Heterocyclic RIP1 inhibitory compounds

Abstract

Disclosed herein are kinase inhibitory compounds, such as receptor-interacting protein-1 (RIP1) kinase inhibitor compounds, and pharmaceutical compositions and combinations comprising such inhibitory compounds. The compounds may have a structure according to Formula I. The disclosed compounds, pharmaceutical compositions and / or combinations may be used to treat or prevent kinase-related diseases or conditions, particularly RIP1-related diseases or conditions.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of earlier filing dates of U.S. Provisional Patent Application No. 62 / 932,404 filed on November 7, 2019, U.S. Provisional Patent Application No. 63 / 001,016 filed on March 27, 2020, U.S. Provisional Patent Application No. 63 / 004,290 filed on April 2, 2020, U.S. Provisional Patent Application No. 63 / 004,319 filed on April 2, 2020, and U.S. Provisional Patent Application No. 63 / 004,301 filed on April 2, 2020. Technical Field

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

[0004] Receptor-interacting protein-1 kinase (herein referred to as "RIP1") belongs to the tyrosine kinase-like family and is a serine / threonine protein kinase involved in innate immune signaling. RIP1 plays a key 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 inflammatory and / or necroptotic cell death. Summary of the invention

[0005] The disclosed compounds according to the present disclosure may have formula I

[0006]

[0007] or a pharmaceutically acceptable salt thereof. With respect to Formula I, Ring B is a heteroaryl, such as a five-membered or six-membered heteroaryl, and may be a pyridyl, pyrazolyl, triazolyl or oxadiazolyl. Y is O, or Y is -CH2-. m is 1, 2, 3 or 4, such as 1, 2 or 3, and may be 1 or 2. In certain embodiments, m is 1. n is 0, 1 or 2. In certain embodiments, n is 0, and in other embodiments, n is 1.

[0008] Each R 1 is independently a heterocyclic group, optionally substituted by at least one R 6 substituted, wherein each R, if present, 6 Independently for R c . R 2 For R a , such as H or C 1-6alkyl, and in some embodiments, R 2 is CH3 or CD3. 3 For R a or R 3 Together with the -NC(O) moiety to which it is attached and the two ring atoms from ring B, it can form a five-membered or six-membered heterocyclyl fused to ring B. And if present, each R 4 Independently for R e .

[0009] L is a heteroatom or R a , the condition is R a is not H or D. In some embodiments, L is a heteroatom or C 1-10 Aliphatic groups, such as C 1-6 alkyl, and may be O or -CH2-. And Z is C 1-10 an aliphatic group or an aromatic group.

[0010] R a Each occurrence is independently C 1-10 Aliphatic groups (such as C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 3-6 Cycloalkyl), C 1-10 Halogenated aliphatic group, C 5-10 Aromatic groups, C 3-6 Heterocyclic group or C 3-10 spiroheterocyclic group; or H or D, except where L is R a outside the implementation plan.

[0011] R b Each occurrence is independently -OH, -SH, -OR c 、-SR c 、-NR d R d 、-Si(R a )3, -C(O)OH, -C(O)OR c 、-C(O)NR d R d 、-OC(O)NR d R d 、-OC(O)C 1-10 Alkyl, which is replaced by one or two NR d R d , carboxyl, or a combination thereof, and is optionally further substituted with an aromatic moiety, -SH, -O-acyl, or -C(O)NH2.

[0012] R c Each occurrence is independently C 1-10Alkyl, which can be replaced by 1, 2 or 3 R e Replacement, C 2-10 Alkenyl, which can be substituted by 1, 2 or 3 R e Replace; C 2-10 Alkynyl, which can be substituted by 1, 2 or 3 R e Replace; C 3-6 Cycloalkyl, which can be substituted by 1, 2 or 3 R e Replace; or C 5-10 Aromatic groups, which can be substituted by 1, 2 or 3 R e replace.

[0013] R d Each occurrence is independently H; C 1-6 Alkyl, which can be replaced by 1, 2 or 3 R e or C 3-9 Heterocyclic substitution; C 3-6 Cycloalkyl, which can be substituted by 1, 2 or 3 R e Replace; C 3-6 A heterocyclic group, which can be replaced by 1, 2 or 3 R e Replace; C 5-10 Aryl, which can be replaced by 1, 2 or 3 R b Replace; C 5-10 Heteroaryl, which can be replaced by 1, 2 or 3 R e Replace; or two R d The groups together with the nitrogen to which they are bonded provide C 3-9 A heterocyclic group, which can be replaced by one or more R e Replace), or C 5-10 Heteroaryl, which can be replaced by one or more R e replace.

[0014] R e Each occurrence is independently 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 .

[0015] And R f Each occurrence is independently -alkyl-phosphate, R a , R b or R e , or two R f The groups, together with the carbon atom to which they are bonded, provide C 2-6 Alkenyl group; C 3-6 Cycloalkyl groups, which can be replaced by one or more R eReplace; or C 3-10 A heterocyclic group, which can be replaced by one or more R e or acyl substitution.

[0016] And with respect to Formula I, in some embodiments, the compound is not:

[0017] (S)-N-(7-(4-(chloromethyl)-4-(hydroxymethyl)piperidin-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide;

[0018] (S)-1-(4-fluorobenzyl)-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0019] (S)-5-benzyl-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)isoxazole-3-carboxamide;

[0020] (S)-1-(4-fluorobenzyl)-N-(5-methyl-4-oxo-7-(2-oxa-7-azaspiro[3.5]nonan-7-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0021] (S)-5-Benzyl-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0022] N-((S)-7-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-5-benzylisoxazole-3-carboxamide;

[0023] N-((S)-7-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide;

[0024] (S)-1-(4-fluorobenzyl)-N-(5-methyl-7-(1,4-oxazepan-4-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepan-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0025] (S)-5-benzyl-N-(5-methyl-7-(1,4-oxazepan-4-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepan-3-yl)isoxazole-3-carboxamide;

[0026] (S)-5-(4-fluorobenzyl)-N-(5-methyl-7-(1,4-oxazepan-4-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepan-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0027] (S)-5-(4-fluorobenzyl)-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0028] (S)-5-benzyl-N-(5-methyl-7-(1,4-oxazepan-4-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepan-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0029] N-((3S)-7-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-5-benzylisoxazole-3-carboxamide;

[0030] (S)-N-(7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-5-benzylisoxazole-3-carboxamide;

[0031] (S)-5-Benzyl-N-(5-methyl-4-oxo-8-(3-oxa-9-azaspiro[5.5]undec-9-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0032] (S)-N-(7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-5-benzyl-1H-1,2,4-triazole-3-carboxamide;

[0033] (S)-5-benzyl-N-(7-((3-chloropropyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0034] (S)-5-Benzyl-N-(5-methyl-4-oxo-7-(1-oxa-8-azaspiro[4.5]decan-8-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0035] (S)-5-(4-fluorobenzyl)-N-(5-methyl-4-oxo-7-(1-oxa-8-azaspiro[4.5]decan-8-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0036] (S)-N-(7-(azetidin-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-5-benzyl-1H-1,2,4-triazole-3-carboxamide;

[0037] (S)-5-Benzyl-N-(5-methyl-4-oxo-7-(2-oxa-8-azaspiro[4.5]decan-8-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0038] (S)-5-Benzyl-N-(5-methyl-4-oxo-7-(8-oxa-2-azaspiro[4.5]decan-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0039] (S)-5-Benzyl-N-(7-(2-benzyl-1-oxo-2,8-diazaspiro[4.5]decan-8-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0040] (S)-5-Benzyl-N-(7-(2-benzyl-1-oxo-2,9-diazaspiro[5.5]undec-9-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0041] (S)-5-Benzyl-N-(5-methyl-4-oxo-7-(3-oxa-9-azaspiro[5.5]undec-9-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0042] (S)-5-benzyl-N-(7-(3,3-difluoroazetidin-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide; or

[0043] (S)-5-Benzyl-N-(7-(3-fluoroazetidin-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide.

[0044] And in certain embodiments of Formula I, the compound is not:

[0045] I-1: (S)-1-benzyl-4-fluoro-N-(5-methyl-4-oxo-7-(8-oxa-2-azaspiro[4.5]decane-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-3-carboxamide;

[0046] I-2: (S)-1-benzyl-4-fluoro-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-3-carboxamide;

[0047] I-3: (S)-4-(4-fluorobenzyl)-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide;

[0048]

[0049] .

[0050] In some embodiments, at least one R 1 is an optionally substituted 8- to 12-membered spiro heterocyclyl, an optionally substituted monocyclic or bridged non-aromatic heterocyclyl, or an optionally substituted heteroaryl. And in certain embodiments, at least one R 1 for

[0051] .

[0052] Z can be , where each R 5 Independently for R e , and p is 0, 1, 2, 3, 4, or 5. In some embodiments, p is 0, 1, or 2. In certain embodiments, p is 0, but in other embodiments, p is 1. In such embodiments, R 5 It can be a halogen, such as chlorine or fluorine. And in certain embodiments, the -LZ moiety is phenoxy, benzyl, 4-fluorobenzyl or 1-phenylcyclopropyl.

[0053] Also disclosed is a pharmaceutical composition comprising a compound according to any embodiment disclosed herein. The pharmaceutical composition may further comprise an excipient, a therapeutic agent, or a combination thereof.

[0054] Embodiments of methods of using the compounds are also disclosed. The methods may include administering to a subject a compound according to the disclosed embodiments or a composition thereof. Additionally or alternatively, the methods may include contacting a receptor interacting protein-1 (RIP1) kinase with a compound disclosed herein or a composition thereof.

[0055] Certain embodiments relate to a method for treating a disease in a subject, comprising administering to the subject (i) a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt, stereoisomer, N-oxide, tautomer, hydrate, solvate, isotope, or prodrug thereof; or (ii) a therapeutically effective amount of a pharmaceutical composition of the compound; wherein the subject has, or is suspected of having or developing, a disease, wherein the disease is a disease involving receptor-interacting protein-1 (RIP1) kinase. The disease may be an inflammatory or immunoregulatory disorder, or the disease may be an aging disorder.

[0056] In some embodiments, the disease is selected from amyotrophic lateral sclerosis (ALS), autoimmune syndrome, rheumatoid arthritis, type I diabetes, inflammatory bowel disease, including Crohn's disease and ulcerative colitis, biliary cirrhosis, multiple sclerosis, Wegener's granulomatosis, ichthyosis, asthma, pollen allergy, reversible obstructive airway disease, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, chronic or habitual asthma, delayed asthma and airway hyperresponsiveness, allergic rhinitis, spondyloarthritis, ankylosing spondylitis, autoimmune hepatitis, autoimmune hepatobiliary disease, cerebrovascular accident, allergic disease, chronic obstructive pulmonary disease, emphysema, Friedreich's ataxia disorders, Lewy body diseases, diabetic neuropathy, polyglutamine (polyQ) diseases, Fahr's disease, Menke's disease, Wilson's disease, prion disorders, destructive bone disorders such as bone resorption diseases, multiple myeloma-related bone disorders; 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 multiforme erythema, linear IgA bullous dermatitis, cement dermatitis, gingivitis, periodontitis, lesions of the gums, alveolar bone, cementum, sepsis, pancreatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, vascular oedema, vasculitis, erythema, cutaneous eosinophilia, obesity, eosinophilic fasciitis, acne, alopecia areata, male pattern baldness, senile alopecia, keratoconjunctivitis, vernal conjunctivitis, corneal alkali burns, Behcet's disease, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, keratoconus, corneal epithelial dystrophy, corneal leukoplakia, pemphigus vulgaris, Mooren's ulcer, scleritis, Vogt-Koyanagi-Harada syndrome, hematological disorders, hematological malignancies, lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, breast cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, ABC diffuse large B-cell lymphoma (DLBCL), Waldenström's macroglobulinemia, primary cutaneous T-cell lymphoma, smoldering or indolent multiple myeloma, Leukemia, acute myeloid leukemia (AML), DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt lymphoma / leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, myelodysplastic syndrome (MDS), myelofibrosis, polycythemia vera, Kaposi's sarcoma, splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, intravascular large B-cell lymphoma, IL-1 driven disorders,MyD88-driven disorders, drug-resistant malignancies such as JAK inhibitor-resistant malignancies and ibrutinib-resistant malignancies such as ibrutinib-resistant hematologic malignancies, ibrutinib-resistant CLL and ibrutinib-resistant Waldenström's macroglobulinemia, acute myeloid leukemia, chronic myeloid leukemia; angiogenic disorders such as angiogenic disorders including solid tumors, ocular neovascularization, hemangiomas such as infantile hemangiomas; sepsis, septic shock, shigellosis; migraine, bronchitis, gastric ulcer, necrotizing enterocolitis, intestinal damage associated with thermal burns, celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, interleukin-1 converting enzyme-related febrile syndrome, tumor necrosis factor receptor-associated periodic syndrome, NEMO-deficient syndrome, HOIL-1 deficiency, linear ubiquitination chain assembly complex deficiency syndrome, lysosomal storage diseases, Gaucher disease, GM2 gangliosidosis, alpha-mannosidosis, aspartylglucosaminuria, cholesterol ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Farber disease, fucosidosis, galactosialidosis, GM1 gangliosidosis, mucolipidosis, infantile free sialic acid storage disease, juvenile hexosaminidase A deficiency, Krabbe disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucolipidosis Polysaccharidosis disorders, multiple sulfatase deficiency, Niemann-Pick disease, neuronal ceroid lipofuscinosis, Pompe disease, pycnodystrophy, 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 and CMV retinitis, such as associated neurocognitive disorders or dementia, fibrotic conditions such as nonalcoholic steatohepatitis and cardiac conditions such as ischemia-reperfusion; allergic, adult respiratory distress syndrome, chronic Obstructive lung disease, glomerulonephritis, systemic lupus erythematosus, chronic thyroiditis, Graves' disease, autoimmune gastritis, autoimmune neutropenia, thrombocytopenia, graft-versus-host disease, inflammatory response induced by endotoxin, pulmonary tuberculosis, atherosclerosis, muscle degeneration, cachexia, Reiter's syndrome, rubella arthritis, acute synovitis, pancreatic beta-cell disease; diseases characterized by massive neutrophil infiltration; rheumatoid spondylitis, gouty arthritis, psoriatic arthritis, and other arthritic conditions, cerebral malaria, chronic 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; viral diseases including acute hepatitis infection (including hepatitis A, B and C), AIDS, ARC or malignant tumors, herpes; stroke, myocardial infarction, atherosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, myocardial ischemia, local ischemia in stroke heart attack, organ hypoxia, angiogenesis, heart and kidney reperfusion injury, ischemia-reperfusion injury of organs during storage, transplantation or ischemic disease, cardiac hypertrophy, thrombin-induced platelet aggregation, endotoxemia and / or toxic shock syndrome, and prostaglandin endoperoxidase synthetase-2 Related conditions, pemphigus vulgaris, autoimmune / polymyositis, dermatomyositis, vitiligo vulgaris, photoallergic sensitivity, ischemia-reperfusion injury, cardiac ischemia-reperfusion injury due to myocardial infarction, multiple system atrophy, Parkinson-Chiari 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 onset juvenile idiopathic arthritis (SoJIA) or Still's disease, systemic lupus erythematosus (SLE), sjögren's syndrome, antiphospholipid syndrome (APS), primary sclerosing cholangitis ( PSC), renal transplantation, surgery, acute kidney injury (AKI), systemic inflammatory response syndrome (SIRS), cytokine release syndrome (CRS), acute respiratory distress syndrome (ARDS), ARDS caused by COVID-19, post-infectious autoimmune disease, rheumatic fever, post-infectious glomerulonephritis, systemic sclerosis, cerebrovascular accident (CVA), chronic obstructive pulmonary disease (COPD), NEMO-deficiency syndrome (F-κ-B essential regulator gene (also known as IKKγ or IKKG) deficiency syndrome), solid organ malignancies, lysosomal storage diseases, glaucoma, retinal degenerative diseases, retinal local ischemia / reperfusion injury, renal ischemia-reperfusion injury, cataract, siderosis, pigmentary Retinitis, retinal degeneration, retinal detachment, age-related macular degeneration, vitreous scarring, anthrax lethal toxin-induced septic shock, LPS-induced cell death, transmissible encephalopathy, encephalitis, allergic encephalomyelitis, autoimmune uveoretinitis, giant cell arteritis, regional enteritis, granulomatous enteritis, distal ileitis, regional ileitis, terminal ileitis, insulin-dependent diabetes mellitus, scleroderma, systemic scleroderma, yellow spots, edema, diabetic retinopathy, central halo choroidal dystrophy, BEST disease, adult yolk disease, pattern dystrophy, myopic degeneration, central serous retinopathy, Stargardt's disease, cone-rod dystrophy, North Carolina dystrophy,Infectious retinitis, inflammatory retinitis, uveitis, posterior uveitis, toxic retinitis and light-induced toxicity, yellow spot edema, central halo choroidal dystrophy, BEST disease, yolk disease in adults, pattern dystrophy, optic nerve injury, optic neuritis, optic neuropathy, central retinal artery occlusion, ischemic optic neuropathy (e.g., arteritic or nonarteritic anterior ischemic neuropathy and posterior ischemic optic neuropathy), compressive optic neuropathy, infiltrative optic neuropathy, traumatic optic neuropathy, mitochondrial optic neuropathy (e.g., Leber's optic neuropathy), nutritional optic neuropathy, toxic optic neuropathy and hereditary optic neuropathy, significant optic atrophy, Behr's syndrome, Creutz Feldt-Jakob disease), progressive supranuclear palsy, hereditary spastic paresis, subarachnoid hemorrhage, perinatal brain injury, subclinical brain injury, spinal cord injury, hypoxic-ischemic brain injury, cerebral ischemia, focal cerebral ischemia, global cerebral ischemia, and hypoxic hypoxia, peritoneal 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 system cancer, bladder cancer, colorectal cancer, colon cancer, breast cancer, prostate cancer, prostatic hyperplasia, renal cancer, kidney cancer, liver cancer, adrenal cancer, thyroid cancer, gallbladder cancer, peritoneal cancer, ovarian cancer, cervical cancer, gastric cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, neuroendocrine cancer, CNS cancer, brain tumors (e.g., brain cancer, glioma, anaplastic oligodendroglioma, glioblastoma multiforme in adults, and anaplastic astrocytoma in adults), bone cancer, soft tissue sarcoma, retinoblastoma, neuroblastoma, peritoneal effusion, malignant pleural effusion, mesothelioma, Wilms tumor, trophoblastic tumor, epithelial neoplasia, gastric cancer, ovarian cancer, rectal cancer, prostate cancer, pancreatic cancer, lung cancer, vaginal cancer, cervical cancer, testicular cancer, genitourinary tract cancer, esophageal cancer, laryngeal cancer, skin cancer, bone cancer, thyroid cancer, sarcoma, glioblastoma Tumors, neuroblastoma, gastrointestinal cancer, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma, colon cancer, colorectal adenoma, hemangiopericytoma, myxoid carcinoma, round cell carcinoma, squamous cell carcinoma, esophageal squamous cell carcinoma, oral cancer, vulvar cancer, adrenal cortical carcinoma, tumors that produce ACTH, and leukemia, respiratory infectious viruses, such as influenza virus, rhinovirus, coronavirus, parainfluenza virus, RS virus, adenovirus, reovirus, etc.), herpes zoster caused by herpes virus, diarrhea caused by rotavirus, viral hepatitis, AIDS, bacterial infectious diseases, such as Bacillus cereus, Vibrio parahaemolyticus, enterohemorrhagic Escherichia coli, Staphylococcus aureus, MRS A, Salmonella, Clostridium botulinum, Candida,Paget's disease, achondroplasia, osteochondritis, hyperparathyroidism, osteogenesis imperfecta, partial hepatectomy, acute liver necrosis, necrosis caused by toxins, necrosis caused by viral hepatitis, necrosis caused by shock, necrosis caused by hypoxia, viral hepatitis B, non-A, non-B hepatitis, cirrhosis, alcoholic liver disease, alcoholic cirrhosis, alcoholic steatohepatitis, non-alcoholic steatohepatitis (NASH), acetaminophen toxicity, hepatotoxicity, liver failure, fulminant liver failure, delayed liver failure, "acute on chronic" liver failure, chronic kidney disease, renal impairment / injury, Renal damage / injury caused by nephritis, renal damage / injury caused by renal transplantation, renal damage / injury caused by surgery, renal damage / injury caused by administration of nephrotoxic drugs, increased chemotherapy effects, cytomegalovirus infection, HCMV infection, AIDS, cancer, Alzheimer's disease, trauma, chronic bacterial infection, diseases caused by environmental pollution, aging, hypotension, diseases caused by the release of histamine or leukotriene-C4, muscular dystrophy, pyoderma and Sezary's syndrome, Addison's disease, pseudomembranous colitis, colitis caused by drugs or radiation, ischemia acute renal insufficiency, chronic renal insufficiency, toxic diseases caused by pulmonary oxygen or drugs, congenital hypophosphatasia, fibromatosis, fibrous dysplasia, bone turnover, osteolytic bone disease, treatment after traumatic bone surgery, treatment after prosthetic joint surgery, treatment after plastic surgery, treatment after dental surgery, bone chemotherapy or bone radiotherapy, bone cancer, fragile plaque, obstruction, occlusive obstruction, stenosis, coronary artery obstruction, peripheral arterial obstruction, arterial occlusion, aneurysm formation, post-traumatic aneurysm formation, restenosis, postoperative graft obstruction, Guillain-Barre syndrome syndrome, Meniere's disease, polyneuritis, polyneuritis, mononeuritis, radiculopathy, hyperthyroidism, Basedow's disease, autoimmune idiopathic thrombocytopenic purpura (autoimmune ITP), membranous nephritis, autoimmune thyroiditis, Hashimoito's thyroiditis, myasthenia gravis, cold and warm agglutinin diseases, Evan's syndrome, hemolytic uremic syndrome / thrombotic thrombocytopenic purpura (HUS / TTP), autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, agenesis of erythropoiesis, or a combination thereof.

[0057] In certain embodiments, the disease is atopic dermatitis, rheumatoid arthritis, or ankylosing spondylitis, and in other embodiments, the disease is myelodysplastic syndrome.

