; allergies, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, erythroderma, chronic thyroiditis, Graves' disease, autoimmune gastritis, autoimmune neutropenia, thrombocytopenia, graft-versus-host disease, endotoxin-induced inflammatory responses, tuberculosis, atherosclerosis, muscle degeneration, cachexia, Reiter's syndrome, rubella-associated arthritis,acute synovitis, pancreatic beta-cell disease; diseases characterized by massive neutrophil infiltration; ankylosing spondylitis, gouty arthritis, psoriatic arthritis, and other arthritic conditions; cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, fibrotic lung, idiopathic interstitial pneumonia, allograft rejection, bone marrow rejection, fever and myalgia due to infection, keloid formation, scar tissue formation, fever, influenza, chronic myeloid leukemia; angiogenic disorders including solid tumors; acute hepatitis infection (including hepatitis A, B, and C), AIDS, ARC or malignant tumors, viral diseases including herpes; stroke, myocardial infarction, Arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, myocardial ischemia, ischemia in heart attack, organ hypoxia, vascular hyperplasia, cardiac and renal reperfusion injury, ischemia-reperfusion injury of organs occurring during preservation, transplantation, or ischemic disease, cardiac hypertrophy, thrombin-induced platelet aggregation, endotoxemia and / or toxic shock syndrome, prostaglandin endoperoxide synthase 2-related conditions, pemphigus vulgaris, autoimmune / polymyositis, dermatomyositis, vitiligo, photoallergic sensitivity, ischemia-reperfusion injury, cardiac ischemia-reperfusion injury resulting from myocardial infarction, multiple system atrophy, Parkinson's plus 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 diseases, 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 resulting from COVID-19, post-infectious autoimmune diseases, rheumatic fever, post-infectious glomerulonephritis, systemic sclerosis, cerebrovascular accident (CVA), chronic obstructive pulmonary disease (COPD), NEMO deficiency syndrome (F-kappa-B essential modulator 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, anthrax toxin-induced septic shock,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 sclerosis, macular edema, diabetic retinopathy, central areolar choroidal dystrophy, BEST disease, adult vitelliform disease, pattern dystrophy, myopic degeneration, central serous retinopathy, Stargardt disease, cone-rod dystrophy, North Carolina dystrophy, infectious retinitis, inflammatory retinitis, uveitis, posterior uveitis, central Toxic retinitis and light-induced toxicity, macular edema, central areolar 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., arterial or non-arterial anterior ischemic neuropathy and posterior ischemic optic neuropathy), compressive optic neuropathy, infiltrative optic neuropathy, traumatic optic neuropathy, mitochondrial optic neuropathy (e.g., Leber optic neuropathy), nutritional optic neuropathy, toxic optic neuropathy and hereditary optic neuropathy, dominant optic neuropathy, Beer syndrome, Creutzfeldt-Jakob disease), progressive supranuclear palsy, Hereditary spastic paraplegia, subarachnoid hemorrhage, perinatal brain injury, subclinical brain injury, spinal cord injury, anoxic-ischemic brain injury, cerebral ischemia, focal cerebral ischemia, global cerebral ischemia, and hypoxic hypoxia, peritoneal damage caused by peritoneal dialysis fluid (PDF) and PD-related side effects, glomerular disease, tubulointerstitial disease, interstitial nephritis, obstruction, polycystic kidney disease), focal glomerulosclerosis, immune complex nephropathy, diabetic nephropathy, Goodpasture's syndrome, hepatocellular carcinoma, pancreatic cancer, urinary tract cancer, bladder cancer, colorectal cancer, colon cancer, breast cancer, prostate cancer, prostate hyperplasia, renal cancer, kidney carcinoma, liver carcinoma , adrenal carcinoma, thyroid cancer, gallbladder cancer, peritoneal cancer, ovarian cancer, cervical cancer, gastric cancer, endometrial cancer, esophageal cancer, stomach cancer, head and neck cancer, neuroendocrine cancer, CNS cancer, brain tumors (e.g., brain carcinoma, glioma, anaplastic oligodendroglioma, adult glioblastoma, and adult anaplastic astrocytoma), bone cancer, soft tissue sarcoma, retinoblastoma, neuroblastoma, peritoneal effusion, malignant pleural effusion, mesothelioma, Wilms' tumor, trophoblastic neoplasm, epithelial neoplasm, gastric carcinoma, ovarian carcinoma, rectal carcinoma, prostate carcinoma, pancreatic carcinoma, lung carcinoma, vaginal carcinoma, cervical carcinoma, testicular carcinoma, genitourinary carcinoma,Esophageal carcinoma, laryngeal carcinoma, skin carcinoma, bone carcinoma, thyroid carcinoma, sarcoma, glioblastoma, neuroblastoma, gastrointestinal cancer, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung carcinoma, lymphoma, colon carcinoma, colorectal adenoma, hemangiopericytoma, mucinous carcinoma, round cell carcinoma, squamous cell carcinoma, esophageal squamous cell carcinoma, oral carcinoma, vulvar cancer, adrenal cortical carcinoma, ACTH-producing tumors, and leukemia, respiratory infectious viruses such as influenza virus, rhinovirus, coronavirus, parainfluenza virus, respiratory syncytial virus, adenovirus, and reovirus, herpes zoster caused by herpes virus, diarrhea caused by rotavirus, viral hepatitis, AIDS, Bacillus cereus, Vibrio parahaemolyticus, Enterohemorrhagic Escherichia coli, Staphylococcus Bacterial infections such as Mycobacterium aureus, MRS A, Salmonella, botulinum, and Candida, Paget's disease, achondroplasia, osteoporosis, hyperparathyroidism, osteogenesis imperfecta, partial liver resection, acute liver necrosis, necrosis caused by toxins, necrosis caused by viral hepatitis, necrosis caused by shock, necrosis caused by anoxia, 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 hepatic failure, delayed onset liver failure, acute exacerbation of chronic liver failure, chronic kidney disease, kidney damage / injury, kidney damage / injury caused by nephritis, kidney damage / injury caused by kidney transplantation, kidney damage / injury caused by surgery, kidney damage / injury caused by administration of nephrotoxic drugs, enhanced chemotherapy effects, cytomegalovirus infection, HCMV infection, AIDS, cancer, senile dementia, trauma, chronic bacterial infection, diseases caused by environmental pollution, aging, altitude sickness, diseases caused by histamine or leukotriene-C4 release, muscular dystrophy, pyoderma and Sézary syndrome, Addison's disease, pseudomembranous colitis, colitis caused by drugs or radiation, ischemic acute renal failure, chronic renal failure,Toxicosis caused by pulmonary oxygen or drugs, congenital hypophosphatasia, fibromatous lesions, fibrous dysplasia, bone metabolism, osteolytic bone disease, treatment of post-traumatic bone surgery, treatment after artificial joint surgery, treatment after orthopedic bone surgery, treatment after dental surgery, bone chemotherapy treatment or bone radiotherapy treatment, bone cancer, arteriosclerotic lesions, disorders, occlusive disorders, stenosis, coronary artery disorders, peripheral arterial disorders, arterial occlusion, aneurysm formation, post-traumatic aneurysm formation, restenosis, occlusion after graft surgery, Guillain-Barre syndrome, Meniere's disease, polyneuritis, multiple neuritis, mononeuritis, radiculopathy, hyperthyroidism, Graves' disease, autoimmune idiopathic thrombocytopenic purpura (autoimmune ITP), membranous nephritis, autoimmune thyroiditis, Hashimoito thyroiditis, myasthenia gravis, cold and warm agglutinin disease, Evan's syndrome, hemolytic uremic syndrome / thrombotic thrombocytopenic purpura (HUS / TTP), autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, red blood cell hypoplasia, and combinations thereof.

[0176] B. Formulation and Administration Pharmaceutical compositions containing one or more active compounds of the disclosure may be manufactured by any suitable method, such as mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, encapsulating, entrapping, or lyophilizing processes. One or more physiologically acceptable excipients (e.g., diluents, carriers, or auxiliary agents), one or more adjuvants, or a combination thereof, may be used to formulate the pharmaceutical composition to provide a pharmaceutically usable preparation.

[0177] The active compound(s) may be formulated in the pharmaceutical composition itself or in the form of their pharmaceutically acceptable salts, stereoisomers, N-oxides, tautomers, hydrates, solvates, isotopes, or prodrugs. Typically, such salts are more soluble in aqueous solution than the corresponding free acids and bases, although salts having lower solubility than the corresponding free acids and bases may also be formed.

[0178] The disclosed pharmaceutical compositions can be in a form suitable for virtually any mode of administration, including, for example, topical, ophthalmic, oral, buccal, systemic, nasal, by injection such as iv or ip, transdermal, rectal, vaginal, etc., or in a form suitable for administration by inhalation or insufflation.

[0179] For topical administration, the active compound(s), pharmaceutically acceptable salts, stereoisomers, N-oxides, tautomers, hydrates, solvates, isotopes, or prodrugs may be formulated as solutions, gels, ointments, creams, suspensions, etc., as known in the art.

[0180] Systemic formulations include those designed for administration by injection, e.g., subcutaneous, intravenous, intramuscular, intrathecal, or intraperitoneal injection, as well as those designed for transdermal, transmucosal oral, or pulmonary administration.

[0181] Useful injectable preparations include sterile suspension, solution or emulsion of active compound(s) in aqueous or oily vehicle.Pharmaceutical compositions can also contain compounding agents such as suspending agent, stabilizing agent and / or dispersing agent.The preparation for injection can be presented in unit dosage form, for example, in ampoules or in multi-dose containers, and can contain added preservatives.

[0182] Alternatively, injectable formulations may be provided in powder form for reconstitution with a suitable vehicle including, but not limited to, sterile pyrogen-free water, buffer, dextrose solution, etc. before use. To this end, the active compound(s) may be dried by any art-known technique, such as lyophilization, and reconstituted prior to use.

[0183] For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are known in the art.

[0184] For oral administration, the pharmaceutical compositions can be in the form of lozenges, tablets, or capsules prepared by conventional means with pharmaceutically acceptable excipients, such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone, or hydroxypropylmethylcellulose); fillers (e.g., lactose, microcrystalline cellulose, or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc, or silica); disintegrants (e.g., potato starch or sodium starch glycolate); and / or wetting agents (e.g., sodium lauryl sulfate). Tablets can be coated, for example, with sugars, films, or enteric coatings by methods well known in the art.

[0185] Liquid preparations for oral administration can be in the form of, for example, elixirs, solutions, syrups or suspensions, or can be presented as dry products to be reconstituted with water or other suitable vehicles before use.Such liquid preparations can be prepared by conventional means using pharmaceutically acceptable excipients such as suspending agents (e.g., sorbitol syrup, cellulose derivatives, or hydrogenated edible fats and oils); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol, cremophore™, or fractionated vegetable oils); and preservatives (e.g., methyl or propyl-p-hydroxybenzoic acid or sorbic acid).Preparation can also contain buffer salts, preservatives, flavoring agents, coloring agents, and sweeteners as needed.

