EA047748B1 - HETEROCYCLIC COMPOUNDS THAT INHIBITE RIP1 - Google Patents

Description

Cross reference to related application

This application claims priority based on the earlier filing date of U.S. Provisional Patent Application Nos. 62/932,404, filed November 7, 2019; 63/001,016, filed March 27, 2020; 63/004,290, filed April 2, 2020; 63/004,319, filed April 2, 2020; and 63/004,301, filed April 2, 2020.

Field of technology

The present invention relates to compounds and methods for preparing and using said compounds, for example, for inhibiting receptor-interacting protein kinase-1 (RIP1), and for treating diseases and/or conditions associated with RIP1.

State of the art

Receptor-interacting protein kinase 1 (herein referred to as RIP1) belongs to the tyrosine kinase-like protein kinase family and is a serine-threonine protein kinase involved in innate immune signaling. RIP1 plays a central role in the regulation of cell signaling, and its role in programmed cell death has been linked to various inflammatory diseases such as inflammatory bowel disease, psoriasis, and other diseases and/or conditions associated with inflammation and/or necroptotic cell death.

Brief description of the invention

The disclosed compounds of the present invention may have formula I:

ABOUT

Formula I or a pharmaceutically acceptable salt thereof. In formula I, ring B is heteroaryl, such as a 5-membered or 6-membered heteroaryl, and may be pyridinyl, 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 some embodiments, m is 1. n is 0, 1, or 2. In some embodiments, n is 0, and in other embodiments, n is 1.

Each R ¹ is independently heterocyclyl optionally substituted with at least one R ⁶ , wherein each R ⁶ , if present, is independently R ^c . R ² is ^Ra , such as H or C 1-6 alkyl, and in some embodiments, R ² is CH3 or CD ₃ . R ³ is ^Ra , or R ³ together with the -NC(O) moiety to which it is attached and two ring atoms from ring B can form a 5- or 6-membered heterocyclyl that is fused to ring B. And each R ⁴ , if present, is independently ^Re .

L is a heteroatom or ^Ra , provided that ^Ra is not H or D. In some embodiments, L is a heteroatom or a _C1-10 aliphatic group such as _C1-6 alkyl, and can be O or -CH2-. And Z is a _C1-10 aliphatic or aromatic group.

R ^a is independently in each occurrence a C _1-10 aliphatic group (e.g., C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, or C _3-6 cycloalkyl), C _1-10 haloaliphatic, C _5-10 aromatic, C _3-6 heterocyclic, or C _3-10 spiroheterocyclic group, or H or D, except for embodiments wherein L is R ^a .

R ^b independently in each occurrence is -OH, -SH, -ORc, -SRc, -NR ^d R ^d , -Si(R ^a )3, -C(O)OH, -C(O)ORc, -C(O)NR ^d R ^d , -OC(O)NR ^d R ^d , -OC(O)Cl.10alkyl substituted with one or two NR ^d R ^d , carboxyl or a combination thereof, and optionally further substituted with an aromatic moiety, -SH, -O-acyl or -C(O)NH2.

R ^c independently in each occurrence is C1-10 alkyl which may be substituted with 1, 2 or 3 R ^e , C2-10 alkenyl which may be substituted with 1, 2 or 3 R ^e , C2-10 alkynyl which may be substituted with 1, 2 or 3 R ^e , C3-6 cycloalkyl which may be substituted with 1, 2 or 3 R ^e , or _C5-10 aromatic group which may be substituted with 1, 2 or 3 R ^e .

R ^d is independently in each occurrence H; C1-6 alkyl which may be substituted with 1, 2 or 3 R ^e or C3-9 heterocyclyl; _C3-6 cycloalkyl which may be substituted with 1, 2 or 3 R ^e ; C3-6 heterocyclic group which may be substituted with 1, 2 or 3 R ^e ; C5-10 aryl which may be substituted with 1, 2 or 3 R ^b ; C5-10 heteroaryl which may be substituted with 1, 2 or 3 R ^e ; or two R ^d groups together with the nitrogen atom bonded thereto form a C3-9 heterocyclic group which may be substituted with one or more R ^e , or _C5-10 heteroaryl which may be substituted with one or more R ^e .

R ^e independently in each occurrence is 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

- 1 047748

And R ^f independently in each occurrence is -alkyl phosphate, ^Ra , R ^b or ^Re , or two R ^f groups together with the carbon atom bound thereto form a C2.6 alkenyl group, a C3.6 cycloalkyl group which may be substituted by one or more ^Re , or a _C3.10 heterocyclic group which may be substituted by one or more ^Re or acyl.

Also in formula I, in some embodiments, the compound is not:

(8)-X-(7-(4-(chloromethyl)-4-(hydroxymethyl)piperidin-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide;

(8)-1-(4-fluorobenzyl)-M-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5tetrahydrobe iso[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

(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]oxazepin-3-yl)isoxazole-3-carboxamide;

(8)-1-(4-fluorobenzyl)-M-(5-methyl-4-oxo-7-(2-oxa-7-azaspiro[3.5]nonan-7-yl)-2,3,4,5tetrahydrobe nzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

(S)-5-benzyl-M-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

R-((8)-7-((18,48)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-5-benzylisoxazole-3-carboxamide;

K-((8)-7-((18,48)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-5-methyl-4-oxo-2,3,4,5tetrahydrobis[b][1,4]oxazepin-3-yl)-1-(4-fluorobenzyl)-1H-1,2,4-triazole-3-carboxamide;

(8)-1-(4-fluorobenzyl)-M-(5-methyl-7-(1,4-oxazepan-4-yl)-4-oxo-2,3,4,5tetrahydrobe iso[b][1 ,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

(8)-5-benzyl-N-(5-methyl-7-(1,4-oxazepan-4-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)isoxazole-3-carboxamide;

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

(8)-5-(4-fluorobenzyl)-M-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5tetrahydrobe nzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

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

X-((38)-7-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-benzylisoxazole-3-carboxamide;

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

(S)-5-benzyl-N-(5-methyl-4-oxo-8-(3-oxa-9-azaspiro[5.5]undecan-9-yl)-2,3,4,5tetrahydrobe iso[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

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

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

(8)-5-benzyl-M-(5-methyl-4-oxo-7-(1-oxa-8-azaspiro[4.5]decan-8-yl)-2,3,4,5tetrahydrobenzo[b] [ 1,4]oxase pin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

(8)-5-(4-fluorobenzyl)-M-(5-methyl-4-oxo-7-(1-oxa-8-azaspiro[4.5]decan-8-yl)-2,3,4,5tetrahydrobe nzo[b][1,4]oxase pin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

(8)-M-(7-(azetidin-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5benzyl -1H-1,2,4-triazole-3-carboxamide;

- 2 047748 (8)-5-benzyl-I-(5-methyl-4-oxo-7-(2-oxa-8-azaspiro[4.5]decan-8-yl)-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

(8)-5-benzyl-M-(5-methyl-4-oxo-7-(8-oxa-2-azaspiro[4.5]decan-2-yl)-2,3,4,5tetrahydrobenzo [b] [ 1,4]oxase pin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

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

(8)-5-benzyl-N-(7-(2-benzyl-1-oxo-2,9-diazaspiro[5.5]undecan-9-yl)-5-methyl-4-oxo2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

(8)-5-benzyl-M-(5-methyl-4-oxo-7-(3-oxa-9-azaspiro[5.5]undecan-9-yl)-2,3,4,5tetrahydrobenzo[b] [ 1,4]oxase pin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

(8)-5-benzyl-N-(7-(3,3-difluoroazetidin-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide; or (S)-5-benzyl-N-(7-(3-fluoroazetidin-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide.

And in certain embodiments of formula I, the compound is not:

1-1: (S)-1-benzyl-4-fluoro-N-(5-methyl-4-oxo-7-(8-oxa-2-azaspiro[4.5]decan-2-yl)-2,3,4,5-tetrahydrobenzo[b]1,41-oxazepin-3-yl)-1H-pyrazole-3-carboxamide;

1-2: (S)-1-benzyl-4-φτορ-Ν-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3 ,4,5tetrahydrobenzo[L1G1,41oxazepin-3-yl)-1H-pyrazole-3-carboxamide;

1-3: (8)-4-(4-fluorobenzyl)-M-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3 ,4,5tetrahydrobenzoGl] G 1,41 oxazepin-3-yl) - 1H-pyrazo l-1 -carboxamide;

In some embodiments, at least one R ¹ is an optionally substituted 8-12 membered spiroheterocyclyl, an optionally substituted monocyclic or bridged non-aromatic heterocyclyl, or an optionally substituted heteroaryl. And in particular embodiments, at least one R ¹ is

where each R ⁵ independently represents

Z can represent

- 3 047748

R ^e , and p is 0, 1, 2, 3, 4, or 5. In some embodiments, p is 0, 1, or 2. In some embodiments, p is 0, and in other embodiments, p is 1. In such embodiments, R ⁵ can be a halogen, such as chloro or fluoro. And in some embodiments, the -LZ moiety is phenoxy, benzyl, 4-fluorobenzyl, or 1-phenylcyclopropyl.

Also disclosed is a pharmaceutical composition comprising a compound according to any of the embodiments disclosed herein. The pharmaceutical composition may further comprise an excipient, a therapeutic agent, or a combination thereof.

Embodiments of a method of using a compound are also disclosed. The method may comprise administering to a subject a compound according to the disclosed embodiments or a composition comprising the same. Additionally or alternatively, the method may comprise contacting a receptor-interacting protein kinase-1 (RIP1) with a compound disclosed herein or a composition comprising the same.

Certain embodiments relate to a method of treating a disease in a subject, comprising administering to said 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 comprising said compound; wherein said subject has, or is suspected of having or developing said disease, wherein said disease is a receptor interacting protein kinase-1 (RIP1)-associated disease. The disease may be an inflammatory or immunoregulatory disorder, or the disease may be a disorder associated with aging.

In some embodiments, the disease is selected from amyotrophic lateral sclerosis (ALS), autoimmune syndrome, rheumatoid arthritis, type I diabetes mellitus, inflammatory bowel diseases including Crohn's disease and ulcerative colitis, biliary cirrhosis, multiple sclerosis, Wegener's granulomatosis, ichthyosis, asthma, pollen allergies, reversible obstructive airway disease, bronchial asthma, allergic asthma, congenital asthma, acquired asthma, dust asthma, chronic or intractable asthma, late-onset asthma and airway hyperreactivity, allergic rhinitis, spondyloarthritis, ankylosing spondylitis, autoimmune hepatitis, autoimmune diseases of the hepatobiliary system, cerebrovascular accident, allergic diseases, chronic obstructive pulmonary disease, pulmonary emphysema, ataxia Friedreich's disease, Lewy body disease, diabetic neuropathy, polyglutamine (poly Q) diseases, Fahr's disease, Menkes disease, Wilson's disease, prion disease, destructive bone disorders such as bone resorption disease, multiple myeloma-associated bone disease; benign tumor, proliferative disorders, inflammatory and hyperproliferative skin disorders, epidermal hyperproliferation, psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis, seborrheic dermatitis, pustular psoriasis, bullous dermatitis, dermatitis, erythema multiforme, linear IgA-dependent bullous dermatosis, cement dermatitis, gingivitis, periodontitis, gingival lesions, periodontium, alveolar process, dental cementum, sepsis, pancreatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia, obesity, eosinophilic fasciitis, acne, alopecia areata, male pattern alopecia, senile alopecia, keratoconjunctivitis, vernal conjunctivitis, corneal alkali burn, Behcet's disease, Behcet's disease uveitis, keratitis, herpetic keratitis, keratoconus, corneal epithelial dystrophy, corneal leukoma, conjunctival pemphigus, Mooren's ulcer, scleritis, Vogt-Koyanagi-Harada syndrome, hematological disorders, hemoblastoses, lymphomas, Hodgkin's lymphoma, non-Hodgkin's lymphoma, breast carcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, diffuse large B-cell lymphoma (DLBCL) ABC type, Waldenstrom's macroglobulinemia, primary cutaneous T-cell lymphoma, indolent or smoldering multiple myeloma, leukemia, acute myeloid leukemia (AML), DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt's lymphoma/leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, myelodysplastic syndromes (MDS), myelofibrosis, polycythemia vera, Kaposi's sarcoma, splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, intravascular large B-cell lymphoma, IL-1-mediated disorders, disorders, MyD88-mediated, drug-resistant malignancies such as JAK inhibitor-resistant malignancies and ibrutinib-resistant malignancies such as ibrutinib-resistant hematological malignancies, ibrutinib-resistant CLL and ibrutinib-resistant Waldenstrom's macroglobulinemia, acute myelogenous leukemia, chronic myelogenous leukemia; angiogenic disorders such as angiogenic disorders including solid tumors, ocular neovascularization, hemangiomas such as infantile hemangiomas; sepsis, septic