[0058] The foregoing and other objects and features of the present disclosure will become more apparent from the following detailed description. DETAILED DESCRIPTION

[0059] I. Definition of Terms

[0060] The following explanations of terms and methods are provided to better describe the present disclosure and to guide those of ordinary skill in the art to practice the present disclosure. The singular forms "a / an" and "the" refer to one / a or more than one / a, unless the context clearly indicates otherwise. The term "or" refers to a single element of the stated alternative element or a combination of two or more elements, unless the context clearly indicates otherwise. As used herein, "comprises" means "includes". Therefore, "comprising A or B" means "comprising A, B, or A and B," without excluding other elements.

[0061] Unless otherwise stated, all numbers expressing quantities of components, molecular weights, percentages, temperatures, times, etc., as used in the specification or claims will be understood to be modified by the term "about". Therefore, unless otherwise indicated, implicitly or explicitly, the numerical parameters displayed are approximate values ​​that may depend on the desired properties sought and / or the detection limits under standard test conditions / methods. When directly and clearly distinguishing between an embodiment and the prior art being discussed, the numbers of the embodiments are not approximate values ​​unless the word "about" is explicitly stated.

[0062] Unless otherwise explained, all technical and scientific terms used herein have the same meaning as those generally understood by those of ordinary skill in the art to which the present disclosure belongs. Although methods and materials similar to or equivalent to those described herein may be employed in the implementation or testing of the present disclosure, suitable methods and materials are described below. Materials, methods, and embodiments are illustrative only and are not intended to be limiting.

[0063] When depicting or describing chemical structures, unless otherwise explicitly stated, it is assumed that all carbons include hydrogen so that each carbon meets the valence of four. For example, in the structure on the left hand side of the schematic diagram below, nine hydrogen atoms are implied. The nine hydrogen atoms are depicted in the right hand structure.

[0064]

[0065] Sometimes specific atoms in a structure are described in literal formulae as having hydrogen or a hydrogen atom, such as -CH2CH2-. One of ordinary skill in the art will appreciate that the above descriptive techniques are common in the chemical arts to provide brevity and simplicity in the description of organic structures.

[0066] If the R group is depicted as "floating" on the ring system, such as in the following group R 1 :

[0067]

[0068] Then, unless otherwise defined, a substituent R (e.g., R 1 ) may be present on any atom of a fused bicyclic ring system, excluding those carrying The atoms of the bonds with the symbols can form a stable structure.

[0069] When the group R is depicted as being present on a ring system containing a saturated carbon, such as in the following formula:

[0070]

[0071] Wherein, in this example, y can be greater than 1, assuming that each replaces the currently depicted, implicit or clearly defined hydrogen on the ring; then, unless otherwise defined, two R can be located on the same carbon. A simple example is when R is a methyl group. The depicted structure can be present in the form of paired dimethyl on the carbon ("annular" carbon) of the depicted ring. In another example, two R on the same carbon, including the same carbon, can be included in the ring, thereby producing a spirocyclic ring ("spirocyclyl" group) structure.

[0072] As used herein, the term "substituted" refers to all subsequent modifications in the term, for example, in the term "substituted aryl C 1-8 In the case of an alkyl group, substitution can occur on the aromatic C 1-8 The alkyl group "C 1-8 on the "alkyl" portion, the "aryl" portion, or both.

[0073] When used to modify a specific group or part, "substituted" means that at least one, possibly two or more hydrogen atoms of a specific group or part are independently replaced with the same or different substituent groups defined below. In a particular embodiment, a group, part or substituent can be substituted or unsubstituted, unless explicitly defined as "unsubstituted" or "substituted". Therefore, any group specified herein can be unsubstituted or substituted, unless the context otherwise indicates or a particular structural formula excludes substitution. In a particular embodiment, a substituent may or may not be explicitly defined as substituted, but is still considered to be optionally substituted. For example, an "aliphatic" or "cyclic" part can be unsubstituted or substituted, but an "unsubstituted aliphatic" or "unsubstituted cyclic" is not substituted.

[0074] Unless otherwise specified, a "substituent" or "substituent group" used to replace one or more hydrogen atoms on a saturated carbon atom in a particular group or moiety may be -R 60 , halogen, =O, -OR 70 , -SR70 , -N(R 80 )2, haloalkyl, perhaloalkyl, -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(NR 70 )R 70 and -NR 70 C(NR 70 )N(R80 )2, where R 60 It is C 1-10 aliphatic, heteroaliphatic, or cycloaliphatic, typically C 1-6 Aliphatic, more typically C 1-6 Alkyl, where R 60 may be optionally substituted; for each occurrence, each R 70 are independently hydrogen or R 60 ; For each existence, each R 80 Independently R 70 Or alternatively, two R 80 The groups, taken together with the nitrogen atom to which they are bound, form a 3- to 7-membered heterocycloaliphatic, which optionally includes 1-4 identical or different additional heteroatoms selected from O, N and S, wherein N optionally has R 70 substituted, such as H or C1-C3 alkyl; and each M + is a counterion with a net single positive charge. For each occurrence, each M + independently are, for example, alkali metal ions such as K + , Na + , Li + ; ammonium ions, such as + N(R 60 )4; protonated amino acid ions, such as lysine ions, or arginine ions; or alkaline earth metal ions, such as [Ca 2+ ] 0.5 , [Mg 2+ ] 0.5 , or [Ba 2+ ] 0.5 (The subscript "0.5" means, for example, that one of the counterions of such a divalent alkaline earth (metal) ion can be the compound of the present invention in ionized form and the other typical counterion such as chloride, or both ionized compounds can serve as the counterions of such a divalent alkaline earth (metal) ion, or doubly ionized compounds can serve as the counterions of such a divalent alkaline earth (metal) ion). As a specific example, -N(R 80 )2 includes -NH2, -NH-alkyl, -NH-pyrrolidin-3-yl, N -pyrrolidyl, N -piperazinyl, 4N -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.

[0075] Unless otherwise specified, the substituent group used to replace the hydrogen atom on the unsaturated carbon atom in the group containing unsaturated carbon is, -R 60 , halogen, -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 ) - 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)OR70 , -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 independent embodiments, the substituent is not -O - M + , -OR 70 , -SR 70 , or -S - M + .

[0076] Unless otherwise specified, the substituent groups used to replace hydrogen atoms on nitrogen atoms in groups containing such nitrogen atoms are, -R 60 , -O - M + , -OR 70 , -SR 70 , -S - M + , -N(R 80 )2, perhaloalkyl, -CN, -NO, -NO2, -S(O)2R 70 , -SO3 - M + , -SO3R 70 , -OS(O)2R 70 ,-OSO3 - M + ,-OSO3R 70 ,-PO3 2- (M + )2, -PO3 2- M 2+ , -P(O)(OR 70 ) - M + , -P(O)(OR 70 )(OR 70 ), -C(O)R 70 , -C(S)R 70 , -C(NR 70 )R 70 , -CO2R 70 , -C(S)OR 70 , -C(O)NR 80 R 80 , -C(NR70 )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 defined previously.

[0077] In one embodiment, a substituted group has at least one substituent, up to the number of substituents possible for the particular moiety, such as 1 substituent, 2 substituents, 3 substituents, or 4 substituents.

[0078] In addition, in the embodiment where the group or part is substituted by a substituted substituent, the nesting of such a substituted substituent is limited to three, thereby preventing the formation of a polymer. Therefore, in a group or part comprising a first group (the first group is a substituent on a second group, the second group itself is a substituent on a third group, and the third group is connected to a parent structure), the first (outermost) group can be replaced only by an unsubstituted substituent. For example, in a group comprising -(aryl-1)-(aryl-2)-(aryl-3), aryl-3 can be replaced only by a substituent that is itself unsubstituted.

[0079] Any group or moiety defined herein may be linked to any other part of the disclosed structure, such as a parent or core structure, as understood by one of ordinary skill in the art, such as by considering valence rules, comparison with exemplary substances, and / or considering functionality, unless the connectivity of the group or moiety to the rest of the structure is explicitly stated or is implied by the context.

[0080] "Acyl" refers to the radical -C(O)R, where R is H, aliphatic, heteroaliphatic, or aromatic (including aryl and heteroaryl). Exemplary acyl moieties include, but are not limited to, -C(O)H, -C(O)alkyl, -C(O)C1-C6alkyl, -C(O)C1-C6haloalkyl, -C(O)cycloalkyl, -C(O)alkenyl, -C(O)cycloalkenyl, -C(O)aryl, -C(O)heteroaryl, or -C(O)heterocyclyl. Specific examples include, -C(O)H, -C(O)Me, -C(O)Et, or -C(O)cyclopropyl.

[0081] "Aliphatic" refers to a radical or moiety that is substantially hydrocarbon-based. Aliphatic radicals or moieties may be non-cyclic, including alkyl, alkenyl, or alkynyl radicals (as well as alkylene, alkenylene, alkynylene radicals), cyclic versions thereof, such as cycloaliphatic radicals or moieties (including cycloalkyl, cycloalkenyl, or cycloalkynyl, and further including straight and branched chain arrangements, as well as all stereo and positional isomers. Unless expressly stated otherwise, aliphatic radicals contain from 1 to 25 carbon atoms (C 1-25 ); for example, for a non-cyclic aliphatic group or moiety, 1 to 15 carbon atoms (C 1-15 ), 1 to 10 carbon atoms (C 1-10 ), 1 to 6 carbon atoms (C 1-6 ), or 1 to 4 carbon atoms (C 1-4 ), or for a cycloaliphatic radical or moiety, 3 to 15 carbon atoms (C 3-15 ), 3 to 10 carbon atoms (C 3-10 ), 3 to 6 carbon atoms (C 3-6 ), or 3 to 4 carbon atoms (C 3-4 ). Aliphatic groups may be substituted or unsubstituted unless specifically referred to as "unsubstituted aliphatic" or "substituted aliphatic". Aliphatic groups may be substituted with one or more substituents (up to two substituents for each methylene carbon in the aliphatic chain, or up to one substituent for each carbon of a -C=C- double bond in the aliphatic chain, or up to one substituent for a terminal methine carbon).

[0082] "Lower aliphatic" refers to a group containing 1 to 10 carbon atoms (C 1-10 ), such as 1 to 6 carbon atoms (C 1-6 ), or 1 to 4 carbon atoms (C 1-4 ) aliphatic groups; or for lower cycloaliphatic groups, 3 to 10 carbon atoms (C 3-10 ), such as 3 to 6 carbon atoms (C 3-6 ).

[0083] "Alkoxy" refers to a 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 or C 3-6 Cycloalkyl groups. Methoxy (-OCH3) and ethoxy (-OCH2CH3) are exemplary alkoxy groups. In substituted alkoxy groups, R is a substituted alkyl or a substituted cycloalkyl, examples of which in the presently disclosed compounds include haloalkoxy groups, such as -OCF2H.

[0084] "Alkoxyalkyl" refers to the group -alkyl-OR, where R is a substituted or unsubstituted alkyl or a substituted or unsubstituted cycloalkyl group; -CH2CH2-O-CH2CH3 is an exemplary alkoxyalkyl group.

[0085] "Alkyl" refers to a group having 1 to at least 25 carbon atoms (C 1-25 ), more typically 1 to 10 carbon atoms (C 1-10 ), such as 1 to 6 carbon atoms (C 1-6 ) saturated aliphatic hydrocarbon groups. The alkyl moiety may be substituted or unsubstituted. The term includes, for example, linear and branched hydrocarbon groups such as methyl (CH3), ethyl (-CH2CH3), n-propyl (-CH2CH2CH3), isopropyl (-CH(CH3)2), n-butyl (-CH2CH2CH2CH3), isobutyl (-CH2CH2(CH3)2), sec-butyl (-CH(CH3)(CH2CH3), tert-butyl (-C(CH3)3), n-pentyl (-CH2CH2CH2CH2CH3), and neopentyl (-CH2C(CH3)3).

[0086] "Amino" refers to the radical -NH2, -NHR, or -NHR, wherein each R is independently selected from H, aliphatic, heteroaliphatic, aromatic, including both aryl and heteroaryl, or heterocycloaliphatic, or two R groups taken together with the nitrogen to which they are attached form a heterocyclic ring. Examples of such heterocyclic rings include those wherein the two R groups taken together with the nitrogen to which they are attached form a heterocyclic ring optionally substituted by one or two heteroatom groups such as -O- or -N(R g )Interrupted-(CH2) 2-5 - those of rings, such as radicals and , where R g YesR 70 , -C(O)R 70 , -C(O)OR 60 or -C(O)N(R 80 )2.

[0087] "Amide" refers to the group -N(R)acyl, where R is hydrogen, heteroaliphatic or aliphatic, such as alkyl, especially C 1-6 alkyl.

[0088] "Aromatic group" means, unless otherwise specified, a cyclic conjugated group or moiety of 5 to 15 ring atoms having a single ring (e.g., phenyl, pyridyl or pyrazolyl) or multiple fused rings, at least one of which is aromatic (e.g., naphthyl, indolyl or pyrazolopyridinyl), i.e., at least one ring, and optionally multiple fused rings, having a continuous 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, However, in some instances, the context or explicit disclosure may indicate that the point of attachment is through the non-aromatic portion of the fused ring system. For example An aromatic group or moiety may include only carbon atoms in the ring, as in an aryl group or moiety, or it may include one or more ring carbon atoms and one or more ring heteroatoms containing a lone pair of electrons (e.g., S, O, N, P, or Si), as in a heteroaryl group or moiety. Unless otherwise stated, an aromatic group may be substituted or unsubstituted.

[0089] "Aryl" means, unless otherwise specified, an aromatic carbocyclic group of 6-15 carbon atoms having a single ring (e.g., phenyl) or multiple fused rings in which at least one ring is aromatic (e.g., 1,2,3,4-tetrahydroquinoline, benzodioxole, etc.). If any aromatic ring portion contains heteroatoms, the group is a heteroaryl group, not an aryl group. An aryl group can be, for example, monocyclic, bicyclic, tricyclic or tetracyclic. Unless otherwise stated, an aryl group can be substituted or unsubstituted.

[0090] "Araliphatic" refers to an aryl group attached to the parent moiety through an aliphatic portion. Araliphatic includes aralkyl or arylalkyl groups such as benzyl and phenethyl.

[0091] "Carboxyl" refers to -CO2H.

[0092] "Carboxamide" refers to a -C(O)amino group.

[0093] "Carboxyl ester" or "carboxy ester" refers to the group -C(O)OR, where R is aliphatic, heteroaliphatic, or aromatic (including aryl and heteroaryl).

[0094] "Carboxylate" refers to -C(O)O- or a salt thereof.

[0095] "Cyano" refers to the radical -CN.

[0096] "Cycloaliphatic group" refers to a cyclic aliphatic group having a single ring (e.g., cyclohexyl), or multiple rings, such as in a fused, bridged, or spiro ring system, wherein at least one of the rings or multiple rings in the system is aliphatic. Typically, the point of attachment to the parent structure is through the aliphatic portion of the polycyclic system. Cycloaliphatics include saturated and unsaturated systems, including cycloalkyl, cycloalkenyl, and cycloalkynyl. Cycloaliphatic groups may contain 3 to 25 carbon atoms; for example, 3 to 15, 3 to 10, or 3 to 6 carbon atoms. Unless otherwise stated, cycloaliphatic groups may be substituted or unsubstituted. Exemplary cycloaliphatic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, or cyclohexenyl.

[0097] "Halo", "halide" or "halogen" refers to fluoro, chloro, bromo or iodo.

[0098] "Haloalkyl" refers to an alkyl moiety substituted with one or more halogens. Exemplary haloalkyl moieties include -CH2F, -CHF2 and -CF3.

[0099] A "heteroaliphatic group" refers to an aliphatic compound or group having at least one heteroatom and at least one carbon atom, i.e., an aliphatic compound or group containing at least two carbon atoms in which at least one carbon atom has been replaced by an atom having at least one lone pair of electrons, typically nitrogen, oxygen, phosphorus, silicon or sulfur). The heteroaliphatic compound or group may be substituted or unsubstituted, branched or unbranched, chiral or achiral, and / or acyclic or cyclic, such as a heterocycloaliphatic group.

[0100] "Heteroaryl" refers to an aromatic group or moiety, unless otherwise specified, having 5-15 ring atoms, including at least one carbon atom and at least one heteroatom, such as N, S, O, P, or Si. Heteroaryl groups or moieties can include a single ring (e.g., pyridyl, pyrimidinyl, or pyrazolyl) or multiple fused rings (e.g., indolyl, benzopyrazolyl, or pyrazolopyridinyl). Heteroaryl groups or moieties can be, for example, monocyclic, bicyclic, tricyclic, or tetracyclic. Unless otherwise stated, heteroaryl groups or moieties can be substituted or unsubstituted.

[0101] "Heterocyclyl", "heterocyclic" and "heterocycle" refer to aromatic and non-aromatic ring systems, and more specifically to stable 3 to 15 membered ring moieties containing at least one carbon atom and typically multiple carbon atoms and at least one (e.g., 1 to 5 heteroatoms). The heteroatom may be a nitrogen, phosphorus, oxygen, silicon or sulfur atom. The heterocyclyl moiety may be a monocyclic moiety, or may include multiple rings, such as in a bicyclic or tricyclic ring system, provided that at least one of the multiple rings contains a heteroatom. Such polycyclic moieties may include fused or bridged ring systems as well as spiro ring systems; and any nitrogen, phosphorus, carbon, silicon or sulfur atom in the heterocyclyl moiety may be optionally oxidized to various oxidation states. For convenience, nitrogen, particularly, but not exclusively, those defined as cyclic aromatic nitrogen, are meant to include their corresponding N-oxide forms, although not explicitly defined as such in a particular instance. Thus, for example, for a compound having a pyridyl ring, as another compound of the invention, the corresponding pyridyl-N-oxide is included unless explicitly excluded or excluded by the context. In addition, the cyclic nitrogen atom may be optionally quaternized. The heterocycle includes a heteroaryl moiety and a heteroalicyclic or heterocycloaliphatic moiety, which is a partially or completely saturated heterocyclic ring. Examples of heterocyclic radicals include, but are not limited to, azetidinyl, oxetanyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazolyl, cinnolinyl, dioxolyl, indolizinyl, naphthyridinyl, perhydroazacycloheptatrienyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolyl, isoquinolyl, tetrazolyl, tetrahydroisoquinoline pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolidinyl, oxazolidinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, isoxadiazolyl,

[00136] The invention also includes but is not limited to oxadiazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolyl, octahydroindolyl, octahydroisoindolyl, quinolinyl, isoquinolinyl, decahydroisoquinolinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furanyl, diazabicycloheptane, diazapane, diazepine, tetrahydrofuranyl, tetrahydropyranyl, thienyl, benzothieliyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphospholyl, and oxadiazolyl.

[0102] "Hydroxy" refers to the group -OH.

[0103] "Nitro" refers to the radical -NO2.

[0104] "Phosphate" refers to the group -OP(O)(OR')2, wherein 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 -O - M + , where M + is a counter ion with a single positive charge. + Can be an alkali ion such as K + , Na + , Li + ; ammonium ions, such as + N(R")4, wherein R" is H, aliphatic, heteroaliphatic, or aromatic (including both aryl and heteroaryl); or an alkaline earth ion such as [Ca 2+ ] 0.5 , [Mg 2+ ] 0.5 , or [Ba 2+ ] 0.5 Phosphonyloxyalkyl refers to the group -alkyl-phosphate, such as, for example, -CH2OP(O)(OH)2, or a salt thereof, such as -CH2OP(O)(O-Na+)2, and (((dialkoxyphosphoryl)oxy)alkyl) refers to the dialkyl ester of the phosphonyloxyalkyl group, such as, for example, -CH2OP(O)(O-tert-butyl)2.

[0105] "Phosphonate" refers to the group -P(O)(OR')2, wherein 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 + is a counter ion with a single positive charge. + is a positively charged counterion and may be, for example, an alkali metal ion such as K + , Na + , Li + ; ammonium ions, such as + N(R")4, wherein R" is H, aliphatic, heteroaliphatic, or aromatic (including both aryl and heteroaryl); or an alkaline earth metal ion, such as [Ca 2+ ] 0.5 , [Mg 2+ ] 0.5 , or [Ba 2+ ]0.5 Phosphonoalkyl refers to the group -alkyl-phosphonate, such as, for example, -CH2P(O)(OH)2, or -CH2P(O)(O-Na+)2, and ((dialkoxyphosphoryl)alkyl) refers to the dialkyl ester of phosphonoalkyl, such as, for example, -CH2P(O)(O-tert-butyl)2.

[0106] "Patient" or "subject" may generally refer to any organism, but more typically refers to mammals and other animals, especially humans. The disclosed methods are therefore applicable to both human treatment and veterinary applications.

[0107] "Pharmaceutically acceptable excipient" refers to a substance other than the active ingredient that is included in a composition containing an active ingredient. As used herein, an excipient may be incorporated into the particles of the pharmaceutical composition, or it may be physically mixed with the particles of the pharmaceutical composition. An excipient may be used, for example, to dilute the active agent and / or to change the properties of the pharmaceutical composition. An excipient may include, but is not limited to, an anti-adhesive, a binder, a coating, an enteric coating, a disintegrant, a flavoring agent, a sweetener, a colorant, a lubricant, a glidant, an adsorbent, a preservative, a carrier or a vehicle. An excipient may be starch and modified starches, cellulose and cellulose derivatives, sugars and their derivatives, such as disaccharides, polysaccharides and sugar alcohols, proteins, synthetic polymers, cross-linked polymers, antioxidants, amino acids or preservatives. Exemplary excipients include, but are not limited to, magnesium stearate, stearic acid, vegetable stearin, sucrose, lactose, starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, xylitol, sorbitol, maltitol, gelatin, polyvinylpyrrolidone (PVP), polyethylene glycol (PEG), tocopheryl polyethylene glycol 1000 succinate (also known as vitamin E TPGS, or TPGS), carboxymethylcellulose, dipalmitoylphosphatidylcholine (DPPC), vitamin A, vitamin E, vitamin C, retinyl palmitate, selenium, cysteine, methionine, citric acid, sodium citrate, methylparaben, propylparaben, sugar, silicon dioxide, talc, magnesium carbonate, sodium starch glycolate, tartrate, aspartame, benzalkonium chloride, sesame oil, propyl gallate, sodium metabisulfite or lanolin.

[0108] An "adjuvant" is a component that modifies the effect of other agents (typically active ingredients). Adjuvants are typically pharmacological and / or immunological agents. Adjuvants can modify the effect of active ingredients by increasing the immune response. Adjuvants can also act as stabilizers for formulations. Exemplary adjuvants include, but are not limited to, aluminum hydroxide, alum, aluminum phosphate, inactivated bacteria, squalene, detergents, cytokines, paraffin oil, and combination adjuvants, such as Freund's complete adjuvant or Freund's incomplete adjuvant.