[0186] Preparations for oral administration can, as is well known, be suitably formulated to give controlled release of the active compound.

[0187] For buccal administration, the pharmaceutical compositions may take the form of tablets or lozenges formulated in conventional manner.

[0188] For rectal and vaginal routes of administration, the active compound(s) may be formulated as solutions (for retention enemas) suppositories or ointments containing conventional suppository bases such as cocoa butter or other glycerides.

[0189] For nasal administration or administration by inhalation or insufflation, the active compound(s), 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 pack or a nebulizer using a suitable propellant, such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, fluorocarbons, carbon dioxide, or other suitable gas. 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 (e.g., gelatin capsules and cartridges) for use in an inhaler or insufflator can be formulated containing a powder mix of the compound and a suitable powder base, such as lactose or starch.

[0190] A specific example of an aqueous suspension formulation suitable for nasal administration using a commercially available nasal spray device contains 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); phenylethanol (1-4 mg / mL); and dextrose (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 pH of about pH 5.5 being typical.

[0191] Another specific example of an aqueous suspension suitable for administering a compound via inhalation contains 20 mg / mL of a disclosed compound(s), 1% (v / v) polysorbate 80 (TWEEN® 80), 50 mM citrate, and / or 0.9% sodium chloride.

[0192] For ocular administration, active compound(s) can be formulated as a solution, emulsion, suspension, etc. suitable for ocular administration.A variety of vehicles suitable for administering compounds to the eye are known in the art.Specific non-limiting examples are described in U.S. Patent 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.

[0193] For long-term delivery, the active compound(s) can be formulated as a depot preparation for administration by implantation or intramuscular injection. The active ingredient can be formulated with a suitable polymer or hydrophobic material (e.g., as an emulsion in an acceptable oil), or an ion exchange resin, or as a sparingly soluble derivative, e.g., as a sparingly soluble salt. Alternatively, a transdermal delivery system can be used, manufactured as an adhesive disc or patch that slowly releases the active compound(s) for percutaneous absorption. To this end, penetration enhancers can be used to facilitate percutaneous penetration of the active compound(s). Suitable transdermal patches are described, for example, in U.S. Pat. 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.

[0194] Alternatively, other pharmaceutical delivery systems can be used.Liposome and emulsion are well-known examples of delivery vehicles that can be used to deliver active compound(s).In addition, certain organic solvents such as dimethyl sulfoxide (DMSO) can be used, but usually at the expense of higher toxicity.

[0195] The pharmaceutical compositions may, if desired, be presented in a pack or dispenser device that may contain one or more unit dosage forms containing the active compound(s). The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration.

[0196] There are several approaches to 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 of transporting compounds across the blood-brain barrier include, but are not limited to, bypassing the blood-brain barrier entirely and / or creating an opening in the blood-brain barrier. Circumvention methods include, but are not limited to, direct injection (e.g., Papanastassiou et al., Gene Therapy 9:398-406, 2002), interstitial injection / convection-enhanced delivery (Bobo et al., Proc. Natl. Acad. Sci. USA 91:2076-2080, 1994), and implantation of a delivery device into the brain (e.g., Gill et al., Nature Med. 9:589-595, 2003. Opening of the blood-brain barrier includes, but is not limited to, ultrasound, administration of (e.g., hypertonic mannitol), and osmotic pressure, e.g., by permeabilization with bradykinin or permeabilizing agent A-7 (see, e.g., U.S. Pat. Nos. 5,112,596, 5,268,164, 5,506,206, and 5,686,416). Compounds can also be encapsulated in liposomes that bind to antibody-binding fragments that bind to receptors on the vascular endothelium of the blood-brain barrier.

[0197] In certain embodiments, the compound may be administered continuously by infusion into a fluid reservoir of the CNS or by bolus injection. The compound may be administered using an indwelling catheter and a means of continuous administration, such as a pump, or The compound can be administered by implantation of a sustained-release vehicle. For example, the compound can be injected over a long period of time through an implanted cannula, or can be infused over a long period of time with the aid of an osmotic minipump. A subcutaneous pump can deliver the compound to the cerebral ventricles.

[0198] C. Dosage The disclosed compounds, pharmaceutical compositions, or combinations of disclosed compounds will generally be used in an effective amount to achieve the intended result, e.g., an effective amount to inhibit RIP1 kinase and / or an effective amount to treat, prevent, or ameliorate a particular condition. The disclosed compound(s) or their pharmaceutical compositions can be administered therapeutically to achieve a therapeutic benefit or prophylactically to achieve a prophylactic benefit. Therapeutic benefit refers to the eradication or amelioration of the underlying disorder during treatment and / or the eradication or amelioration of one or more symptoms associated with the underlying disorder, such that the patient reports a sensory or physical improvement, even though the patient may still be suffering from the underlying disorder. For example, administration of a compound to a patient suffering from allergies provides therapeutic benefit not only when the underlying allergic reaction is eradicated or ameliorated, but also when the patient reports a decrease in the severity or duration of allergy-related symptoms after exposure to an allergen. As another example, therapeutic benefit in the context of asthma includes improved breathing after the onset of an asthma attack or a reduction in the frequency or severity of asthma episodes. Therapeutic benefit also includes halting or slowing the progression of the disease, regardless of whether improvement is realized.

[0199] As known by those skilled in the art, the preferred dosage of the disclosed compounds may depend on various factors, including age, weight, general health, and the severity of the condition of the patient or subject being treated. When administered by inhalation, the dosage may also need to be adjusted to the individual's gender and / or lung capacity. The dosage may also be adjusted for individuals suffering from two or more conditions, or for individuals with additional conditions that affect lung capacity and normal breathing ability, such as emphysema, bronchitis, pneumonia, respiratory distress syndrome, chronic obstructive pulmonary disease, and respiratory infections. The dosage and frequency of administration of the disclosed compound(s) or pharmaceutical compositions thereof will also depend on whether the disclosed compound(s) are formulated for the treatment of an acute episode of a condition or for the prophylactic treatment of a disorder. Those skilled in the art will be able to determine the optimal dose for a particular individual.

[0200] In prophylactic administration, the disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof can be administered to patients or subjects at risk of developing one of the aforementioned conditions. For example, if it is unknown whether a patient or subject is allergic to a particular drug, the disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof can be administered before the drug is administered to avoid or ameliorate an allergic reaction to the drug. Alternatively, prophylactic administration can be used to avoid or ameliorate the onset of symptoms in patients diagnosed with an underlying disorder. For example, the disclosed compounds(s) or pharmaceutical compositions thereof can be administered to allergy sufferers before anticipated exposure to an allergen. The disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof can also be administered prophylactically to healthy individuals who are repeatedly exposed to a known agent for one of the above-mentioned diseases to prevent the onset of the disorder. For example, the disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof can be administered to healthy individuals who are repeatedly exposed to an allergen known to induce allergies, such as latex, to prevent the individual from developing the allergy. Alternatively, a disclosed compound, a combination of disclosed compounds, or a pharmaceutical composition thereof can be administered to a patient suffering from asthma prior to participating in activities that induce asthma attacks in order to reduce the severity of or completely avoid asthma episodes.

[0201] An effective dosage can be estimated initially from in vitro assays. For example, an initial dosage for use in a subject may be determined to be IC 50 or EC 50The active compound may be formulated to achieve a circulating blood or serum concentration of the above specific compound. Taking into account the bioavailability of the specific compound, the dosage to achieve such a circulating blood or serum concentration can be calculated. Fingl & Woodbury, "General Principles," in: Goodman and Gilman's The Pharmaceutical Basis of Therapeutics, Chapter 1, pages 1-46, Pergamon Press, and the references cited therein, provide additional guidance regarding effective dosages.

[0202] In some embodiments, disclosed compounds have an EC50 of 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, or greater than 0 to 0.05 μM. 50 It has.

[0203] Initial dosage can also be estimated from in vivo data such as animal models.Animal models useful for testing the effectiveness of compounds for treating or preventing the above-mentioned various diseases are well known in the art.Suitable animal models of hypersensitivity or allergic reaction are described in Foster, (1995) Allergy 50(21Suppl):6-9, discussion 34-38 and Tumas et al., (2001), J.Allergy Clin.Immunol.107(6):1025-1033. Suitable animal models of 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. Those skilled in the art can adapt such information to determine suitable dosages for administration to humans.

[0204] In some embodiments, assays suitable for determining RIP1 activity can be used. Such assay methods can be used to evaluate the efficacy of compound embodiments disclosed herein and / or to determine amounts / dosages of compound embodiments that can provide the desired efficacy. In some embodiments, the assay can be an ADP-Glo™ assay, which evaluates the ability of compound embodiments to inhibit RIP1. 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 safe and effective doses of compounds that can be used in human in vivo studies. These whole-cell assays can be used to evaluate the activity of compounds against human and / or mouse RIP1 in an in vitro context, allowing one of skill in the art to determine safe and effective dosages for use in vivo. Yet another assay that can be used to evaluate the activity of compound embodiments described herein for treating diseases or conditions involving RIP1 is an acute hypothermia mouse model, which evaluates the ability of compounds to inhibit TNF-alpha-induced hypothermia. Each of these assays, and various results from the use of these assays, are described in detail in the Examples section of this disclosure.

[0205] Dosages of the disclosed compounds will typically be in the range of 0 mg / kg / day, such as 0.0001 mg / kg / day, or 0.001 mg / kg / day, or 0.01 mg / kg / day, up to at least about 100 mg / kg / day. More typically, dosages (or effective amounts) can range from about 0.0025 mg / kg to about 1 mg / kg per at least one daily administration, such as 0.01 mg / kg to about 0.5 mg / kg, or about 0.05 mg / kg to about 0.15 mg / kg. Total daily dosages will typically range from 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. Dosages may be higher or lower depending on, among other factors, the activity of the disclosed compound, its bioavailability, the mode of administration, and the various factors discussed above.

[0206] Dosage amount and dosage interval can be adjusted for each individual to provide the plasma level of the disclosed compound that is sufficient to maintain therapeutic effect or preventive effect.For example, compound can be administered once a day, multiple times a day, once a week, multiple times a week (for example, every other day), once a month, multiple times a month, or once a year, depending on, among other things, the mode of administration, the specific symptoms being treated, and the judgment of the prescribing physician.Those skilled in the art will be able to optimize effective local dosage without undue experimentation.

[0207] Pharmaceutical compositions comprising one or more of the disclosed compounds typically contain from greater than 0 up to 99% total weight percent of the disclosed compound(s) and / or other therapeutic agents. More typically, pharmaceutical compositions comprising one or more of the disclosed compounds contain from about 1 to about 20 total weight percent of the disclosed compound(s) and other therapeutic agents, and from about 80 to about 99 weight percent of a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition may further comprise an adjuvant.