- 4 047748 shock, shigellosis; migraine, bronchitis, gastric ulcers, necrotizing enterocolitis, intestinal lesions associated with thermal burns, celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, interleukin-1-converting enzyme-associated fever syndrome, tumor necrosis factor receptor-associated periodic syndrome, NEMO deficiency, HOIL-1 deficiency, linear ubiquitin 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-onset free sialic acid storage disease, juvenile-onset hexosaminidase A deficiency, Krabbe disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidosis disorders, multiple sulfatase deficiency, Niemann-Pick disease, neuronal ceroid lipofuscinosis, Pompe disease, pycnodysostosis, Sandhoff disease, Schindler's disease, sialic acid storage disease, Tay-Sachs disease, Wolman disease, Huntington's disease, Parkinson's disease, neurodegenerative diseases, Huntington's disease, Parkinson's disease, metastatic melanoma, HIV-associated neurodegeneration and cytomegalovirus retinitis, such as associated neurocognitive disorders or dementias, fibrotic conditions such as nonalcoholic steatohepatitis and cardiac diseases such as ischemia-reperfusion; allergies, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, erythematosus, chronic thyroiditis, Graves' disease, autoimmune gastritis, autoimmune neutropenia, thrombocytopenia, graft-versus-host disease, endotoxin-induced inflammatory reaction, tuberculosis, atherosclerosis, muscular degeneration, cachexia, Reiter's syndrome, rubella arthritis, acute synovitis, pancreatic β-cell disease; diseases characterized by pronounced neutrophilic infiltration; rheumatoid spondylitis, gouty arthritis, psoriatic arthritis and other arthritic conditions, cerebral malaria, chronic inflammatory lung disease, silicosis, pulmonary sarcoidosis, pulmonary fibrosis, idiopathic interstitial pneumonia, allograft rejection, bone marrow rejection, fever and myalgia due to infection, keloid formation , scar tissue formation, fever, influenza, chronic myelogenous leukemia; angiogenic disorders including solid tumors; viral diseases including acute hepatitis virus infection (including hepatitis A, hepatitis B, and hepatitis C), AIDS, SAH (AIDS-associated complex), or malignancy , herpes; stroke, myocardial infarction, arteriosclerosis, atherosclerosis, aortitis, polyarteritis nodosa, myocardial ischemia, ischemic stroke, organ hypoxia, vascular hyperplasia, reperfusion injury of the heart and kidneys, ischemia-reperfusion injury of organs arising from organ-preserving treatment, transplantation or ischemic disease, cardiac hypertrophy , thrombin-induced platelet aggregation, endotoxemia and/or toxic shock syndrome, prostaglandin-endoperoxide synthase-2-associated conditions, pemphigus vulgaris, autoimmune/multiple myositis, dermatomyositis, leukoderma vulgaris, photoallergic reaction, ischemia-reperfusion injury, ischemia-reperfusion heart damage due to myocardial infarction, multiple system atrophy, syndromes related to parkinsonism-plus, frontotemporal dementia, intracranial hemorrhage, cerebral hemorrhage, progressive muscular atrophy, pseudobulbar syndrome, progressive bulbar palsy, spinal muscular atrophy, hereditary muscular atrophy, peripheral neuropathies, progressive supranuclear palsy, corticobasal degeneration, demyelinating diseases, systemic juvenile idiopathic arthritis (sJIA) or Still's disease, systemic lupus erythematosus (SLE), Sjogren's syndrome, antiphospholipid syndrome (APS), primary sclerosing cholangitis (PSC), kidney transplant, surgery, acute renal failure ( ARF), systemic inflammatory response syndrome (SIRS), cytokine release syndrome (CRS), acute respiratory distress syndrome (ARDS), ARDS due to COVID-19, post-infectious autoimmune diseases, rheumatism, post-infectious glomerulonephritis, systemic sclerosis, cerebrovascular accident (CVA), chronic obstructive pulmonary disease (COPD), NEMO deficiency syndrome (essential modulator gene deficiency syndrome) F-kappa-B (also known as IKKgamma or IKKG)), solid organ malignancies, lysosomal storage diseases, glaucoma, retinal degenerative disease, retinal ischemia-reperfusion injury, renal ischemia-reperfusion injury, cataracts, siderosis, retinitis pigmentosa, degeneration retina, retinal detachment, age-related macular degeneration, vitreous scarring, septic shock caused by lethal anthrax toxin, cell death, LPS (lipopolysaccharide)-induced infectious encephalopathy, encephalitis, allergic encephalomyelitis, autoimmune uveoretinitis, giant cell arteritis, regional enteritis, granulomatous enteritis, distal ileitis, regional ileitis, terminal ileitis, insulin-dependent diabetes mellitus, scleroderma, systemic scleroderma, macular edema, diabetic retinopathy, central areolar choroidal dystrophy, BEST disease, vitelliform ma

- 5 047748 adult macular degeneration, pattern dystrophy, myopic degeneration, central serous retinopathy, Stargardt disease, cone-rod dystrophy, North Carolina dystrophy, infectious retinitis, inflammatory retinitis, uveitis, posterior uveitis, toxic retinitis and light-induced toxicity, macular edema, central areolar choroidal dystrophy, BEST disease, adult vitelliform macular degeneration, pattern dystrophy, optic nerve injury, optic neuritis, optic neuropathies, central retinal artery occlusion, ischemic optic neuropathy (e.g., arteritic or non-arteritic anterior ischemic neuropathy and posterior ischemic optic neuropathy), compressive optic neuropathy, infiltrative optic neuropathy, traumatic optic neuropathy, mitochondrial optic neuropathy (e.g. Leber's optic neuropathy), nutritional optic neuropathy, toxic optic neuropathy and hereditary optic neuropathy, dominant optic atrophy, Beer'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 hypoxic hypoxia, peritoneal dialysis solution (PDS)-induced peritoneal injury and PD-related adverse events, glomerular diseases, tubulointerstitial diseases, interstitial nephritis, occlusion, polycystic disease kidney), focal glomerulosclerosis, immune complex deposition nephropathy, diabetic nephropathy, Goodpasture's syndrome, hepatocellular carcinoma, pancreatic cancer, genitourinary cancer, bladder cancer, colorectal cancer, colon cancer, breast cancer, prostate cancer, prostatic hyperplasia, renal cell carcinoma, renal cell carcinoma, liver carcinoma, adrenal carcinoma, 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 carcinoma, glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma), bone cancer, soft tissue sarcoma, tissues, retinoblastomas, neuroblastomas, peritoneal effusions, malignant pleural effusions, mesotheliomas, Wilms' tumors, trophoblastic neoplasms, epithelial neoplasia, gastric carcinoma, ovarian carcinoma, rectal carcinoma, prostate carcinoma, pancreatic carcinoma, lung carcinoma, vaginal carcinoma, cervical carcinoma, testicular carcinoma, genitourinary tract carcinoma, esophageal carcinoma, laryngeal carcinoma, skin carcinoma, bone carcinoma, thyroid carcinoma, sarcomas, glioblastomas, neuroblastomas, gastrointestinal cancer, adenomas, adenocarcinomas, keratoacanthomas, epidermoid carcinomas, large cell carcinomas, non-small cell lung carcinoma, lymphoma, colon carcinoma, colorectal adenoma, hemangiopericytoma, myxoid carcinoma, round cell carcinoma, squamous cell carcinoma, esophageal squamous cell carcinoma, oral cavity carcinoma, vulvar cancer, adrenal cortex cancer, ACTH (adrenocorticotropic hormone)-producing tumors and leukemia, respiratory viral infections such as influenza virus, rhinovirus, coronavirus, parainfluenza virus, RS (respiratory syncytial virus), adenovirus, reovirus, etc.), herpes zoster caused by the herpes virus, rotavirus-induced diarrhea, viral hepatitis, AIDS, bacterial infectious diseases such as Bacillus cereus, Vibrio parahaemolyticus, Enterohemorrhagic Escherichia coli, Staphylococcus aureus, MRSA, Salmonella, Botulinus, Candida, Paget's disease, chondrodysplasia, osteochondritis, hyperparathyroidism, osteogenesis imperfecta, partial liver resection, acute liver necrosis, toxin-induced necrosis, viral hepatitis necrosis, shock-induced necrosis, hypoxia-induced necrosis, viral hepatitis B, non-A, non-B hepatitis, cirrhosis, alcoholic liver disease, alcoholic cirrhosis, alcoholic steatohepatitis, non-alcoholic steatohepatitis (NASH), acetaminophen toxicity, hepatotoxicity, liver failure, fulminant liver failure, late-onset liver failure, exacerbation of chronic hepatitis liver failure, chronic kidney disease, kidney injury/damage, kidney injury/damage caused by nephritis, kidney injury/damage caused by kidney transplantation, kidney injury/damage caused by surgery, kidney injury/damage caused by administration of nephrotoxic drugs, enhancement of chemotherapeutic effect, cytomegalovirus infection, HCMV (human cytomegalovirus) infection, AIDS, cancer, senile dementia, trauma, chronic bacterial infection, diseases caused by environmental pollution, aging, hypobaropathy, histamine or leukotriene C4 release disease, muscular dystrophy, pyoderma and Sezary syndrome, Addison's disease, pseudomembranous colitis, drug- or radiation-induced colitis, ischemic acute renal failure, chronic renal failure, toxicosis caused by inhaled oxygen or drugs, congenital hypophosphatasia, fibromatous lesions, fibrous dysplasia,

- 6 047748 bone resorption, osteolytic bone lesion, treatment after traumatic bone surgery, treatment after joint replacement surgery, treatment after bone grafting, treatment after dental surgery, chemotherapy to bone or radiotherapy to bone, bone cancer, unstable atherosclerotic plaque, disorder, occlusive disease, stenosis, coronary artery disease, peripheral arterial disease, arterial occlusion, aneurysm formation, posttraumatic aneurysm formation, restenosis, postoperative graft occlusion, Guillain-Barré syndrome, Meniere's disease, polyneuritis, multiple neuritis, mononeuritis, radiculopathy, hyperthyroidism, Graves' disease, autoimmune idiopathic thrombocytopenic purpura (autoimmune ITP), membranous nephritis, autoimmune thyroiditis, Hashimoto's thyroiditis, myasthenia gravis, cold and warm agglutinin disease, Evans syndrome, hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP), autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, anerythroplasia, or a combination thereof.

In some embodiments, the disease is atopic dermatitis, rheumatoid arthritis, or ankylosing spondylitis, and in other embodiments, the disease is myelodysplastic syndrome.

The above and other objects and features of the present invention will become more apparent from the following detailed description of the invention.

Detailed description of the invention

I. Review of terms.

The following explanations of terms and methods are provided to better describe the present invention and to provide guidance to those skilled in the art in practicing the present invention. The singular forms "a" or "an" refer to one or more than one unless the context clearly indicates otherwise. The term "or" refers to one of the stated alternative elements or a combination of two or more elements unless the context clearly indicates otherwise. As used herein, "comprises" means "includes." Thus, "comprising" A or B means "comprising" A, B, or A and B, without excluding additional elements.

Unless otherwise stated, all numbers expressing quantities of components, molecular weights, percentages, temperatures, time intervals, etc., used in the description or claims of the invention are to be understood as being indicated with the term approximately. Accordingly, unless otherwise explicitly or implicitly stated, the numerical parameters given are approximate and may depend on the desired properties sought and/or detection limits under standard conditions/test methods. When it is directly and unambiguously said that embodiments differ from the discussed prior art, the numbers in the embodiments are not approximate, unless the word approximately is explicitly stated.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below. The materials, methods, and examples are illustrative only and are not limiting.

When drawing or describing chemical structures, unless explicitly stated otherwise, it is assumed that all carbon atoms contain hydrogen, so that each carbon has a valence of four. For example, in the structure on the left side of the diagram below, there are nine hydrogen atoms. These nine hydrogen atoms are depicted in the structure on the right.

Sometimes a particular atom in a structure is described in the text formula as having hydrogen or hydrogen atoms, for example, -CH2CH2-. One skilled in the art will appreciate that the above description methods are common in the field of chemistry to ensure brevity and simplicity in describing organic structures.

If the R group is shown floating in a ring system, such as R ¹ in the group:

then, unless otherwise specified, the substituent R (e.g. R ¹ above) may be located on any atom of the fused bicyclic ring system, except the atom bearing the bond with the symbol :**, provided that a stable structure is formed.