[0109] "Pharmaceutically acceptable carrier" refers to an excipient that serves as a carrier or vehicle, such as a suspending aid, a solubilizing aid, or an aerosolizing aid. Remington: The Science and Practice of Pharmacy , The University of the Sciences in Philadelphia, Editor, Lippincott, Williams, & Wilkins, Philadelphia, PA, 21st edition (2005), incorporated herein by reference, describes exemplary compositions and formulations suitable for the pharmaceutical delivery of one or more therapeutic compositions and additional pharmaceutical agents.

[0110] Typically, the nature of the carrier will depend on the specific mode of administration adopted. For example, parenteral preparations typically include injectable fluids, which include pharmaceutically and physiologically acceptable fluids, such as water, saline, balanced salt solutions, dextrose aqueous solutions, glycerol, etc., as vehicles. In some instances, pharmaceutically acceptable carriers can be sterile to be suitable for administering to a subject (e.g., by parenteral, intramuscular or subcutaneous injection). In addition to biologically neutral carriers, the pharmaceutical composition to be administered may contain a small amount of non-toxic auxiliary substances, such as wetting agents or emulsifiers, preservatives and pH buffers, such as sodium acetate or sorbitan monolaurate.

[0111] "Pharmaceutically acceptable salts" refers to pharmaceutically acceptable salts of compounds derived from various organic and inorganic counterions as would be known to one of ordinary skill in the art, and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, methanesulfonate, acetate, maleate, oxalate, and the like. "Pharmaceutically acceptable acid addition salts" are a subset of "pharmaceutically acceptable salts" that are formed with acids while retaining the biological effectiveness of the free bases. In particular, the disclosed compounds form salts with various pharmaceutically acceptable acids, including, without limitation, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, and organic acids such as amino acids, formic acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, carotene acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, benzenesulfonic acid, hydroxyethanesulfonic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, 1-hydroxy-2-naphthoic acid (xinafoic acid), and the like. "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, aluminum salts, and the like. Exemplary salts are ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, tris(hydroxymethyl)aminomethane (Tris), ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins, and the like. Exemplary organic bases are isopropylamine, diethylamine, tris(hydroxymethyl)aminomethane (Tris), ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. (See, e.g., SM Berge et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977; 66: 1-19, which is incorporated herein by reference.) In particularly disclosed embodiments, the compound can be a formate salt, a trifluoroacetate salt, a hydrochloride salt, or a sodium salt.

[0112] An "effective amount" with respect to a compound or pharmaceutical composition refers to an amount of the compound or pharmaceutical composition sufficient to obtain a specific desired result, such as inhibition of a protein or enzyme. In particular embodiments, an "effective amount" is an amount sufficient to inhibit RIP1; to induce a desired biological or medical response in a tissue, system, subject or patient; to treat a specific disorder or disease; to ameliorate or eradicate one or more of its symptoms; and / or to prevent the occurrence of a disease or disorder. The amount of a compound that constitutes an "effective amount" may vary depending on the compound, the desired result, the disease state and its severity, the size, age and sex of the patient to be treated, etc., as will be understood by those of ordinary skill in the art.

[0113] "Prodrug" refers to a compound that is transformed in vivo to produce a biologically active compound, or a compound that is more biologically active than the parent compound. The conversion in vivo may occur, for example, by hydrolysis or enzymatic conversion. Common examples of prodrug moieties include, but are not limited to, ester and amide forms of compounds having an active form with a carboxylic acid moiety. Examples of pharmaceutically acceptable esters of the compounds of the invention include, but are not limited to, esters of phosphate groups and carboxylic acids, such as aliphatic esters, particularly alkyl esters (e.g., C 1-6 Other prodrug moieties include phosphate esters, such as -CH2-OP(O)(OR')2 or salts thereof, wherein R' is H or C 1-6 Alkyl. Acceptable esters also include cycloalkyl esters and arylalkyl esters such as, but not limited to benzyl. Examples of pharmaceutically acceptable amides of the compounds of the present invention include, but are not limited to, primary amides and secondary alkyl amides and tertiary alkyl amides (e.g., having about 1 to about 6 carbon atoms). Amides and esters of the disclosed exemplary embodiments of the compounds of the present invention can be prepared according to conventional methods. An in-depth discussion of prodrugs is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Volume 14 of the ACSSymposium Series, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference for all purposes.

[0114] "Solvate" refers to a complex formed by the combination of solvent molecules with molecules or ions of a solute. The solvent may be an organic solvent, an inorganic solvent, or a mixture of the two. Exemplary solvents include, but are not limited to, alcohols such as methanol, ethanol, propanol; amides such as N,N-dialiphatic amides such as N,N-dimethylformamide; tetrahydrofuran; alkyl sulfoxides such as dimethyl sulfoxide; water; and combinations thereof. The compounds described herein may exist in unsolvated and solvated forms when combined with a solvent, pharmaceutically acceptable or not, such as water, ethanol, and the like. Solvated forms of the compounds disclosed herein are within the scope of the embodiments disclosed herein.

[0115] "Sulfonamide" refers to the radical or moiety -SO2amino, or -N(R)sulfonyl, where R is H, aliphatic, heteroaliphatic, or aromatic (including both aryl and heteroaryl).

[0116] "Sulfanyl" refers to the radical or -SH, -S-aliphatic, -S-heteroaliphatic, -S-aromatic, (including both -S-aryl and -S-heteroaryl).

[0117] "Sulfinyl" refers to the radical or moiety -S(O)H, -S(O)aliphatic, -S(O)heteroaliphatic, or -S(O)aromatic (including both -S(O)aryl and -S(O)heteroaryl).

[0118] "Sulfonyl" refers to the radical: -SO2H, -SO2aliphatic, -SO2heteroaliphatic, -SO2aromatic (including both -SO2aryl and -SO2heteroaryl).

[0119] As used herein, "treat" or "treatment" refers to treating a disease or condition of interest in a patient or subject, particularly a human having the disease or condition of interest, and includes, for example, and without limitation:

[0120] (i) preventing the occurrence of the disease or condition in a patient or subject, in particular, when the patient or subject is susceptible to the condition but has not yet been diagnosed as having it;

[0121] (ii) inhibiting the disease or condition, such as arresting or slowing its progression;

[0122] (iii) alleviate the disease or condition, such as causing a decrease in symptoms or regression of the disease or condition or its symptoms; or

[0123] (iv) stabilizing the disease or condition.

[0124] As used herein, the terms "disease" and "condition" may be used interchangeably, or may be distinct, wherein a particular disease or condition may not have a known etiology (such that a cause has not been determined), and therefore it is not yet considered a disease but merely as an undesirable condition or syndrome in which a more or less specific set of symptoms has been recognized by a clinician.

[0125] The above definitions and the following formulae are not intended to include impermissible substitution patterns (eg, a methyl group substituted with 5 fluoro groups). One of ordinary skill in the art would readily recognize such impermissible substitution patterns.

[0126] It will be understood by those skilled in the art that compounds may exhibit tautomerism, structural isomerism, geometric isomerism, and / or optical isomerism. For example, certain disclosed compounds may include one or more chiral centers and / or double bonds and may therefore exist in the form of stereoisomers, such as double bond isomers (i.e., geometric isomers), 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. Since the various compound names, chemical formulas, and compound structures in the specification and claims may represent only one of the possible tautomeric, structural, optical, or geometric isomeric forms, it will be understood by those skilled in the art that the disclosed compounds include any tautomeric, structural, optical, and / or geometric isomeric forms of the compounds described herein, as well as mixtures of these various different isomeric forms. Mixtures of different isomeric forms, including mixtures of enantiomers and / or stereoisomers, can be separated using techniques known to those of ordinary skill in the art, particularly with the benefit of this disclosure, to provide each individual enantiomer and / or stereoisomer. In cases of limited rotation, for example around an amide bond or between two directly connected rings such as a pyridine ring, biphenyl, etc., atropisomers are also possible and are also explicitly included in the compounds of the invention.

[0127] In any embodiment, any or all hydrogens present in the compound, or in a specific group or moiety within the compound, may be replaced by deuterium or tritium. Thus, the recitation of alkyl includes deuterated alkyls in which one to the maximum number of hydrogens present may be replaced by deuterium. For example, ethyl may be C2H5 or C2H5 in which 1 to 5 hydrogens are replaced by deuterium, such as in C2D x H 5-x middle.

[0128] II. RIP1-active compounds and pharmaceutical compositions comprising RIP1-active compounds

[0129] A. Compounds

[0130] Disclosed herein are compounds and pharmaceutical compositions comprising such compounds that can be used to inhibit RIP1 and / or to treat diseases and / or conditions associated with RIP1. In some embodiments, the compounds are selective kinase inhibitors. For example, exemplary compounds can selectively inhibit RIP1 relative to RIP2, RIP3, or both RIP2 and RIP3.

[0131] In some embodiments, the compounds of the present disclosure have a structure according to Formula I

[0132]

[0133] Or a pharmaceutically acceptable salt thereof. Those of ordinary skill in the art will appreciate that compounds within the scope of Formula I also include stereoisomers, N-oxides, tautomers, hydrates, solvates, isotopes, and / or prodrugs thereof, unless otherwise specified. With respect to Formula I, Ring B is a heteroaryl, such as a five-membered or six-membered heteroaryl, and may contain 1, 2 or 3 heteroatoms independently selected from N or O. In some embodiments, Ring B is a five-membered or six-membered heteroaryl, wherein the heteroaryl has one, two or three ring nitrogen atoms and the remaining ring atoms are independently selected from carbon or oxygen. In certain embodiments, Ring B is pyrazolyl, pyridyl, triazolyl or oxadiazolyl.

[0134] Each R 1 is independently a heterocyclic group, optionally substituted by at least one, for example 1, 2 or 3 R 6 Substituted, where each R 6 Independently for R c In some embodiments, R 6 C 1-6 Alkyl or C optionally substituted by OH 2-10 In certain embodiments, R 6 Methyl or .

[0135] R 2 For R a .

[0136] R 3 For R a or R 3 Together with the -NC(O) moiety to which it is attached and two ring atoms from ring B, a five-membered or six-membered heterocyclic group fused to ring B can be formed.

[0137] If present, each R 4 Independently for R e .

[0138] L is a heteroatom or R a , the condition is Ra Not H or D.

[0139] Y is O or CH2.

[0140] Z is C 1-10 an aliphatic group or an aromatic group.

[0141] m is 1, 2, 3 or 4, and n is 0, 1 or 2.

[0142] R a Each occurrence is independently C 1-10 Aliphatic groups (such as C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 3-6 Cycloalkyl), C 1-10 Halogenated aliphatic group, C 5-10 Aromatic groups, C 3-6 Heterocyclic group or C 3-10 spiroheterocyclic group; or H or D, except where L is R a outside the implementation plan.

[0143] R b Each occurrence is independently -OH, -SH, -OR c 、-SR c 、-NR d R d 、-Si(R a )3, -C(O)OH, -C(O)OR c 、-C(O)NR d R d 、-OC(O)NR d R d 、-OC(O)C 1-10 Alkyl, which is replaced by one or two NR d R d , carboxyl, or a combination thereof, and is optionally further substituted with an aromatic moiety, -SH, -O-acyl, or -C(O)NH2.

[0144] R c Each occurrence is independently C 1-10 Alkyl, which can be replaced by 1, 2 or 3 R e Replacement, C 2-10 Alkenyl, which can be substituted by 1, 2 or 3 R e Replacement, C 2-10 Alkynyl, which can be substituted by 1, 2 or 3 R e Replacement, C 3-6 Cycloalkyl, which can be substituted by 1, 2 or 3 R e Substitution or C 5-10Aromatic groups, which can be substituted by 1, 2 or 3 R e replace.

[0145] R d Each occurrence is independently H; C 1-6 Alkyl, which can be replaced by 1, 2 or 3 R e or C 3-9 Heterocyclic substitution; C 3-6 Cycloalkyl, which can be substituted by 1, 2 or 3 R e Replace; C 3-6 A heterocyclic group, which can be replaced by 1, 2 or 3 R e Replace; C 5-10 Aryl, which can be replaced by 1, 2 or 3 R b Replace; C 5-10 Heteroaryl, which can be replaced by 1, 2 or 3 R e Replace; or two R d The groups together with the nitrogen to which they are bonded provide C 3-9 A heterocyclic group, which can be replaced by one or more R e Replaced); or C 5-10 Heteroaryl, which can be replaced by one or more R e replace.

[0146] R e Each occurrence is independently 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 .

[0147] And R f Each occurrence is independently -alkyl-phosphate, R a , R b or R e , or two R f The groups, together with the carbon atom to which they are bonded, provide C 2-6 Alkenyl group; C 3-6 Cycloalkyl groups, which can be replaced by one or more R e Replace; or C 3-10 A heterocyclic group, which can be replaced by one or more R e or acyl substitution.

[0148] In a separate embodiment, the compound is not any of the following:

[0149] (S)-N-(7-(4-(chloromethyl)-4-(hydroxymethyl)piperidin-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide;

[0150] (S)-1-(4-fluorobenzyl)-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0151] (S)-5-benzyl-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)isoxazole-3-carboxamide;

[0152] (S)-1-(4-fluorobenzyl)-N-(5-methyl-4-oxo-7-(2-oxa-7-azaspiro[3.5]nonan-7-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0153] (S)-5-Benzyl-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0154] N-((S)-7-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-5-benzylisoxazole-3-carboxamide;

[0155] N-((S)-7-((1S,4S)-2-oxa-5-azabicyclo[2.2.1]heptane-5-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide;

[0156] (S)-1-(4-fluorobenzyl)-N-(5-methyl-7-(1,4-oxazepan-4-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepan-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0157] (S)-5-benzyl-N-(5-methyl-7-(1,4-oxazepan-4-yl)-4-oxo-2,3,4,5 tetrahydrobenzo[b][1,4]oxazepan-3-yl)isoxazole-3-carboxamide;

[0158] (S)-5-(4-fluorobenzyl)-N-(5-methyl-7-(1,4-oxazepan-4-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepan-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0159] (S)-5-(4-fluorobenzyl)-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0160] (S)-5-benzyl-N-(5-methyl-7-(1,4-oxazepan-4-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepan-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0161] N-((3S)-7-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-5-benzylisoxazole-3-carboxamide;

[0162] (S)-N-(7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-5-benzylisoxazole-3-carboxamide;

[0163] (S)-5-Benzyl-N-(5-methyl-4-oxo-8-(3-oxa-9-azaspiro[5.5]undec-9-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0164] (S)-N-(7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-5-benzyl-1H-1,2,4-triazole-3-carboxamide;

[0165] (S)-5-benzyl-N-(7-((3-chloropropyl)amino)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0166] (S)-5-Benzyl-N-(5-methyl-4-oxo-7-(1-oxa-8-azaspiro[4.5]decan-8-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0167] (S)-5-(4-fluorobenzyl)-N-(5-methyl-4-oxo-7-(1-oxa-8-azaspiro[4.5]decan-8-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0168] (S)-N-(7-(azetidin-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-5-benzyl-1H-1,2,4-triazole-3-carboxamide;

[0169] (S)-5-Benzyl-N-(5-methyl-4-oxo-7-(2-oxa-8-azaspiro[4.5]decan-8-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0170] (S)-5-Benzyl-N-(5-methyl-4-oxo-7-(8-oxa-2-azaspiro[4.5]decan-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0171] (S)-5-Benzyl-N-(7-(2-benzyl-1-oxo-2,8-diazaspiro[4.5]decan-8-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0172] (S)-5-Benzyl-N-(7-(2-benzyl-1-oxo-2,9-diazaspiro[5.5]undec-9-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0173] (S)-5-Benzyl-N-(5-methyl-4-oxo-7-(3-oxa-9-azaspiro[5.5]undec-9-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0174] (S)-5-benzyl-N-(7-(3,3-difluoroazetidin-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide; and

[0175] (S)-5-Benzyl-N-(7-(3-fluoroazetidin-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-1,2,4-triazole-3-carboxamide.

[0176] In another independent embodiment, the compound is not any of the following:

[0177] I-1: (S)-1-benzyl-4-fluoro-N-(5-methyl-4-oxo-7-(8-oxa-2-azaspiro[4.5]decane-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-3-carboxamide;

[0178] I-2: (S)-1-benzyl-4-fluoro-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-3-carboxamide;

[0179] I-3: (S)-4-(4-fluorobenzyl)-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide;

[0180]

[0181] .

[0182] In certain embodiments of Formula I, Ring B is pyridyl, pyrazolyl, triazolyl or oxadiazolyl; L is a heteroatom or C 1-10 aliphatic group; Y is O or CH2; Z is an aromatic group; each R 1 is an optionally substituted heterocyclic group; R 2 H or C1-10 Aliphatic group; R 3 H, or R 3 Together with the -NC(O) moiety to which it is attached and the two ring atoms from ring B, it forms a five-membered or six-membered non-aromatic heterocyclic group fused to ring B; each R 4 are independently halogen; m is 1, 2, 3 or 4; and n is 0, 1 or 2.

[0183] In some embodiments, each R 1 are independently optionally R 6 In some embodiments, at least one R 1 It can be an 8- to 12-membered spiroheterocyclyl. In other embodiments, at least one R 1 is a monocyclic or bridged heterocyclic group, such as a monocyclic or bridged non-aromatic heterocyclic group. 1 is an optionally substituted heteroaryl, but in other embodiments, R 1 is an optionally substituted non-aromatic heterocyclic group.

[0184] In some embodiments, m is 1, 2, or 3, and can be 1 or 2, and in certain embodiments, m is 1.

[0185] R 2 Can be H or C 1-6 Alkyl, such as methyl or CD3.

[0186] R 3 It can be H. Or, R 3 Together with the -NC(O)- moiety to which it is attached and the two ring atoms from ring B, a five-membered or six-membered heterocyclic group fused to ring B can be formed.

[0187] Each R 4 Can be independently halogen, such as F, Br, Cl or I. In some embodiments, each R 4 are independently chlorine or fluorine.

[0188] In certain embodiments, n is 0, and in other specific embodiments, n is 1.

[0189] In addition, with respect to Formula I, L is a heteroatom or R a , the condition is R a Not H or D. L can be oxygen, C 1-10 Alkyl or C 3-10 Cycloalkyl, such as oxygen, C 1-6 Alkyl or C 3-6 Cycloalkyl, more specifically, methylene (-CH2-), cyclopropyl or O. Z is heteroaryl or aryl, and may be substituted. In some embodiments, Z is heteroaryl, such as pyridyl, or Z is , where each R 5 Independently for R e , and p is 0, 1, 2, 3, 4 or 5. In such embodiments, each R 5 can be independently halogen or C 1-6 Alkyl, such as methyl or fluorine. In some embodiments, p is 1 or 2, but in other embodiments, p is 0. And in certain embodiments, the -LZ moiety is phenoxy, 4-fluorophenoxy, 3-fluorophenoxy, 2-fluorophenoxy, 2,4-difluorophenoxy, 2,6-difluorophenoxy, 4-fluorobenzyl, 2,6-dimethylphenoxy, cyclobutyloxy, cyclopentyloxy, methoxy, 4-methylphenoxy, benzyl, 1-phenylcyclopropyl, (6-methylpyridin-2-yl)methyl or (6-fluoropyridin-2-yl)methyl. In specific embodiments, the -LZ moiety is phenoxy, benzyl, 4-fluorobenzyl or 1-phenylcyclopropyl.

[0190] In some embodiments of Formula I, the compound may have a structure according to Formula I-1 or I-2:

[0191] .

[0192] In some embodiments, the compound may have a structure according to one or more of the following formulas

[0193]

[0194]

[0195] .

[0196] Regarding Formulas I-1 to I-20, Ring B, L, Y, Z, R 1 , R 2 , R 3 , R 4 , m and n, if present, are as defined herein for Formula I. and wherein R 3 In embodiments that form, together with the NC(O) moiety and the two ring atoms from ring B, a heterocyclic group fused to ring B, the compound may have a structure according to one of the following formulae:

[0197]

[0198] .

[0199] And with respect to formulas I-21 to I-23, L, Y, Z, R 1 , R 2 , R 4As defined herein for Formula I, and n is 0 or 1. In some embodiments of Formulas 1-21 to 1-23, r is 0, but in other embodiments of Formulas 1-21 to 1-23, r is 1.

[0200] In some embodiments of formulae 1-1 to 1-23, Y is oxygen. In other embodiments of formulae 1-1 to 1-23, Y is -CH2-.

[0201] In any of the above embodiments regarding Formula I and / or Formulas I-1 to I-23, R 1 Can be selected from any of the following:

[0202]

[0203] .

[0204] In some embodiments, the compounds of the present disclosure can have a structure satisfying Formula IA

[0205]

[0206] Or a pharmaceutically acceptable salt, stereoisomer, N-oxide, tautomer, hydrate, solvate, isotope or prodrug thereof. One of ordinary skill in the art will understand that the disclosed formulae include within their scope all stereoisomers, N-oxides, tautomers, hydrates, solvates, isotopes and / or prodrugs of compounds that otherwise have the structural features required by such formulae.