[0208] Preferably, the disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof will provide therapeutic or prophylactic benefits without causing substantial toxicity. The toxicity of the disclosed compounds can be determined using standard pharmaceutical procedures. The dose ratio between toxic effects and therapeutic (or prophylactic) effects is the therapeutic index. Disclosed compounds that exhibit a high therapeutic index are preferred. [Example]

[0209] V. Working Examples Example 1 Scheme 7 provides a method for making 4-phenoxypicolinonitrile and 4-phenoxypyridine-2-carboxylic acid. [ka]

[0210] Referring to Scheme 7, to a solution of 4-fluoropicolinonitrile 90 (7.00 g, 57.4 mmol, 1.0 equiv.) and phenol 92 (5.66 g, 60.2 mmol, 1.05 equiv.) in dimethylformamide (90 mL) was added cesium carbonate (20.58 g, 63.1 mmol, 1.1 equiv.). The reaction was heated to 80° C. for 8 hours and allowed to cool. The reaction was poured into ice water (1 L). A precipitate formed which was isolated by filtration to give 4-phenoxypicolinonitrile 94 as a white solid (10.7 g, 95%): 1 H nmr(400MHz,CDCl3)δ8.52(1H,d,J 6.0Hz,pyH-6),7.50-7.45(2H,m,2H of C6H5),7.33(1H,tt,J 7.5,1.0Hz,1H of C6H5),7.20(1H,d,J 2.0Hz,pyH-3),7.11-7.08(2H,m,2H of C6H5),7.02(1H,dd,J 5.5,2.5Hz,pyH-5);m / z:197[M+H] +。

[0211] Example 2 This example describes a method for preparing 4-phenoxypyridine-2-carboxylic acid 96 from 4-phenoxypicolinonitrile 94. A suspension of picolinonitrile 94 (10.7 g, 54.6 mmol) in hydrochloric acid (6 M, 100 mL) was heated to 100° C. for 8 hours. The reaction was cooled to room temperature, forming a precipitate that was isolated by filtration. The filtrate was cooled to produce additional solid, which was isolated by filtration and added to the initial crop. 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, pyrH-6), 7.57-7.53 (3H, m, pyrH-3, 2H of CH6H5), 7.38 (1H, tt, J 7.5, 1.0 Hz, 1H of CH6H5), 7.33 (1H, dd, J 6.0 2.5 Hz, pyrH-5), 7.28-7.26 (2H, m, 2H of CH6H5); m / z: 216 [M+H] + .

[0212] Example 3 This example describes a method for preparing 5-(4-fluorophenoxy)pyridine-2-carboxylic acid. To a mixture of methyl fluoropicolinate (0.400 g, 2.58 mmol, 1.0 equiv.), 4-fluorophenol (0.318 g, 2.84 mmol, 1.1 equiv.), and cesium carbonate (0.925 g, 2.84 mmol, 1.1 equiv.) was added N-methylpyrrolidinone (5 mL). The reaction was stirred at 95° C. for 75 minutes. The reaction was cooled and added to ice water (150 mL), causing the formation of a precipitate. After stirring for 15 minutes, the precipitate was isolated by filtration. as a white solid; (0.540 g, 85%); 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]+.

[0213] To a solution of the methyl ester (0.54 g, 2.19 mmol, 1.0 equiv) in tetrahydrofuran (12 mL) was added aqueous lithium hydroxide (0.14 g, 3.28 mmol, 1.5 equiv in 5 mL of water). The reaction was stirred at room temperature for 35 minutes and concentrated to remove the organics. The solution was diluted with water (5 mL) and hydrochloric acid (3 M, approximately 1 mL) was added until the pH was ∼3. A white precipitate formed which was isolated by filtration. Additional hydrochloric acid (3 M, 10 drops) was added to the filtrate, causing the formation of a further precipitate which was isolated by filtration. The precipitates were combined and dried under vacuum to give the title compound as a white solid (0.49 g, 75%); 1H nmr (400 MHz, D6-DMSO) δ 8.43 (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, CHF); 19F nmr (380 MHz, D6-DMSO) δ −117.7; m / z: 234 [M+H]+.

[0214] Example 4 This example relates to a method for making 4-cyclobutyloxypyridine-2-carboxylic acid, as shown in Scheme 8 below. [ka]

[0215] A solution of cyclobutanol 102 (0.30 mL, 3.84 mmol, 1.2 equiv) in tetrahydrofuran (20 mL) was cooled to 0 °C. Sodium hydride (0.154 g of a 60% suspension, 3.84 mmol, 1.2 equiv) was added and the reaction was stirred at 0 °C for 25 min. Fluoropicolinonitrile 100 (0.390 g, 3.20 mmol, 1.0 equiv) was added and the reaction was stirred at room temperature for 2 h. The reaction was quenched by adding NH Cl (5 mL). The reaction was diluted with EtOAc (80 mL) and washed with NaHCO (80 mL). The aqueous phase was extracted with EtOAc (30 mL). The combined organics were washed with brine (60 mL), dried (Na SO ), and concentrated under reduced pressure. MPLC (10→60% EtOAc-hexanes) gave 4-cyclobutyloxypicolinonitrile 104 as a colorless oil (0.487 g, 88%). 1 H nmr(400MHz,CDCl3)δ8.46(1H,d,J 5.5Hz,pyH-6),7.10(1H,d,J 2.5Hz,pyH-3),6.88(1H,dd,J 5.5,2.5Hz,pyH-5),4.72(1H,pentet,J 7.0Hz,cBuH-1),2.53-2.46(2H,m,cBuH-2,H-4),2.26-2.16(2H,m,cBuH 2H of -2, H-4), 1.98-1.89 (1H, m, 1H of cBuH-3), 1.82-1.71 (1H, m, 1H of cBuH-3).

[0216] To 4-cyclobutyloxypicolinonitrile 104 (0.487 g, 2.80 mmol) was added hydrochloric acid (6 M, 7 mL), and the reaction was heated to 100 °C for 18 h. The reaction was cooled, but no precipitate formed. The solution was concentrated to dryness to give 4-cyclobutyloxypyridine-2-carboxylic acid 106 as a beige solid, which was used without further purification. 1H nmr(400MHz,D6-DMSO)δ8.66(1H,d,J 6.5Hz,pyH-6),7.69(1H,dd,J 2.5Hz,pyH-3),7.50(1H,dd,J 6.5,2.5Hz,pyH-5),5.12(1H,pentet,J 7.0Hz,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] + .

[0217] A. Synthesis of tert-butyl 3-ethynyl-3-hydroxyazetidine-1-carboxylate [ka] A solution of (trimethylsilyl)acetylene 1302 (0.71 g, 1.00 mL, 6.28 mmol, 1.1 equiv) in tetrahydrofuran (30 mL) was cooled to -78 °C, and butyllithium (2.51 mL of a 2.5 M solution in hexanes, 6.28 mmol, 1.1 equiv) was added dropwise. The reaction was stirred at -78 °C for 1 h, after which Boc-azetidinone 1300 (0.98 g, 5.71 mmol, 1.0 equiv) was added. The reaction was stirred from -78 °C to room temperature for 20 h before being quenched by the addition of NHCl (20 mL). The reaction was partitioned between EtOAc (100 mL) and NHCl-water (1:1, 100 mL). The organics were washed with brine (100 mL), dried (NaSO), and concentrated under reduced pressure.

[0218] The residue containing 1304 was dissolved in tetrahydrofuran (30 mL) and cooled to 0 °C before adding tetrabutylammonium fluoride trihydrate (1.80 g, 5.71 mmol, 1.0 equiv). The reaction was stirred at 0 °C for 3 h before adding NH Cl (20 mL). The reaction was partitioned between EtOAc (100 mL) and NH Cl-water (1:1, 100 mL). The organics were washed with NH Cl (100 mL) and brine (100 mL), dried (Na SO ), and concentrated under reduced pressure to give 1306 as a pale yellow oil. 1 H nmr (400 MHz, CDCl) δ 4.20 (2H, dd, J 9.0, 1.0 Hz, 2H, H-4 of azetidine H-2), 4.02 (2H, dd, J 9.0, 1.0 Hz, 2H, H-4 of azetidine H-2), 2.68 (1H, s, CCH), 1.44 (9H, s, C(CH)).

[0219] Example 5 This example provides a method for making N-substituted-4-[(aryl)methyl]-1H-pyrazole-1-carboxamides via the intermediate pyrazole-1-carbonyl chloride formation according to Scheme 10. [ka]

[0220] To a stirred heterogeneous mixture of 4-[(aryl)methyl]-1H-pyrazole hydrochloride 1400 (1 equiv.) and triphosgene (1.5 equiv.) in CHCl (15 mL / mmol) under nitrogen at 0 °C, i-PRNEt (5–9 equiv.) was added over time (15 min / mmol). The red reaction solution was stirred at 0 °C for 1 h, warmed to room temperature (2 h), analyzed for 4-[(aryl)methyl]-1H-pyrazole consumption by LC / MS, and concentrated to dryness to give 1402. The red semi-solid concentrate was added to 1404, or the corresponding amine or its salt (1 equiv.), and DMAP (0.1 equiv.) and cooled in an ice bath under nitrogen. CHCl (15 mL / mmol) was added to the flask and stirred for 15 min. The red solution was treated with i-PRNEt (5–9 equiv.) gradually (15 min / mmol) with stirring. After 1 h, the ice bath was removed and the reaction solution was allowed to warm to room temperature. To analyze the reaction progress, the reaction solution was concentrated to dryness, diluted with water, and subjected to extractive workup with either EtOAc or CHCl. ​​Silica gel flash column chromatography purification of the crude concentrate afforded the desired N-substituted-4-[(aryl)methyl]-1H-pyrazole-1-carboxamides 1406 (yields: 20–75%).

[0221] Example 6 This example provides a method for making N-substituted-4-[(aryl)methyl]-1H-pyrazole-1-carboxamides through the formation of an intermediate isocyanate according to Scheme 11. [ka]

[0222] To a stirred heterogeneous mixture of compound 1420, or its corresponding amine or its salt (1 equiv.), and triphosgene (2.3 equiv.) in CHCl (15 mL / mmol) under nitrogen at 0 °C, i-PrNEt (10–15 equiv.) was added gradually (20 min / mmol). The pale yellow reaction solution was stirred at 0 °C for 1 h, warmed to room temperature (2 h), analyzed for corresponding amine consumption by LC / MS, and concentrated to dryness. 4-[(aryl)methyl]-1H-pyrazole hydrochloride 1424 (0.9 equiv.) and DMAP (0.1 equiv.) were added to the red semi-solid concentrate containing compound 1422 and cooled in an ice bath under nitrogen. CHCl (15 mL / mmol) was added to the flask, stirred for 15 min, and the red solution was treated gradually (15 min / mmol) with i-PrNEt (10–15 equiv.) while stirring. After 1 h, the ice bath was removed and the reaction solution was allowed to warm to room temperature (6–8 h). To analyze the progress, the reaction solution was concentrated to dryness, diluted with water, and subjected to extractive workup using either EtOAc or CHCl. ​​Silica gel flash column chromatography purification of the resulting crude material afforded the required N-substituted-4-[(aryl)methyl]-1H-pyrazole-1-carboxamides 1426 (yields: 19–73%).