- 7 047748

When the R group is depicted as existing in a ring system containing saturated carbon atoms, as in the formula:

where, in this example, y may be more than one, provided that each one replaces an currently depicted, implied, or unambiguously defined hydrogen in the ring; then, unless otherwise stated, two R's may be on the same carbon. A simple example is when R is a methyl group. The structure depicted may exist as a geminal dimethyl on the depicted ring carbon (the ring carbon). In another example, two R's on the same carbon, including the same carbon, may be included in the ring, thus creating a spirocyclic ring structure (spirocyclyl group).

As used herein, the term substituted refers to all subsequent modifiers in the term, for example, in the term substituted arylC _1-8 alkyl, the substitution may occur on the C _1-8 alkyl portion, the aryl portion, or both portions of the arylC _1-8 alkyl group.

The term substituted, when used to modify a defined group or moiety, means that at least one and optionally two or more hydrogen atoms of said group or moiety are independently replaced with the same or different substituent groups, as defined below. In a particular embodiment, a group, moiety or substituent may be substituted or unsubstituted unless expressly identified as unsubstituted or substituted. Accordingly, any of the groups defined herein may be unsubstituted or substituted unless the context dictates otherwise or the specific structural formula precludes substitution. In particular embodiments, a substituent may or may not be expressly identified as substituted, but is still intended to be optionally substituted. For example, an aliphatic or cyclic moiety may be unsubstituted or substituted, but an unsubstituted aliphatic or unsubstituted cyclic moiety is not substituted.

Substituents or substituent groups for replacing one or more hydrogen atoms on saturated carbon atoms in said group or moiety may be, unless otherwise specified, -R ⁶⁰ , halogen, =O, -Or ⁷⁰ , -SR ⁷⁰ , -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 )OM + -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(R ⁸⁰ )2, wherein R ⁶⁰ is a C1-10 aliphatic, heteroaliphatic or cycloaliphatic group, typically a C1-6 aliphatic group, more often C1-6 alkyl, wherein R ⁶⁰ may optionally be substituted; each R ⁷⁰ is independently at each occurrence hydrogen or R ⁶⁰ ; each R ⁸⁰ is independently at each occurrence R ⁷⁰ or, alternatively, two R ⁸⁰ groups together with the nitrogen atom to which they are bonded form a 3- to 7-membered heterocycloaliphatic group which optionally comprises from 1 to 4 identical or different additional heteroatoms selected from O, N and S, of which N is optionally substituted by R ⁷⁰ , such as by H or by C1-C3 alkyl; and each M' is a counterion with a net unit positive charge. Each M' is independently in each instance, for example, an alkali metal ion such as K ⁺ , Na ⁺ , Li ⁺ ; an ammonium ion such as ⁺ N( ^R60 )4; a protonated amino acid ion such as a lysine ion or an arginine ion; or an alkaline earth metal ion such as [Ca2 ⁺ ]0.5, [Mg2 ⁺ ]0.5 or [ ^Ba2 +]0.5 (the subscript 0.5 means, for example, that one of the counterions for such divalent alkaline earth metal ions may be an ionized form of a compound according to the invention and the other a typical counterion such as chloride, or two ionized compounds may serve as counterions for such divalent alkaline earth metal ions, or a doubly ionized compound may serve as a counterion for such divalent alkaline earth metal ions). As specific examples, -N(R ⁸⁰ ) ₂ includes -NH2, -NH-alkyl, -NH-pyrrolidin-3-yl, N-pyrrolidinyl, N-piperazinyl, 4N-methyl-piperazin-1-yl, N-morpholinyl, and the like. Any two hydrogen atoms on one carbon may also be replaced by, for example, =O, =NR ⁷⁰ , =N-OR ⁷⁰ , =N2, or =S.

Substituent groups for replacing hydrogen atoms on unsaturated carbon atoms in groups containing unsaturated carbon atoms are, unless otherwise specified, -R⁶⁰, halogen, -O M+, -OR⁷⁰, -SR⁷⁰, -S^-M+, -N(R⁸⁰)2, perhaloalkyl, -CN, -OCN, -SCN, -NO, -NO2, -N3, -SO2R⁷⁰, -SO3^-M⁺, -SO3R⁷⁰, -OSO2R⁷⁰, -OSO3 M + -OSO3R⁷⁰, -PO3-2(M⁺)2, -PO3^-2M²⁺, -P(O)(OR )O M + -P(O)(OR⁷⁰)2, -C(O)R⁷⁰, -C(S)R⁷⁰, -C(NR⁷⁰)R⁷⁰, -CO2M+, -CO2R⁷⁰, -C(S)OR⁷⁰, -C(O)NR⁸⁰R⁸⁰, -C(NR⁷⁰)N(R⁸⁰)2, -OC(O)R⁷⁰, -OC(S)R⁷⁰, -OCO2M+, -OCO2R⁷⁰, -OC(S)OR⁷⁰, -NR⁷⁰C(O)R⁷⁰, -NR⁷⁰C(S)R⁷⁰, -NR⁷⁰CO2^-M⁺, -NR⁷⁰CO2R⁷⁰, -NR⁷⁰C(S)OR⁷⁰, -NR⁷⁰C(O)N(R⁸⁰)2, -NR⁷⁰C(NR⁷⁰)R⁷⁰and -NR⁷⁰C(NR⁷⁰)N(R⁸⁰)2, where R⁶⁰, R⁷⁰, R⁸⁰and M' are as previously defined. In an independent embodiment, the substituents are not -O-M', -OR⁷⁰, -SR⁷⁰or -S^-M⁺.

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Substituent groups for replacing hydrogen atoms on nitrogen atoms in groups containing such nitrogen atoms are, unless otherwise specified, -R ⁶⁰ , -O-M+, -OR ⁷⁰ , -SR ⁷⁰ , -S-M+, -N(R ⁸⁰ )2, perhaloalkyl, -CN, -NO, -NO2, -S(O)2R ⁷⁰ , -SO3-M+, -SO3R ⁷⁰ , -OS(O)2R ⁷⁰ , -OSO3-M+, -OSO3R ⁷⁰ , -PO3 ^2- (M ⁺ )2, -РОз ^2- М ²⁺ , -P(O)(OR )OM', -P(O)(OR ⁷⁰ )(OR ⁷⁰ ), -C(O)R ⁷⁰ , -C(S)R ⁷⁰ , -C(NR ⁷⁰ )R ⁷⁰ , -CO2R ⁷⁰ , -C(S)OR ⁷⁰ , -C(O)NR ⁸⁰ R ⁸⁰ , -C(NR ⁷⁰ )NR ⁸⁰ R ⁸⁰ , -OC(O)R ⁷⁰ , -OC(S)R ⁷⁰ , -OCO2R ⁷⁰ , -OC(S)OR ⁷⁰ , -NR ⁷⁰ C(O)R ⁷⁰ , -NR ⁷⁰ C(S) R ⁷⁰ , -NR ⁷⁰ CO ₂ R 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 ⁺ are as defined previously.

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

Furthermore, in embodiments where a group or moiety is substituted with a substituted substituent, the nesting of such substituted substituents is limited to three, which prevents the formation of polymers. Thus, in a group or moiety containing a first group that is a substituent of a second group, which itself is a substituent of a third group attached to the parent structure, the first (outer) group can only be substituted with unsubstituted substituents. For example, in a group containing -(aryl-1)-(aryl-2)-(aryl-3), aryl-3 can only be substituted with substituents that are themselves unsubstituted.

Any group or moiety defined herein may be related to any other part of the disclosed structure, such as a parent or base structure, as will be apparent to one skilled in the art, for example, by consideration of valency rules, comparison with illustrative compounds, and/or consideration of functionality, unless the relationship of the group or moiety to another part of the structure is clearly indicated or is apparent from the context.

Acyl refers to the group -C(O)R, where R is H, an aliphatic, heteroaliphatic, or aromatic group (including both aryl and heteroaryl). Examples of acyl moieties include, but are not limited to, -C(O)H, -C(O)alkyl, -C(O)C1- _C6 -alkyl, -C(O)C1- _C6- haloalkyl, -C(O)cycloalkyl, -C(O)alkenyl, -C(O)cycloalkenyl, -C(O)aryl, -C(O)heteroaryl, or -C(O)heterocyclyl. Specific examples include -C(O)H, -C(O)Me, -C(O)Et, or -C(O)cyclopropyl.

Aliphatic refers to a group or moiety primarily based on hydrocarbons. An aliphatic group or moiety may be acyclic, including alkyl, alkenyl, or alkynyl groups (as well as alkylene, alkenylene, or alkynylene groups), cyclic variants thereof, such as cycloaliphatic groups or moieties, including cycloalkyl, cycloalkenyl, or cycloalkynyl, and further including straight-chain and branched-chain configurations, as well as all stereoisomers and positional isomers. Unless explicitly stated otherwise, an aliphatic group contains from one to twenty-five carbon atoms (C _1-25 ); for example, from one to fifteen (C _1-15 ), one to ten (C _1-10 ), one to six (C _1-6 ), or one to four (C _1-4 ) carbon atoms for an acyclic aliphatic group or moiety, or from three to fifteen (C _3-15 ), three to ten (C _3-10 ), three to six (C _3-6 ), or three to four (C _3-4 ) carbon atoms for a cycloaliphatic group or moiety. An aliphatic group may be substituted or unsubstituted unless it is clearly designated as unsubstituted aliphatic or substituted aliphatic. An aliphatic group may be substituted by one or more substituents (up to two substituents on each methylene carbon in the aliphatic chain, or up to one substituent on each carbon of the -C=C- double bond in the aliphatic chain, or up to one substituent on the carbon of the terminal methine group).

A lower aliphatic group refers to an aliphatic group containing from one to ten carbon atoms ( _C1-10 ), such as from one to six ( _C1-6 ) or from one to four ( _C1-4 ) carbon atoms; or from three to ten ( _C3-10 ), such as from three to six ( _C3-6 ) carbon atoms for a lower cycloaliphatic group.

Alkoxy refers to the group -OR, wherein R is a substituted or unsubstituted alkyl or a substituted or unsubstituted cycloalkyl group. In some examples, R is a C _1-6 alkyl group or a C _3-6 cycloalkyl group. Methoxy (-OCH3) and ethoxy (-OCH2CH3) are examples of alkoxy groups. In substituted alkoxy, R is a substituted alkyl or substituted cycloalkyl, examples of which in the compounds disclosed herein include haloalkoxy groups such as -OCF2H.

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 example of an alkoxyalkyl group.

Alkyl refers to a saturated aliphatic hydrocarbyl group having from 1 to at least 25 (C _1-25 ) carbon atoms, more typically from 1 to 10 (C _1-10 ) carbon atoms, such as from 1 to 6 (C _1-6 ) carbon atoms. An alkyl group may be substituted or unsubstituted. This term includes, by way of example, linear and branched hydrocarbon groups such as methyl (CH ₃ ), ethyl (-CH ₂ CH ₃ ), n-propyl (-CH ₂ CH ₂ CH ₃ ), isopropyl (-CH(CH ₃ ) ₂ ), n-butyl (-CH ₂ CH ₂ CH ₂ CH ₃ ), isobutyl (-CH ₂ CH ₂ (CH ₃ ) ₂ ), sec-butyl (-CH(CH ₃ )(CH ₂ CH ₃ ), tert-butyl (-C(CH ₃ ) ₃ ), n-pentyl

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(-CH2CH2CH2CH2CH3) and neopentyl (-CH ₂ C(CH3)3).

Amino refers to a -NH2, -NHR, or -NRR group, wherein each R is independently selected from H, an aliphatic, a heteroaliphatic, an aromatic group including both aryl and heteroaryl, or a heterocycloaliphatic group, or two R groups, together with the nitrogen atom attached thereto, form a heterocyclic ring. Examples of such heterocyclic rings include rings in which two R groups, together with the nitrogen atom to which they are attached, form a -( _CH2 ) _2.5- ring, optionally interrupted by one or two heteroatom groups such as -O- or -N( ^Rg ), for example as in the groups

-l·/ S \---/ and where R ^g is R ⁷⁰ , -C(O)R ⁷⁰ , -C(O)OR ⁶⁰ or -C(O)N(R ⁸⁰ )2.

An amide refers to the group -N(R)acyl, where R is hydrogen, a heteroaliphatic or an aliphatic group such as alkyl, particularly C _1-6 alkyl.

Aromatic refers to a cyclic conjugated group or moiety consisting, unless otherwise noted, of 5 to 15 ring atoms, having a single ring (e.g., phenyl, pyridinyl, or pyrazolyl) or multiple fused rings, wherein at least one ring is aromatic (e.g., naphthyl, indolyl, or pyrazolopyridinyl), that is, at least one ring, and optionally multiple fused rings, have a continuous, delocalized π electron system. Typically, the number of out-of-plane π electrons follows the Huckel rule (4n+2). The point of attachment to the parent structure typically passes through the aromatic portion of the fused ring system. For example,

However, in some instances, it may be evident from context or explicit disclosure that the point of attachment is through a non-aromatic portion of the fused ring system. For example,

An aromatic group or moiety may contain only carbon atoms in a ring, such as in an aryl group or moiety, or it may contain one or more ring carbon atoms and one or more ring heteroatoms containing a lone pair of electrons (e.g., S, O, N, P, or Si), such as in a heteroaryl group or moiety. Unless otherwise specified, an aromatic group may be substituted or unsubstituted.