[0207] About Formula IA:

[0208] Ring B is a five-membered or six-membered heteroaryl group;

[0209] L is a heteroatom or R a , the condition is R a Not H or D;

[0210] Y is O or CH2;

[0211] R 1 is an optionally substituted heterocyclyl as defined above for formula I;

[0212] R 2 and R 3 Independently for R a ;

[0213] R 4 and R 5 Independently for R e ;

[0214] R a Each occurrence is independently C1-10 Aliphatic groups (such as C 1-10 Alkyl, C 2-10 Alkenyl, C 2-10 Alkynyl or C 3-6 Cycloalkyl), C 1-10 Halogenated aliphatic group, C 5-10 Aromatic groups, C 3-6 Heterocyclic group or C 3-10 spiroheterocyclic group; or H or D, except where L is R a In addition to the implementation plan;

[0215] R b Each occurrence is independently -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 ;

[0216] R c Each occurrence is independently C 1-10 Alkyl (which can be 1, 2 or 3 R e Replace), C 2-10 Alkenyl (which can be replaced by 1, 2 or 3 R e Replace), C 2-10 Alkynyl (which can be substituted by 1, 2 or 3 R e Replace), C 3-6 Cycloalkyl (which can be 1, 2 or 3 R e Replace) or C 5-10 Aromatic groups (which can be substituted by 1, 2 or 3 R e replace);

[0217] R d Each occurrence is independently H; C 1-6 Alkyl (which can be 1, 2 or 3 R e Replacement); C 3-6 Cycloalkyl (which can be 1, 2 or 3 R e Replacement); C 3-6 Heterocyclic groups (which can be replaced by 1, 2 or 3 R e Replacement); C 5-10 Aryl (which can be substituted by 1, 2 or 3 R b Replacement); C 5-10 Heteroaryl (which can be replaced by 1, 2 or 3 R e or two R dThe groups together with the nitrogen to which they are bonded provide C 3-9 Heterocyclic groups (which can be replaced by one or more R e Replaced); or C 5-10 Heteroaryl (which can be replaced by one or more R e replace);

[0218] R e Each occurrence is independently 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

[0219] R f Each occurrence is independently R a , R b or R e or two R f The groups, together with the carbon atom to which they are bonded, provide C 3-6 Cycloalkyl groups (and in some embodiments, the C 3-6 The cycloalkyl group is replaced by one or more R e Replace), or C 3-10 Heterocyclic groups (and in some embodiments, the C 3-10 The heterocyclic group is replaced by one or more R e replace);

[0220] m is 1 to 4, for example 1, 2, 3 or 4, in a particular embodiment 1 or 2;

[0221] n is 0, 1, or 2; and

[0222] p is 0, 1, 2, 3, 4 or 5.

[0223] In certain embodiments of Formula I or IA, a five-membered heteroaryl group can have a The structure of wherein at least one W is nitrogen, and each remaining W is independently selected from carbon, CH, oxygen, sulfur, nitrogen or NH. In some embodiments, the five-membered heteroaryl group is diazole, triazole, oxadiazole or oxazole. Exemplary triazoles include any of the following:

[0224]

[0225] .

[0226] Exemplary oxadiazoles are selected from any one of the following:

[0227] .

[0228] Exemplary oxazoles are selected from any one of the following:

[0229] .

[0230] Exemplary oxadiazoles are selected from any one of the following:

[0231] .

[0232] In certain embodiments of Formula I or IA, L is oxygen or R a , where R a C 1- C4 alkyl, such as -CH2-, -CH2CH2-, -CH2CH2CH2- or -CH2CH2CH2CH2-, or C 3-6 Cycloalkyl, such as cyclopropyl, in some embodiments, L is -CH2-, or oxygen.

[0233] In some embodiments, R 2 and R 3 Each of the R a , where R a Each occurrence is independently hydrogen, methyl, ethyl, propyl, butyl, pentyl or hexyl, or a deuterated analog thereof. In a specific embodiment, R 2 and R 3 Each of the R a , which is independently hydrogen, methyl or ethyl at each occurrence or a deuterated analog thereof. In an exemplary embodiment, R 2 Methyl or CD3 and R 3 For hydrogen.

[0234] In some embodiments, each R 4 Independently and / or each R 5 Independently for R e , where R e is alkyl, alkenyl, alkynyl, chlorine, bromine, iodine or fluorine. In a specific embodiment, each R 4 and / or each R 5 Independently for R e , where R e is a lower aliphatic group (such as methyl), fluorine or chlorine.

[0235] In some embodiments, m is 1; n is 0 or 1; and p is 0, 1 or 2. In specific embodiments, m is 1, n is 0 and p is 0, 1 or 2.

[0236] The compound of formula I or IA can also have a structure satisfying any one or more of formula II and IIA-IIF

[0237]

[0238]

[0239]

[0240]

[0241]

[0242]

[0243]

[0244] Regarding Formula II and IIA-IIF, Ring B, LY, R 1 and R 5 Each of, if present, is as described above for Formula I and / or IA, and R 2 is methyl or CD3. In certain embodiments, there are 0, 1 or 2 R 5 Group. R 5 Can be R e , where R e In other specific embodiments, R 5 With respect to formulae IIA-IIF, each W is independently nitrogen or oxygen, and particularly nitrogen.

[0245] Certain disclosed embodiments have Formula IIG.

[0246]

[0247] About Formula IIF, R 1 , R 2 , R 3 and R 5 As described above. In certain embodiments, there is no R 5 or halogen, for example fluorine or chlorine, in particular fluorine, or C 1-6 Alkyl, such as methyl. Certain disclosed exemplary compounds within the scope of one or more of Formulas I, I-1 to 1-23, IA, II, and IIA-IIG include:

[0248]

[0249]

[0250] .

[0251] Exemplary compounds within the scope of one or more of Formulas I, I-1 to I-23, IA, II, and IIA-IIG include:

[0252] I-1: (S)-1-benzyl-4-fluoro-N-(5-methyl-4-oxo-7-(8-oxa-2-azaspiro[4.5]decane-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-3-carboxamide;

[0253] I-2: (S)-1-benzyl-4-fluoro-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-3-carboxamide;

[0254] I-3: (S)-4-(4-fluorobenzyl)-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide;

[0255] I-4: (S)-N-(5-methyl-4-oxo-8-(3-oxa-9-azaspiro[5.5]undec-9-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-phenoxypyridine-2-carboxamide;

[0256] I-5: (S)-N-(5-methyl-7-(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-phenoxypyridine-2-carboxamide;

[0257] I-6: (S)-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-phenoxypyridine-2-carboxamide;

[0258] I-7: (S)-3-(2-benzyl-3-chloro-6-oxo-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-5-methyl-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one;

[0259] I-8: (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one;

[0260] I-9: (S)-N-(5-methyl-4-oxo-7-(8-oxa-2-azaspiro[4.5]decane-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-phenoxypyridine-2-carboxamide;

[0261] I-10: (S)-N-(8-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-4-phenoxypyridine-2-carboxamide;

[0262] I-11: 5-benzyl-N-(2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0263] I-12: N-(8-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-5-benzyl-1H-1,2,4-triazole-3-carboxamide;

[0264] I-13: 5-benzyl-N-(1-methyl-2-oxo-8-(2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0265] I-14: 5-benzyl-N-(1-methyl-2-oxo-8-(3-oxa-9-azaspiro[5.5]undec-9-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0266] I-15: 5-benzyl-N-(1-(methyl-d3)-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0267] I-16: (S)-5-benzyl-N-(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-1,2,4-triazole-3-carboxamide;

[0268] I-17: 4-benzyl-N-(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-pyrazole-1-carboxamide;

[0269] I-18: N-(1-methyl-2-oxo-8-(3-oxa-9-azaspiro[5.5]undec-9-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-4-phenoxypyridine-2-carboxamide;

[0270] I-19: N-(1-(methyl-d3)-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-4-phenoxypyridine-2-carboxamide;

[0271] I-20: N-(1-methyl-2-oxo-8-(2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-4-phenoxypyridine-2-carboxamide;

[0272] I-21: N-(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-4-phenoxypyridine-2-carboxamide;

[0273] I-22: (S)-1-benzyl-N-(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-pyrazole-3-carboxamide;

[0274] I-23: (S)-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-5-(1-phenylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide;

[0275] I-24: (S)-5-benzyl-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1,3,4-oxadiazole-2-carboxamide;

[0276] I-25: 4-benzyl-N-(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-pyrazole-1-carboxamide;

[0277] I-26: (S)-4-benzyl-N-(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-pyrazole-1-carboxamide;

[0278] I-27: (R)-4-benzyl-N-(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-pyrazole-1-carboxamide;

[0279] I-28: (S)-4-Benzyl-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide; or

[0280] I-29: (S)-4-(4-Fluorobenzyl)-N-(5-methyl-7-(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide.

[0281] Additional compounds within the scope of one or more of Formulas I, I-1 to I-23, IA, II, and IIA-IIG include:

[0282]

[0283]

[0284]

[0285]

[0286] .

[0287] In some embodiments, one or more compounds may be included in a pharmaceutical composition or medicament, and in some embodiments, the one or more compounds may be in the form of a parent compound or a pharmaceutically acceptable salt, stereoisomer, N-oxide, tautomer, hydrate, solvate, isotope or prodrug thereof. The pharmaceutical composition typically includes at least one additional component in addition to the disclosed one or more compounds, such as a pharmaceutically acceptable excipient, adjuvant, additional therapeutic agent (described in the following section) or any combination thereof.

[0288] Pharmaceutically acceptable excipients may be included in pharmaceutical compositions for a variety of purposes, such as diluting the pharmaceutical composition for delivery to a subject, facilitating processing of the formulation, providing favorable material properties to the formulation, facilitating dispersion from a delivery device, stabilizing the formulation (e.g., antioxidants or buffers), providing a pleasant or palatable taste or consistency to the formulation, etc. Pharmaceutically acceptable excipients may include pharmaceutically acceptable carriers. Exemplary excipients include, but are not limited to: monosaccharides, disaccharides and polysaccharides, sugar alcohols and other polyols, such as lactose, glucose, raffinose, melezitose, lactitol, maltitol, trehalose, sucrose, mannitol, starch, or a combination thereof; surfactants, such as sorbitol, diphosphatidylcholine, and lecithin; bulking agents; agents); buffers, such as phosphate and citrate buffers; antiadherents, such as magnesium stearate; binders, such as carbohydrates (including disaccharides, such as sucrose and lactose), polysaccharides (such as starch, cellulose, microcrystalline cellulose, cellulose ethers (such as hydroxypropyl cellulose), gelatin, synthetic polymers (such as polyvinyl pyrrolidone, polyalkylene glycols); coatings (such as cellulose ethers, including hydroxypropyl methylcellulose, shellac, zein, and gelatin); release aids (such as enteric coatings); disintegrants (such as crospovidone, croscarmellose sodium, and sodium starch glycolate); fillers (such as dibasic calcium phosphate, vegetable fats and oils, lactose, Sucrose, dextrose, mannitol, sorbitol, calcium carbonate and magnesium stearate); flavorings and sweeteners (such as mint, cherry, anise, peach, apricot or licorice, raspberry and vanilla); lubricants (e.g. minerals such as talc or silicon dioxide, fats such as vegetable stearin, magnesium stearate or stearic acid); preservatives (e.g. antioxidants such as vitamin A, vitamin E, vitamin C, retinyl palmitate and selenium, amino acids such as cysteine ​​and methionine, citric acid and sodium citrate, parabens such as methylparaben and propylparaben); coloring agents; compression aids; emulsifiers; encapsulating agents; gums; granulating agents; and combinations thereof.

[0289] B. Combinations of Therapeutic Agents

[0290] The compounds described herein can be used alone, in combination with each other, in separate pharmaceutical compositions, together in a single pharmaceutical composition, or as an adjunct to or in combination with other established therapies. The one or more compounds or compositions comprising the compound(s) can be administered once or in multiple administrations. In certain embodiments, the compounds of the present invention can be used in combination with other therapeutic agents useful for the disorder or condition being treated. These other therapeutic agents can be administered simultaneously, sequentially in any order, by the same administration route as the compounds disclosed herein, or by a different route. For sequential administration, the compound(s) and the therapeutic agent(s) can be administered so that the effective time period of at least one compound and therapeutic agent overlaps with the effective time period of at least one other compound and / or therapeutic agent. In an exemplary embodiment of a combination comprising four components, the effective time period of the first component administered can overlap with the effective time period of the second, third, and fourth components, but the effective time periods of the second, third, and fourth components independently may or may not overlap with each other. In another exemplary embodiment of a combination comprising four components, the effective time period of the administered first component overlaps with the effective time period of the second component, but not with the effective time period of the third or fourth component; the effective time period of the second component overlaps with the effective time period of the first and third components; and the effective time period of the fourth component overlaps only with the effective time period of the third component. In some embodiments, the effective time periods of all compounds and / or therapeutic agents overlap with each other.

[0291] 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 non-steroidal anti-inflammatory agent. In certain embodiments, the non-steroidal anti-inflammatory agent is selected from aminosalicylate, a cyclooxygenase inhibitor, diclofenac, etodolac, famotidine, fenoprofen, flurbiprofen, ketoprofen, ketorolac, ibuprofen, indomethacin, meclofenamate, mefenamic acid, meloxicam, nambumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin, or a combination thereof. In some embodiments, the immunosuppressant is a mercaptopurine, a corticosteroid, an alkylating agent, a calcineurin inhibitor, an inosine monophosphate dehydrogenase inhibitor, an antilymphocyte globulin, an antithymocyte globulin, an anti-T cell antibody, or a combination thereof. In one embodiment, the antibody is infliximab.

[0292] In some embodiments, the compounds of the invention can be used together with anticancer or cytotoxic agents. Various types of anticancer and antitumor compounds include, but are not limited to, alkylating agents, antimetabolites, BCL-2 inhibitors, vinca alkaloids, taxanes, antibiotics, enzymes, cytokines, platinum coordination complexes, proteasome inhibitors, substituted ureas, kinase inhibitors, hormones and hormone antagonists, and hypomethylating agents, such as DNMT inhibitors, such as azacitidine and decitabine. Exemplary alkylating agents include, without limitation, mechlorothamine, cyclophosphamide, ifosfamide, phenylalanine mustard, chlorambucil, ethyleneimine, methylmelamine, alkyl sulfonates (e.g., busulfan), and carmustine. Exemplary antimetabolites include, for example and without limitation, the folic acid analog methotrexate; the pyrimidine analogs fluorouracil, cytosine arabinoside; the purine analogs mercaptopurine, thioguanine and thioazapurine. Exemplary vinca alkaloids include, for example and without limitation, vinblastine, vincristine, paclitaxel and colchicine. Exemplary antibiotics include, for example and without limitation, actinomycin D, daunorubicin and bleomycin. Exemplary enzymes effective as antitumor agents include L-asparaginase. Exemplary coordination compounds include, for example and without limitation, cisplatin and carboplatin. Exemplary hormones and hormone-related compounds include, by way of example and without limitation, the adrenocortical steroids prednisone and dexamethasone; the aromatase inhibitors aminoglutethimide, formestane, and anastrozole; the progestin compounds hydroxyprogesterone caproate, medroxyprogesterone; and the anti-estrogen compound tamoxifen.

[0293] These and other useful anticancer compounds are described in the Merck Index, 13th Ed. (O'Neil MJ et al.) Merck Publishing Group (2001) and Goodman and Gilman, The Pharmacological Basis of Therapeutics, 12th Edition, Brunton LL, Chapters 60-63, McGraw Hill, (2011), both of which are incorporated herein by reference.

[0294] Among the CTLA 4 antibodies that may be used in combination with the inhibitors disclosed herein is ipilimumab, which is sold as YERVOY® by Bristol-Myers Squibb.

[0295] Other chemotherapeutic agents for combination include immunooncology 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).

[0296] Other chemotherapeutic agents for use in combination with the inhibitors disclosed herein 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).

[0297] The compounds disclosed herein may also be advantageously used with CAR-T therapies. Examples of currently available CAR-T therapies are axicabtagene ciloleucel and tisagenlecleucel.

[0298] Additional anti-proliferative compounds that can be used in combination with the compounds of the invention include, for example and without limitation, antibodies directed against growth factor receptors (eg, anti-Her2); and cytokines such as interferon-α and -γ, interleukin-2 and GM-CSF.

[0299] Additional chemotherapeutic agents that may be used in combination with the compounds of the invention include proteasome inhibitors such as bortezomib, carfilzomib, marizomib, and the like.

[0300] Examples of kinase inhibitors that can be used in combination with the compounds disclosed herein, particularly in the treatment of malignancies, include: Btk inhibitors such as ibrutinib; CDK inhibitors such as palbociclib; EGFR inhibitors 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, tadalafil ... axitinib, lenvatinib, nintedanib, pazopanib; BCR-Abl inhibitors such as bosutinib, dasatinib, imatinib, and nilotinib; FLT-3 inhibitors such as gilteritinib and quizartinib, PI3-kinase inhibitors such as idelalisib, Syk inhibitors such as fostamatinib; and JAK inhibitors such as ruxolitinib and fedratinib.

[0301] In other embodiments, the second therapeutic agent may be selected from any of the following:

[0302] pain medication--morphine, fentanyl, hydromorphone, oxycodone, codeine, acetaminophen, hydrocodone, buprenorphine, tramadol, venlafaxine, flupirtine, meperidine, pentazocine, dextromorphamide, dipipanone;

[0303] 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, cefalotin, cephalexin, cefaclor, cefmandole, cefoxitin, cefprozil, cephalosporins) cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, and cefobiprole), glycopeptides (e.g., teicoplanin, vancomycin, ncomycin, and telavancin), lincosamides (e.g., clindamycin and incomysin), lipopeptides (e.g., daptomycin), macrolides (azithromycin, clarithromycin, dirithromycin, erythromycin, roxithromycin, troleandomycin, telithromycin), ), and spectinomycin), monobactams (e.g., aztreonam), 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 / sulbactam, piperacillin / tazobactam, and ticarcillin / clavulanate), Peptides (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, sulfonamidochrysoidine, sulfacetamide, sulfadiazine, silver sulfadiazine), sulfadiazine, sulfamethizole, sulfamethoxazole, sulfanilimide, sulfasalazine, sulfisoxazole, trimethoprim, and trimethoprim-sulfamethoxazole), tetracyclines (e.g., demeclocycline, doxycycline, doxycycline, minocycline, oxytetracycline, and tetracycline), antimycobacterial compounds (e.g., clofazimine, dapsone, capreomycin, cycloserine, ethambutol, ethionamide, isoniazid,pyrazinamide, rifampicin (rifampin), rifabutin, rifapentine, and streptomycin), and others, such as arsphenamine, chloramphenicol, fosfomycin, fusidic acid, linezolid, metronidazole, mupirocin, platensimycin, quinuprisin / dalfopristin, rifaximin, thiamphenicol, tigecycline, and timidazole;

[0304] Antibodies - anti-TNF-α antibodies, e.g., infliximab (RemicadeTM), adalimumab, golimumab, certolizumab; anti-B cell antibodies, e.g., rituximab; anti-IL-6 antibodies, e.g., tocilizumab; anti-IL-1 antibodies, e.g., anakinra; anti-PD-1 and / or anti-PD-L1 antibodies, e.g., nivolumab, pembrolizumab, pidilizumab, BMS-936559, MPDL3280A, AMP -224, MEDI4736; ixekizumab, brodalumab, ofatumumab, sirukumab, clenoliximab, clazakiumab, fezakinumab, fletikumab, mavrilimumab, ocrelizumab, sarilumab, secukinumab, toralizumab, zanolimumab;

[0305] Anticoagulants - warfarin (Coumadin™), acenocoumarol, phenprocoumon, atromentin, phenindione, heparin, fondaparinux, idraparinux, rivaroxaban, apixaban, hirudin, lepirudin, bivalirudin, argatrobam, dabigatran, ximelagatran, batroxobin, hementin;

[0306] Anti-inflammatory agents - steroids, e.g., budesonide, nonsteroidal anti-inflammatory agents, 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 acid, meloxicam, nambumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin;

[0307] Immunosuppressants - mercaptopurine, corticosteroids such as dexamethasone, hydrocortisone, prednisone, methylprednisolone, and prednisolone, alkylating agents such as cyclophosphamide, calcineurin inhibitors such as cyclosporine, sirolimus, and tacrolimus, inosine monophosphate dehydrogenase inhibitors (IMPDH) such as mycophenolate mofetil, mycophenolate mofetil mofetil) and azathioprine, as well as agents designed to suppress cellular immunity while preserving the integrity of the recipient's humoral immunological response, including various antibodies (e.g., antilymphocyte globulin (ALG), antithymocyte globulin (ATG), monoclonal anti-T-cell antibody (OKT3)) and irradiation.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.; and methylprednisolone is currently available from Roxane Laboratories, Inc. prednisolone is currently available from Pfizer; sirolimus (rapamycin) is currently available from Wyeth-Ayerst under the brand name Rapamune; tacrolimus is currently available from Fujisawa under the brand name Prograf; cyclosporine is currently available from Novartis under the brand name Sandimmune and from Abbott under the brand name Gengraf; IMPDH inhibitors such as mycophenolate mofetil and mycophenolic acid are currently available from Roche under the brand name Cellcept and from Novartis under the brand name Myfortic; azathioprine is currently available from GlaxoSmith Kline under the brand name Imuran; and antibodies are currently available from Ortho Biotech under the trade name Orthoclone, available from Novartis under the trade name Simulect (basiliximab) and from Roche under the trade name Zenapax (daclizumab); and.

[0308] Guanylate cyclase-C receptor agonists or intestinal secretagogues, such as linaclotide, which is sold under the name Linzess.

[0309] These various agents can be used according to their standard or conventional dosages as indicated in the prescribing information accompanying commercially available forms of the drugs (see also, prescribing information in the 2006 edition of The Physician's Desk Reference), the disclosure of which is incorporated herein by reference.

[0310] III. Methods of preparing compounds

[0311] The disclosed compounds can be prepared by any acceptable synthetic method that will be understood by those of ordinary skill in the art with the benefit of this disclosure. A suitable method is illustrated below, as shown by the specific compounds in the Examples. An exemplary method for preparing the compounds may include the following first reaction step according to Scheme 1.

[0312]

[0313] Referring to Scheme 1, the starting compound 100 is reacted with a R-containing 1 The reagent 102 reacts to provide R 1 -functionalized product 104. X is a suitable group for metal-mediated cross-coupling, such as a halogen or triflate group, and PG is an amine protecting group, which can be selected from, but not limited to, a 9-fluorenylmethoxycarbonyl ("Fmoc") group, a tert-butyloxycarbonyl ("Boc") group, a trityl ("Tr") group, an allyloxycarbonyl ("Alloc") group, a benzyloxycarbonyl ("Cbz") group, and the like. In some embodiments, the metal-mediated cross-coupling conditions include the use of a transition metal catalyst, such as a Pd(0) catalyst (e.g., Pd2(dba)3, Pd(dba)2, Pd(PPh3)4, and the like) with a ligand component, such as a ligand capable of generating Pd(II) from a Pd(0) catalyst (e.g., a BINAP ligand, a BINOL ligand, and the like), a base (e.g., t -BuONa) and a solvent. In some embodiments, the cross-coupling step involves heating the reaction mixture at a suitable temperature (eg, 60°C or higher, such as 70°C to 140°C, or 80°C to 120°C, or 85°C to 100°C).

[0314] Representative examples of the process shown in Scheme 1 are provided below in Schemes 2A-2C.

[0315]

[0316]

[0317]

[0318] Embodiments of the method for preparing the compound may further include the step of 1 - Additional steps to convert the functionalized product 104 to a desired compound within the scope of the present disclosure. In some embodiments, these additional steps may include a first deprotection step to provide an amine compound 300. The amine compound 300 is then converted to an amide compound 304 by reacting the amine compound with a suitable acid coupling partner 302 as shown in Scheme 3.