[0223] Example 7 This example provides a method for making embodiments of the disclosed alkynyl-substituted compounds according to Scheme 12. [ka]

[0224] Nitrogen was bubbled through a stirred solution of aryl halide 1440 (1 equiv.), CuI (0.1–0.2 equiv.), and Pd(PPh3)4 (0.05–0.1 equiv.) in dry DMF (3–4 mL / mmol) in a vial for 3 min. NEt3 (10 equiv.) was then added to the dark reaction solution, followed by the corresponding alkyne 1442 (1.5–3 equiv.) 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 analyzing the reaction progress by LC / MS analysis, the dark reaction solution was concentrated to dryness. The crude residue was diluted with ice water, sonicated, and the slurry was allowed to warm to room temperature. The resulting gray / dark solid was collected by filtration, sucked dry, dissolved in THF (20 mL), filtered through a Celite® / silica gel 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%).

[0225] Example 8 This example provides a method for making embodiments of the disclosed 4-[(aryl)methyl]-1H-pyrazole compounds according to Scheme 13. [ka]

[0226] 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:HO (9:1, 10 mL / mmol) was degassed by high vacuum, back-purged with argon in a balloon for three cycles over periods of 5-10 min, and heated at 70-75 °C for 2-6 h. The reaction mixture was cooled and concentrated to dryness. The crude residue was diluted with EtOAc (or CHCl2), water, and saturated aqueous Na2CO3 (6 mL / mmol). The organic layer was separated, and the aqueous layer was extracted with EtOAc (or CHCl2). The combined organic layers were washed with aqueous NaCl, stirred with anhydrous Na2SO4, and filtered through Celite®. After concentration of the filtrate, the crude material was purified by silica gel chromatography to give tert-butyl 4-[(aryl)methyl]-1H-pyrazole-1-carboxylate 1454 (49–85% yield). To a stirred solution of 4-[(aryl)methyl]-1H-pyrazole (1 equiv.) in CHCl (3–6 mL / mmol) was added 4.0 N HCl in 1,4-dioxane (5–7 equiv.) at room temperature. The reaction mixture was stirred until tert-butyl 4-[(aryl)methyl]-1H-pyrazole-1-carboxylate was consumed and then concentrated to dryness. The crude solid was sonicated in EtOAc (6–7 mL / mmol), filtered, washed with EtOAc on the funnel, and briefly vacuum-dried. The collected semi-dry 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%).

[0227] Example 9 This example provides a general method for making (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]azepin-3-yl)-4-phenoxypicolinamide (I-2), shown in Scheme 14. [ka]

[0228] After three cycles of vacuum degassing followed by argon back-purging, a stirred mixture of (S)—N-(8-bromo-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-phenoxypicolinamide (71 mg, 0.152 mmol)—see below for data—2-chloropyridine-5-boronic acid pinacol ester (47 mg, 0.196 mmol), Pd(PPh) (13 mg, 0.01 mmol), and CsCO (149 mg, 0.456 mmol) in 1,4-dioxane (3 mL):water (0.3 mL) was heated at 75° C. After 6 h, the reaction mixture was cooled to room temperature, diluted with THF (10 mL), and filtered through Celite®. The filtrate was concentrated, and the resulting crude material was diluted with water (3 mL) and extracted with EtOAc (3 × 15 mL). The combined organic layers were washed with saturated aqueous NaCl (10 mL), stirred with anhydrous NaSO, polished, filtered, and concentrated to dryness. The resulting crude material was dissolved in CHCl (2 mL), loaded onto a hexane-treated silica gel cartridge, and purified by flash chromatography (Combiflash® Teledyne RediSep® hexane-conditioned silica gel column (12G gold) and eluted with 0–35% EtOAc / hexane) to give (S)—N-(8-(6-chloropyridin-3-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-phenoxypicolinamide as an off-white solid (35 mg, 46%). 1H NMR(400MHz,CDCl3)δ8.85(d,J=7.8Hz,1H),8.58(dd,J=2.6,0.7Hz,1H),8.43(dd,J=5.6, 0.5Hz,1H),7.81(dd,J=8.3,2.6Hz,1H),7.60(dd,J=2.6,0.5Hz,1H),7.45-7.31(m,6H),7. 23(ddt,J=7.9,7.0,1.1Hz,1H),7.10-7.02(m,2H),6.93(dd,J=5.6,2.6Hz,1H),4.68(dt, J=11.3,7.3Hz,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) + 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-1H-benzo[b]azepin-3-yl)-4-phenoxypicolinamide (35 mg, 0.07 mmol) and 2-methylpyridin-3-yl were reacted 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. (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]azepin-3-yl)-4-phenoxypicolinamide (11 mg, 28%, white solid) was prepared in a similar manner to the Sonogashira reaction conditions described in the general procedure by reaction of 1-methyl-3-butyn-2-ol (9 mg, 0.01 mL, 0.11 mmol). 1H NMR(400MHz,CD2Cl2)δ8.80(dd,J=2.4,0.9Hz,1H),8.77(d,J=7.6Hz,1H),8.46(d,J= 5.6Hz,1H),7.87(dd,J=8.1,2.4Hz,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=5.6,2.6Hz,1H),4.59 (dt,J=11.1,7.4Hz,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) + .

[0229] (±)-5-Benzyl-N-(8-bromo-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-1H-1,2,4-triazole-3-carboxamide [ka] 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) + .

[0230] (S)-N-(8-bromo-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[bazepin-3-yl]-4-(4-fluorobenzyl)-1H-pyrazole-1-carboxamide [ka] Route 2. 1 H NMR (400MHz, chloroform-d) δ7.94(d,J=7.6Hz,1H),7.86(q,J=0.9Hz,1H),7.43(d,J=0.8Hz,1H),7.34(dt,J=4.4,2.1Hz,2H),7.17-7.08(m,3H),7 .02-6.92(m,2H),4.46(dt,J=11.1,7.4Hz,1H),3.78(s,2H),3.41(s,3 H),2.90-2.77(m,1H),2.75-2.59(m,2H),2.08(td,J=11.4,7.6Hz,1H). 19 F 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). + .

[0231] (±)-N-(3-bromo-9-methyl-8-oxo-6,7,8,9-tetrahydro-5H-pyrido[2,3-b]azepin-7-yl)-4-(4-fluorophenoxy)picolinamide [ka] 1 H NMR (400MHz, chloroform-d) δ8.90(d,J=7.4Hz,1H),8.45-8.39(m,2H),7.71(d,J=2.4Hz,1H),7.56(d,J=2.5Hz,1H),7.14-6.98(m,4H),6.90(dd,J =5.6,2.6Hz,1H),4.58(dt,J=11.1,7.1Hz,1H),3.47(s,3H),2.90-2.72(m,2H),2.64(p,J=5.9,5.5Hz,1H),2.10(ddd,J=12.4,9.4,5.9Hz,1H). 19F 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). + .

[0232] (S)-N-(8-bromo-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-(4-fluorophenoxy)picolinamide [ka] 1 H NMR (400MHz, methylene chloride-d2) δ8.68(d,J=7.5Hz,1H),8.45(d,J=5.6Hz,1H),7.56(d,J=2.5Hz,1H),7.43(s,1H),7.34(dd,J=8.1,2.0Hz,1H) ,7.23-7.03(m,6H),6.96(dd,J=5.6,2.6Hz,1H),4.60(dt,J=11.2,7.6Hz,1H),3.02-2.89(m,1H),2.84-2.66(m,2H),2.16-2.02(m,1H). 19 F NMR (376MHz, methylene chloride-d2) δ-117.55 (ddd, J=12.4,8.2,4.7Hz). LCMS: Purity 97%, MS(m / e)471(M+H) + .

[0233] Exemplary embodiments of compounds according to the present disclosure have been made according to the disclosed synthetic schemes, and characterization data for such compounds is provided below.

[0234] (S)-4-(4-Fluorobenzyl)-N-(8-((3-hydroxyoxetan-3-yl)ethynyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-1H-pyrazole-1-carboxamide (I-1) [ka] Route 3. 1H NMR (400MHz, chloroform-d) δ7.97(d,J=7.2Hz,1H),7.85(q,J=0.9Hz,1H),7.46(d, J=0.8Hz,1H),7.35-7.30(m,2H),7.19-7.08(m,3H),7.02-6.92(m,2H),4.94(d, J=6.9Hz,2H),4.91-4.83(m,1H),4.80(dd,J=6.6,0.9Hz,2H),4.70(dd,J=9.8,7 .2Hz,1H),4.33(dd,J=11.3,9.8Hz,1H),3.78(s,2H),3.43(s,3H),2.60(s,1H). LC / MS: Purity 94%, MS(m / e)491(M+H) + .

[0235] (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]azepin-3-yl)-1H-1,2,4-triazole-3-carboxamide [ka] 1 H NMR(400MHz,chloroform-d)δ8.25(app d,J=6.8Hz,2H),8.11(d,J=7.4Hz,1H),7.95(s,1H),7.42(dd,J=8.0,0.9Hz,2H), 7.32(dd,J=8.9,7.2Hz,1H),7.19(d,J=4.1Hz,3H),6.69-6.62(m,2H),5.70(s,2H) ),4.69(dt,J=10.8,7.4Hz,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=5.2Hz,2H),2.07-1.95(m,1H). LCMS: Purity 93%, MS(m / e)620(M+H) + .

[0236] (±)-5-Benzyl-N-(1-methyl-2-oxo-8-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-1H-1,2,4-triazole-3-carboxamide (I-4) [ka] 1 H NMR (400 MHz, chloroform-d) δ 8.25 (app d,J=6.8Hz,2H),8.12(d,J=7.7Hz,1H),7.31(d,J=3.8Hz,4H),7.27-7.14(m,7 H),6.70-6.62(m,2H),4.66(dt,J=11.2,7.6Hz,1H),4.15(s,2H),3.54(s,2H), 3.42(s,3H),3.38(t,J=5.2Hz,4H),2.86(td,J=12.3,7.7Hz,2H),2.80-2.67(m ,2H),2.67-2.62(m,2H),2.59(d,J=10.3Hz,4H),2.06(td,J=11.4,7.3Hz,1H). LCMS: Purity 97%, MS(m / e)551(M+H) + .

[0237] (±)-1-(2,6-Dichlorobenzyl)-N-(2-oxo-8-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-1H-1,2,4-triazole-3-carboxamide (I-5) [ka] 1H NMR(400MHz,DMSO-d6)δ9.96(s,1H),8.78(s,1H),8.19(d,J=7.6Hz,1H),8.13-8.07(m,2H),7.53(dd,J=8.0,0.9Hz,2H),7.43(dd,J=8.9,7.2Hz,1H ),7.24(d,J=7.6Hz,1H),7.07(dd,J=7.6,1.7Hz,1H),6.97(d,J=1.6Hz,1H ),6.79-6.73(m,2H),5.65(s,2H),4.26(dt,J=11.5,7.8Hz,1H),3.46(app q,J=13.3Hz,2H),3.26(m,4H),2.77-2.60(m,2H),2.47-2.33(m,5H),2.14(td,J=12.2,7.2Hz,1H). LCMS: Purity 95%, MS(m / e)606(M+H) + .