Aryl refers to an aromatic carbocyclic group of 6 to 15 carbon atoms, unless otherwise specified, having a single ring (e.g., phenyl) or multiple fused rings, wherein at least one ring is aromatic (e.g., 1,2,3,4-tetrahydroquinoline, benzodioxole, etc.). If any portion of the aromatic ring contains a heteroatom, the group is heteroaryl rather than aryl. Aryl groups may be, for example, monocyclic, bicyclic, tricyclic, or tetracyclic. Unless otherwise specified, an aryl group may be substituted or unsubstituted.

Arylaliphatic refers to an aryl group attached to the parent structure through an aliphatic moiety. Arylaliphatic groups include aralkyl or arylalkyl groups such as benzyl and phenylethyl.

Carboxyl refers to _-CO2H .

Carboxamide belongs to -C(O)amino.

A carboxylic acid ester or carboxy ester refers to the group -C(O)OR, where R is an aliphatic, heteroaliphatic, or aromatic group (including both aryl and heteroaryl).

Carboxylate refers to -C(O)O or its salts.

Cyano belongs to the -CN group.

Cycloaliphatic refers to a cyclic aliphatic group having a single ring (e.g., cyclohexyl) or multiple rings, such as in a fused, bridged, or spirocyclic system, wherein the ring or at least one of the rings in the system is aliphatic. Typically, the point of attachment to the parent structure is through the aliphatic portion of the multiple ring system. A cycloaliphatic group includes saturated and unsaturated systems, including cycloalkyl, cycloalkenyl, and cycloalkynyl. A cycloaliphatic group may contain from three to twenty-five carbon atoms; for example, from three to fifteen, from three to ten, or from three to six carbon atoms. Unless otherwise specified, a cycloaliphatic group may be substituted

- 10 047748 substituted or unsubstituted. Examples of cycloaliphatic groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, or cyclohexenyl.

Halogen, halide, or halogen refers to fluorine, chlorine, bromine, or iodine.

Haloalkyl refers to an alkyl moiety substituted with one or more halogen atoms. Examples of haloalkyl moieties include -CH2F, -CHF2, and -CF3.

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

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

Heterocyclyl, heterocyclo and heterocycle refer to both aromatic and non-aromatic ring systems and more particularly refer to a stable ring moiety of three to fifteen members containing at least one carbon atom and typically several carbon atoms and at least one heteroatom, such as one to five. The heteroatom(s) may be nitrogen, phosphorus, oxygen, silicon or sulfur atom(s). The heterocyclyl moiety may be a monocyclic moiety or may contain several rings, such as in a bicyclic or tricyclic ring system, provided that at least one of the rings contains a heteroatom. Such a multiple ring moiety may include fused or bridged ring systems as well as spirocyclic systems; and any nitrogen, phosphorus, carbon, silicon or sulfur atoms in the heterocyclyl moiety may be optionally oxidized to various oxidation states. For convenience, nitrogen atoms, particularly but not exclusively those defined as aromatic ring nitrogen atoms, are meant to include their corresponding N-oxide form, although they are not explicitly defined as such in a particular example. Thus, for a compound having, for example, a pyridinyl ring, the corresponding pyridinyl N-oxide is included as a further compound according to the invention, unless this is expressly excluded or excluded by the context. Furthermore, the ring nitrogen atoms may optionally be quaternized. Heterocycle includes heteroaryl moieties and heteroalicyclyl or heterocycloaliphatic moieties, which are partially or fully saturated heterocyclyl rings. Examples of heterocyclyl groups include, but are not limited to, azetidinyl, oxetanyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazoyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazolyl, tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, пиразолидинил, имидазолил, имидазолинил, имидазолидинил, дигидропиридинил, тетрагидропиридинил, пиридинил, пиразинил, пиримидинил, пиридазинил, оксазолил, оксазолинил, оксазолидинил, триазолил, изоксазолил, изоксазолидинил, морфолинил, тиазолил, тиазолинил, тиазолидинил, изотиазолил, хинуклидинил, изотиазолидинил, индолил, изоиндолил, индолинил, изоиндолинил, октагидроиндолил, октагидроизоиндолил, хинолил, изохинолил, декагидроизохинолил, бензимидазолил, тиадиазолил, бензопиранил, бензотиазолил, бензоксазолил, фурил, диазабициклогептан, diazapane, diazepine, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphospholanyl and oxadiazolyl.

Hydroxyl belongs to the -OH group.

Nitro belongs to the -NO2 group.

Phosphate refers to the group -OP(O)(OR') ₂ , where each -OR' is independently -OH; -O-aliphatic such as -O-alkyl or -O-cycloalkyl; -O-aromatic including both -O-aryl and -O-heteroaryl; -O-arylalkyl; or -OR' is -O ^- M+, where M+ is a counterion with a single positive charge. Each M+ can be an alkali metal ion such as K ⁺ , Na ⁺ , Li ⁺ ; an ammonium ion such as ⁺ N(R)4, where R is H, an aliphatic, heteroaliphatic, or aromatic group (including both aryl and heteroaryl); or an alkaline earth metal ion such as [Ca2 ⁺ ] _0.5 , [Mg2 ⁺ ]0.5, or [Ba2 ⁺ ] _0.5 . Phosphonooxyalkyl refers to an -alkyl phosphate group such as, for example, -CH ₂ OP(O)(OH) ₂ , or a salt thereof such as

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-CH2OP(O)(O ^- Na ⁺ )2, and (((dialkoxyphosphoryl)oxy)alkyl) refers to a dialkyl ether of a phosphonooxyalkyl group, such as, for example, -CH ₂ OP(O)(O-tert-butyl)2.

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-arylalkyl; or -OR' is -O ^- M'. and M ⁺ is a counterion with a single positive charge. Each M+ is a positively charged counterion and can be, for example, an alkali metal ion such as K, Na ⁺ , Li ⁺ ; an ammonium ion such as +N(R)4, where R is H, an aliphatic, heteroaliphatic, or aromatic group (including both aryl and heteroaryl); or an alkaline earth metal ion such as [Ca2 ⁺ ]0.5, [Mg2 ⁺ ]0.5 or [Ba2 ⁺ ]0.5. Phosphonoalkyl refers to an -alkyl phosphonate group such as, for example, _-CH2P (O)(OH) ₂ or -CH2P(O)(O ^- Na ⁺ )2, and ((dialkoxyphosphoryl)alkyl) refers to a dialkyl ether of a phosphonoalkyl group such as, for example, -CH2P(O)(O-tert-butyl)2.

The Patient or Subject may generally refer to any living being, but most commonly refers to mammals and other animals, particularly humans. Thus, the disclosed methods are applicable to both human and veterinary medicine.

A pharmaceutically acceptable excipient refers to a substance other than the active ingredient that is included in a composition containing the active ingredient. As used herein, an excipient may be included in the particles of the pharmaceutical composition or 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. Excipients may include, but are not limited to, anti-adhesives, binders, coatings, enteric coatings, disintegrants, flavors, sweeteners, colorants, lubricants, glidants, sorbents, preservatives, carriers or vehicles. Excipients may be starches and modified starches, cellulose and cellulose derivatives, saccharides and their derivatives such as disaccharides, polysaccharides and sugar alcohols, protein, synthetic polymers, cross-linked polymers, antioxidants, amino acids or preservatives. Examples of excipients include, but are not limited to, magnesium stearate, stearic acid, vegetable stearin, sucrose, lactose, starches, hydroxypropyl cellulose, hydroxypropyl methylcellulose, 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, tartrazine, aspartame, benzalkonium chloride, sesame oil, propyl gallate, sodium metabisulfite or lanolin.

An adjuvant is a component that modifies the action of other agents, usually the active ingredient. Adjuvants are often pharmacological and/or immunological agents. An adjuvant may modify the action of the active ingredient by enhancing the immune response. An adjuvant may also act as a stabilizing agent for the formulation. Examples of adjuvants include, but are not limited to, aluminum hydroxide, alum, aluminum phosphate, killed bacteria, squalene, detergents, cytokines, paraffin oil, and combination adjuvants such as Freund's complete adjuvant or Freund's incomplete adjuvant.

A pharmaceutically acceptable carrier refers to an excipient that is 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 delivering one or more therapeutic compositions and additional pharmaceutical agents for pharmaceutical purposes.

Typically, the nature of the carrier will depend on the particular route of administration employed. For example, parenteral formulations typically contain injection fluids that include pharmaceutically and physiologically acceptable liquids such as water, saline, balanced salt solutions, aqueous dextrose, glycerol, and the like as a carrier medium. In some examples, the pharmaceutically acceptable carrier may be sterile so as to be suitable for administration to a subject (e.g., by parenteral, intramuscular, or subcutaneous injection). In addition to biologically neutral carriers, the pharmaceutical compositions to be administered may contain minor amounts of non-toxic auxiliary ingredients such as wetting or emulsifying agents, preservatives, and pH buffering agents, and the like, for example, sodium acetate or sorbitan monolaurate.

A pharmaceutically acceptable salt refers to pharmaceutically acceptable salts of a compound that are derivatives of various organic and inorganic counterions known

- 12 047748 to those skilled in the art, and including, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functional group, salts of organic or inorganic acids such as hydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate, oxalate, and the like. Pharmaceutically acceptable acid addition salts are a subset of pharmaceutically acceptable salts that retain the biological effectiveness of the free bases while being formed with acid partners. In particular, the disclosed compounds form salts with various pharmaceutically acceptable acids, including, but not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like, as well as organic acids such as amino acids, formic acid, acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, benzenesulfonic acid, isethionic acid, methanesulfonic acid, ethanesulfonic acid, ptoluenesulfonic acid, salicylic acid, xinafoic acid, and the like. Pharmaceutically acceptable base addition salts are a subset of pharmaceutically acceptable salts prepared with inorganic bases, such as sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts, etc. Examples of salts are ammonium, potassium, sodium, calcium, and magnesium salts. Salts prepared with 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. Examples of organic bases include isopropylamine, diethylamine, tris(hydroxymethyl)aminomethane (Tris), ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. (See, e.g., S. M. Berge, et al., Pharmaceutical Salts, J. Pharm. Sci., 1977; 66:1-19, which is incorporated herein by reference.) In particular disclosed embodiments, the compounds can be a formate, trifluoroacetate, hydrochloride, or sodium salt.

An effective amount, when applied to a compound or pharmaceutical composition, refers to an amount of the compound or pharmaceutical composition sufficient to achieve 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 elicit a desired biological or medical response in a tissue, system, subject or patient; to treat a particular disorder or disease; to alleviate or eliminate one or more symptoms thereof; and/or to prevent the occurrence of a disease or disorder. The amount of compound that constitutes an effective amount may vary depending on the compound, the desired result, the pathological condition and its severity, the size, age and sex of the patient to be treated, etc., as will be clear to one of skill in the art.

A prodrug refers to compounds that are transformed in vivo to produce a biologically active compound or a compound more biologically active than the parent compound. The transformation in vivo can occur, for example, by hydrolysis or enzymatic conversion. Common examples of prodrug moieties include, but are not limited to, ester and amide forms of a compound having an active form bearing a carboxylic acid moiety. Examples of pharmaceutically acceptable esters of the compounds of the present invention include, but are not limited to, esters of phosphate groups and carboxylic acids, such as aliphatic esters, in particular alkyl esters (e.g., _C1-6 alkyl esters). Other prodrug moieties include phosphoric acid esters, such as _-CH2 -OP(O)(OR') ₂ or a salt thereof, wherein R' is H or _C1-6 alkyl. Suitable 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, as well as secondary and tertiary alkyl amides (e.g., containing from about one to about six carbon atoms). Amides and esters of the disclosed illustrative embodiments of the compounds of the present invention can be prepared according to conventional methods. A detailed discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol 14 of the ACS Symposium Series, and in 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. A solvate refers to a complex formed by the combination of solvent molecules with solute molecules or ions. The solvent can be an organic solvent, an inorganic solvent, or a mixture thereof. Examples of solvents include, but are not limited to, alcohols such as methanol, ethanol, propanol; amides such as N,N-dialiphatic amides such as N-dimethylformamide; tetrahydrofuran; alkyl sulfoxides such as dimethyl sulfoxide; water; and combinations thereof. The compounds described herein can exist in both unsolvated and solvated forms when combined with solvents, whether pharmaceutically acceptable or non-pharmaceutically acceptable solvents, such as water, ethanol, and the like. Solvated forms of the compounds disclosed herein are within the scope of the embodiments disclosed herein.