[0319]

[0320] Referring to Scheme 3, deprotection can involve the use of any suitable reagent capable of removing an amine protecting group ("PG", as shown in Schemes 1 and 3). In some embodiments, an acid, such as TFA, is used in the deprotection step. In other embodiments, a base, such as piperidine, can be used in the deprotection step. Other acids and bases suitable for deprotection will be readily recognized by one of ordinary skill in the art with the benefit of this disclosure. The amide formation step can be carried out using a reagent capable of promoting the formation of an amide between the free amine of the amine compound 300 and the acid functional group of the acid coupling partner 302. Suitable coupling partners can be synthesized using methods recognized by one of ordinary skill in the art with the benefit of this disclosure or can be purchased from commercial sources. In some embodiments, propylphosphonic anhydride can be used in combination with a base, such as diisopropylethylamine, to form an amide; however, other reagents, such as 2-(7-aza-1H-benzotriazol-1-yl)-N,N,N',N'-tetramethylammonium hexafluorophosphate, 2-(1H-benzotriazol-1-yl)-N,N,N',N'-hexafluorophosphate, 2-(6-chloro-1H-benzotriazol-1-yl)-N,N,N',N'-tetramethylammonium hexafluorophosphate, N'-tetramethylammonium hexafluorophosphate, 1-hydroxybenzotriazole, dicyclohexylcarbodiimide, diisopropylcarbodiimide, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide.HCl, benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate, benzotriazol-1-yloxy-tripyrrolidino-phosphonium hexafluorophosphate, bromo-tripyrrolidino-phosphonium hexafluorophosphate, and the like, as well as diisopropylethylamine, isopropylamine, and the like. A suitable solvent such as dichloromethane ("DCM") is also used.

[0321] Referring to Scheme 3 above, the acid coupling partner 302 can be prepared using the following procedure: A solution of a suitable heterocyclyl carboxylate (e.g., ethyl 5-benzyl-1H-1,2,4-triazole-3-carboxylate) is partitioned into a solution of NaOH in MeOH and water. After standing at 20°C for a suitable time, the solvent is removed in vacuo. The residue is acidified with dilute HCl and then extracted with EtOAc. The organic phase is washed with water and saturated brine, dried over sodium sulfate, and then evaporated in vacuo. Other acid coupling partners suitable for Scheme 3 can be prepared using similar methods from suitable starting materials (e.g., ethyl 5-benzyl-1,3,4-oxadiazole-2-carboxylate, ethyl 4-benzyl-1H-pyrazole-1-carboxylate, ethyl 1-benzyl-1H-pyrazole-3-carboxylate, ethyl 4-phenoxypicolinate, and fluorinated versions thereof).

[0322] IV. Methods of Using the Compounds

[0323] A. Disease / Disorder

[0324] The disclosed compounds, and combinations and / or pharmaceutical compositions thereof, can be used to inhibit RIP1 kinase by contacting the kinase with one or more compounds of the disclosure, or compositions comprising one or more compounds of the disclosure, in vivo or in vitro. One or more disclosed compounds, or compositions comprising one or more disclosed compounds, can also be used to improve, treat or prevent a variety of diseases and / or disorders. In particular embodiments, the disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof can be used to treat conditions in which inhibition of RIP1 or a channel involving RIP1 is therapeutically useful. In some embodiments, the compounds directly inhibit RIP1 kinase activity. In certain embodiments, the disclosed compounds can be used to treat autoimmune diseases, inflammatory disorders, cardiovascular diseases, neurological disorders, neurodegenerative disorders, allergic disorders, respiratory diseases, kidney diseases, cancer, ischemic conditions, red blood cell deficiency, lung and brain damage (e.g., induced by ischemia-reperfusion or cisplatin and / or cerebrovascular accident), and bacterial and viral infections.

[0325] 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, biliary cirrhosis, uveitis, multiple sclerosis, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmune myositis, Wegener's granulomatosis, ichthyosis, Graves' ophthalmyopathy, or asthma.

[0326] The disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof, may also be used to treat immunoregulatory disorders associated with bone marrow or organ transplant rejection or graft-versus-host disease. Examples of inflammatory and immunoregulatory disorders that may be treated with the compounds (or pharmaceutical compositions or combinations thereof) include, but are not limited to, organ or tissue transplantation, graft-versus-host disease caused by transplantation, autoimmune syndromes including rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, systemic sclerosis, systemic inflammatory response syndrome, myasthenia gravis, type I diabetes, uveitis, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, post-infectious autoimmune diseases including rheumatic fever and post-infectious glomerulonephritis, inflammatory and hyperproliferative skin diseases, psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis, seborrheic dermatitis, inflammation, lichen planus, pemphigus, bullous pemphigoid, bullous epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia, lupus erythematosus, acne, alopecia areata, keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, keratoconus, corneal epithelial dystrophy, leukoplakia, ocular pemphigus, Mooren's ulcer, scleritis, Graves' opthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, pollen allergy, reversible obstructive airway disease, bronchial asthma, allergic asthma, intrinsic asthma, exogenous Asthma, dust asthma, chronic or habitual asthma, delayed asthma and airway hyperresponsiveness, bronchitis, gastric ulcer, vascular damage caused by ischemic disease and thrombosis, ischemic bowel disease, ischemia-reperfusion injury, inflammatory bowel disease, necrotizing enterocolitis, intestinal damage 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-Barre syndrome, Meniere's disease, polyneuritis, Polyneuritis, mononeuritis, radiculopathy, hyperthyroidism, Basedow's disease, pure red cell aplasia, aplastic anemia, aplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, erythropoiesis, osteoporosis, sarcoidosis, fibrosing lung, idiopathic interstitial pneumonia, dermatomyositis, vitiligo vulgaris, ichthyosis vulgaris, photoallergic sensitivity, cutaneous T-cell lymphoma, chronic lymphocytic leukemia, arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa, non-inflammatory cardiomyopathy or myocardial infarction, scleroderma (including systemic scleroderma),Antiphospholipid syndrome, Wegener's granuloma, Sjögren's syndrome, obesity, eosinophilic fasciitis, lesions of the gums, periodontium, alveolar bone, cementum, glomerulonephritis, male pattern baldness or senile alopecia (by preventing hair loss or providing hair initiation and / or promoting hair production and hair growth), muscular dystrophy, pyoderma and Sezary's syndrome, Addison's disease, ischemia-reperfusion injury of organs during storage, transplantation or ischemic diseases, endocrine dysfunction Toxin shock, pseudomembranous colitis, colitis caused by drugs or radiation, ischemic acute renal failure, chronic renal failure, toxic diseases caused by pulmonary oxygen or drugs, lung cancer, emphysema, cataracts, siderosis, retinitis pigmentosa, retinal degeneration, retinal detachment, age-related macular degeneration, vitreous scarring, corneal alkali burns, dermatitis erythema multiforme, linear IgA bullous dermatitis and cement dermatitis, gingivitis, periodontitis, sepsis, pancreatitis, environmental Diseases caused by pollution, aging, carcinogenesis, metastasis and hypotension, diseases caused by the release of histamine or leukotriene-C4, Behcet's disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, partial hepatectomy, acute hepatic necrosis, necrosis caused by toxins, viral hepatitis, shock, or hypoxia, hepatitis B, non-A, non-B hepatitis, cirrhosis, alcoholic liver disease, including alcoholic cirrhosis, alcoholic steatohepatitis, non-alcoholic fatty liver NASH, autoimmune hepatobiliary disease, acetaminophen toxicity, hepatotoxicity, liver failure, fulminant liver failure, delayed liver failure, "acute-on-chronic" liver failure, chronic kidney disease, renal impairment / injury (e.g., caused by nephritis, kidney transplantation, surgery, administration of nephrotoxic drugs, acute kidney injury), increased effects of chemotherapy, cytomegalovirus infection, HCMV infection, AIDS, cancer, Alzheimer's disease, Parkinson's disease, trauma, or chronic bacterial infection.

[0327] In certain embodiments, the compounds of the invention are useful for treating neurological pain, including neuropathic pain and inflammation-induced pain.

[0328] In certain embodiments, the compounds are useful for treating interleukin-1 converting enzyme-associated febrile syndrome, tumor necrosis factor receptor-associated periodic syndrome, NEMO-deficient syndrome, HOIL-1 deficiency, linear ubiquitination chain assembly complex deficiency syndrome, lysosomal storage diseases (e.g., Gaucher disease, GM2 gangliosidosis, alpha-mannosidosis, aspartylglucosaminuria, cholesterol ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Farber disease, rock algal storage diseases, 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, pycnodysostosis, Sandhoff disease, Schindler disease, sialic acid storage diseases, Tay-Sachs disease, and Wolman disease).

[0329] In certain embodiments, the disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof, are useful for treating and / or preventing rheumatoid arthritis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, lupus nephritis, ankylosing spondylitis, osteoporosis, systemic sclerosis, multiple sclerosis, psoriasis, particularly pustular psoriasis, type I diabetes, type II diabetes, inflammatory bowel disease (Crohn's disease and ulcerative colitis), hyperimmunoglobulinemia d and periodic fever syndromes, cryopyrin-associated periodic syndromes, Schnitzler syndrome, systemic juvenile idiopathic arthritis, adult-onset Still's disease, gout, gout flares, pseudogout, sapho 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.

[0330] The combination of the compounds of the present invention with other therapies is particularly useful in treating hyperproliferative disorders. The compounds of the present invention can be used to treat disorders such as cancer, leukemia and lymphoma in combination with the standard of care. As an example, myelodysplastic syndrome (MDS) can be treated with the compounds disclosed herein together with the standard of care. Therapeutic agents used in combination with the compounds of the present invention include hypomethylating agents such as azacitidine and decitabine, and other chemotherapeutic agents such as cytarabine, daunorubicin and idarubicin. Immunomodulatory therapies, such as lenalidomide and CAR-T therapy, can also be used in combination with the compounds of the present invention for the treatment of MDS.

[0331] Proliferative diseases that can be treated by the disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof include benign or malignant tumors, solid tumors, brain cancer, kidney cancer, liver cancer, adrenal cancer, bladder cancer, breast cancer, stomach cancer, gastric tumors, ovarian cancer, colon cancer, rectal cancer, prostate cancer, pancreatic cancer, lung cancer, vaginal cancer, cervical cancer, testicular cancer, genitourinary tract cancer, esophageal cancer, laryngeal cancer, skin cancer, bone cancer or thyroid cancer, sarcoma, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancer, especially colon cancer or colorectal adenoma, tumors of the neck and head, epidermal hyperplasia, psoriasis, prostatic hyperplasia, neoplasia, epithelial neoplasia, adenoma, adenocarcinoma, keratoacanthoma, epidermal hyperplasia, leukemia ... Dermoid carcinoma, large cell carcinoma, non-small cell lung cancer, lymphomas such as Hodgkin and non-Hodgkins lymphomas, breast cancer, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, IL-1 driven disorders, hematopoietic neoplasms such as the lymphomas listed above, MyD88 driven disorders (such as ABC diffuse large B-cell lymphoma (DLBCL) and Waldenström's macroglobulinemia), Hodgkin's lymphoma, primary cutaneous T-cell lymphoma, or chronic lymphocytic leukemia), smoldering or indolent multiple myeloma, or hematologic malignancies (including leukemias, acute myeloid leukemia (AML), DLBCL, ABC DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt lymphoma / leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, myelodysplastic syndrome (MDS), myelofibrosis, polycythemia vera, Kaposi's sarcoma, Waldenström's macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, intravascular large B-cell lymphoma). In particular, the compounds disclosed herein can be used to treat drug-resistant malignancies, such as those resistant to JAK inhibitors, ibrutinib-resistant malignancies, including ibrutinib-resistant hematological malignancies, such as ibrutinib-resistant CLL and ibrutinib-resistant Waldenström's macroglobulinemia.

[0332] Examples of allergic disorders that can be treated using the disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof include, but are not limited to, asthma (e.g., atopic asthma, allergic asthma, atopic bronchial IgE-mediated asthma, non-atopic asthma, bronchial asthma, non-allergic asthma, essential asthma, true asthma, intrinsic asthma caused by pathophysiological disturbances, essential asthma of unknown or unexplained cause, emphysematous asthma, exercise-induced asthma, emotion-induced asthma, extrinsic asthma caused by environmental factors, cold air-induced asthma, occupational asthma, infectious asthma caused by or associated with bacterial, fungal, protozoan or viral infection, incipient asthma, wheezing infant syndrome (wheezinfant syndrome), syndrome, bronchiolitis, cough variant asthma or drug-induced asthma), allergic bronchopulmonary aspergillosis (ABPA), allergic rhinitis, perennial allergic rhinitis, perennial rhinitis, vasomotor rhinitis, postnasal drip, purulent or nonpurulent sinusitis, acute or chronic sinusitis, and ethmoid, frontal, palatine, or sphenoid sinusitis.

[0333] As another example, rheumatoid arthritis (RA) usually causes swelling, pain, loss of mobility and tenderness of target joints throughout the body. RA is characterized by a chronic inflammatory synovium of dense lymphocytes. The synovium, which is usually one cell layer thick, becomes densely packed with cells and presents a form similar to lymphoid tissue, including dendritic cells, T cells, B cells and NK cells, macrophages and plasma cell clusters. This process and a large number of immunopathological mechanisms including the formation of antigen-immunoglobulin complexes ultimately lead to the destruction of the integrity of the joint, resulting in deformity at or near the joint, permanent loss of function and / or bone erosion. The disclosed compound, the combination of the disclosed compound, or its pharmaceutical composition can be used to treat, improve or prevent any one, several or all of these symptoms of RA. Therefore, in the context of RA, when achieving the alleviation or improvement of any symptom usually associated with RA, it is believed that the compound provides a therapeutic benefit, regardless of whether the treatment results in a concomitant treatment of essential RA and / or a reduction in the amount of circulating rheumatoid factor ("RF").

[0334] The American College of Rheumatology (ACR) has developed criteria for defining improvement and clinical remission of RA. Once such a parameter, ACR20 (ACR criteria for 20% clinical improvement) requires a 20% improvement in tender and swollen joint counts, and a 20% improvement in 3 of the following 5 parameters: patient global assessment, physician global assessment, patient pain assessment, disability level, and acute phase reactant levels. These criteria have been extended to 50% and 70% improvement in ACR50 and ACR70, respectively. Other criteria include Paulu's criteria and radiographic progression (e.g., Sharp score).

[0335] In certain embodiments, a therapeutic benefit is achieved in patients suffering from RA when the patient exhibits an ACR of 20. In specific embodiments, an ACR improvement of ACR 50 or even ACR 70 may be achieved.

[0336] In one embodiment, the compounds disclosed herein can be used to slow the onset of the consequences of aging. For example, the compounds of the invention reduce the increased chronic inflammation associated with advanced age ("inflammaging"). Countless symptoms and conditions are associated with inflammatory aging, and such conditions that can be treated with the compounds of the invention include, by way of example, 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 of the invention include those described in the following references: 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 of the invention can be used to reduce the effects of aging on the reproductive system. For example, necroptosis induced by RIP1 signaling has been implicated in aging of reproductive organs, see Li et al. eLife 2017;6:e27692 and Chaudhary et al. Journal of Biomedical Science (2019) 26:11, therefore the compounds of the present invention can be used to treat symptoms associated with aging, such as decreased testosterone levels, decreased fertility and prostate hyperplasia.

[0337] Additional diseases or disorders that can be treated and / or prevented using the compounds and compositions of the present invention include amyotrophic lateral sclerosis (ALS), autoimmune syndromes, rheumatoid arthritis, type I diabetes, inflammatory bowel disease, including Crohn's disease and ulcerative colitis, biliary cirrhosis, multiple sclerosis, Wegener's granulomatosis, ichthyosis, asthma, pollen allergy, reversible obstructive airway disease, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, dust asthma, chronic or habitual asthma, delayed asthma and airway hyperresponsiveness, allergic rhinitis, spondyloarthritis, ankylosing spondylitis, autoimmune hepatitis, autoimmune hepatobiliary disease, cerebrovascular accident, allergic disease, chronic obstructive pulmonary disease, Lung disease, emphysema, Friedreich's ataxia, Lewy body disease, diabetic neuropathy, polyglutamine (polyQ) disease, Fahr's disease, Menke's disease, Wilson's disease, prion disorders, destructive bone disorders such as bone resorption diseases, multiple myeloma-related bone disorders; 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 multiforme erythema, linear IgA bullous dermatitis, cement dermatitis, gingivitis, periodontitis, lesions of the gums, alveolar bone, cementum, sepsis, pancreatitis, lichen planus, pemphigus, bullous Pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia, obesity, eosinophilic fasciitis, acne, alopecia areata, male pattern baldness, senile alopecia, keratoconjunctivitis, vernal conjunctivitis, corneal alkali burns, Behcet's disease, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, keratoconus, corneal epithelial dystrophy, corneal leukoplakia, ocular pemphigus, Mooren's ulcer, scleritis, Vogt-Koyanagi-Harada syndrome, hematological disorders, hematological malignancies, lymphoma, Hodgkins lymphoma, non-Hodgkins lymphoma, breast cancer, follicular carcinoma, undifferentiated carcinoma, nipple carcinoma, seminoma, melanoma, ABC diffuse large B-cell lymphoma (DLBCL), Waldenström's macroglobulinemia, primary cutaneous T-cell lymphoma, smoldering or indolent multiple myeloma, leukemia, acute myeloid leukemia (AML), DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt lymphoma / leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, myelodysplastic syndrome (MDS), myelofibrosis, polycythemia vera, Kaposi's sarcoma, splenic marginal zone lymphoma, multiple myeloma, plasmacytoma,Intravascular large B-cell lymphoma, IL-1 driven disorders, MyD88 driven disorders, resistant malignancies such as JAK inhibitor-resistant malignancies and ibrutinib-resistant malignancies such as ibrutinib-resistant hematologic malignancies, ibrutinib-resistant CLL and ibrutinib-resistant Waldenström's macroglobulinemia, acute myeloid leukemia, chronic myeloid leukemia; angiogenic disorders such as angiogenic disorders including solid tumors, ocular neovascularization, hemangiomas such as infantile hemangiomas; sepsis, septic shock , shigellosis; migraine, bronchitis, gastric ulcer, necrotizing enterocolitis, intestinal damage associated with thermal burns, celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, interleukin-1 converting enzyme-associated febrile syndrome, tumor necrosis factor receptor-associated periodic syndrome, NEMO-deficient syndrome, HOIL-1 deficiency, linear ubiquitination chain assembly complex deficiency syndrome, lysosomal storage disease, Gaucher disease, GM2 gangliosidosis, alpha-mannosidosis, aspartylglucosaminuria, Cholesterol ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Farber disease, fucosidosis, galactosialidosis, GM1 gangliosidosis, mucolipidosis, infantile free sialic acid storage disease, juvenile hexosaminidase A deficiency, Krabbe disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidosis, multiple sulfatase deficiency, Niemann-Pick disease, neuronal ceroid lipofuscinosis, Pompe disease, pycnodystrophy, S Hoff 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 and CMV retinitis, such as associated neurocognitive disorders or dementia, fibrotic conditions such as nonalcoholic steatohepatitis, steatohepatitis) and cardiac conditions such as ischemia reperfusion; allergies, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, systemic lupus erythematosis, chronic thyroiditis, Graves' disease, autoimmune gastritis, autoimmune neutropenia, thrombocytopenia, graft-versus-host disease, inflammatory reactions induced by endotoxin, tuberculosis, atherosclerosis, muscle degeneration, cachexia, Reiter's syndrome, rubella arthritis, acute synovitis,beta-cell disease; diseases characterized by massive neutrophil infiltration; rheumatoid 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, pyresis, influenza, chronic myeloid 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 stroke heart attack, organ hypoxia, angiogenesis, cardiac and renal reperfusion injury, ischemia-reperfusion injury of organs during preservation, transplantation or ischemic disease, cardiac hypertrophy, thrombin-induced platelet aggregation, endotoxemia and / or toxic shock syndrome, conditions associated with prostaglandin endoperoxidase synthetase (syndase)-2, pemphigus vulgaris, autoimmune / polymyositis, dermatomyositis, vitiligo vulgaris, photoallergic sensitivity, ischemia-reperfusion injury, cardiac ischemia-reperfusion injury due to myocardial infarction perfusion injury, multiple system atrophy, Parkinson-Jackson 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 onset juvenile idiopathic arthritis (SoJIA) or Still's disease, systemic lupus erythematosus (SLE), Sjögren's syndrome, antiphospholipid syndrome (APS), primary sclerosing cholangitis (PSC), renal transplantation, surgery, acute kidney injury (AKI), systemic inflammatory response syndrome (SIRS), Cytokine release syndrome (CRS), Acute respiratory distress syndrome (ARDS), ARDS caused by COVID-19, Post-infectious autoimmune disease, Rheumatic fever, Post-infectious glomerulonephritis, Systemic sclerosis, Cerebrovascular accident (CVA), Chronic obstructive pulmonary disease (COPD), NEMO-deficiency syndrome (F-κ-B essential regulator gene (also known as IKKγ or IKKG) deficiency syndrome), Solid organ malignancies, Lysosomal storage diseases, Glaucoma, Retinal degenerative diseases, Retinal ischemia / reperfusion injury, Renal ischemia / reperfusion injury, Cataract, Siderosis, Retinitis pigmentosa, Retinal degeneration, Retinal detachment,Age-related macular degeneration, vitreous scarring, anthrax lethal toxin-induced septic shock, LPS-induced cell death, transmissible encephalopathy, encephalitis, allergic encephalomyelitis, autoimmune uveoretinitis, giant cell arteritis, Crohn's disease, granulomatous enteritis, distal ileitis, Crohn's disease, terminal ileitis, insulin-dependent diabetes mellitus, scleroderma, systemic scleroderma, yellow spots, diabetic retinopathy, central halo choroidal dystrophy, BEST disease, adult yolk disease, pattern dystrophy dystrophy, myopic degeneration, central serous retinopathy, Stargardt's disease, cone-rod dystrophy, North Carolina dystrophy, infectious retinitis, inflammatory retinitis, uveitis, posterior uveitis, toxic retinitis and light-induced toxicity, yellow spot edema, central halo choroidal dystrophy, BEST disease, adult yolk disease, pattern dystrophy dystrophy), optic nerve injury, optic neuritis, optic neuropathy, central retinal artery occlusion, ischemic optic neuropathy (e.g., arteritic or nonarteritic anterior ischemic neuropathy and posterior ischemic optic neuropathy), compressive optic neuropathy, infiltrative optic neuropathy, traumatic optic neuropathy, mitochondrial optic neuropathy (e.g., Leber's optic neuropathy), nutritional optic neuropathy, toxic optic neuropathy and hereditary optic neuropathy, significant optic atrophy, Behr's syndrome, Creutzfeldt-Jakob disease), progressive supranuclear palsy, hereditary spastic paresis, subarachnoid hemorrhage, perinatal brain injury, subclinical brain injury, spinal cord injury, hypoxic-ischemic brain injury, cerebral ischemia, focal cerebral ischemia, global cerebral ischemia, and anoxic hypoxia, peritoneal injury 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 system cancer, bladder cancer, colorectal cancer, colon cancer, breast cancer, prostate cancer, prostatic hyperplasia, renal cancer, kidney cancer, liver cancer, adrenal cancer, thyroid cancer, gallbladder cancer, peritoneal cancer, ovarian cancer, cervical cancer, gastric cancer, endometrial cancer, esophageal cancer, gastric cancer, head and neck cancer, neuroendocrine cancer , CNS cancer, brain tumors (e.g., brain cancer, glioma, anaplastic oligodendroglioma, glioblastoma multiforme in adults, and anaplastic astrocytoma in adults), bone cancer, soft tissue sarcoma, retinoblastoma, neuroblastoma, peritoneal effusion, malignant pleural effusion, mesothelioma, Wilms tumor, trophoblastic tumor, epithelial neoplasia, gastric cancer, ovarian cancer, colorectal cancer, prostate cancer, pancreatic cancer, lung cancer, vaginal cancer, cervical cancer, testicular cancer,Genitourinary tract cancer, esophageal cancer, laryngeal cancer, skin cancer, bone cancer, thyroid cancer, sarcoma, glioblastoma, neuroblastoma, gastrointestinal cancer, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma, colon cancer, colorectal adenoma, hemangiopericytoma, myxoid carcinoma, round cell carcinoma, squamous cell carcinoma, esophageal squamous cell carcinoma, oral cancer, vulvar cancer, adrenal cortical carcinoma, ACTH-producing tumors, and leukemia, respiratory infectious viruses such as influenza virus, rhinovirus, coronavirus, parainfluenza virus, RS virus, adenovirus, reovirus, etc.), herpes zoster caused by herpes virus, diarrhea caused by rotavirus, viral hepatitis, AIDS, bacterial infectious diseases such as Bacillus cereus, Vibrio parahaemolyticus, enterohemorrhagic Escherichia coli, Staphylococcus aureus, MRS A, Salmonella, Clostridium botulinum, Candida species, Paget's disease, achondroplasia, osteochondritis, hyperparathyroidism, osteogenesis imperfecta, partial hepatectomy, acute liver necrosis, necrosis caused by toxins, necrosis caused by viral hepatitis, necrosis caused by shock, necrosis caused by hypoxia, hepatitis B, non-A, non-B hepatitis, cirrhosis, alcoholic liver disease, alcoholic cirrhosis, alcoholic steatohepatitis, non-alcoholic steatohepatitis (NASH), acetaminophen toxicity, hepatotoxicity, liver failure, fulminant liver failure, delayed liver failure, "acute on chronic" liver failure, chronic kidney disease, renal damage / injury, renal damage / injury caused by nephritis, renal damage / injury caused by kidney transplantation, renal damage / injury caused by surgery, nephrotoxic drugs Renal impairment / injury caused by administration, increased chemotherapy effects, cytomegalovirus infection, HCMV infection, AIDS, cancer, Alzheimer's disease, trauma, chronic bacterial infection, diseases caused by environmental pollution, aging, hypotension, diseases caused by histamine or leukotriene-C4 release, muscular dystrophy, pyoderma and Sezary's syndrome, Addison's disease, pseudomembranous colitis, colitis caused by drugs or radiation, ischemic acute renal insufficiency, chronic renal insufficiency, toxic diseases caused by pulmonary oxygen or drugs, congenital hypophosphatasia, fibromatosis, fibrous dysplasia, bone turnover, osteolytic bone disease, treatment of trauma after bone surgery, treatment of prosthetic joint surgery, treatment of plastic bone surgery, treatment of dental surgery, bone chemotherapy or bone radiotherapy, bone cancer, fragile plaque (fragile plaque) plaque), obstruction, occlusive obstruction, stenosis, coronary artery obstruction, peripheral arterial obstruction, arterial occlusion, aneurysm formation, post-traumatic aneurysm formation, restenosis, post-operative graft occlusion, Guillain-Barre syndrome, Meniere's disease, polyneuritis, polyneuritis, mononeuritis, radiculopathy, hyperthyroidism, Basedow's disease,Autoimmune idiopathic thrombocytopenic purpura (autoimmune ITP), membranous nephritis, autoimmune thyroiditis, Hashimoito's 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, erythropoiesis, and combinations thereof. ,