[0238] (±)-5-Benzyl-N-(2-oxo-8-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-1H-1,2,4-triazole-3-carboxamide (I-6) [ka] 1 H NMR(400MHz,DMSO-d6)δ9.96(s,1H),8.27-8.21(m,1H),8.15(d,J=7.1Hz,2H),7.33-7.16(m,6H),7.08(dd,J=7.7,1.7Hz,1H),7.00-6.92(m,3 H),4.30(dt,J=11.5,7.9Hz,1H),4.07(s,2H),3.56-3.41(m,6H),2.78-2.60(m,2H),2.40(ddd,J=12.7,7.9,5.0Hz,3H),2.19(d,J=8.3Hz,1H). LCMS: Purity 94%, MS(m / e)537(M+H) + .

[0239] (±)-5-Benzyl-N-(2-oxo-8-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-1H-1,2,4-triazole-3-carboxamide (I-7) [ka] LCMS: Purity 94%, MS(m / e)629(M-HCOOH+H) + .

[0240] (±)-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]azepin-3-yl)-1H-1,2,4-triazole-3-carboxamide (I-8) [ka] 1 H NMR(400MHz,chloroform-d)δ11.74(s,1H),8.07(d,J=7.6Hz,1H),7.83(s,1H),7.34-7.15(m,7H),4.61(d,J=10.0Hz,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=10.6Hz,1H),2.70(s,1H),2.62(s,1H),2.08-2.00(m,1H). LCMS: Purity 94%, MS(m / e)512(M+H) + .

[0241] (±)-5-Benzyl-N-(2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-1H-1,2,4-triazole-3-carboxamide (I-9) [ka] LCMS: Purity 95%, MS(m / e)487(M+H) + .

[0242] (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]azepin-3-yl)-1H-1,2,4-triazole-3-carboxamide (I-10) [ka] 1 H NMR (400MHz, methanol-d4) δ7.37(s,1H),7.33-7.18(m,7H),5.46(app s,1H),4.48(dd,J=11.5,7.8Hz,1H),4.13(s,2H),3.36(s,3H),2.91-2.79(m,1H),2.71(dd, J=13.7,7.0Hz,1H),2.50(tt,J=13.5,7.5Hz,1H),2.14(td,J=12.2,7.8Hz,1H),1.54(s,6H). LCMS: Purity 97%, MS(m / e)440(M-H2O+H) + .

[0243] (±)-N-(8-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-5-benzyl-1H-1,2,4-triazole-3-carboxamide (I-11) [ka] 1H NMR (400MHz, methanol-d4) δ7.34-7.17(m,5H),7.10(d,J=8.4Hz,1H),6.79-6.69(m,2H) ,4.53(dd,J=11.4,7.8Hz,1H),4.13(s,2H),3.62(t,J=5.6Hz,2H),3.36(s,3H),3.22- 3.11(m,7H),2.72(td,J=13.3,7.7Hz,1H),2.57(dd,J=13.7,7.0Hz,1H),2.53-2.38(m ,1H),2.18(s,2H),2.07(td,J=11.9,7.4Hz,1H),1.88(dtt,J=14.9,10.1,4.9Hz,2H). LCMS: Purity 97%, MS(m / e)500(M+H) + .

[0244] (±)-5-Benzyl-N-(1-methyl-2-oxo-8-(2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-1H-1,2,4-triazole-3-carboxamide (I-12) [ka] 1 H 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, 7.7 Hz, 1H), 4.12 (s, 2H), 3.54 (s, 4H), 3.3 6(s,3H),2.73(dd,J=12.9,7.3Hz,1H),2.62(ddd,J=19.9,12.9,7.1Hz,1H),2.49(dd,J=13. 1,6.5Hz,1H),1.95(td,J=11.6,7.2Hz,1H),1.68(d,J=6.2Hz,4H),1.46(s,4H),1.40(s,2H). LCMS: Purity 97%, MS(m / e)499(M+H) + .

[0245] (±)-5-Benzyl-N-(1-methyl-2-oxo-8-(3-oxa-9-azaspiro[5.5]undecan-9-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-1H-1,2,4-triazole-3-carboxamide (I-13) [ka] 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=5.8Hz,4H),2.82-2.69(m,1H),2.62(ddd,J= 19.6,12.6,7.1Hz,1H),2.52(dd,J=12.9,6.6Hz,1H),1.97(td,J=11.6,7.3Hz,1H),1.69(app t,J=5.8Hz,4H),1.62-1.53(m,4H). LCMS: Purity 95%, MS(m / e)529(M+H) + .

[0246] (±)-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]azepin-3-yl)-1H-1,2,4-triazole-3-carboxamide (I-14) [ka] 1H NMR (400MHz, methanol-d4) δ7.37(t,J=1.0Hz,1H),7.34-7.18(m,7H),4.49(dd,J=11.5,7.8Hz,1H),4.14(s,2H),2.85( td,J=13.4,7.9Hz,1H),2.72(dd,J=13.7,6.8Hz,1H),2.51(tt,J=13.0,7.4Hz,1H),2.21-2.09(m,1H),1.54(s,6H). LCMS: Purity 98%, MS(m / e)443(M-H2O+H) + .

[0247] (±)-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]azepin-3-yl)-1H-1,2,4-triazole-3-carboxamide (I-15) [ka] 1 H NMR (400MHz, methanol-d4) δ7.32-7.16(m,5H),7.07(d,J=8.1Hz,1H),6.39(d,J=2. 3Hz,1H),6.35(dd,J=8.1,2.3Hz,1H),4.51(dd,J=11.4,7.7Hz,1H),4.11(s,2H) ,3.68-3.61(m,4H),3.62(s,4H),2.71(td,J=13.4,7.6Hz,1H),2.55(dd,J=13.8 ,6.9Hz,1H),2.44(tt,J=12.8,7.4Hz,1H),2.12-1.99(m,1H),1.84-1.77(m,4H). LCMS: Purity 948, MS (m / e) 504 (M+H) + .

[0248] (±)-5-Benzyl-N-(8-((3-hydroxyoxetan-3-yl)ethynyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-1H-1,2,4-triazole-3-carboxamide (I-16) [ka] 1 H NMR (400MHz, methanol-d4) δ7.46(d,J=1.5Hz,1H),7.38-7.18(m,7H),4.86(dd,J=6.3,0.9Hz,2H),4.69(dd,J=6.3,0.8Hz,2H),4.49(dd,J=11.5,7.8Hz,1H) ,4.14(s,2H),3.38(s,3H),2.86(td,J=13.3,7.9Hz,1H),2.74(dd,J=13.6,6 .9Hz,1H),2.52(ddd,J=20.4,13.0,7.5Hz,1H),2.16(td,J=12.1,7.7Hz,1H). LCMS: Purity 95%, MS(m / e)472(M+H) + .

[0249] (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]azepin-3-yl)-1H-1,2,4-triazole-3-carboxamide (I-17) [ka] 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=12.9,7.5Hz,1H),2.62(ddd,J=19.8, 12.9,7.3Hz,1H),2.51(dd,J=13.1,6.6Hz,1H),1.98(td,J=11.6,7.2Hz,1H),1.89-1.82(m,4H). LCMS: room temperature 1.50 min (A), purity 96%, MS (m / e) 501 (MH + ).

[0250] (S)-5-Benzyl-N-(1-methyl-2-oxo-8-(pyridin-3-ylethynyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-1H-1,2,4-triazole-3-carboxamide (I-18) [ka] 1 H NMR (400MHz, chloroform-d) δ8.77(dd,J=2.1,0.9Hz,1H),8.56(dd,J=4.9,1.7Hz,1H),8.08(d,J=7.5Hz,1H),7.82(dt,J=7.9,1.9Hz,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=12.3,11.7,7.7Hz,1H),2.80-2.63(m,2H),2.13-2.01(m,1H). LCMS: Purity 95%, MS(m / e)477(M+H) + .

[0251] (±)-5-Benzyl-N-(1-methyl-2-oxo-8-(pyridin-4-ylethynyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-1H-1,2,4-triazole-3-carboxamide (I-19) [ka] 1 H NMR (400MHz, methanol-d4) δ8.60-8.53(m,2H),7.61(d,J=1.6Hz,1H),7.57-7.52(m,2 H),7.48(dd,J=7.8,1.6Hz,1H),7.39(d,J=7.8Hz,1H),7.35-7.20(m,5H),4.53(dd, J=11.5,7.8Hz,1H),4.16(s,2H),3.43(s,3H),2.91(td,J=13.3,7.9Hz,1H),2.78( dd,J=13.6,6.9Hz,1H),2.56(tt,J=13.4,7.0Hz,1H),2.20(td,J=12.2,8.0Hz,1H). 1H NMR (400MHz, chloroform-d) δ11.59(s,1H),8.65-8.59(m,2H),8.08(d,J=7.6Hz,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=12.3,11.8,6.9Hz,2H),2.14-2.02(m,1H). LCMS: Purity 94%, MS(m / e)477(M+H) + .

[0252] (±)-5-Benzyl-N-(1-methyl-2-oxo-8-(pyridin-2-ylethynyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-1H-1,2,4-triazole-3-carboxamide (I-20) [ka] 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=8.1Hz,1H),4.15(s,2H),3.43(s,3H),2.89(td,J=12.5,12.0,7.6Hz,1H) ,2.75(dd,J=13.0,6.9Hz,1H),2.67(dd,J=12.4,6.7Hz,1H),2.06(td,J=11.3,7.5Hz,1H). LCMS: Purity 91%, MS(m / e)477(M+H) + .

[0253] (S)-5-Benzyl-N-(8-(3,3-dimethylbut-1-yn-1-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-1H-1,2,4-triazole-3-carboxamide (I-21) [ka] 1 H NMR (400MHz, methanol-d4) δ7.36-7.18(m,8H),4.50(dd,J=11.5,7.8Hz,1H),4.15(s,2H),3.38(s,3H),2.85(td,J =13.3,7.9Hz,1H),2.71(dd,J=13.6,6.9Hz,1H),2.52(tt,J=12.8,7.4Hz,1H),2.22-2.09(m,1H),1.32(s,9H). LCMS: Purity 94%, MS(m / e)456(M+H) + .

[0254] (S)-N-(8-((3-hydroxyoxetan-3-yl)ethynyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-phenoxypicolinamide (I-22) [ka] 1 H nmr (400 MHz, CDCl3) δ 8.84 (1H, d, J 7.5 Hz, NH), 8.42 (1H, d, J 5.5 Hz, pyrH-6), 7.60 (1H, d, J 2.0 Hz, pyrH-3), 7.42-7.38 (2H, m, 2H of C6H5), 7.29-7.20 (4H, m, 1H of HC6H5, Bz azapine 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, pyrH-5), 4.93 (2H, d, J 7.0 Hz, 2H of oxetane H-2, H-4), 4.79 (2H, dd, J 7.0, 1.0 Hz, H oxetane H-2, H-4), 4.60 (1H, td, J 11.0, 7.5 Hz, Bz azapine H-3), 3.42 (3H, s, NCH3), 2.95-2.86 (1H, m, 1H of Bz azapine H-5), 2.75-2.63 (2H, m, 1H of Bz azapine H-5, 1H of Bz azapine H-4), 2.12-2.04 (1H, m, 1H of Bz azapine H-4); m / z: 484 [M+H] + (Measured value [M+H] + ,484.1867,C 28 H25 N3O5 is [M+H] + (Requires 484.1867).