Sulfanilamide refers to a ((O2-amino or -MK)sulfonyl) group or moiety, where R is H, an aliphatic, heteroaliphatic, or aromatic group (including both aryl and heteroaryl).

Sulfanyl belongs to the group: -SH, -S-aliphatic, -S-heteroaliphatic, -S-aromatic (including both -S-aryl and -S-heteroaryl).

Sulfinyl refers to the group or moiety: -S(O)H, ^(O)aliphatic, ^(O)heteroaliphatic, or ^(O)aromatic (including both ^(O)aryl and ^(O)heteroaryl).

Sulfonyl belongs to the group: -SO2H, ^O2-aliphatic, ^O2-heteroaliphatic, ^O2-aromatic (including both ^O2-aryl and ^O2-heteroaryl).

Treatment or treatment in the context of this document refers to the treatment of a disease or condition of interest in a patient or subject, in particular a human, having said disease or condition of interest, and includes, by way of example and without limitation:

(i) preventing the occurrence of a disease or condition in a patient or subject, in particular where such patient or subject is predisposed to developing the condition but has not yet been diagnosed with it;

(ii) inhibiting a disease or condition, such as stopping or slowing its progression;

(iii) alleviation of the disease or condition, such as relief of a symptom or regression of the disease or condition, or a symptom thereof; or (iv) stabilization of the disease or condition.

In the context of this document, the terms disease and condition may be used interchangeably or may be distinguished in that a particular disorder or condition may have no known etiologic factor (so that the etiology is not yet defined) and therefore is not yet recognized as a disease, but only as an undesirable condition or syndrome in which clinicians identify a more or less defined set of symptoms.

The above definitions and the following general formulas are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluorine groups). Such impermissible substitution patterns are readily recognized by a person skilled in the art.

It will be understood by one skilled in the art that the compounds may exhibit tautomerism, conformational isomerism, geometric isomerism, and/or optical isomerism. For example, some disclosed compounds may include one or more chiral centers and/or double bonds and, as a result, may exist as stereoisomers, such as double bond isomers (i.e., geometric isomers), enantiomers, diastereomers, and mixtures thereof, such as racemic mixtures. As another example, some disclosed compounds may exist in multiple tautomeric forms, including an enol form, a keto form, and mixtures thereof. Since the various compound names, formulas and compound schemes in the specification and claims may represent only one of the possible tautomeric, conformational isomeric, optical isomeric or geometric isomeric forms, it will be clear to one skilled in the art that the disclosed compounds encompass any tautomeric, conformational isomeric, optical isomeric and/or geometric isomeric forms of the compounds described herein, as well as mixtures of these various isomeric forms. Mixtures of various isomeric forms, including mixtures of enantiomers and/or stereoisomers, can be separated to obtain each individual enantiomer and/or stereoisomer using methods known to those skilled in the art, particularly in view of the present invention. In cases of limited rotation, such as around an amide bond or between two directly attached rings such as pyridinyl rings, biphenyl groups and the like, atropisomers are also possible and are also specifically encompassed by the compounds of the invention.

In any embodiments, hydrogen atoms present in the compound or in a particular group or moiety of the compound may be partially or completely replaced by deuterium or tritium. Thus, a reference to alkyl includes deuterated alkyl in which from one to the maximum number of hydrogen atoms present may be replaced by deuterium. For example, ethyl refers to both _C2H5 and _C2H5 where from 1 to 5 hydrogen atoms are replaced by deuterium, such as in _{C2DxH5 -x} .

II. RIPl-active compounds and pharmaceutical compositions containing RIPl-active compounds.

- 14 047748

A. Connections.

Disclosed herein are compounds and pharmaceutical compositions comprising such compounds that are effective for inhibiting RIP1 and/or for treating diseases and/or conditions associated with RIP1. In some embodiments, the compounds are selective kinase inhibitors. For example, exemplary compounds are capable of selectively inhibiting RIP1 over RIP2, RIP3, or both RIP2 and RIP3.

In some embodiments, a compound of the present invention has a structure according to formula I:

ABOUT

Formula I or is a pharmaceutically acceptable salt thereof. It will be understood by one of skill in the art that compounds encompassed by Formula I also include stereoisomers, Noxides, tautomers, hydrates, solvates, isotopes and/or prodrugs thereof, unless otherwise specified. In Formula I, Ring B is a heteroaryl, such as a 5-membered or 6-membered heteroaryl, and may contain 1, 2 or 3 heteroatoms independently selected from N or O. In some embodiments, Ring B is a 5-membered or 6-membered heteroaryl, wherein the heteroaryl has one, two or three nitrogen ring atoms and the remaining ring atoms are independently selected from carbon or oxygen. In particular embodiments, Ring B is pyrazolyl, pyridinyl, triazolyl or oxadiazolyl.

Each R ¹ is independently heterocyclyl optionally substituted with at least one R ⁶ , such as 1, 2, or 3, wherein each R ⁶ is independently R ^c . In some embodiments, R ⁶ is C ^ alkyl or C ₂ . ₁₀ alkynyl optionally substituted with CH ₃ j = ^ -CH 3

OH. In particular embodiments, R ⁶ is methyl or ·

R ² is R ^a .

R ³ is R ^a , or R ³ together with the -NC(O)- moiety to which it is attached and two ring atoms from ring B can form a 5- or 6-membered heterocyclyl that is fused to ring B.

Each R ⁴ , if present, independently represents a R ^e .

L is a heteroatom or R ^a , provided that R ^a is not H or D.

Y represents O or CH2.

Z represents a _C1.10 aliphatic or aromatic group.

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

R ^a is independently at each occurrence a _C1.10 aliphatic group (e.g., _C1.10 alkyl, _C2.10 alkenyl, _C2.10 alkynyl _{, or C3.6 cycloalkyl), a C1.10 haloaliphatic, a C5.10 aromatic, a C3.6 heterocyclic, or a C3.10 spiroheterocyclic group , or H or D , except} for embodiments _wherein L is R ^a .

R ^b independently in each occurrence is -OH, -SH, -ORc, -SRc, -NR ^d R ^d , -Si(R ^a )3, -C(O)OH, -C(O)ORc, -C(O)NR ^d R ^d , -OC(O)NR ^d R ^d , -OC(O)Cl.10alkyl substituted with one or two NR ^d R ^d , carboxyl, or a combination thereof, and optionally further substituted with an aromatic moiety, -SH, -O-acyl, or -C(O)NH ₂ .

R ^c is independently in each occurrence C1.10 alkyl which may be substituted with 1, 2 or 3 R ^e , _C2.10 alkenyl which may be substituted with 1, 2 or 3 R ^e , C2.10 alkynyl which may be substituted with 1, 2 or 3 R ^e , _C3.6 cycloalkyl which may be substituted with 1, 2 or 3 R ^e , or _C5.10 aromatic group which may be substituted with 1 _, 2 or 3 R ^e .

R ^d is independently in each occurrence H; C3.9 alkyl which may be substituted by 1, 2 or 3 R ^e or C3.9 heterocyclyl; C3.6 cycloalkyl which may be substituted by 1, 2 or 3 R ^e ; _C3.6 heterocyclic group which may be substituted by 1, 2 or 3 R ^e ; C5.10 aryl which may be substituted by 1, 2 or 3 R ^e ; _C5.10 heteroaryl which may be substituted by 1, 2 or 3 R ^e ; or two R ^d groups together with the nitrogen atom bonded thereto form a C3.9 heterocyclic group which may be substituted by one or more R ^e , or _C5.10 heteroaryl which may be substituted by one or more R ^e .

R ^e independently in each occurrence is halogen, ^^alkyl, C ₂ . ₁₀ alkenyl, C ₂ . ₁₀ alkynyl, C ₁ . ₆ haloalkyl, C ₃ . ₆ cycloalkyl, C ₅ . ₁₀ heteroaryl or -OR ^a

And R ^f independently in each occurrence is -alkyl phosphate, ^Ra , R ^b or ^Re , or two R ^f groups together with the carbon atom bound thereto form a C2.6 alkenyl group, a C3.6 cycloalkyl group which may be substituted by one or more ^Re , or a _C3.10 heterocyclic group which

- 15 047748 may be substituted by one or more R ^e or acyl.

In an independent embodiment, the connection is none of the following:

(8)-N-(7-(4-(chloromethyl)-4-(hydroxymethyl)piperidin-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1-(4-fluorobenzyl)-1H-1,2,4-1-riazole-3-carboxamide;

(S)-l D4-fluorobenzyl)44-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5 tetrahydrobenzo[b ][1,4]oxazepin-3-yl)-1H-1,2,4-1riazol-3-carboxamide;

(8)-5-benzyl44-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5tetrahydrobenzo[b][1, 4]oxazepin-3-yl)isoxazole-3-carboxamide;

(S)-l D4-fluorobenzyl)44-(5-methyl-4-oxo-7-(2-oxa-7-azaspiro[3.5]nonan-7-yl)-2,3,4,5 tetrahydrobenzo[b ][1,4]oxazepin-3-yl)-1H-1,2,4-1riazol-3-carboxamide;

(8)-5-benzyl44-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5tetrahydrobenzo[b][1, 4]oxazepin-3-yl)-1H-1,2,4-1riazol-3-carboxamide;

- 16 047748

N-((S)-7-((18,48)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-benzylisoxazole-3-carboxamide;

M-((8)-7-((18.48)-2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)-5-methyl-4-oxo-2,3,4,5tetrahydrobenzo [b][1,4]oxazepin-3-yl)-1-(4-fluorobenzyl)-1H-1,2,4-triazol-3-carboxamide;

(8)-1-(4-fluorobenzyl)-M-(5-methyl-7-(1,4-oxazepan-4-yl)-4-oxo-2,3,4,5tetrahydrobenzo[b][1, 4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

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

(8)-5-(4-fluorobenzyl)-M-(5-methyl-7-(1,4-oxazepan-4-yl)-4-oxo-2,3,4,5tetrahydrobenzo[b][1, 4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

(8)-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]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

(8)-5-benzyl-N-(5-methyl-7-(1,4-oxazepan-4-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

M-((38)-7-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-benzylisoxazole-3-carboxamide;

(S)-N-(7-(1,4-diazabicyclo[3.2,2]nonan-4-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-benzylisoxazole-3-carboxamide;

(8)-5-benzyl-N-(5-methyl-4-oxo-8-(3-oxa-9-azaspiro[5.5]undecan-9-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

(S)-N-(7-(1,4-diazabicyclo[3.2,2]nonan-4-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-5-benzyl-1H-1,2,4-triazole-3-carboxamide;

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

(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]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

(8)-5-(4-fluorobenzyl)-M-(5-methyl-4-oxo-7-(1-oxa-8-azaspiro[4.5]decan-8-yl)-2,3,4, 5tetrahydrobenzo[b][1,4]oxase pin-3-yl)-1H-1,2,4-triazol-3-carboxamide;

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

(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]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

(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]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

(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]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

(8)-5-benzyl-N-(7-(2-benzyl-1-oxo-2,9-diazaspiro[5.5]undecan-9-yl)-5-methyl-4-oxo2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

(8)-5-benzyl-N-(5-methyl-4-oxo-7-(3-oxa-9-azaspiro[5.5]undecan-9-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide;

(8)-5-benzyl-N-(7-(3,3-difluoroazetide yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide; and (8)-5-benzyl-N-(7-(3-fluoroazetide yn-1-yl)-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide.

- 17 047748

In another independent embodiment, the compound is none of the following: 1-1: (8)-1-benzyl-4-fluoro-N-(5-methyl-4-oxo-7-(8-oxa-2-azaspiro[4.5]decan-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide;

1-2: (8)-1-benzyl-4-fluoro-K-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3 ,4,5tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide;

1-3: (8)-4-(4-fluorobenzyl)-K-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3 ,4,5tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazol-1-carboxamide;

In certain embodiments of Formula I, ring B is pyridinyl, pyrazolyl, triazolyl, or oxadiazolyl; L is a heteroatom or a _C1-10 aliphatic; Y is O or CH2; Z is an aromatic group; each ^R1 is an optionally substituted heterocyclyl; ^R2 is H or a _C1-10 aliphatic; ^R3 is H or ^R3 together with the -NC(O) moiety to which it is attached and two ring atoms from ring B form a 5- or 6-membered non-aromatic heterocyclyl that is fused to ring B; each ^R4 is independently halogen; m is 1, 2, 3, or 4; and n is 0, 1, or 2.