[0338] For a particular embodiment, at least one compound according to the invention or a composition comprising at least one compound is administered to a subject having or potentially developing atopic dermatitis. In another particular embodiment, at least one compound according to the invention or a composition comprising at least one compound is administered to a subject having or potentially developing rheumatoid arthritis. In another particular embodiment, at least one compound according to the invention or a composition comprising at least one compound is administered to a subject having or potentially developing ankylosing spondylitis. In another particular embodiment, at least one compound according to the invention or a composition comprising at least one compound is administered to a subject having or potentially developing myelodysplastic syndrome.

[0339] B. Preparation and Administration

[0340] The pharmaceutical composition comprising one or more active compounds of the present invention can be prepared by any suitable method, such as mixing, dissolving, granulating, making dragees, grinding, emulsifying, encapsulating, embedding or lyophilizing. The pharmaceutical composition can be formulated using one or more physiologically acceptable excipients (e.g., diluents, carriers, or auxiliary agents), one or more adjuvants, or a combination thereof, to provide a pharmaceutically usable product.

[0341] The active compound (one or more) itself, or in the form of its pharmaceutically acceptable salt, stereoisomer, N-oxide, tautomer, hydrate, solvate, isotope, or prodrug, can be formulated into a pharmaceutical composition. Typically, such salts are more soluble in aqueous solution than the corresponding free acids and bases, but salts with lower solubility than the corresponding free acids and bases can also be formed.

[0342] The pharmaceutical compositions of the present invention may be in a form suitable for nearly any mode of administration including, for example, topical, ocular, oral, buccal, systemic, nasal, injectable (e.g., intravenous or intraperitoneal), transdermal, rectal, vaginal, etc., or in a form suitable for administration by inhalation or insufflation.

[0343] For topical administration, the active compound(s), pharmaceutically acceptable salts, stereoisomers, N-oxides, tautomers, hydrates, solvates, isotopes or prodrugs may be formulated into solutions, gels, ointments, creams, suspensions, etc. as is well known in the art.

[0344] Systemic formulations include those designed for administration by injection (eg, subcutaneous, intravenous, intramuscular, intrathecal or intraperitoneal injection), as well as those designed for transdermal, transmucosal, oral or pulmonary administration.

[0345] Useful injectable formulations include sterile suspensions, solutions or emulsions of the active compound(s) in aqueous or oily vehicles. The pharmaceutical composition may also contain a formulation agent, such as a suspending agent, a stabilizer and / or a dispersant. The formulation for injection may be in unit dosage form, for example, in an ampoule or in a multidose container, and may contain an added preservative.

[0346] Alternatively, the injectable preparation may be provided in powder form to be reconstituted prior to use with a suitable vehicle, including, but not limited to, sterile, pyrogen-free water, buffer, dextrose solution, etc. For this purpose, the active compound(s) may be dried by any technique known in the art, such as lyophilization, and reconstituted prior to use.

[0347] For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are known in the art.

[0348] For oral administration, the pharmaceutical composition can be in the form of, for example, lozenges, tablets or capsules, which are prepared by conventional means with pharmaceutically acceptable excipients, such as: binders (e.g., pregelatinized corn starch, polyvinyl pyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silicon dioxide); disintegrants (e.g., potato starch or sodium starch glycolate); and / or wetting agents (e.g., sodium lauryl sulfate). The tablets can be coated with, for example, sugar, film or enteric coatings by methods well known in the art.

[0349] Liquid preparations for oral administration may be in the form of, for example, elixirs, solutions, syrups or suspensions, or they may be presented as dry products that are constructed with water or other suitable vehicles before use. Such liquid preparations may be prepared in a conventional manner with pharmaceutically acceptable excipients, such as: suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifiers (e.g., lecithin or gum arabic); non-aqueous vehicles (e.g., almond oil, oily esters, ethanol, cremophore™ or fractionated vegetable oils); and preservatives (e.g., methylparaben or propylparaben or sorbic acid). The preparations may also contain buffer salts, preservatives, flavoring agents, coloring agents and sweeteners as desired.

[0350] Preparations for oral administration may be suitably formulated to give controlled release of the active compound, as is well known.

[0351] For buccal administration, the pharmaceutical compositions may take the form of tablets or lozenges formulated in conventional manner.

[0352] 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.

[0353] For nasal administration or administration by inhalation or insufflation, the active compound(s), pharmaceutically acceptable salt, stereoisomer, N-oxide, tautomer, hydrate, solvate, isotope, or prodrug may be conveniently delivered as an aerosol spray from a pressurized pack or 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 may be determined by providing a valve to deliver a metered amount. Capsules and cartridges (e.g., those comprising gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

[0354] A specific example of an aqueous suspension formulation suitable for nasal administration using a commercially available nasal spray device includes the following ingredients: active compound (0.5-20 mg / mL); benzalkonium chloride (0.1-0.2 mg / mL); polysorbate 80 (TWEEN® 80; 0.5-5 mg / mL); sodium carboxymethylcellulose or microcrystalline cellulose (1-15 mg / mL); phenylethyl alcohol (1-4 mg / mL); and dextrose (20-50 mg / mL). The pH of the final suspension may be adjusted to about pH 5 to pH 7, with a pH of about pH 5.5 being typical.

[0355] Another specific example of an aqueous suspension suitable for administration of 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.

[0356] For ocular administration, the active compound(s) may be formulated into solutions, emulsions, suspensions, etc. suitable for administration to the eye. A variety of vehicles suitable for administering compounds to the eye are known in the art. Specific non-limiting examples are described in the following U.S. Patents: 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.

[0357] For the delivery of extension, active compound (one or more) can be formulated into the long-acting (depot) preparation for giving by implantation or intramuscular injection. Active component can be formulated together with suitable polymer or hydrophobic material (for example, in the form of emulsion in acceptable oil) or ion exchange resin, or be formulated into the form of slightly soluble derivative, for example, the form of slightly soluble salt. Alternatively, a transdermal delivery system can be used, which is prepared as an adhesive disc or patch for slowly releasing active compound (one or more) with percutaneous absorption. For this purpose, penetration enhancer can be used to promote the transdermal penetration of active compound (one or more). For example, suitable transdermal patches are described in U.S. Patent Nos. 5,407,713; 5,352,456; 5,332,213; 5,336,168; 5,290,561; 5,254,346; 5,164,189; 5,163,899; 5,088,977; 5,087,240; 5,008,110; and 4,921,475, which are incorporated herein by reference.

[0358] Alternatively, other drug delivery systems may be employed. Liposomes and emulsions are well-known examples of delivery vehicles that can be used to deliver the active compound(s). Certain organic solvents such as dimethyl sulfoxide (DMSO) may also be employed, although usually at the expense of greater toxicity.

[0359] If desired, the pharmaceutical composition may be presented in a package or dispenser device which may contain one or more unit dosage forms containing the active compound(s). The package may comprise, for example, metal or plastic foil, such as a blister pack. The package or dispenser device may be accompanied by instructions for administration.

[0360] There are several schemes for transporting molecules across the blood-brain barrier. These include, but are not limited to physical methods, lipid-based methods, and receptor- and channel-based methods. Physical methods for transporting compounds across the blood-brain barrier include, but are not limited to completely bypassing the blood-brain barrier and / or creating openings in the blood-brain barrier. Bypass methods include, but are not limited to direct injection (e.g., Papanastassiou et al., Gene Therapy 9:398-406, 2002), interstitial infusion / convection-enhanced delivery (Bobo et al., Proc. Natl. Acad. Sci. USA 91:2076-2080, 1994), and implanting delivery devices in the brain (see, e.g., Gill et al., Nature Med. 9:589-595, 2003). Openings in the blood-brain barrier include, but are not limited to, ultrasound, osmotic pressure (e.g., by administration of hypertonic mannitol), and by permeabilization with, for example, bradykinin or the permeabilizing agent A-7 (see, e.g., U.S. Pat. Nos. 5,112,596, 5,268,164, 5,506,206, and 5,686,416). The compound may also be encapsulated in liposomes coupled to an antibody binding fragment that binds to receptors on the vascular endothelium of the blood-brain barrier.

[0361] For certain embodiments, the compound can be continuously administered by infusion into a fluid reservoir of the CNS or by rapid bolus injection. The compound can be administered using an indwelling catheter and a continuous administration method (such as a pump) or by implanting a sustained release vehicle. For example, the compound can be injected by long-term implantation of a cannula or long-term infusion with the help of an osmotic mini pump. A subcutaneous pump can deliver the compound to the ventricles of the brain.

[0362] C. Dosage

[0363] The disclosed compounds, pharmaceutical compositions, or combinations of disclosed compounds will generally be used in an amount effective to achieve the desired result, for example, an amount effective to inhibit RIP1 kinase and / or to treat, prevent or improve a particular condition. The disclosed compound(s), or pharmaceutical compositions thereof, may be administered therapeutically to achieve a therapeutic benefit or prophylactically to achieve a preventive benefit. The therapeutic benefit refers to the eradication or improvement of the underlying disorder being treated, and / or the eradication or improvement of one or more symptoms associated with the underlying disorder, so that although the patient may still be afflicted with the underlying disorder, the patient reports an improvement in feeling or condition. For example, administering a compound to a patient suffering from allergy provides a therapeutic benefit not only when the underlying allergic response is eradicated or improved, but also when the patient reports a decrease in the severity or duration of symptoms associated with the allergy after exposure to the allergen. As another example, the therapeutic benefit in terms of asthma includes an improvement in breathing after the onset of an asthma attack or a decrease in the frequency or severity of asthma attacks. Whether or not an improvement is achieved, the therapeutic benefit also includes stopping or slowing the progression of the disease.

[0364] As known to those of ordinary skill in the art, the preferred dosage of the disclosed compounds may depend on a variety of factors, including the age, weight, general health, and severity of the condition of the patient or subject being treated. When administered by inhalation, the dosage may also need to be adjusted to accommodate the sex of the individual and / or the lung capacity of the individual. The dosage may also be adjusted to accommodate individuals with more than one condition or those with additional conditions that affect lung capacity and normal breathing ability (e.g., emphysema, bronchitis, pneumonia, respiratory distress syndrome, chronic obstructive pulmonary disease, and respiratory tract infections). The dosage and frequency of administration of the disclosed compound (one or more) or its pharmaceutical composition will also depend on whether the disclosed compound (one or more) is formulated for the treatment of acute attacks of the condition or for the preventive treatment of the disorder. One of ordinary skill in the art will be able to determine the optimal dosage for a particular individual.

[0365] For prophylactic administration, the disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof, can be administered to a patient or subject at risk of developing one of the previously described conditions. For example, if it is not known whether the patient or subject is allergic to a particular drug, the disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof can be administered prior to administration of the drug to avoid or ameliorate an allergic response to the drug. Alternatively, prophylactic administration can be used to avoid or ameliorate the onset of symptoms in a patient diagnosed with an underlying disorder. For example, the disclosed compound(s), or pharmaceutical compositions thereof, can be administered to an allergic victim prior to an 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 agents known to be one of the above-mentioned ailments 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 allergens known to induce allergies (such as latex) in an attempt to prevent the individual from developing allergies. 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 engaging in an activity that provokes an asthma attack to reduce the severity of the asthma attack or to avoid the asthma attack altogether.

[0366] Effective doses can be estimated initially from in vitro assays. For example, an initial dose for a subject can be formulated to achieve an IC value equal to or greater than that of a particular compound as measured in an in vitro assay. 50 or EC 50 The circulating blood or serum concentration of the active compound is calculated to achieve such a circulating blood or serum concentration. The dose can be calculated to achieve such a circulating blood or serum concentration, taking into account the bioavailability of a particular compound. Fingl & Woodbury, "General Principles," In: Goodman and Gilman's The Pharmaceutical Basis of Therapeutics, Chapter 1, pages 1-46, Pergamon Press, and references cited therein, provide additional guidance on effective doses.

[0367] In some embodiments, the 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.

[0368] Initial doses can also be estimated from in vivo data such as animal models. Animal models that can be used to test the efficacy of compounds for treating or preventing the various diseases described above are well known in the art. Suitable animal models for hypersensitivity or allergic reactions are described in Foster, (1995) Allergy 50 (21 Suppl): 6-9, discussing 34-38 and Tumas et al., (2001), J. Allergy Clin. Immunol. 107 (6): 1025-1033. Suitable animal models for allergic rhinitis are described in Szelenyi et al., (2000), Arzneimittelforschung 50 (11): 1037-42; Kawaguchi et al., (1994), Clin. Exp. Allergy 24 (3): 238-244 and Sugimoto et al., (2000), Immunopharmacology 48 (1): 1-7. One of ordinary skill in the art can adapt such information to determine appropriate dosages for human administration.

[0369] In some embodiments, tests suitable for determining the activity of RIP1 can be used. Such test methods can be used to evaluate the efficacy of the compound embodiments disclosed herein and / or can be used to determine the quantity / dose of the compound embodiments that can provide the desired efficacy. In some embodiments, the test can be an ADP-Glo™ test, which evaluates the ability of the compound embodiments to inhibit RIP1. In other embodiments, whole cell tests using mouse and / or human cells, such as U937 and / or L929 cell necrosis (necroptosis) tests, can be performed to determine the safe and effective doses of the compounds that can be used for in vivo studies. Using these whole cell tests, the activity of the compounds on human and / or mouse RIP1 can be evaluated in an in vitro context, which then allows a person of ordinary skill in the art to determine a safe and effective dose for in vivo use. Another test that can be used to evaluate the activity of the compound embodiments described herein for the treatment of diseases or conditions involving RIP1 is an acute hypothermic mouse model, which evaluates the ability of the compound to inhibit TNF-α-induced hypothermia. Each of these tests, and the various results from using these tests, are described in detail in the Examples section of the present disclosure.

[0370] The dosage amount of the disclosed compound will typically be in the range of from greater than 0 mg / kg / day (such as 0.0001 mg / kg / day or 0.001 mg / kg / day or 0.01 mg / kg / day) up to at least about 100 mg / kg / day. More representatively, the dosage (or effective amount) can be about 0.0025 mg / kg to about 1 mg / kg, such as 0.01 mg / kg to about 0.5 mg / kg or about 0.05 mg / kg to about 0.15 mg / kg, given at least once a day. The total daily dose is typically about 0.1 mg / kg / day to about 5 mg / kg / day or to about 20 mg / kg / day, such as 0.5 mg / kg / day to about 10 mg / kg / day or about 0.7 mg / kg / day to about 2.5 mg / kg / day. The dosage can be higher or lower, depending on, among other factors, the activity of the disclosed compound, its bioavailability, mode of administration, and various factors discussed above.

[0371] The dose amount and dose interval can be adjusted for the individual to provide a plasma level of the disclosed compound sufficient to maintain a therapeutic or preventive effect. For example, the compound can be administered once a day, multiple times a day, once a week, multiple times a week (e.g., every other day), once a month, multiple times a month, or once a year, depending on the mode of administration, the specific indication being treated, and the judgment of the prescribing physician, among other factors. One of ordinary skill in the art will be able to optimize the effective topical dose without undue experimentation.

[0372] The pharmaceutical composition comprising one or more of the disclosed compounds generally comprises greater than 0 up to 99% of the disclosed one or more compounds, and / or other therapeutic agents (by total weight %). More representatively, the pharmaceutical composition comprising one or more of the disclosed compounds comprises about 1 to about 20 total weight % of the disclosed compounds and other therapeutic agents, and about 80 to about 99 weight % of pharmaceutically acceptable excipients. In some embodiments, the pharmaceutical composition may further comprise an adjuvant.

[0373] Preferably, the disclosed compounds, combinations of disclosed compounds, or pharmaceutical compositions thereof, will provide therapeutic or preventive benefits without causing substantial toxicity. The toxicity of the disclosed compounds can be determined using standard pharmaceutical procedures. The dose ratio between toxicity and therapeutic (or preventive) effects is the therapeutic index. Disclosed compounds that exhibit high therapeutic indices are preferred.

[0374] V. Examples

[0375] Example 1

[0376] Compounds of the present disclosure can be prepared using suitable starting compounds as exemplified in the above schemes, such as compound 200 or compound 206. A representative method for preparing compound 200 is illustrated in Scheme 4A, and a representative method for preparing compound 206 is illustrated in Scheme 4B.

[0377]

[0378]

[0379] 3-( S )- N Spectral characterization of triphenylmethyl-amino-7-bromo-5-methyl-4-oxobenzoxazepine (200): 1 H nmr (400 MHz, CDCl3) δ 7.41-7.38 (6H, m, 6H of C(C6H5)3), 7.25-7.15 (10H, m, oxybenzoxazepine H-8, 9H of C(C6H5)3), 7.00 (1H, d, J 2.5 Hz, oxybenzoxazepine H-6), 6.91 (1H,d, J 8.5 Hz, oxybenzoxazepine H-9),4.50 (1H, dd, J 10.0, 7.5 Hz, oxybenzoxazepine H-2 1H),4.37 (1H, dd, J 11.5, 10.0 Hz, 1H, s, NH4+, 3.53 (1H, dd, J 11.5, 7.5 Hz, 1H, s, NCH3+).

[0380] Example 2

[0381] Scheme 5 provides a method for preparing 4-phenoxypyridine-2-carbonitrile and 4-phenoxypyridine-2-carboxylic acid.