[0255] (±)-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]azepin-3-yl)-1H-pyrazole-1-carboxamide (I-23) [ka] 1 H NMR (400MHz, methanol-d4) δ7.87(q,J=0.8Hz,1H),7.51(s,1H),7.31-7.23(m,2 H),7.26-7.14(m,3H),7.10(d,J=8.1Hz,1H),6.45-6.35(m,2H),4.38(dd,J= 11.4,7.7Hz,1H),3.82(s,2H),3.66(d,J=4.3Hz,8H),3.37(s,3H),2.74(td, J=13.3,7.6Hz,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) + .

[0256] (±)-N-(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-phenoxypicolinamide (I-24) [ka] 1H NMR(400MHz,chloroform-d)δ8.83(d,J=7.6Hz,1H),8.41(dd,J=5.6,0.5Hz,1H),7.6 0(dd,J=2.5,0.5Hz,1H),7.44-7.34(m,2H),7.27-7.13(m,4H),7.09-7.01(m,2H) ,6.91(dd,J=5.6,2.5Hz,1H),4.58(dt,J=11.2,7.5Hz,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) + .

[0257] (±)-N-(1-methyl-2-oxo-8-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-phenoxypicolinamide (I-25) [ka] 1 H NMR (400MHz, chloroform-d) δ8.87(d,J=7.6Hz,1H),8.42(dd,J=5.6,0.5Hz,1H),8.25(d,J=5.8Hz,2H),7.60(dd,J =2.6,0.5Hz,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=11.3,7.5Hz,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=11.2,10.6,7.3Hz,1H). LCMS: Purity 95%, MS(m / e)563(M+H) + .

[0258] (±)-N-(2-oxo-8-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-phenoxypicolinamide (I-26) [ka] 1 H NMR (400MHz, chloroform-d) δ8.79(d,J=7.7Hz,1H),8.42(dd,J=5.6,0.6Hz,1H),8.2 8-8.22(m,2H),7.62(d,J=2.5Hz,1H),7.45-7.35(m,3H),7.28-7.19(m,2H),7.1 4(dd,J=7.7,1.6Hz,1H),7.10-7.02(m,2H),7.00(d,J=1.6Hz,1H),6.93(dd,J=5 .6,2.6Hz,1H),6.66-6.60(m,2H),4.70(dt,J=11.4,7.7Hz,1H),3.56-3.44(app m,2H),3.33(dd,J=6.1,4.3Hz,4H),2.99(td,J=12.9,7.9Hz,1H),2.80(tt,J=12.1,7.4Hz,1 H),2.70(dd,J=13.1,7.0Hz,1H),2.56(dd,J=6.2,4.2Hz,4H),2.11(td,J=11.7,7.6Hz,1H). LCMS: Purity 99%, MS(m / e)549(M+H) + .

[0259] (±)-N-(1-methyl-2-oxo-8-(3-oxa-9-azaspiro[5.5]undecan-9-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-phenoxypicolinamide (I-27) [ka] 1H NMR (400MHz, chloroform-d) δ8.82(d,J=7.7Hz,1H),8.41(dd,J=5.6,0.5Hz,1H),7.59(dd,J=2.6,0.5Hz,1H),7.43-7.3 4(m,2H),7.26-7.17(m,1H),7.10-7.01(m,3H),6.91(dd,J=5.6,2.6Hz,1H),6.75(dd,J=8.4,2.5Hz,1H),6.69(d,J =2.4Hz,1H),4.63(dt,J=11.2,7.7Hz,1H),3.71-3.64(m,4H),3.39(s,3H),3.18-3.10(m,4H),2.79(td,J=12.7,7. 6Hz,1H),2.70-2.57(m,1H),2.53(dd,J=13.0,6.8Hz,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) + .

[0260] (±)-N-(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-1-(methyl-d3)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-phenoxypicolinamide (I-28) [ka] 1 H NMR (400 MHz, chloroform-d) δ 8.82 (d, J = 7.6 Hz, 1H), 8.40 (dd, J = 5.6, 0.5 Hz, 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=11.2,7.5Hz,1H),2.86(t d,J=12.4,11.9,7.8Hz,1H),2.75-2.57(m,2H),2.04(td,J=11.5,8.4Hz,1H),1.60(s,6H). LCMS: Purity 97%, MS(m / e)473(M+H) + .

[0261] (±)-N-(1-(methyl-d3)-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-phenoxypicolinamide (I-29) [ka] 1 H NMR (400MHz, chloroform-d) δ8.80(d,J=7.8Hz,1H),8.41(dd,J=5.6,0.5Hz,1H),7.59(dd,J=2.5,0.5Hz,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=5.6,2.6Hz,1H),6.27( dd,J=8.1,2.3Hz,1H),6.20(d,J=2.3Hz,1H),4.63(dt,J=11.3,7.7Hz,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=13.1,6.9Hz,1H),2.05-1.93(m,1H),1.87-1.79(m,4H). LCMS: Purity 97%, MS(m / e)516(M+H) + .

[0262] (±)-N-(1-methyl-2-oxo-8-(2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-phenoxypicolinamide (I-30) [ka] 1H NMR (400MHz, chloroform-d) δ8.81(d,J=7.8Hz,1H),8.41(d,J=5.6Hz,1H),7.60(d,J=2.5Hz,1H),7.45-7.34(m,2H),7.26-7. 17(m,1H),7.09-7.01(m,2H),7.00(d,J=8.1Hz,1H),6.91(dd,J=5.6,2.6Hz,1H),6.25(dd,J=8.2,2.3Hz,1H),6.19(d,J= 2.3Hz,1H),4.64(dt,J=11.2,7.7Hz,1H),3.52(s,4H),3.37(s,3H),2.77(td,J=12.9,7.5Hz,1H),2.61(tt,J=12.3,7.3H z,1H),2.50(dd,J=13.2,6.8Hz,1H),2.06-1.92(m,1H),1.68(t,J=5.7Hz,4H),1.45(d,J=5.9Hz,4H),1.45-1.35(m,2H). LCMS: Purity 98%, MS(m / e)511(M+H) + .

[0263] (±)-N-(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-phenoxypicolinamide (I-31) [ka] 1H NMR(400MHz,chloroform-d)δ8.81(d,J=7.8Hz,1H),8.41(dd,J=5.6,0.5Hz,1H), 7.60(dd,J=2.6,0.5Hz,1H),7.46-7.34(m,2H),7.25-7.18(m,1H),7.09-7.00 (m,3H),6.91(dd,J=5.6,2.6Hz,1H),6.27(dd,J=8.1,2.3Hz,1H),6.21(d,J= 2.3Hz, 1H), 4.64 (dt, J=11.2, 7.7Hz, 1H), 3.66 (t, J=5.2Hz, 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=11.6,7.3Hz,1H),1.87-1.80(m,4H). LCMS: Purity 96%, MS(m / e)513(M+H) + .

[0264] (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]azepin-3-yl)-1H-pyrazole-3-carboxamide (I-32) [ka] 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=11.0,7.6Hz,1H),3.68(t,J=5.2Hz,4H),3.65(s,4H),3.39(s,3 H),2.79-2.59(m,2H),2.52(dd,J=13.0,6.5Hz,1H),2.04-1.92(m,1H),1.89-1.82(m,4H). LCMS: Purity 95%, MS(m / e)500(M+H) + .

[0265] (S)-1-Benzyl-N-(8-(3,3-dimethylbut-1-yn-1-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-1H-pyrazole-3-carboxamide (I-33) [ka] 1 H NMR(400MHz,chloroform-d)δ7.80(d,J=7.4Hz,1H),7.40-7.28(m,4H),7.26-7.1 8(m,4H),7.15(d,J=7.7Hz,1H),6.73(d,J=2.3Hz,1H),5.30(d,J=4.7Hz,2H), 4.62(dt,J=11.0,7.5Hz,1H),3.41(s,3H),2.85(td,J=12.6,7.6Hz,1H),2.7 9-2.66(m,1H),2.61(dd,J=12.7,6.6Hz,1H),2.09-1.97(m,1H),1.32(s,9H). LCMS: Purity 97%, MS(m / e)455(M+H) + .

[0266] (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]azepin-3-yl)-1H-pyrazole-1-carboxamide (I-34) [ka] 1H NMR (400MHz, chloroform-d) δ7.94(d,J=7.6Hz,1H),7.85(q,J=0.9Hz,1H),7.42(d,J=0.8Hz,1H),7.3 0-7.26(m,2H),7.21(d,J=7.7Hz,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=11.8,4.5Hz,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, 4.0Hz, 2H). 19 F NMR (376MHz, chloroform-d) δ-116.87 (ddd, J=14.2, 8.8, 5.3 Hz). LC / MS: Purity 99%, MS(m / e)517(M+H) + .

[0267] (S)-4-(4-Fluorophenoxy)-N-(8-(3-hydroxy-3-methylbut-1-yn-1-yl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)picolinamide (I-35) [ka] 1 H NMR(400MHz,DMSO-d6)δ10.07(s,1H),8.77(d,J=7.5Hz,1H),8.53 (d,J=5.6Hz,1H),7.36-7.21(m,6H),7.14(ddd,J=9.4,6.7,2.2Hz,2H),6.96(d,J=1.6Hz,1H),5.44(s,1H),4 .29(dt,J=11.5,7.8Hz,1H),2.81-2.64(m,2H),2.53-2.49(m,1H),2.14(td,J=11.9,6.3Hz,1H),1.42(s,6H). 19 F NMR (376MHz, DMSO-d6) δ-116.70 (tt, J=8.8, 4.7Hz). LCMS: Purity 98%, MS(m / e)474(M+H) + .

[0268] 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]azepin-3-yl)-1H-pyrazole-1-carboxamide (I-36) [ka] Route 3. 1 H NMR (400MHz, methylene chloride-d2) δ7.94-7.80(app m,2H),7.46(app d,J=0.9Hz,1H),7.28(dd,J=6.1,1.7Hz,2H),7.23(d,J=8.2Hz,1H),7.21-7.14(m,2H),7.03-6.95 (m,2H),4.39(dt,J=11.5,7.4Hz,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 F NMR (376MHz, methylene chloride-d2) δ-117.84 (ddd, J=14.3,9.0,5.4 Hz). LC / MS: Purity 98%, MS(m / e)478(M+H) + .