In some embodiments, each R ¹ is independently heterocyclyl optionally substituted with R ⁶ . In some embodiments, at least one R ¹ can be an 8-12 membered spiroheterocyclyl. In other embodiments, at least one R ¹ is a monocyclic or bridged heterocyclyl, such as a monocyclic or bridged non-aromatic heterocyclyl. In certain embodiments, R ¹ is an optionally substituted heteroaryl, and in other embodiments, R ¹ is an optionally substituted non-aromatic heterocyclyl.

In some embodiments, m is 1, 2, or 3, and may be 1 or 2, and in some embodiments, m is 1.

R ² may be H or C _1-6 alkyl such as methyl or CD ₃ .

R ³ may be H. Alternatively, R ³ together with the -NC(O)- moiety to which it is attached and two ring atoms from ring B may form a 5- or 6-membered heterocyclyl that is fused to ring B.

Each R ⁴ can independently be a halogen, such as F, Br, Cl, or I. In some embodiments, each R ⁴ is independently chlorine or fluorine.

In certain embodiments, n is 0, and in other particular embodiments, n is 1.

Also in the formula, IL is a heteroatom or ^Ra , provided that ^Ra is not H or D. L can be oxygen, _C1-10 alkyl or _C3-10 cycloalkyl, such as oxygen, _C1-6 alkyl or _C3-6 cycloalkyl, in particular methylene (-CH2-), cyclopropyl or O. Z is heteroaryl or aryl and may be substituted. In some embodiments, Z is heteroaryl, such as pyridinyl, or „ ₅ „.

Z is , where each R is independently R, and p is 0, 1,

2, 3, 4, or 5. In such embodiments, each R ⁵ can independently be halogen or C _1-6 alkyl, such as methyl or fluoro. In some embodiments, p is 1 or 2, and in other embodiments, p is 0. And in particular 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

- 18 047748 methylphenoxy, benzyl, 1-phenylcyclopropyl, (6-methylpyridin-2-yl)methyl or (6-fluoropyridin-2yl)methyl. In particular embodiments, the -L-Z moiety is phenoxy, benzyl, 4-fluorobenzyl or 1-phenylcyclopropyl. In some embodiments of formula I, the compound may have a structure according to formulas I-1 or I-2:

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

- 19 047748

In formulas I-1 through 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 in embodiments where R ³ together with the NC(O) moiety and two ring atoms from ring B form a heterocyclic ring that is fused to ring B, the compound can have a structure according to one of the following formulas:

R ¹

R ²

R ²

Formula 1-21

Formula 1-22

Z (R ⁴ )n or

R ¹

Z r2 (R )п

Formula 1-23

And in formulas I-21 through I-23, L, Y, Z, R ¹ , R ² , R ⁴ are as defined herein for formula I, and n is 0 or 1. In some embodiments of formulas I-21 through I-23, r is 0, and in other embodiments of formulas I-21 through I-23, r is 1.

In some embodiments of formulas I-1 through I-23, Y is oxygen. In other embodiments of formulas I-1 through I-23, Y is -CH2-.

In any of the above embodiments relating to formula I and/or formulas I-1 through I-23, R ¹ may be selected from any of the following:

In some embodiments, a compound of the present invention may have a structure corresponding to formula IA

- 20 047748 ⁰

Formula IA, or be a pharmaceutically acceptable salt, stereoisomer, N-oxide, tautomer, hydrate, solvate, isotope, or prodrug thereof. It will be clear to one skilled in the art that the disclosed general formulae encompass all stereoisomers, N-oxides, tautomers, hydrates, solvates, isotopes, and/or prodrugs of compounds otherwise having the structural features required by such formulae.

In case of formula IA:

ring B is a 5-membered or 6-membered heteroaryl;

L is a heteroatom or R ^a , provided that R ^a is not H or D;

Y represents O or CH2;

R ¹ is optionally substituted heterocyclyl as defined previously for formula I;

R2 and ^R3 independently represent R ^a ; ^R4 and ^R5 independently represent R ^e ;

R ^a is independently at each occurrence a C ₁ . ₁₀ aliphatic group (e.g., C ₁ . ₁₀ alkyl, C ₂ . ₁₀ alkenyl, C ₂ . ₁₀ alkynyl, or C ₃ . ₆ cycloalkyl), C ₁ . ₁₀ haloaliphatic, C ₅ . ₁₀ aromatic, C ₃ . ₆ heterocyclic, or C ₃ . ₁₀ spiroheterocyclic group, or H or D, except for embodiments wherein L is R ^a ;

R ^b independently in each occurrence is -OH, -SH, -ORc, -SRc, -NR ^d R ^d , -Si(R ^a ) ₃ , -C(O)OH, -C(O)ORc or -C(O)NR ^d R ^d ;

R ^c independently in each occurrence is C1.10 alkyl (which may be substituted with 1, 2 or 3 R ^e ), _C2.10 alkenyl (which may be substituted with 1, 2 or 3 R ^e ), C2.10 alkynyl (which may be substituted with 1, 2 or 3 R ^e ), _C3.6 cycloalkyl (which may be substituted with 1, 2 or 3 R ^e ) _{or C5.10 aromatic} (which may be substituted with 1, 2 or 3 R ^e );

R ^d is independently at each occurrence H; C^alkyl (which may be substituted by 1, 2 or 3 R ^e ); C3.6cycloalkyl (which may be substituted by 1, 2 or 3 R ^e ); _{C3.6heterocyclic} (which may be substituted by 1, 2 or 3 R ^e ); C5.10aryl (which may be substituted by 1, 2 or 3 R ^e ); _{C5.10heteroaryl} (which may be substituted by 1, 2 or 3 R ^e ); or two R ^d groups, together with the nitrogen atom bound thereto, form a C3.9heterocyclic (which may be substituted by one or more R ^e ) or _{C5.10heteroaryl} (which may be substituted by one or more R ^e );

R ^e is independently in each occurrence halogen, _{C1.6 alkyl} , _{C2.10 alkenyl, C2.10 alkynyl, C1.6 haloalkyl, C3.6 cycloalkyl , C5.10 heteroaryl or} -OR ^a ; _and

R ^f is independently at each occurrence ^Ra , R ^b , or ^Re , or two R ^f groups together with the carbon atom bonded thereto form a C3.6 cycloalkyl group (and in some embodiments, the C3.6 cycloalkyl group is substituted with one or more ^Re ) or a _C3.10 heterocyclic group (and in some embodiments, _{the C3.10 heterocyclic} group is substituted with one or more ^Re ); m is from 1 to 4, such as 1, 2, 3, or 4, in particular embodiments is 1, or n is 0, 1, or 2; and p is 0, 1, 2, 3, 4, or 5.

In particular embodiments of Formulas I or IA, the 5-membered heteroaryl group may have a structure corresponding to the formula ' wherein at least one W is nitrogen and each remaining W is independently selected from carbon, CH, oxygen, sulfur, nitrogen, or NH. In some embodiments, the 5-membered heteroaryl group is a diazole, triazole, oxadiazole, or oxazole. Examples of triazoles include any of the following:

Examples of diazoles are selected from any of the following:

- 21 047748

Examples of oxadiazoles are selected from any of the following:

Examples of oxazoles are selected from any of the following:

In particular embodiments of Formulas I or IA, L is oxygen or ^Ra , where ^Ra is _C1 - _C4 -alkyl, such as -CH2-, -CH2CH2-, -CH2CH2CH2-, or -CH2CH2CH2CH2-, or C3.6cycloalkyl, such as cyclopropyl. In some embodiments, L is

-CH2-, or oxygen.

In some embodiments, each of R2 and R3 is independently ^Ra , wherein ^Ra is independently at each occurrence hydrogen, methyl, ethyl, propyl, butyl, pentyl, or hexyl, or a deuterated analog thereof. In particular embodiments, each of ^R2 and ^R3 is independently ^Ra , which is independently at each occurrence hydrogen, methyl, or ethyl, or a deuterated analog thereof. In exemplary embodiments, ^R2 is methyl or CD3, and ^R3 is hydrogen.

In some embodiments, each R ⁴ and/or each R ⁵ is independently R ^e , wherein R ^e is alkyl, alkenyl, alkynyl, chloro, bromo, iodino, or fluoro. In particular embodiments, each R ⁴ and/or each R ⁵ is independently R ^e , wherein R ^e is a lower aliphatic group (e.g., methyl), fluoro, or chloro.

In some embodiments, m is 1; n is 0 or 1; and p is 0, 1, or 2. In particular embodiments, m is 1, n is 0, and p is 0, 1, or 2.

Compounds of formulas I or IA may also have structures corresponding to any one or more of formulas II and IIA-IIF.

Formula II

- 22 047748

PA formula

Formula PV

Formula PS

Formula IID

Formula NOT

Formula IIF

In the case of formulas II and IIA-IIF, each of ring B, LY, R ¹ and R ⁵ , if present, is as defined above for formulas I and/or IA, and R ² is methyl or CD3. In particular embodiments, 0, 1 or 2 R ⁵ groups are present. R ⁵ can be ^Re , where ^Re is fluorine or chlorine. In other particular embodiments, R ⁵ is absent. In the case of formulas IIA-IIF, each W is independently nitrogen or oxygen, and in particular nitrogen.

Certain disclosed embodiments have formula IIG.

Formula IIG

In the case of formula IIF, R ¹ , R ² , R ³ and R ⁵ are as defined above. In certain embodiments, R ⁵ is absent or is halogen, such as fluorine or chlorine, particularly fluorine, or π-alkyl, such as methyl. Some disclosed illustrative compounds corresponding to one or more of formulae I, I-1 through I-23, IA, II and IIA-IIG include:

- 23 047748

- 24 047748

- 25 047748

1-29.

Examples of compounds encompassed by one or more of formulas I, I-1 through I-23, IA, II, and IIA-IIG include

1-1: (8)-1-benzyl-4-fluoro-N-(5-methyl-4-oxo-7-(8-oxa-2-azaspiro[4.5]decan-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazol-3-carboxamide;

1-2: (8)-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]oxazepin-3-yl)-1 H-pyrazol-3-carboxamide;

1-3: (8)-4-(4-fluorobenzyl)-M-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3 ,4,5tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazol-1-carboxamide;

1-4: (8)-b1-(5-methyl-4-oxo-8-(3-oxa-9-azaspiro[5.5]undecan-9-yl)-2,3,4,5tetrahydrobenzo[b][ 1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

1-5: (8)-N-(5-methyl-7-(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

1-6: (S)-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5tetrahydrobenzo[b] [ 1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

1-7: (8)-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]oxazepin-4(5H)-one;

- 26 047748

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

1-9: (8)-M-(5-methyl-4-oxo-7-(8-oxa-2-azaspiro[4.5]decan-2-yl)-2,3,4,5tetrahydrobenzo[b][ 1,4]oxazepin-3-yl)-4-phenoxypicolinamide;

1-10: (8)-H-(8-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-1-methyl-2-oxo-2,3,4,5tetrahydro-1H-benzo[b]azepin-3-yl)-4-phenoxypicolinamide;

1-11: 5-benzyl-M-(2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1Hbenzo[b]azepine -3-yl)-1H-1,2,4-triazol-3-carboxamide;

1-12: N-(8-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1Hbenzo[L]azepin-3-yl)-5-benzyl-1H-1,2,4-triazole-3-carboxamide;

1-13: 5-benzyl-M-(1-methyl-2-oxo-8-(2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1Hbenzo[b]azepine -3-yl)-1H-1,2,4-triazol-3-carboxamide;

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

1-15: 5-benzyl-N-(1-(methyl-c13)-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5tetrahydro-1 H-benzo[b]azepin-3-yl)-1 H-1,2,4-triazole-3-carboxamide;

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

1-17: 4-benzyl-M-(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro1 H- benzo[b]azepin-3-yl)-1 H-pyrazol-1-carboxamide;

1-18: N-(l-methyl-2-oxo-8-(3-oxa-9-azaspiro[5.5]undecan-9-yl)-2,3,4,5-tetrahydro-1Hbenzo[b]azepine -3-yl)-4-phenoxypicolinamide;

1-19: M-(1-(methyl-c13)-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1Hbenzo [b]azepin-3-yl)-4-phenoxypicolinamide;

1-20: N-(l-methyl-2-oxo-8-(2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1Hbenzo[L]azepin-3-yl)-4-phenoxypicolinamide;

1-21: N-(l-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1Hbenzo[b]azepine -3-yl)-4-phenoxypicolinamide;

1-22: (8)-1-benzyl-M-(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5tetrahydro -1 H-benzo[b]azepin-3-yl) -1 H-pyrazo l-3-carboxamide;

1-23: (8)-M-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-5-(1-phenylcyclopropyl)-1,3,4-oxadiazol-2-carboxamide;

1-24: (8)-5-benzyl-N-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydrobis[b][1,4]oxazepin-3-yl)-1,3,4-oxadiazole-2-carboxamide;

1-25: 4-benzyl-M-(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro1 H- benzo[b]azepin-3-yl)-1 H-pyrazol-1-carboxamide;

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

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

1-28: (8)-4-benzyl-M-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5tetrahydrobenzo [b][1,4]oxase pin-3-yl)-1 H-pyrazo l-1-carboxamide; or

1-29: (8)-4-(4-fluorobenzyl)-N-(5-methyl-7-(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)-4-oxo2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-1-carboxamide.