[0382]

[0383] Referring to Scheme 5, cesium carbonate (20.58 g, 63.1 mmol, 1.1 eq) was added to a solution of 4-fluoropyridine-2-carbonitrile 90 (7.00 g, 57.4 mmol, 1.0 eq) and phenol 92 (5.66 g, 60.2 mmol, 1.05 eq) in dimethylformamide (90 mL). The reaction was heated to 80 °C for 8 hours and cooled. The reaction was poured into ice water (1 L). A precipitate was formed, which was isolated by filtration to obtain 4-phenoxypyridine-2-carbonitrile 94 (10.7 g, 95%) as a white solid; 1 H nmr (400 MHz, CDCl3) δ 8.52 (1H, d, J 6.0 Hz, pyH-6), 7.50-7.45 (2H, m, 2H of C6H5), 7.33 (1H, tt, J 7.5, 1.0 Hz, 1H of C6H5), 7.20 (1H, d, J 2.0 Hz,pyH-3), 7.11-7.08 (2H, m, 2H of C6H5), 7.02 (1H, dd, J 5.5, 2.5 Hz, pyH-5); m / z :197 [M+H] + .

[0384] Example 3

[0385] This example relates to a method for preparing 4-phenoxypyridine-2-carboxylic acid 96 from 4-phenoxypyridine-2-carbonitrile 94. A suspension of pyridine-2-carbonitrile 94 (10.7 g, 54.6 mmol) in hydrochloric acid (6M, 100 mL) was heated to 100°C for 8 hours. The reaction was cooled to room temperature and a precipitate formed which was isolated by filtration. The filtrate was cooled and further solids formed which were isolated by filtration and added to the first batch. The solids were dried under vacuum to obtain 4-phenoxypyridine-2-carboxylic acid 96 (12.6 g, 92%) as a white solid; 1 H nmr (400 MHz, D6-DMSO) δ 8.64 (1H, d, J 6.0 Hz, pyH-6), 7.57-7.53 (3H, m, pyH-3, 2H of C6H5), 7.38 (1H, tt, J 7.5, 1.0 Hz, 1H of C6H5), 7.33 (1H, dd, J 6.0 2.5 Hz, pyH-5), 7.28-7.26 (2H, m, 2H of C6H5); m / z : 216[M+H] + .

[0386] Example 4

[0387] This example relates to a method for preparing 5-(4-fluorophenoxy)pyridine-2-carboxylic acid. N-Methylpyrrolidone (5 mL) was added to a mixture of fluoropyridine-2-carboxylic acid methyl ester (0.400 g, 2.58 mmol, 1.0 eq), 4-fluorophenol (0.318 g, 2.84 mmol, 1.1 eq) and cesium carbonate (0.925 g, 2.84 mmol, 1.1 eq). The reaction was stirred at 95 ° C for 75 minutes. The reaction was cooled and added to ice water (150 mL) to form a precipitate. After stirring for 15 minutes, the precipitate 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, J9.0, 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]+.

[0388] Aqueous lithium hydroxide (0.14 g in 5 mL water, 3.28 mmol, 1.5 eq) was added to a solution of the methyl ester (0.54 g, 2.19 mmol, 1.0 eq) in tetrahydrofuran (12 mL). The reaction was stirred at room temperature for 35 minutes and concentrated to remove organic matter. The solution was diluted with water (5 mL) and hydrochloric acid (3M, about 1 mL) was added to pH ~ 3. A white precipitate was obtained, which was isolated by filtration. Further hydrochloric acid (3M, 10 batches) was added to the filtrate to form 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 8.50.5 Hz, pyH-2), 7.39 (1H, dd, J 8.5, 3.0 Hz, pyH-4), 7.33-7.22 (4H, m, C6H4F); 19F nmr (380 MHz, D6-DMSO) δ -117.7; m / z: 234 [M+H]+.

[0389] Example 5

[0390] This example relates to a method for preparing 4-cyclobutoxypyridine-2-carboxylic acid as shown in Scheme 6 below.

[0391]

[0392] A solution of cyclobutanol 102 (0.30 mL, 3.84 mmol, 1.2 eq) in tetrahydrofuran (20 mL) was cooled to 0°C. Sodium hydride (0.154 g of a 60% suspension, 3.84 mmol, 1.2 eq) was added and the reaction was stirred at 0°C for 25 minutes. Fluoropyridine-2-carbonitrile 100 (0.390 g, 3.20 mmol, 1.0 eq) was added and the reaction was stirred at room temperature for 2 hours. The reaction was quenched by the addition of NH4Cl (5 mL). The reaction was diluted with EtOAc (80 mL) and washed with NaHCO3 (80 mL). The aqueous phase was extracted with EtOAc (30 mL). The combined organics were washed with brine (60 mL), dried (Na2SO4) and concentrated under reduced pressure. MPLC (10→60% EtOAc-hexanes) afforded 4-cyclobutoxypyridine-2-carbonitrile 104 (0.487 g, 88%) as a colorless oil. 1H nmr (400 MHz, CDCl3) δ 8.46 (1H, d, J 5.5 Hz, pyH-6), 7.10 (1H, d,J 2.5 Hz, pyH-3), 6.88 (1H, dd, J 5.5, 2.5 Hz,pyH-5), 4.72 (1H, quintet, J 7.0 Hz, cBuH-1), 2.53-2.46 (2H, m, cBuH-2, 2H of H-4),2.26-2.16 (2H, m, cBuH-2, 2H of H-4), 1.98-1.89 (1H, m, 1H of cBuH-3), 1.82-1.71 (1H, m, 1H of cBuH-3).

[0393] Hydrochloric acid (6M, 7 mL) was added to 4-cyclobutoxypyridine-2-carbonitrile 104 (0.487 g, 2.80 mmol) and the reaction was heated to 100 °C for 18 hours. The reaction was cooled but no precipitate was formed. The solution was concentrated to dryness to give a light brown solid 4-cyclobutoxypyridine-2-carboxylic acid 106, which was used without further purification. 1 H nmr (400 MHz, D6-DMSO) δ 8.66 (1H, d, J 6.5 Hz, pyH-6), 7.69 (1H, dd, J 2.5 Hz, pyH-3), 7.50 (1H, dd, J 6.5, 2.5 Hz,pyH-5), 5.12 (1H, quintet, J 7.0 Hz, cBuH-1), 2.53-2.46 (2H, m, cBuH-2, 2H of H-4), 2.19-2.09 (2H, m, cBuH-2, 2H of 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] + .

[0394] Example 6

[0395] This example provides the preparation of pyrazole-1-carbonyl chloride according to Scheme 7 by forming an intermediate N -substituted-4-[(aryl / heteroaryl)methyl]-1 H -pyrazole-1-carboxamide method.

[0396]

[0397] To a stirred heterogeneous mixture of 4-[(aryl / heteroaryl)methyl]-1H-pyrazole hydrochloride 1400 (1 eq) and triphosgene (1.5 eq) in CHCl (15 mL / mmol) at 0°C under nitrogen was added i-PrNEt (5-9 eq) over time (15 min / mmol). The red reaction solution was stirred at 0°C for 1 h, warmed to room temperature (2 h), analyzed by LC / MS for consumption of 4-[(aryl / heteroaryl)methyl]-1H-pyrazole, and concentrated to dryness to provide 1402. The red semi-solid concentrate was added to 1404 or the corresponding amine or its salt (1 eq) and DMAP (0.1 eq) and cooled in an ice bath under nitrogen. CHCl (15 mL / mmol) was added to the flask, stirred for 15 min, and the stirred red solution was treated with i-PrNEt (5-9 eq) over time (15 min / mmol). The ice bath was removed after 1 hour and the reaction solution was warmed to room temperature. When analyzing the reaction progress, the reaction solution was concentrated to dryness, diluted with water and extracted with EtOAc or CH Cl. The silica gel rapid column chromatography purification of the crude concentrate provided the required N-substituted-4-[(aryl / heteroaryl)methyl]-1H-pyrazole-1-carboxamide 1406 (yield: 20-75%).

[0398] Example 7

[0399] This example provides a method for preparing N-substituted-4-[(aryl / heteroaryl)methyl]-1H-pyrazole-1-carboxamides according to Scheme 8 via formation of an intermediate isocyanate.

[0400]

[0401] i-Pr2NEt (10-15 eq) was added to a stirred heterogeneous mixture of compound 1420, or its corresponding amine or its salt (1 eq), and triphosgene (2.3 eq) in CH2Cl2 (15 mL / mmol) at 0°C over time (20 min / mmol) under nitrogen. The light yellow reaction solution was stirred at 0°C for 1 h, warmed to room temperature (2 hours), analyzed for corresponding amine consumption by LC / MS, and concentrated to dryness. 4-[(aryl / heteroaryl)methyl]-1H-pyrazole hydrochloride 1424 (0.9 eq) and DMAP (0.1 eq) were added to the red semi-solid concentrate containing compound 1422 and cooled in an ice bath under nitrogen. CH2Cl2 (15 mL / mmol) was added to the flask, stirred for 15 minutes, and the stirred red solution was treated with i-Pr2NEt (10-15 eq) over time (15 min / mmol). The ice bath was removed after 1 hour and the reaction solution was warmed to room temperature (6-8 hours). During the analysis process, the reaction solution was concentrated to dryness, diluted with water, and extracted with EtOAc or CH Cl. The silica gel rapid column chromatography purification of the crude obtained provided the required N-substituted-4-[(aryl / heteroaryl)methyl]-1H-pyrazole-1-carboxamide 1426 (yield: 19-73%).

[0402] Example 8

[0403] This example provides the preparation of disclosed 4-[(aryl / heteroaryl)methyl]-1- H - A method of an embodiment of a pyrazole compound.

[0404]

[0405] A stirred mixture of 1-boc-pyrazole-4-boronic acid pinacol ester 1450 (1 mmol), (chloromethyl)arene / heteroarene (1.3 mmol) 1452, XPhos-Pd-G2 (0.05 mmol) and K2CO3 (3-4 mmol) in 1,4-dioxane:H2O (9:1, 10 mL / mmol) was degassed by high vacuum and backflushed with argon in a balloon in three cycles over a period of 5-10 minutes and heated at 70-75°C for 2-6 hours. The reaction mixture was cooled and concentrated to dryness. The crude residue was diluted with EtOAc (or CH2Cl2), water and saturated aqueous Na2CO3 solution (6 mL / mmol). The organic layer was separated and the aqueous layer was extracted with EtOAc (or CH2Cl2). The combined organic layers were washed with aqueous NaCl solution, stirred over anhydrous Na2SO4, and filtered through celite®. After the filtrate was concentrated, the crude product was purified by silica gel chromatography to obtain tert-butyl 4-[(aryl / heteroaryl) methyl]-1H-pyrazole-1-carboxylate (yield 49-85%) 1454. 4.0N HCl / 1,4-dioxane (5-7eq) was added to a stirred solution of 4-[(aryl / heteroaryl) methyl]-1H-pyrazole (1 eq) in CH2Cl2 (3-6 mL / mmol) at room temperature. The reaction mixture was stirred until tert-butyl 4-[(aryl / heteroaryl) methyl]-1H-pyrazole-1-carboxylate was exhausted and concentrated to dryness. The crude solid was sonicated in EtOAc (6-7 mL / mmol), filtered, washed on a funnel with EtOAc, and suction dried for a short time. Thus, the collected semi-dried solid was further dried under high vacuum and gave 4-[(aryl / heteroaryl)methyl]-1H-pyrazole hydrochloride 1456 (80-98%) and used in the next step without further purification (purity >95%).

[0406] Example 9

[0407]

[0408] ( S )-5-Benzyl- N -(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[ b [1,4]oxazepine-3-yl)-1 H -1,2,4-triazole-3-carboxamide

[0409] 1H nmr (400 MHz, CDCl3) δ 8.10 (1H, d, J Hz, NH), 7.33 (1H, m, oxobenzoxazepine H-6), 7.31 (1H, dd, J 8.0, 2.5 Hz, oxobenzoxazepine H-8), 7.15 (5H, br s, C6H5), 7.02 (1H, dd, J 8.0, 1.0 Hz, oxobenzoxazepine H-9), 4.10 (2H, s, C H 2C6H5), 3.36 (3H, s, NCH3); 13 C (100 MHz, 100 MHz) δ 168.7,158.9, 149.1, 137.4, 135.8,130.6, 128.8, 128.7, 127.1, 126.4, 118.1, 77.2,49.2, 35.5, 32.9; m / z : 458, 456 [M+H] + (Measured value [M+H] + , 458.0651, C 20 H 18 BrN5O3 requires [M+H] + 458.0645).

[0410]

[0411] ( S )-5-Benzyl- N -(7-bromo-4-oxo-2,3,4,5-tetrahydrobenzo[ b [1,4]oxazepine-3-yl)-1 H -1,2,4-triazole-3-carboxamide

[0412] 1H nmr (400 MHz, CD3OD) δ 7.32-7.21 (7H, m, C6H5, oxobenzoxazepine H-6, H-8), 7.06 (1H, d, J 8.0 Hz, oxobenzoxazepine H-9), 5.00 (1H, dd, J 10.5, 6.5 Hz, oxobenzoxazepine H-3), 4.61 (1H, dd, J 10.5, 6.5 Hz, 1H of oxobenzoxazepine H-2), 4.40 (1H, t, J 9.5 Hz, 1H of oxobenzoxazepine H-2), 4.15 (2H, s, CH2C6H5); m / z : 444, 442 [M+H] + (Measured value [M+H] + , 444.0492,C 19 H 16 BrN5O3 requires [M+H] + 444.0489).

[0413] The following examples provide synthetic procedures for preparing embodiments of pyridine-containing compounds as disclosed by this application.

[0414] ( S )-1-Benzyl-4-fluoro- N -(5-methyl-4-oxo-7-(8-oxa-2-azaspiro[4.5]decane-2-yl)-2,3,4,5-tetrahydrobenzo[ b [1,4]oxazepine-3-yl)-1 H -Pyrazole-3-carboxamide (I-1).

[0415]

[0416] MS (ESI, m / e ) Calculated value 533.2438; Found 534.1 M+H] + .

[0417] (±)-4-Benzyl- N -(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1 H -Benzo[ b ]azepine-3-yl)-1-pyrazole-1-carboxamide (racemic version of I-2)

[0418]

[0419] 1 H NMR (400 MHz, methanol- d 4) δ 7.87 (q, J = 0.8 Hz, 1H), 7.51 (s, 1H), 7.31– 7.23 (m, 2H), 7.26 – 7.14 (m, 3H), 7.10 (d, J = 8.1 Hz, 1H), 6.45 – 6.35 (m,2H), 4.38 (dd, J = 11.4, 7.7 Hz, 1H), 3.82 (s, 2H), 3.66 (d, J = 4.3 Hz, 8H), 3.37 (s, 3H), 2.74 (td, J = 13.3, 7.6 Hz, 1H), 2.63 – 2.42 (m, 2H), 2.15 – 1.98(m, 1H), 1.87 – 1.80 (m, 4H). LC / MS: purity 99%, MS (m / e) 500 (M+H) + .

[0420] ( S )-4-(4-fluorobenzyl)- N -(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydrobenzo[ b [1,4]oxazepine-3-yl)-1 H -Pyrazole-1-carboxamide (I-3)

[0421]

[0422] Route 2 1 H NMR (400 MHz, chloroform- d ) δ 7.96 (d, J = 7.5 Hz, 1H), 7.85 (q, J =0.9 Hz, 1H), 7.45 (d, J = 0.9 Hz, 1H), 7.17 – 7.08 (m, 2H), 7.07 – 6.92 (m, 3H), 6.28 (dd, J = 8.6, 2.7 Hz, 1H), 6.21 (d, J = 2.7 Hz, 1H), 4.90 (dt,J = 11.0, 7.5Hz, 1H), 4.61 (dd, J = 9.7, 7.6 Hz, 1H), 4.20 (dd, J = 11.1, 9.8 Hz, 1H), 3.78(s, 2H), 3.71 – 3.61 (m, 8H), 3.40 (s, 3H), 1.86 (t, J = 5.3 Hz, 4H). LC / MS: purity 97%, MS (m / e) 520 (M+H) + .

[0423] (S)- N -(5-methyl-7-(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[ b [1,4]Oxazepine-3-yl)-4-phenoxypyridine-2-carboxamide (I-5)

[0424]

[0425] 1 H NMR (400 MHz, dichloromethane- d 2) δ 8.74 (d, J = 7.4 Hz, 1H), 8.48 (d, J = 5.6Hz, 1H), 7.57 (d, J = 2.5 Hz, 1H), 7.51 – 7.41 (m, 2H), 7.34 – 7.25 (m, 1H), 7.14 – 7.09 (m, 2H), 7.07 (d, J = 8.8 Hz, 1H), 6.99 (dd, J = 5.6, 2.6 Hz, 1H),6.80 (dd, J = 8.8, 2.9 Hz, 1H), 6.75 (d, J = 2.8 Hz, 1H), 4.97 (dt, J = 11.1, 7.4Hz, 1H), 4.63 (dd, J = 9.7, 7.5 Hz, 1H), 4.16 (dd, J= 11.1, 9.7 Hz, 1H), 3.40(s, 3H), 3.18 – 3.10 (app m, 4H), 2.41 – 2.34 (app m, 4H), 2.26 (s, 3H), 1.66– 1.54(m, 8H). LCMS: purity 98%, MS (m / e) 556 (M+H) + .

[0426] (±)-5-Benzyl- N -(2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-1 H -1,2,4-Triazole-3-carboxamide (I-11)

[0427]

[0428] LCMS: purity 95%, MS (m / e) 487 (M+H) + .

[0429] (±)- N -(8-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-5-benzyl-1H-1,2,4-triazole-3-carboxamide (I-12)

[0430]

[0431] 1 H NMR (400 MHz, methanol- d 4) δ 7.34 – 7.17 (m, 5H), 7.10 (d, J = 8.4 Hz,1H), 6.79 – 6.69 (m, 2H), 4.53 (dd, J = 11.4, 7.8 Hz, 1H), 4.13 (s, 2H), 3.62(t, J = 5.6 Hz, 2H), 3.36 (s, 3H), 3.22 – 3.11 (m, 7H), 2.72 (td, J = 13.3, 7.7Hz, 1H), 2.57 (dd, J= 13.7, 7.0 Hz, 1H), 2.53 – 2.38 (m, 1H), 2.18 (s, 2H), 2.07 (td, J = 11.9, 7.4 Hz, 1H), 1.88 (dtt, J = 14.9, 10.1, 4.9 Hz, 2H). LCMS: purity 97%, MS (m / e) 500 (M+H) + .

[0432] (±)-5-Benzyl- N -(1-methyl-2-oxo-8-(2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1 H -Benzo[b]azepine-3-yl)-1 H -1,2,4-Triazole-3-carboxamide (I-13)

[0433]

[0434] 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), 3.36 (s, 3H), 2.73 (dd, J =12.9, 7.3 Hz, 1H), 2.62 (ddd, J = 19.9, 12.9, 7.1 Hz, 1H), 2.49 (dd, J = 13.1,6.5 Hz, 1H), 1.95 (td, J = 11.6, 7.2 Hz, 1H), 1.68 (d, J = 6.2 Hz, 4H), 1.46 (s,4H), 1.40 (s, 2H). LCMS: purity 97%, MS (m / e) 499 (M+H) + .

[0435] (±)-5-Benzyl- N -(1-methyl-2-oxo-8-(3-oxa-9-azaspiro[5.5]undec-9-yl)-2,3,4,5-tetrahydro-1 H -Benzo[b]azepine-3-yl)-1 H -1,2,4-Triazole-3-carboxamide (I-14)

[0436]

[0437] 1 H NMR (400 MHz, chloroform- d ) δ 11.58 (s, 1H), 8.05 (d, J = 7.7 Hz, 1H),7.33 – 7.18 (m, 5H), 7.06 (d, J = 8.4 Hz, 1H), 6.76 (dd, J = 8.4, 2.5 Hz, 1H), 6.70 (s, 1H), 4.62 (dt, J = 11.0, 7.6 Hz, 1H), 4.11 (s, 2H), 3.72 – 3.64 (m,4H), 3.37 (s, 3H), 3.15 (t, J = 5.8 Hz, 4H), 2.82 – 2.69 (m, 1H), 2.62 (ddd, J =19.6, 12.6, 7.1 Hz, 1H), 2.52 (dd, J = 12.9, 6.6 Hz, 1H), 1.97 (td, J = 11.6, 7.3Hz, 1H), 1.69 (app t, J = 5.8 Hz, 4H), 1.62 – 1.53 (m, 4H). LCMS: purity 95%, MS (m / e) 529 (M+H) + .

[0438] (±)-5-Benzyl- N -(1-(methyl- d 3 )-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-1 H-1,2,4-Triazole-3-carboxamide (I-15)

[0439]

[0440] 1 H NMR (400 MHz, methanol- d 4) δ 7.32 – 7.16 (m, 5H), 7.07 (d, J = 8.1 Hz,1H), 6.39 (d, J = 2.3 Hz, 1H), 6.35 (dd, J = 8.1, 2.3 Hz, 1H), 4.51 (dd, J = 11.4,7.7 Hz, 1H), 4.11 (s, 2H), 3.68 – 3.61 (m, 4H), 3.62 (s, 4H), 2.71 (td, J =13.4, 7.6 Hz, 1H), 2.55 (dd, J = 13.8, 6.9 Hz, 1H), 2.44 (tt, J = 12.8, 7.4 Hz,1H), 2.12 – 1.99 (m, 1H),1.84 – 1.77 (m, 4H). LCMS: purity 948, MS (m / e) 504 (M+H) + .

[0441] (S)-5-Benzyl- N -(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1 H -1,2,4-Triazole-3-carboxamide (I-16)

[0442]

[0443] 1 H NMR (400 MHz, chloroform- d ) δ 11.79 (s, 1H), 8.07 (d, J = 7.8 Hz, 1H),7.32 –7.21 (app m, 5H), 7.04 (d, J = 8.2 Hz, 1H), 6.29 (dd, J= 8.2, 2.3 Hz, 1H),6.22 (d, J = 2.3 Hz, 1H), 4.65 (app s, 1H), 4.14 (s, 2H), 3.71 (m, 8H), 3.37(s, 3H), 2.76 (td, J = 12.9, 7.5 Hz, 1H), 2.62 (ddd, J = 19.8, 12.9, 7.3 Hz, 1H),2.51 (dd, J = 13.1, 6.6 Hz, 1H), 1.98 (td, J = 11.6, 7.2 Hz, 1H), 1.89 – 1.82 (m,4H). LCMS: rt 1.50 min (A), purity 96%, MS (m / e) 501 (MH + ).