[0269] (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]azepin-3-yl)-4-phenoxypicolinamide (I-37) [ka] 1-Methyl-4-(2-methylbut-3-yn-2-yl)piperazine was prepared as follows: To a stirring pale green solution of CuCl (0.10 g, 10 mmol) in dry THF at room temperature under argon, 1-methylpiperazine (1.10 g, 1.22 mL, 11 mmol) and NEt (1.11 g, 1.53 mL, 11 mmol) were added sequentially over a 20 min period. After stirring the blue heterogeneous mixture for 10 min, 2-methylbut-3-yn-2-yl acetate (1.27 g, 10 mmol) in dry THF (5 mL) was added slowly over a 20 min period, and a mild exotherm was observed. The reaction mixture was continued to stir for 30 min, heated at 58 °C for 7 h, and cooled. The brownish-red reaction mixture was diluted with EtO (70 mL) and aqueous NaHCO (40 mL). After separating the organic layer, the red heterogeneous aqueous layer was extracted with EtO (3 × 75 mL). The combined light green organic layers were washed successively with aqueous NaHCO (40 mL) and then aqueous NaCl, stirred with anhydrous NaSO, and filtered through Celite®. The filtrate was concentrated to give the title compound as a crude yellow solid (1.16 g). Further purification by silica gel chromatography (Combiflash® Teledyne RediSep® 12G Gold column; A: CHCl B; B: 20% MeOH / CHCl @ 15% B / A; detection at λ 220 and 230 nm) afforded an off-white solid (0.54 g, 33% yield). 1 H NMR (400 MHz, chloroform-d) δ 2.67 (br s, 4H), 2.46 (br s, 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.

[0270] According to the method of the present disclosure, 1-methyl-4-(2-methylbut-3-yn-2-yl)piperazine was used to make (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]azepin-3-yl)-4-phenoxypicolinamide. 1 H NMR (400MHz, methylene chloride-d2) δ8.73(d,J=7.6Hz,1H),8.46(dd,J=5.6,0.6Hz,1H),7.57(dd,J=2. 6,0.5Hz,1H),7.50-7.40(m,2H),7.33-7.23(m,3H),7.22(d,J=7.7Hz,1H),7.15-7.07(m,2H) ),6.97(dd,J=5.6,2.6Hz,1H),4.52(dt,J=11.4,7.5Hz,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) + .

[0271] (±)-N-(1-methyl-2-oxo-8-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-phenylpyrimidine-2-carboxamide (I-38) [ka] 1H NMR (400MHz, chloroform-d) δ9.16(d,J=7.4Hz,1H),8.91(d,J=5.3Hz,1H),8.28-8.22(m,2H),8.22-8.14(m,2H),7.80(d, J=5.3Hz,1H),7.58-7.50(m,3H),7.27-7.12(m,3H),6.67-6.61(m,2H),4.75(dt,J=11.3,7.4Hz,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) + .

[0272] (±)-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]azepin-3-yl)-4-phenylpyrimidine-2-carboxamide (I-39) [ka] 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 ,4.1Hz,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=12.5,6.0,4.8Hz,1H). LCMS: Purity 98%, MS(m / e)509(M+H) + .

[0273] Example 10 In this example, the disclosed compounds were evaluated using a biochemical assay employing ADP-Glo™ technology.

[0274] ADP-Glo™ (Promega, Madison, WI, USA) reagent was thawed at ambient temperature. Kinase detection reagent was prepared by mixing kinase detection buffer with lyophilized kinase detection substrate.

[0275] A 500 ml stock volume of 5x reaction kinase buffer was made by mixing 1000 μl of 1 M MgCl, 500 μl of 1 M Tris-HCl (pH 7.4), 0.5 mg / ml (25 mg) BSA, and 3475 μl of distilled H O. A 3 ml 2x working stock volume of reaction kinase buffer was made containing a final concentration of 100 μg MDTT and 4 mM MnCl.

[0276] RIPK1 enzyme (Rigel Pharmaceuticals, South San Francisco, CA, USA) components were thawed on ice. RIPK1 was diluted in 1x kinase reaction buffer (diluted from 2x buffer) to 31 ng / well. A 166 μM working stock ATP assay solution was prepared in 1x kinase reaction buffer (diluted from 2x buffer).

[0277] Compounds were serially diluted in DMSO starting at 250 μM in 4-fold dilutions, then diluted 1:5 in 2x reaction buffer in a 96-well plate. 1.0 μl of diluted compound was added to two 384-well plates. 2 μl of diluted active RIPK1 was added to the 384-well plate (not to column 1), and 2x rxn buffer was added to column 1. 150 nM AKT (Anaspec, Fremont, CA, USA) was combined with an equal volume of ATP working stock and added 2 μl / well to the 384-well plate. The final reaction volume was 5.0 μl.

[0278] The plate was quickly centrifuged and the reaction was incubated at 30°C for 30 minutes. 5 μl of ADP-Glo™ was added to terminate the reaction. The plate was quickly centrifuged and the reaction was incubated at room temperature for 40 minutes. Kinase detection reagent was then added and incubated at room temperature for 30 minutes. Relative light units (RLU) of the kinase reaction were determined by luminescence (Luminescence 0.1 s) using a WallaCVictor2 Luminometer (PerkinElmer, Waltham, MA, USA). IC obtained from this example 50 The values ​​are provided in Table 1. [Table 1]

[0279] Example 11 In this example, U937 and L929 cells were exposed to compounds of the present disclosure and a cell necroptosis assay was performed to evaluate the activity of the compounds against human RIP1 and mouse RIP1.

[0280] 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 with 5% CO2. For necroptosis assays, L929 cells were seeded at 10K cells / well in 100 μL / well medium into Costa R96-well black clear-bottom plates (FisheRScientific, Hampton, NH, USA) for 18 h. On the day of the assay, U937 cells were seeded at 50K cells / well in 50 μL / well medium containing 60 μM zVAD-fmk (Lonza, Basel, Switzerland). The L929 cell medium was removed from the 96-well plate and replaced with 50 μL / well of fresh medium containing 40 μM zVAD-fmk. Each compound of the present disclosure evaluated in this example was serially diluted in DMSO starting at 2.5 mM in 4-fold dilutions, then diluted 1:125 in complete medium. 50 μL / well of 2× compound was then added to the plated cells. After preincubating the cells with compound for 1 hour at 37°C and 5% CO2, 10 μL / well of 11× TNFα (Peprotech, Rocky Hill, NJ, USA) was added to bring the final TNFα concentration to 2 ng / mL. The relative amount of necroptotic cells was determined 18 hours after TNFα stimulation at 37°C and 5% CO2 by luminescence using a WallaCVictor2 Luminometer (PerkinElmer, Waltham, MA, USA) and CellTiter-Glo® Luminescent Cell Viability Reagent Assay (Promega, Madison, WI, USA) added 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, allowing for their evaluation in in vivo mouse models of disease. These results are useful for determining safe and effective dosing in humans. [Table 2]

[0281] Example 12 In this example, an acute hypothermia mouse model assay is used to assess the ability of compounds disclosed herein to inhibit TNF-alpha-induced hypothermia.

[0282] Female C57BL / 6 mice were randomly divided into groups and weighed on day 1. On the day of the study (day 0), mice were orally gavaged with vehicle or test article. 15 minutes after oral administration of the test agent, each mouse received an intraperitoneal (IP) injection of a solution containing recombinant human tumor necrosis factor alpha (TNF-α, 25.0 μg) and zVAD-FMK (200 μg). Body temperature was measured via a rectal probe temperature measurement device at time 0 (before IP injection) and every hour. Three hours after IP injection of TNF-α and zVAD / FMK, mice were euthanized by CO2 asphyxiation, and blood was collected via cardiac puncture. Serum and plasma were collected for determination of cytokine and compound levels, respectively. A separate group of mice (satellite mice) was included to determine compound levels in plasma upon TNFα / zVAD-FMK administration.

[0283] (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide (WO 2014 / 125444), having the structure shown below, was used as a comparative compound and tested using a protocol similar to that described in WO 2014 / 125444. According to WO 2014 / 125444, this comparative compound exhibits 93% inhibition at a dose of 30 mg / kg; however, in the inventor's hands, the compound only exhibited 70% inhibition at 30 mg / kg. In comparison, compounds of the present disclosure can achieve higher inhibition, such as greater than 75% or even greater than 85% inhibition, at lower doses on a mg / kg basis using the same assay protocol described above. [ka]

[0284] Comparative Compound Certain embodiments of the disclosure provide a compound, a plurality of compounds, or compositions thereof for crossing the blood-brain barrier. The disclosed compound and composition embodiments exhibit sufficient brain penetration as a potential therapy for neurological diseases. Brain penetration can be evaluated by assessing the brain-free / plasma ratio (Bu / Pu) measured in in vivo pharmacokinetic studies in rodents. Other methods for assessing brain penetration are known to those skilled in the art. See, for example, Liu, X. et al., J. Pharmacol. Exp. Therap., 325:349-56, 2008.

[0285] In view of the many possible embodiments to which the principles of this disclosure may be applied, it should be recognized that the illustrated embodiments are merely preferred examples and are not to be construed as limiting. Rather, the scope of this disclosure is defined by the following claims. We therefore claim as our invention all that comes within the scope and spirit of these claims.

Claims

1. 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]azepin-3-yl)-4-phenoxypicolinamide; 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]azepin-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]azepin-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]azepin-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]azepin-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]azepin-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]azepin-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]azepin-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]azepin-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]azepin-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]undecan-9-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-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]azepin-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]azepin-3-yl)-1H-1,2,4-triazole-3-carboxamide; I-16: (±)-5-benzyl-N-(8-((3-hydroxyoxetan-3-yl)ethynyl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-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]azepin-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]azepin-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]azepin-3-yl)-4-phenoxypicolinamide; 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]azepin-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]azepin-3-yl)-4-phenoxypicolinamide; I-25: (±)-N-(1-methyl-2-oxo-8-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-phenoxypicolinamide; I-26: (±)-N-(2-oxo-8-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-phenoxypicolinamide; I-27: (±)-N-(1-methyl-2-oxo-8-(3-oxa-9-azaspiro[5.5]undecan-9-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-phenoxypicolinamide; 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]azepin-3-yl)-4-phenoxypicolinamide; 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]azepin-3-yl)-4-phenoxypicolinamide; I-30: (±)-N-(1-methyl-2-oxo-8-(2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-phenoxypicolinamide; 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]azepin-3-yl)-4-phenoxypicolinamide; 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]azepin-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]azepin-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]azepin-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]azepin-3-yl)picolinamide; 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]azepin-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]azepin-3-yl)-4-phenoxypicolinamide; I-38: (±)-N-(1-methyl-2-oxo-8-((4-(pyridin-4-yl)piperazin-1-yl)methyl)-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-phenylpyrimidine-2-carboxamide; 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]azepin-3-yl)-4-phenylpyrimidine-2-carboxamide.

2. A pharmaceutical composition comprising the compound of claim 1.

3. The composition of claim 2 , further comprising an excipient, a therapeutic agent, or a combination thereof.

4. 10. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof for use in therapy.

5. 10. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof for treating a disease in a subject, wherein the subject has, or is suspected of having or developing, a disease involving receptor-interacting protein-1 (RIP1) kinase.