Additional compounds covered by one or more of formulae I, I-1 through I-23, IA, II and IIA-27 047748

IIG, include

- 28 047748

- 29 047748

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

Pharmaceutically acceptable excipients can be included in pharmaceutical compositions for a variety of purposes, such as to dilute the pharmaceutical composition for delivery to a subject, to facilitate processing of the formulation, to impart favorable physical properties to the formulation, to facilitate dispersion from a delivery device, to stabilize the formulation (e.g., antioxidants or buffers), to impart a pleasant or acceptable taste or texture to the formulation, and the like. The pharmaceutically acceptable excipient(s) can include a pharmaceutically acceptable carrier(s). Examples of excipients include, but are not limited to: mono-, di-, and polysaccharides, sugar alcohols and other polyols such as lactose, glucose, raffinose, melcitose, lactitol, maltitol, trehalose, sucrose, mannitol, starch, or combinations thereof; surfactants such as sorbitols, diphosphatidylcholine, and lecithin; bulking agents; buffers such as phosphate and citrate buffers; anti-stick agents such as magnesium stearate; binders such as saccharides (including disaccharides such as sucrose and lactose), polysaccharides (such as starches, cellulose, microcrystalline cellulose, cellulose ethers (such as hydroxypropyl cellulose), gelatin, synthetic polymers (such as polyvinylpyrrolidone, polyalkylene glycols); coatings (such as cellulose ethers including hydroxypropyl methylcellulose, shellac, corn zein, and gelatin); release regulators (such as enteric coatings); disintegrants (such as crospovidone, cross-linked sodium carboxymethylcellulose, and sodium starch glycolate); fillers (such as dibasic calcium phosphate, vegetable fats and oils, lactose, sucrose, glucose, mannitol, sorbitol, calcium carbonate, and magnesium stearate); flavorings and sweetening agents (such as mint, cherry, anise, peach, apricot or liquorice, raspberry and vanilla); lubricants (such as minerals, such as talc or silicon dioxide, fats, such as vegetable stearin, magnesium stearate or stearic acid); preservatives (such as 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); colors; pressing aids; emulsifying agents; encapsulating agents; gums; granulating agents; and combinations thereof.

B. Combinations of therapeutic agents.

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

In some embodiments, the compounds are 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 juice secretagogue, an antiviral agent, an anticancer agent, an antifungal agent, or a combination thereof. The anti-inflammatory agent may be a steroidal or non-steroidal anti-inflammatory agent. In some embodiments, the non-steroidal anti-inflammatory agent is selected from aminosalicylates, cyclooxygenase inhibitors, diclofenac, etodolac, famotidine, fenoprofen, flurbi

- 31 047748 profen, ketoprofen, ketorolac, ibuprofen, indomethacin, meclofenamate, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin, or a combination thereof. In some embodiments, the immunosuppressant is mercaptopurine, a corticosteroid, an alkylating agent, a calcineurin inhibitor, an inosine monophosphate dehydrogenase inhibitor, an antilymphocyte globulin, an antithymocyte globulin, an anti-T-cell antibody, or a combination thereof. In one embodiment, the antibody is infliximab.

In some embodiments, the present compounds can be used with anticancer or cytotoxic agents. Various classes of anticancer and antitumor compounds include, but are not limited to, alkylating agents, antimetabolites, BCL-2 inhibitors, vinca alkyloids, taxanes, antibiotics, enzymes, cytokines, platinum coordination complexes, proteasome inhibitors, substituted ureas, kinase inhibitors, hormones and hormone antagonists, and hypomethylating agents, such as DNMT (DNA methyltransferase) inhibitors such as azacitidine and decitabine. Examples of alkylating agents include, but are not limited to, mechlorothamine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, ethyleneimines, methylmelamines, alkyl sulfonates (e.g., busulfan), and carmustine. Illustrative antimetabolites include, by way of example and not limitation, the folate analog methotrexate; the pyrimidine analog fluorouracil, cytosine arbinoside; the purine analogs mercaptopurine, thioguanine, and azathioprine. Illustrative vinca alkyloids include, by way of example and not limitation, vinblastine, vincristine, paclitaxel, and colchicine. Illustrative antibiotics include, by way of example and not limitation, actinomycin D, daunorubicin, and bleomycin. An illustrative enzyme effective as an antineoplastic agent includes L-asparaginase. Illustrative coordination compounds include, by way of example and not limitation, cisplatin and carboplatin. Illustrative hormones and hormone-related compounds include, by way of example and not limitation, the adrenocorticosteroids prednisone and dexamethasone; the aromatase inhibitors aminoglutethimide, formestane, and anastrozole; the progestin compounds hydroxyprogesterone caproate, medroxyprogesterone; and the antiestrogenic compound tamoxifen.

These and other suitable anticancer compounds are described in Merck Index, 13th Ed. (O'Neil M. J. et al., ed.) Merck Publishing Group (2001) and Goodman and Gilman's The Pharmacological Basis of Therapeutics, 12th Edition, Brunton L.L. ed., Chapters 60-63, McGraw Hill, (2011), both of which are incorporated herein by reference.

Anti-CTLA-4 antibodies that may be used in combination with the inhibitors disclosed herein include ipilimumab, marketed under the name YERVOY® by Bristol-Myers Squibb.

Other chemotherapeutic agents for use in combination include immuno-oncology agents such as checkpoint 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 use in combination with the compounds disclosed herein include anti-LAG-3 agents such as BMS986016 (MDX-1408).

Additional 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).

The compounds disclosed herein may also be effectively used with CAR-T therapy. Examples of currently available CAR-T therapy include axicabtagene siloleucel and tisagenleucel.

Additional antiproliferative compounds useful in combination with the compounds of the present invention include, by way of example and not limitation, antibodies against growth factor receptors (e.g., anti-Her2); and cytokines such as interferon-α and interferon-γ, interleukin-2, and GM-CSF (granulocyte macrophage colony stimulating factor).

Additional chemotherapeutic agents that are effective for use in combination with the present compounds include proteasome inhibitors such as bortezomib, carfilzomib, marizomib, etc.

Examples of kinase inhibitors useful 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, lenvatinib, nintedanib, pazopanib; BCR-Abl inhibitors such as bosutinib,

- 32 047748 dasatinib, imatinib and nilotinib;

FLT-3 inhibitors such as gilteritinib and quizartinib, P13 kinase inhibitors such as idelalisib, Syk inhibitors such as fostamatinib; and JAK inhibitors such as ruxolitinib and fedratinib.

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

analgesics - morphine, fentanyl, hydromorphone, oxycodone, codeine, acetaminophen, hydrocodone, buprenorphine, tramadol, venlafaxine, flupirtine, meperidine, pentazocine, dextromoramide, dipipanone;

aminoglycoside antibiotics (e.g., amikacin, gentamicin, kanamycin, neomycin, netilmicin, tobramycin, and paromycin), carbapenems (e.g., ertapenem, doripenem, imipenem, cilastatin, and meropenem), cephalosporins (e.g., cefadroxil, cefazolin, cephalothin, cephalexin, cefaclor, cefamandole, cefoxitin, cefprozil, cefuroxime, cefixime, cefdinir, cefditoren, cefoperazone, cefotaxime, cefpodoxime, ceftazidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, and ceftobiprole), glycopeptides (e.g., teicoplanin, vancomycin, and telavancin), lincosamides (e.g., clindamycin and lincomycin), 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), combination penicillins (e.g., amoxicillin/clavulanate, ampicillin/sulbactam, piperacillin/tazobactam, and ticarcillin/clavulanate), polypeptides (eg, bacitracin, colistin, and polymyxin B), quinolones (eg, ciprofloxacin, enoxacin, gatifloxacin, levofloxacin, lomefloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin, trovafloxacin, grepafloxacin, sparfloxacin, and temafloxacin), sulfonamides (eg, mafenide, sulfonamidochrysoidine, sulfacetamide, sulfadiazine, silver sulfadiazine, sulfamethizole, sulfamethoxazole, sulfanilimide, sulfasalazine, sulfisoxazole, trimethoprim, and trimethoprim-sulfamethoxazole), tetracyclines (eg, demeclocycline, doxycycline, minocycline, oxytetracycline, and tetracycline), antimycobacterial compounds (eg, clofazimine, dapsone, capreomycin, cycloserine, ethambutol, ethionamide, isoniazid, pyrazinamide, rifampin (rifampin), rifabutin, rifapentine, and streptomycin), and others such as arsphenamine, chloramphenicol, fosfomycin, fusidic acid, linezolid, metronidazole, mupirocin, platensimycin, quinupristin/dalfopristin, rifaximin, thiamphenicol, tigecycline, and tinidazole;

antibodies to TNF-α, such as infliximab (Remicade™), adalimumab, golimumab, certolizumab;

anti-B-cell antibodies, such as rituximab; anti-IL-6 antibodies, such as tocilizumab;

antibodies to IL-1, such as anakinra; antibodies to PD-1 and/or PD-L1, for example, nivolumab, pembrolizumab, pidilizumab, BMS-936559, MPDL3280A, AMP-224, MEDI4736; ixekizumab, brodalumab, ofatumumab, sirukumab, clenoliximab, clazakizumab, fezakinumab, fleticumab, mavrilimumab, ocrelizumab, sarilumab, secukinumab, toralizumab, zanolimumab;

anticoagulants - warfarin (Coumadin™), acenocoumarol, phenprocoumon, atromentin, phenindione, heparin, fondaparinux, idraparinux, rivaroxaban, apixaban, hirudin, lepirudin, bivalirudin, argatroban, dabigatran, ximelagatran, batroxobin, gementin;

anti-inflammatory agents - steroids such as budesonide, non-steroidal anti-inflammatory agents such as aminosalicylates (eg, sulfasalazine, mesalamine, olsalazine, and balsalazide), cyclooxygenase inhibitors (COX-2 inhibitors such as rofecoxib, celecoxib), diclofenac, etodolac, famotidine, fenoprofen, flurbiprofen, ketoprofen, ketorolac, ibuprofen, indomethacin, meclofenamate, mefenamic acid, meloxicam, nambumetone, naproxen, oxaprozin, piroxicam, salsalate, sulindac, tolmetin;

Immunosuppressants-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 (IMP) inhibitors such as mycophenolate, mycophenolate mofetil, and azathioprine, and agents designed to suppress cellular immunity while leaving the recipient's humoral immunologic response intact, including various antibodies (e.g., antilymphocyte globulin (ALG), antithymocyte globulin (ATG), monoclonal anti-T-cell antibodies (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.; methylprednisolone is currently available from Pfizer; sirolimus (rapamycin) is currently available from Wyeth-Ayerst under the trade name Rapamune; tacrolimus is currently available from Fujisawa under the trade name Prograf; cyclosporine is currently available from

- 33 047748

Novartis under the trade name Sandimmune and from Abbott under the trade name Gengraf; IMF inhibitors such as mycophenolate mofetil and mycophenolic acid are currently available from Roche under the trade name Cellcept and from Novartis under the trade name Myfortic; azathioprine is currently available from Glaxo Smith Kline under the trade name Imuran; and antibodies are currently available from Ortho Biotech under the trade name Orthoclone, from Novartis under the trade name Simulect (basiliximab) and from Roche under the trade name Zenapax (daclizumab); and guanylate cyclase-C receptor agonists or intestinal acid secretagogues such as linaclotide, marketed under the name Linzess.

These various agents may be administered according to their standard or usual dosages as indicated in the package inserts accompanying the commercially available forms of the drug (see also the package inserts in The Physician's Desk Reference, 2006), the contents of which are incorporated herein by reference.

III. Methods for obtaining compounds.

The disclosed compounds can be prepared by any suitable synthetic method that will be apparent to one skilled in the art given the present disclosure. An example of one suitable method is provided below, which is illustrated for specific compounds in the examples. An exemplary method for preparing the compounds may include the following first reaction step according to Scheme 1.

Scheme 1.