[0444] (±)-4-Benzyl- N -(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-1H-pyrazole-1-carboxamide (I-17)

[0445]

[0446] 1 H NMR (400 MHz, methanol- d 4) δ 7.87 (q, J = 0.8 Hz, 1H), 7.51 (s, 1H), 7.31– 7.23 (m, 2H), 7.26 – 7.14 (m, 3H), 7.10 (d, J = 8.1 Hz, 1H), 6.45 – 6.35 (m,2H), 4.38 (dd, J = 11.4, 7.7 Hz, 1H), 3.82 (s, 2H), 3.66 (d, J = 4.3 Hz, 8H), 3.37 (s, 3H), 2.74 (td, J= 13.3, 7.6 Hz, 1H), 2.63 – 2.42 (m, 2H), 2.15 – 1.98(m, 1H), 1.87 – 1.80 (m, 4H). LC / MS: purity 99%, MS (m / e) 500 (M+H) + .

[0447] (±)- N -(1-methyl-2-oxo-8-(3-oxa-9-azaspiro[5.5]undec-9-yl)-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-4-phenoxypyridine-2-carboxamide (I-18)

[0448]

[0449] 1 H NMR (400 MHz, chloroform- d ) δ 8.82 (d, J = 7.7 Hz, 1H), 8.41 (dd, J = 5.6,0.5 Hz, 1H), 7.59 (dd, J = 2.6, 0.5 Hz, 1H), 7.43 – 7.34 (m, 2H), 7.26 – 7.17(m, 1H), 7.10 – 7.01 (m, 3H), 6.91 (dd, J = 5.6, 2.6 Hz, 1H), 6.75 (dd, J = 8.4,2.5 Hz, 1H), 6.69 (d, J = 2.4 Hz, 1H), 4.63 (dt, J = 11.2, 7.7 Hz, 1H), 3.71 –3.64 (m, 4H), 3.39 (s, 3H), 3.18 – 3.10 (m, 4H), 2.79 (td, J = 12.7, 7.6 Hz,1H), 2.70 – 2.57 (m, 1H), 2.53 (dd, J = 13.0, 6.8 Hz, 1H), 2.07 – 1.94 (m, 1H),1.73 – 1.65 (m, 4H), 1.57 – 1.50 (m, 4H). LCMS: purity 98%, MS (m / e) 541 (M+H)+ .

[0450] (±)- N -(1-(methyl- d 3 )-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-4-phenoxypyridine-2-carboxamide (I-19)

[0451]

[0452] 1 H NMR (400 MHz, chloroform- d ) δ 8.80 (d, J = 7.8 Hz, 1H), 8.41 (dd, J = 5.6,0.5 Hz, 1H), 7.59 (dd, J = 2.5, 0.5 Hz, 1H), 7.43 – 7.34 (m, 2H), 7.22 (ddt, J =7.9, 7.0, 1.1 Hz, 1H), 7.11 – 6.99 (m, 3H), 6.90 (dd, J = 5.6, 2.6 Hz, 1H),6.27 (dd, J = 8.1, 2.3 Hz, 1H), 6.20 (d, J = 2.3 Hz, 1H), 4.63 (dt, J = 11.3, 7.7Hz, 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, 6.9 Hz, 1H), 2.05 – 1.93 (m, 1H),1.87 – 1.79 (m,4H). LCMS: purity 97%, MS (m / e) 516 (M+H) + .

[0453] (±)- N -(1-methyl-2-oxo-8-(2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1 H -Benzo[ b]Azacycloheptatrien-3-yl)-4-phenoxypyridine-2-carboxamide (I-20)

[0454]

[0455] 1 H NMR (400 MHz, chloroform- d ) δ 8.81 (d, J = 7.8 Hz, 1H), 8.41 (d, J = 5.6 Hz,1H), 7.60 (d, J = 2.5 Hz, 1H), 7.45 – 7.34 (m, 2H), 7.26 – 7.17 (m, 1H), 7.09 –7.01 (m, 2H), 7.00 (d, J = 8.1 Hz, 1H), 6.91 (dd, J = 5.6, 2.6 Hz, 1H), 6.25 (dd, J = 8.2, 2.3 Hz, 1H), 6.19 (d, J = 2.3 Hz, 1H), 4.64 (dt, J = 11.2, 7.7 Hz, 1H), 3.52 (s, 4H), 3.37 (s, 3H), 2.77 (td, J = 12.9, 7.5 Hz, 1H), 2.61 (tt, J = 12.3,7.3 Hz, 1H), 2.50 (dd, J = 13.2, 6.8 Hz, 1H), 2.06 – 1.92 (m, 1H), 1.68 (t, J =5.7 Hz, 4H), 1.45 (d, J = 5.9 Hz, 4H), 1.45 – 1.35 (m, 2H).LCMS: purity 98%, MS(m / e) 511 (M+H) + .

[0456] (±)- N -(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-4-phenoxypyridine-2-carboxamide (I-21)

[0457]

[0458] 1 H NMR (400 MHz, chloroform- d ) δ 8.81 (d, J = 7.8 Hz, 1H), 8.41 (dd, J = 5.6,0.5 Hz, 1H), 7.60 (dd, J = 2.6, 0.5 Hz, 1H), 7.46 – 7.34 (m, 2H), 7.25 – 7.18 (m, 1H), 7.09 – 7.00 (m, 3H), 6.91 (dd, J = 5.6, 2.6 Hz, 1H), 6.27 (dd, J = 8.1,2.3 Hz, 1H), 6.21 (d, J = 2.3 Hz, 1H), 4.64 (dt, J = 11.2, 7.7 Hz, 1H), 3.66 (t, J = 5.2 Hz, 4H), 3.63 (s, 4H). 3.38 (s, 3H), 2.84 – 2.72 (m, 1H), 2.68 – 2.47(m, 2H), 2.00 (td, J = 11.6, 7.3 Hz, 1H), 1.87 – 1.80 (m, 4H).LCMS: purity 96%,MS (m / e) 513 (M+H) + .

[0459] (S)-1-Benzyl- N -(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1 H -Benzo[ b ]Azacycloheptatrien-3-yl)-1 H -Pyrazole-3-carboxamide (I-22)

[0460]

[0461] 1 H NMR (400 MHz, chloroform- d ) δ 7.80 (d, J= 7.6 Hz, 1H), 7.42 – 7.26 (m,4H), 7.26 – 7.18 (m, 2H), 7.04 (d, J = 8.1 Hz, 1H), 6.72 (d, J = 2.3 Hz, 1H),6.29 (dd, J = 8.1, 2.3 Hz, 1H), 6.22 (d, J = 2.3 Hz, 1H), 5.31 (s, 2H), 4.68 (dt, J = 11.0, 7.6 Hz, 1H), 3.68 (t, J = 5.2 Hz, 4H), 3.65 (s, 4H), 3.39 (s, 3H), 2.79 – 2.59 (m, 2H), 2.52 (dd, J = 13.0, 6.5 Hz, 1H), 2.04 – 1.92 (m, 1H), 1.89– 1.82 (m, 4H). LCMS: purity 95%, MS (m / e) 500 (M+H) + .

[0462] Example 10

[0463] This example provides a general method for preparing (S)-N-(8-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-4-phenoxypyridine-2-carboxamide (I-10) as shown in Scheme 10.

[0464]

[0465] After three degassing cycles with argon backsweep after vacuum, the 0 Heating at C S )- N-(8-Bromo-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-4-phenoxypyridine-2-carboxamide (71 mg, 0.152 mmol) – see data below – A stirred mixture of 2-chloropyridine-5-boronic acid pinacol ester (47 mg, 0.196 mmol), Pd(PPh3)4 (13 mg, 0.01 mmol), Cs2CO3 (149 mg, 0.456 mmol) in 1,4-dioxane (3 mL): water (0.3 mL). After 6 h, the reaction mixture was cooled to room temperature, diluted with THF (10 mL) and filtered through Celite®. After the filtrate was concentrated, the crude material was diluted with water (3 mL) and extracted into EtOAc (3 X 15 mL). After washing the combined organic layers with saturated aqueous NaCl (10 mL), stirring over anhydrous Na2SO4, polish filtered and concentrated to dryness. The resulting crude material was dissolved in CH2Cl2 (2 mL), loaded onto hexane-treated silica gel in a cartridge and purified by flash chromatography [Combiflash ® Teledyne RediSep ® Hexane conditioned silica gel column (12 GGold) and eluted with 0-35% EtOAc / hexane solvent] and obtained ( S )- N -(8-(6-chloropyridin-3-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1 H -Benzo[ b ]azepine-3-yl)-4-phenoxypyridine-2-carboxamide (35 mg, 46%). 1 H NMR (400 MHz, CDCl3) δ 8.85 (d, J = 7.8 Hz, 1H), 8.58 (dd, J = 2.6, 0.7 Hz, 1H), 8.43 (dd, J = 5.6, 0.5 Hz, 1H), 7.81 (dd, J = 8.3, 2.6 Hz,1H), 7.60 (dd, J = 2.6, 0.5 Hz, 1H), 7.45 – 7.31 (m, 6H), 7.23 (ddt, J = 7.9,7.0, 1.1 Hz, 1H), 7.10 – 7.02 (m, 2H), 6.93 (dd,J = 5.6, 2.6 Hz, 1H), 4.68(dt, J = 11.3, 7.3 Hz, 1H), 3.48 (s, 3H), 3.02 – 2.87 (m, 1H), 2.79 – 2.64 (m,2H), 2.19 – 2.04 (m, 1H). LCMS: purity 93%, MS (m / e) 500 (M+H) + . In 90 0 C using CuI (2.7 mg, 0.014 mmol) and Pd(PPh3)4 (8.1 mg, 0.007 mmol) / DMF (1 mL) in the presence of NEt3 (70 mg, 0.10 mL, 0.70 mmol) as described by ( S )- N -(8-(6-chloropyridin-3-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1 H -Benzo[ b

[0136] The general procedure for the reaction of 2-methyl-3-butyn-2-ol (35 mg, 0.07 mmol) and 2-methyl-3-butyn-2-ol (9 mg, 0.01 mL, 0.11 mmol) was described in a similar manner to the Sonogashira reaction conditions ( S )- N -(8-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1 H -Benzo[ b ]azepine-3-yl)-4-phenoxypyridine-2-carboxamide (11 mg, 28%, white solid). 1 H NMR (400 MHz, CD2Cl2) δ 8.80 (dd, J = 2.4, 0.9Hz, 1H), 8.77 (d, J = 7.6 Hz, 1H), 8.46 (d, J = 5.6 Hz, 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, 2.6 Hz, 1H), 4.59 (dt, J =11.1, 7.4 Hz, 1H), 3.47 (s, 3H), 3.03 – 2.89 (m, 1H),2.78 – 2.64 (m, 2H),2.27 (br s, 1H), 2.11 – 2.04 (m, 1H), 1.63 (s, 6H). LCMS: purity 92%, MS (m / e) 547 (M+H) + .

[0466] Embodiment 11

[0467] In this example, compounds of the disclosure were evaluated using a biochemical assay using ADP-Glo™ technology.

[0468] ADP-Glo™ (Promega, Madison, WI, USA) reagent was thawed at ambient temperature. Kinase assay reagent was prepared by mixing kinase assay buffer with lyophilized kinase assay substrate.

[0469] Prepare a 500 mL stock volume of 5X reaction kinase buffer by mixing 1000 μL 1 M MgCl 2, 500 μL 1 M Tris-HCL pH 7.4, 0.5 mg / mL (25 mg) of BSA and 3475 μL distilled H 2 O. Prepare a 3 mL 2X working stock volume of reaction kinase buffer containing a final concentration of 100 μM DTT and 4 mM MnCl 2.

[0470] Thaw the components of RIPK1 enzyme (Rigel Pharmaceuticals, South SanFrancisco, CA, USA) on ice. Prepare diluted RIPK1 to 31 ng / well in 1X kinase reaction buffer (diluted from 2X buffer). Prepare 166 μM working stock ATP assay solution in 1X kinase reaction buffer (diluted from 2X buffer).

[0471] In a 96-well plate, compounds were serially diluted in DMSO from 250uM in 4-fold dilutions and then diluted 1:5 in 2X reaction buffer. 1.0uL of diluted compound was added to a 384-well plate in duplicate. 2μL of diluted active RIPK1 was added to a 384-well plate (not added to column 1), and 2X reaction buffer was added to column 1. 150nM AKT (Anaspec, Fremont, CA, USA) was combined with ATP working stock solution in equal volumes and 2uL / well was added to a 384-well plate. The final reaction volume was 5.0μL.

[0472] The plate was centrifuged quickly and the reaction was incubated at 30°C for 30 minutes. 5 μL ADP-GloTM was added to terminate the reaction. The plate was centrifuged quickly and the reaction was incubated at room temperature for 40 minutes. The kinase detection reagent was then added and incubated at room temperature for 30 minutes. The relative light units (RLU) of the kinase reaction were determined by luminescence (luminescence 0.1 s) using a Wallac Victor2 luminometer (PerkinElmer, Waltham, MA, USA). Table 1 provides the IC values ​​obtained from this example. 50 value.

[0473]

[0474] Example 12

[0475] In this example, U937 and L929 cells were exposed to compounds of the disclosure and cell necrosis assays were performed to evaluate the activity of the compounds against human and murine RIP1.

[0476] U937 and L929 cells were obtained from American Type Culture Collection (Manassa, VA, USA). At 37 ° C and 5% CO2, in complete RPMI 1640 culture medium (Sigma, ST Louis, MO, USA) supplemented with 10% fetal bovine serum (Sigma, ST Louis, MO, USA), both cells were maintained in the logarithmic growth phase. For necrosis assay, L929 cells were plated in 100 μL / well culture medium at 10K cells / well in Costar 96-well black transparent bottom plates (Fisher Scientific, Hampton, NH, USA) for 18h; on the day of the test, U937 cells were plated in 50 μL / well culture medium containing 60uM zVAD-fmk (Lonza, Basel, Switzerland) at 50K cells / well. The culture medium was removed from the L929 cells of the 96-well plate and replaced with a new culture medium containing 40uM zVAD-fmk of 50 μL / well. Each compound of the present disclosure evaluated in this embodiment was serially diluted by 4 times dilution in DMSO from 2.5mM, and then diluted 1:125 in complete medium.Then the compound of 2x of 50 μ L / holes was added to the cells in the flat board.The cells were pre-incubated for 1 hour at 37 ° C and 5% CO2 together with the compound, and then the 11x TNFa (Peprotech, Rocky Hill, NJ, the U.S.) of 10 μ L / holes was added to obtain the final concentration 2ng / mL of TNFa.After TNFa stimulated 18 hours at 37 ° C and 5% CO2, WallacVictor2 photometer (PerkinElmer, Waltham, MA, the U.S.) and CellTiter-Glo® luminescent cell viability reagent were used to measure (Promega, Madison, WI, the U.S.) (add according to the manufacturer's instructions), and the relative amount of necrotic cells was determined by luminescence.The results from the present embodiment are summarized in Table 2. This example establishes that embodiments of the compounds described herein have unexpectedly potent activity against human and murine RIP1, which allows their evaluation in in vivo mouse models of disease. These results can be used to determine safe and effective doses for humans.

[0477]

[0478]

[0479] * ND indicates that no activity was detected, or that the inhibition curve showed artifacts. This value does not necessarily indicate an inactive compound, but indicates that the experiment did not produce data for some reason. For example, insoluble compounds or other experimental artifacts can produce an "ND" value.

[0480] Example 13

[0481] In this example, an acute hypothermia mouse model assay was used to evaluate the ability of compounds disclosed herein to inhibit TNF-α-induced hypothermia.

[0482] Female C57BL / 6 mice were randomized and weighed on day -1. On the day of the study (day 0), mice were given vehicle or test article by oral gavage. Fifteen minutes after oral administration of the test agent, each mouse was given an intraperitoneal (IP) injection of a solution containing recombinant human tumor necrosis factor alpha (TNF-a, 25.0 μg) and zVAD-FMK (200 μg). Body temperature was measured at hour 0 (before IP injection) and every hour via a rectal probe temperature measurement device. Three (3) hours after IP injection of TNF-a and zVAD / FMK, mice were euthanized by CO2 asphyxiation and blood was collected via cardiac puncture. Serum and plasma were harvested for determination of cytokine and compound levels, respectively. A separate group of mice (satellite mice) was included for determination of compound levels in plasma at the time of administration of TNFa / zVAD-FMK.

[0483] (S)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4H-1,2,4-triazole-3-carboxamide (WO 2014 / 125444), having the structure exemplified below, was used as a comparative compound and tested using a similar procedure as described in WO 2014 / 125444. According to WO 2014 / 125444, this comparative compound exhibited 93% inhibition at a dose of 30 mg / kg; however, in the inventors' case, the compound exhibited only 70% at 30 mg / kg. In contrast, using a similar assay procedure as described above, Compound I-30 of the present disclosure achieved greater than 85% inhibition at a dose of only 5 mg / kg.

[0484]

[0485] Comparative compounds

[0486] Certain embodiments of the present invention provide compounds (one or more) or compositions thereof that cross the blood-brain barrier. The disclosed compound and composition embodiments exhibit sufficient brain permeability as potential therapeutic agents for neurological diseases. Brain permeability can be assessed by evaluating the free brain / plasma ratio (Bu / Pu), as measured in in vivo pharmacokinetic studies in rodents. Other methods for assessing brain permeability are known to those of ordinary skill in the art. See, for example: Liu, X. et al., J. Pharmacol. Exp. Therap., 325:349-56, 2008.

[0487] Table 3 below provides additional biological data for representative compounds according to the present disclosure.

[0488]

[0489] In view of the many possible embodiments to which the principles of the present disclosure may be applied, it should be appreciated that the illustrated embodiments are merely preferred examples and should not be viewed as limiting. Instead, the scope of the present disclosure is defined by the following claims. We therefore claim as our invention all that falls within the scope and spirit of these claims.

Claims

1. Compounds having formula I or a pharmaceutically acceptable salt thereof, wherein: Ring B is pyridyl, pyrazolyl, triazolyl or oxadiazolyl; Each R 1 Independently R 2 is H or CH3; R 3 is H; L is O or CH2; Y is CH2; Z is Among them, each R 5 Independently for R e ; and p is 0 or 1; m is 1; n is 0; R e Each occurrence is independently halogen or C 1-6 alkyl.

2. The compound of claim 1, wherein p is 0.

3. The compound of claim 1, wherein p is 1 and R 5 It is a halogen.

4. The compound of claim 1, wherein the -LZ moiety is phenoxy, benzyl, 4-fluorobenzyl or 1-phenylcyclopropyl.

5. The compound of claim 1, wherein the compound is: I-11: 5-benzyl-N-(2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-1,2,4-triazole-3-carboxamide; I-12: N-(8-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-5-benzyl-1H-1,2,4-triazole-3-carboxamide; I-13: 5-benzyl-N-(1-methyl-2-oxo-8-(2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-1,2,4-triazole-3-carboxamide; I-14: 5-benzyl-N-(1-methyl-2-oxo-8-(3-oxa-9-azaspiro[5.5]undec-9-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-1,2,4-triazole-3-carboxamide; I-15: 5-benzyl-N-(1-(methyl-d3)-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-1,2,4-triazole-3-carboxamide; I-16: (S)-5-benzyl-N-(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-1,2,4-triazole-3-carboxamide; I-18: N-(1-methyl-2-oxo-8-(3-oxa-9-azaspiro[5.5]undec-9-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-4-phenoxypyridine-2-carboxamide; I-19: N-(1-(methyl-d3)-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-4-phenoxypyridine-2-carboxamide; I-20: N-(1-methyl-2-oxo-8-(2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-4-phenoxypyridine-2-carboxamide; or I-21: N-(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-4-phenoxypyridine-2-carboxamide.

6. A compound, wherein the compound is I-1: (S)-1-benzyl-4-fluoro-N-(5-methyl-4-oxo-7-(8-oxa-2-azaspiro[4.5]decane-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-3-carboxamide; I-2: (S)-1-benzyl-4-fluoro-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-3-carboxamide; I-3: (S)-4-(4-fluorobenzyl)-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide; I-4: (S)-N-(5-methyl-4-oxo-8-(3-oxa-9-azaspiro[5.5]undec-9-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-phenoxypyridine-2-carboxamide; I-5: (S)-N-(5-methyl-7-(9-methyl-3,9-diazaspiro[5.5]undecane-3-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-phenoxypyridine-2-carboxamide; I-6: (S)-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-phenoxypyridine-2-carboxamide; I-7: (S)-3-(2-benzyl-3-chloro-6-oxo-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-5-methyl-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one; I-8: (S)-3-(2-benzyl-3-chloro-7-oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridin-6-yl)-5-methyl-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3-dihydrobenzo[b][1,4]oxazepine-4(5H)-one; I-9: (S)-N-(5-methyl-4-oxo-7-(8-oxa-2-azaspiro[4.5]decane-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-4-phenoxypyridine-2-carboxamide; I-10: (S)-N-(8-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-4-phenoxypyridine-2-carboxamide; I-17: 4-benzyl-N-(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-pyrazole-1-carboxamide; I-22: (S)-1-benzyl-N-(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-pyrazole-3-carboxamide; I-23: (S)-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-5-(1-phenylcyclopropyl)-1,3,4-oxadiazole-2-carboxamide; I-24: (S)-5-benzyl-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1,3,4-oxadiazole-2-carboxamide; I-25: 4-benzyl-N-(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-pyrazole-1-carboxamide; I-26: (S)-4-benzyl-N-(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-pyrazole-1-carboxamide; I-27: (R)-4-benzyl-N-(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b]azepine-3-yl)-1H-pyrazole-1-carboxamide; I-28: (S)-4-benzyl-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide; or I-29: (S)-4-(4-Fluorobenzyl)-N-(5-methyl-7-(9-methyl-3,9-diazaspiro[5.5]undec-3-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepine-3-yl)-1H-pyrazole-1-carboxamide.

7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6, and further comprising one or more excipients or therapeutic agents.

8. Use of a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof in the preparation of a medicament 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.

9. The use according to claim 8, wherein the disease involves inflammation, necrosis or both.

10. The use according to claim 8, wherein the disease is an inflammatory or immunoregulatory disorder.

11. The use according to claim 8, wherein the disease is an aging disorder.

12. The use according to claim 8, wherein the disease is amyotrophic lateral sclerosis (ALS), multiple sclerosis, Parkinson's disease or Alzheimer's disease.

13. The use according to claim 8, wherein the disease is myelodysplastic syndrome.

14. The use according to claim 8, wherein the disease is atopic dermatitis, rheumatoid arthritis or ankylosing spondylitis.

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