6. The disease is The pharmaceutical composition of claim 5, which is an inflammatory or immunoregulatory disorder.

7. The pharmaceutical composition of claim 5 , wherein the disease is a disorder of aging.

8. The disease may be amyotrophic lateral sclerosis (ALS), autoimmune syndromes, rheumatoid arthritis, type I diabetes, inflammatory bowel diseases including Crohn's disease and ulcerative colitis, biliary cirrhosis, multiple sclerosis, Wegener's granulomatosis, ichthyosis, asthma, pollen allergy, persistent 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, diseases caused by autoimmune hepatitis, cerebrovascular accidents, allergic diseases, chronic obstructive pulmonary disease, emphysema, Friedreich's ataxia, diseases with Lewy bodies, diabetic neuropathy, polyglutamine (polyQ) diseases, Fahr's disease, Menkes disease, Wilson's disease, prion disorders, bone resorption diseases, destructive bone disorders such as psoriasis, psoriasis related to multiple myeloma, bone disorders associated with multiple myeloma; benign tumors, proliferative disorders, inflammatory and hyperproliferative skin disorders, epidermal hyperproliferation, psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis, seborrheic dermatitis, pustular psoriasis, bullous dermatitis, erythematous polymorphic dermatitis, erythematous erythema, multiforme), linear IgA bullous dermatosis, cementodermatitis, gingivitis, periodontitis, gingival, alveolar bone, and dental cementum lesions, sepsis, pancreatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia, hyperlipidemia, eosinophilic fasciitis, acne, alopecia areata, male pattern baldness, senile alopecia, keratoconjunctivitis, vernal conjunctivitis, corneal alkali burns, Behçet's disease, uveitis associated with Behçet's disease, keratitis, herpetic keratitis, keratoconus, corneal epithelial dystrophy, corneal leukoplakia, ocular pemphigoid, androgen-binding protein 1 (MMP). Len's ulcer, scleritis, Falk-Koyanagi-Harada disease, hematological disorders, hematological malignancies, lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, breast carcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, ABC diffuse large B-cell lymphoma (DLBCL), Waldenstrom's macroglobulinemia, primary cutaneous T-cell lymphoma, smoldering or asymptomatic multiple myeloma, leukemia, acute myeloid leukemia (AML), DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma,Drug-resistant malignancies such as Burkitt's lymphoma / leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, myelodysplastic syndromes (MDS), myelofibrosis, polycythemia vera, Kaposi's sarcoma, splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, intravascular large B-cell lymphoma, IL-1-mediated disorders, MyD88-mediated disorders, JAK inhibitor-resistant malignancies and ibrutinib-resistant malignancies, e.g., ibrutinib-resistant hematologic malignancies, ibrutinib-resistant CLL, and ibrutinib-resistant Waldenstrom's macroglobulinemia. angiogenic disorders, including neovascularization disorders, including solid tumors, ocular neovascularization, and hemangiomas, such as infantile hemangiomas; sepsis, septic shock, and shigellosis; migraine, bronchitis, gastric ulcers, necrotizing enterocolitis, intestinal lesions associated with thermal burns, celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, interleukin-1 converting enzyme-associated fever syndromes, tumor necrosis factor receptor-associated periodic syndromes, NEMO deficiency syndromes, HOIL-1 deficiency, linear ubiquitin chain assembly complex (IL-1) deficiency, and complex) deficiency syndrome, lysosomal storage disease, Gaucher disease, GM2 gangliosidosis, alpha-mannosidosis, aspartylglucosaminuria, cholesteryl 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, Nephrotic syndrome Mann-Pick disease, neuronal ceroid lipofuscinosis, Pompe disease, pyknodysostosis, Sandhoff disease, Schindler disease, sialic acid storage diseases, 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, fibrotic conditions such as CMV retinitis, non-alcoholic steatohepatitis, and cardiac conditions such as ischemia-reperfusion; allergies, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, erythroderma, 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; ankylosing spondylitis, gouty arthritis, psoriatic arthritis, and other arthritic conditions; cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, fibrotic lung, idiopathic interstitial pneumonia, allograft rejection, bone marrow rejection, fever and myalgia due to infection, keloid formation, scar tissue formation, fever, influenza, chronic bone marrow leukemia; angiogenic disorders 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 in heart attacks, organ hypoxia, vascular hyperplasia, cardiac and renal reperfusion injury, ischemia-reperfusion injury of organs occurring during preservation, transplantation, or ischemic disease, cardiac hypertrophy, thrombin-induced platelet aggregation, endotoxemia and / or toxic shock syndrome, prostaglandin endoperoxidase Oxide synthase 2-related conditions, pemphigus vulgaris, autoimmune / polymyositis, dermatomyositis, vitiligo, photoallergic sensitivity, ischemia-reperfusion injury, cardiac ischemia-reperfusion injury resulting from myocardial infarction, multiple system atrophy, Parkinson's plus 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 diseases, systemic juvenile idiopathic arthritis (SoJIA) or Still's disease, systemic lupus erythematosus (SLE), Sjogren's syndrome, antiphospholipid antibodies 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 resulting from COVID-19, post-infectious autoimmune diseases, rheumatic fever, post-infectious glomerulonephritis, systemic sclerosis, cerebrovascular accident (CVA), chronic obstructive pulmonary disease (COPD), NEMO deficiency syndrome (F-kappa-B essential modulator gene (also known as IKK gamma or IKKG) deficiency syndrome), solid organ malignancies, lysosomal storage diseases,Glaucoma, retinal degenerative disease, retinal ischemia / reperfusion injury, renal ischemia-reperfusion injury, cataract, siderosis, retinitis pigmentosa, retinal degeneration, retinal detachment, age-related macular degeneration, vitreous scarring, anthrax toxin-induced septic shock, 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 sclerosis, macular edema, diabetic retinopathy, central areolar choroidal dystrophy, BEST disease, adult vitellosis vitelliform), 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 light-induced toxicity, macular edema, central areolar 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., arterial or non-arterial 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 neuropathy, Beer's syndrome, Creutzfeldt-Jakob disease), progressive supranuclear palsy, hereditary spastic paraplegia, subarachnoid hemorrhage, Perinatal brain injury, subclinical brain injury, spinal cord injury, anoxic-ischemic brain injury, cerebral ischemia, focal cerebral ischemia, global cerebral ischemia, and hypoxic hypoxia, peritoneal damage caused by peritoneal dialysis fluid (PDF) and PD-related side effects, glomerular disease, tubulointerstitial disease, interstitial nephritis, obstruction, polycystic kidney disease), focal glomerulosclerosis, immune complex nephropathy, diabetic nephropathy, Goodpasture's syndrome, hepatocellular carcinoma, pancreatic cancer, urinary cancer, Bladder cancer, colorectal cancer, colon cancer, breast cancer, prostate cancer, prostatic hyperplasia, kidney cancer, renal carcinoma, liver carcinoma, adrenal carcinoma, thyroid cancer, gallbladder cancer, peritoneal cancer, ovarian cancer, cervical cancer, stomach cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, neuroendocrine cancer, CNS cancer, brain tumors (e.g., brain carcinoma, glioma, anaplastic oligodendroglioma, adult glioblastoma, and adult anaplastic astrocytoma), bone cancer, soft tissue sarcoma, retinoblastoma,Neuroblastoma, peritoneal effusion, malignant pleural effusion, mesothelioma, Wilms' tumor, trophoblastic neoplasm, epithelial neoplasm, gastric carcinoma, ovarian carcinoma, rectal carcinoma, prostate carcinoma, pancreatic carcinoma, lung carcinoma, vaginal carcinoma, cervical carcinoma, testicular carcinoma, genitourinary carcinoma, esophageal carcinoma, laryngeal carcinoma, skin carcinoma, bone carcinoma, thyroid carcinoma, sarcoma, glioblastoma, neuroblastoma, gastrointestinal cancer, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung carcinoma, lymphoma, colon carcinoma, colorectal adenoma, Hemangiopericytoma, mucinous carcinoma, round cell carcinoma, squamous cell carcinoma, esophageal squamous cell carcinoma, oral carcinoma, vulvar cancer, adrenal cortical cancer, ACTH-producing tumor, and leukemia, respiratory infectious viruses such as influenza virus, rhinovirus, coronavirus, parainfluenza virus, respiratory syncytial virus, adenovirus, and reovirus), herpes zoster caused by herpes virus, diarrhea caused by rotavirus, viral hepatitis, AIDS, Bacillus cereus, Vibrio parahaemolyticus, Enterohemorhagic Escherichia coli, Staphylococcus aureus, MRS Bacterial infections such as Salmonella, botulism, and Candida, Paget's disease, achondroplasia, osteoporosis, hyperparathyroidism, osteogenesis imperfecta, partial liver resection, acute liver necrosis, necrosis caused by toxins, necrosis caused by viral hepatitis, necrosis caused by shock, necrosis caused by anoxia, viral hepatitis type B, non-A / non-B hepatitis, cirrhosis, alcoholic liver disease, alcoholic cirrhosis, alcoholic steatohepatitis, non-alcoholic steatohepatitis (NASH), Cetaminophen toxicity, hepatotoxicity, liver failure, fulminant liver failure, delayed liver failure, acute exacerbation of chronic liver failure, chronic kidney disease, kidney damage / injury, kidney damage / injury caused by nephritis, kidney damage / injury caused by kidney transplantation, kidney damage / injury caused by surgery, kidney damage / injury caused by administration of nephrotoxic drugs, enhanced chemotherapy effects, cytomegalovirus infection, HCMV infection, AIDS, cancer, senile dementia, trauma, chronic bacterial infection, diseases caused by environmental pollution, aging, altitude sickness,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 failure, chronic renal failure, pulmonary oxygen or drug-induced toxicosis, congenital Hypophosphatasia, fibromatous lesions, fibrous dysplasia, bone metabolism, osteolytic bone disease, treatment of post-traumatic bone surgery, treatment after joint replacement surgery, treatment after orthopedic bone surgery, treatment after dental surgery, bone chemotherapy or bone radiotherapy, bone cancer, fragile plaque, disorders, occlusive disorders, stenosis, coronary artery disorders, peripheral arterial disorders, arterial occlusion, aneurysm formation, post-traumatic aneurysm formation, restenosis, occlusion after graft surgery, Guillain-Barre syndrome, Meniere's disease, polyneuritis, multiple neuropathy 6. The pharmaceutical composition of claim 5, wherein the autoimmune idiopathic thrombocytopenic purpura (ITP), membranous nephritis, autoimmune thyroiditis, Hashimoito thyroiditis, myasthenia gravis, cold and warm agglutinin disease, Evan's syndrome, hemolytic uremic syndrome / thrombotic thrombocytopenic purpura (HUS / TTP), autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, anerythroplasia, or a combination thereof.

9. The pharmaceutical composition of claim 5 , wherein the disease is myelodysplastic syndrome.

10. 6. The pharmaceutical composition of claim 5, wherein the disease is selected from atopic dermatitis, rheumatoid arthritis, and ankylosing spondylitis.

11. 6. The pharmaceutical composition of claim 5, wherein the disease is selected from Parkinson's disease, Alzheimer's disease, multiple sclerosis, and amyotrophic lateral sclerosis.

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