As shown in Scheme 1, starting compound 100 is reacted with R ¹ -containing reagent 102 using suitable metal-mediated cross-coupling conditions to afford R ¹ -functionalized product 104. X is a suitable group for metal-mediated cross-coupling, such as a halogen or a triflate group, and PG is an amino protecting group that can be selected from, but is 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 comprise using a transition metal catalyst, such as a Pd(0) catalyst (e.g., _Pd2 (dba) ₃ , Pd(dba) ₂ , Pd( _PPh3 ) ₄ , etc.) in combination with a ligand component, such as a ligand capable of generating Pd(II) from the Pd(0) catalyst (e.g., a BINAP ligand, a BINOL ligand, etc.), a base (e.g., t-BuONa), and a solvent. In some embodiments, the cross-coupling step comprises heating the reaction mixture at a suitable temperature (e.g., 60°C or higher, such as from 70°C to 140°C, or from 80°C to 120°C, or from 85°C to 100°C).

Representative examples of the method shown in Scheme 1 are shown below in Schemes 2A-2C.

Scheme 2A.

Scheme 2B.

- 34 047748

Scheme 2C.

^HCI ^> ^ΝΗ ί| I >'>NHTr ______________________________». ζ— ₄ ί| I /NHTr / Ν \/ ^Br / ^N ”o Pd ₂ (dba) ₃ , BINAP,t-BuONa/ toluene, 85 °C, overnight

200

Embodiments of the method for preparing the compounds may further comprise additional steps used to convert the R ¹ -functionalized product 104 into the desired compounds encompassed by the present invention. In some embodiments, these additional steps may comprise a first deprotection step to produce an amine compound 300. The amine compound 300 is then converted into an amide compound 304 by reacting the amine compound with a suitable acidic coupling partner 302, as shown in Scheme 3.

Scheme 3.

As shown in Scheme 3, the deprotection may involve the use of any suitable reagent capable of removing an amino protecting group (PG, as shown in Schemes 1 and 3). In some embodiments, an acid such as TFA (trifluoroacetic acid) is used in the deprotection step. In further embodiments, a base such as piperidine may be used in the deprotection step. Other acids and bases suitable for deprotection may be readily selected by those skilled in the art in view of the present disclosure. The amide forming step may be accomplished using reagents capable of facilitating amide formation between the free amine of the amine compound 300 and the acidic functionality of the acidic coupling partner 302. Suitable coupling partners may be synthesized using methods known to those skilled in the art in view of the present disclosure, or may be purchased from commercial sources. In some embodiments, propylphosphonic anhydride may be used in combination with a base such as diisopropylethylamine to form the amide; however, other reagents can also be used, for example, 2-(7-aza-1H-benzotriazol-1-yl)-N-HN,N-tetramethylaminium hexafluorophosphate, 2-(1H-benzotriazol-1-yl)-N-HN,N-hexafluorophosphate, 2-(6-chloro-1H-benzotriazole-1-ηλ)-N,N,N',N'tetramethylaminium hexafluorophosphate, 1-hydroxybenzotriazole, dicyclohexylcarbodiimide, diisopropylcarbodiimide, N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide HCl, benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate, benzotriazol-1-yloxy-tripyrrolidinophosphonium hexafluorophosphate, bromotripyrrolidinophosphonium hexafluorophosphate, etc., in combination with diisopropylethylamine, isopropylamine, etc. A suitable solvent such as dichloromethane (DCM) is also used.

In the case of Scheme 3 above, the acid partner 302 of the coupling reaction 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 dosed into a solution of NaOH in MeOH and water. After an appropriate time at 20 °C, 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 and dried over sodium sulfate, followed by evaporation in vacuo. Other acidic coupling partners suitable for use in Scheme 3 can be prepared using a similar method starting from a suitable starting material (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 variants thereof).

IV. Methods of using compounds.

A. Diseases/disorders.

- 35 047748

The disclosed compounds, as well as combinations thereof and/or pharmaceutical compositions containing them, can be used to inhibit RIP1 kinase by contacting said kinase in vivo or ex vivo with a compound or compounds of the present invention, or a composition comprising a compound or compounds of the present invention. The disclosed compound or compounds, or compositions comprising the disclosed compound or compounds, can also be used to alleviate, treat or prevent various diseases and/or disorders. In particular embodiments, the disclosed compound, combinations of the disclosed compounds or pharmaceutical compositions containing them can be effective for treating conditions in which inhibition of RIP1 or a pathway involving RIP1 provides a therapeutic benefit. In some embodiments, the compounds directly inhibit RIP1 kinase activity. In certain embodiments, the disclosed compounds are useful for treating autoimmune diseases, inflammatory diseases, cardiovascular diseases, neurological disorders, neurodegenerative disorders, allergic disorders, respiratory diseases, kidney diseases, cancer, ischemic conditions, red blood cell deficiencies, lung and brain injuries (e.g., induced by ischemia-reperfusion or cisplatin and/or cerebrovascular accident), and bacterial and viral infections.

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

The disclosed compound, combinations of the disclosed compounds, or pharmaceutical compositions containing them may also be useful for treating immunoregulatory disorders associated with bone marrow or organ transplant rejection or graft versus host disease. Examples of inflammatory and immunoregulatory disorders treatable with the compounds (or pharmaceutical compositions or combinations thereof) include, but are not limited to, organ or tissue transplantation, transplant-induced graft-versus-host disease, autoimmune syndromes including rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, systemic sclerosis, systemic inflammatory response syndrome, myasthenia gravis, type I diabetes mellitus, 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, lichen planus, pemphigus, bullous pemphigoid, 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, corneal leukoma, conjunctival pemphigus, Mooren's ulcer, scleritis, Graves' ophthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, pollen allergies, reversible obstructive airway disease, bronchial asthma, allergic asthma, congenital asthma, acquired asthma, dust asthma, chronic or intractable asthma, late asthma and airway hyperreactivity, bronchitis, gastric ulcers, vascular injury caused by ischemic diseases and thrombosis, ischemic bowel disease, ischemia-reperfusion injury, inflammatory bowel disease, necrotizing enterocolitis, bowel injury 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, multiple myositis, Guillain-Barré syndrome, Meniere's disease, polyneuritis, multiple neuritis, mononeuritis, radiculopathy, hyperthyroidism, Graves' disease, pure red blood cell nephropathy aplasia, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, anerythroplasia, osteoporosis, sarcoidosis, pulmonary fibrosis, idiopathic interstitial pneumonia, dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, photoallergic reaction, cutaneous T-cell lymphoma, chronic lymphocytic leukemia, arteriosclerosis, atherosclerosis, aortitis, polyarteritis nodosa, myocardosis or myocardial infarction, scleroderma (including systemic sclerosis), antiphospholipid syndrome, Wegener's granuloma, Sjogren's syndrome, obesity, eosinophilic fasciitis, gingival lesions, periodontitis, alveolar bone, dental cementum, glomerulonephritis, male pattern alopecia or senile alopecia by preventing epilation or allowing hair ingrowth and/or stimulating hair formation and growth, muscular dystrophy, pyoderma and Sezary syndrome, Addison's disease, ischemia-reperfusion injury of organs arising from organ-preserving treatment, transplantation or ischemic disease

- 36 047748 endotoxin shock, pseudomembranous colitis, drug-induced or radiation-induced colitis, ischemic acute renal failure, chronic renal failure, oxygen or drug-induced toxicosis, lung cancer, pulmonary emphysema, cataract, siderosis, retinitis pigmentosa, retinal degeneration, retinal detachment, age-related macular degeneration, vitreous scarring, corneal alkali burn, dermatitis, erythema multiforme, linear IgA bullous dermatosis and cement dermatitis, gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by environmental pollution, aging, carcinogenesis, carcinoma metastasis and hypobaropathy, disease caused by the release of histamine or leukotriene C4, Behcet's disease, autoimmune hepatitis, primary biliary cirrhosis, sclerosing cholangitis, partial liver resection, acute liver necrosis, necrosis due to toxin, viral hepatitis, shock or hypoxia, viral hepatitis B, non-A, non-B hepatitis, cirrhosis, alcoholic liver disease including alcoholic cirrhosis, alcoholic steatohepatitis, non-alcoholic steatohepatitis (NASH), autoimmune diseases of the hepatobiliary system, acetaminophen toxicity, hepatotoxicity, liver failure, fulminant liver failure, late-onset liver failure, exacerbation of chronic liver failure, chronic kidney disease, kidney injury/damage (due to, for example, nephritis, kidney transplant, surgery, administration of nephrotoxic drugs, acute kidney injury), enhancement of the chemotherapeutic effect, cytomegalovirus infection, HCMV (human cytomegalovirus) infection, AIDS, cancer, senile dementia, Parkinson's disease, trauma or chronic bacterial infection.

In certain embodiments, the compounds of the present invention are useful for treating nerve-related pain, including neuropathic pain and pain caused by inflammation.

In certain embodiments, the compounds are useful for treating interleukin-1-converting enzyme-associated febrile syndrome, tumor necrosis factor receptor-associated periodic syndrome, NEMO deficiency syndrome, HOIL-1 deficiency, linear ubiquitin chain assembly complex deficiency syndrome, lysosomal storage diseases (e.g., Gaucher disease, GM2 gangliosidosis, alpha-mannosidosis, aspartylglucosaminuria, cholesteryl ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Farber disease, fucosidosis, galactosialidosis, GM1 gangliosidosis, mucolipidosis, infantile-onset free sialic acid storage disease, juvenile-onset hexosaminidase A deficiency, Krabbe disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidosis disorders, multiple sulfatase deficiency, Niemann-Pick disease, neuronal ceroid lipofuscinosis, Pompe disease, pycnodysostosis, Sandhoff disease, Schindler disease, sialic acid storage disease, Tay-Sachs disease, and Wolman disease).

In certain embodiments, the disclosed compound, combinations of the disclosed compounds, or pharmaceutical compositions comprising them are useful for the treatment and/or prevention of rheumatoid arthritis, psoriatic arthritis, osteoarthritis, systemic lupus erythematosus, lupus nephritis, ankylosing spondylitis, osteoporosis, systemic sclerosis, multiple sclerosis, psoriasis, in particular pustular psoriasis, type I diabetes mellitus, type II diabetes mellitus, inflammatory bowel disease (Crohn's disease and ulcerative colitis), hyperimmunoglobulinemia D and periodic fever syndrome, cryopyrin-associated periodic syndromes, Schnitzler syndrome, systemic juvenile idiopathic arthritis, adult-onset Still's disease, gout, gout exacerbation, pseudogout, SAPHO syndrome, Castleman disease, sepsis, stroke, atherosclerosis, celiac disease, DIRA (deficiency of IL-1 receptor antagonist), Alzheimer's disease, Huntington's disease or Parkinson's disease.

The use of the present compounds in combination with other therapies is particularly effective in the treatment of hyperproliferative disorders. The present compounds can be used to treat disorders such as cancers, leukemias, and lymphomas in combination with standard treatment. For example, myelodysplastic syndrome (MDS) can be treated with a compound disclosed herein in addition to standard treatment. Therapeutic agents for use in combination with the present compounds include hypomethylating agents such as azacitidine and decitabine, and other chemotherapeutic agents such as cytarabine, daunorubicin, and idarubicin. Immunomodulatory therapies such as lenalidomide therapy and CAR-T therapy can also be used in combination with the present compounds to treat MDS.

Proliferative diseases treatable with the disclosed compound, combinations of the disclosed compounds or pharmaceutical compositions containing them include benign or malignant tumors, solid tumor, carcinoma of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric tumor, ovary, colon, rectum, prostate, pancreas, lung, vagina, cervix, testicle, genitourinary tract, esophagus, larynx, skin, bone or thyroid gland, sarcoma, glioblastomas, neuroblastomas, multiple myeloma, gastrointestinal cancer, especially colon carcinoma or colorectal adenoma, head and neck tumor, epidermal hy

- 37 047748 hyperproliferation, psoriasis, prostatic hyperplasia, neoplasia, neoplasia of epithelial origin, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung carcinoma, lymphomas such as Hodgkin's lymphoma and non-Hodgkin's lymphoma, breast carcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, IL-1-mediated disorders, hematopoietic neoplasms such as the lymphomas mentioned above, MyD88-mediated disorder (such as diffuse large B-cell lymphoma (DLBCL) of the ABC type and Waldenstrom's macroglobulinemia), Hodgkin's lymphoma, primary cutaneous T-cell lymphoma or chronic lymphocytic leukemia), indolent or indolent multiple myeloma or hematological malignancies (including leukemia, acute myeloid leukemia (AML), DLBCL, ABC-type DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt's lymphoma/leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, myelodysplastic syndromes (MDS), myelofibrosis, polycythemia vera, Kaposi's sarcoma, Waldenstrom's macroglobulinemia (MB), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, intravascular large B-cell lymphoma). In particular, the compounds disclosed herein are useful for the treatment of drug-resistant malignancies, such as JAK inhibitor-resistant, ibrutinib-resistant malignancies, including ibrutinib-resistant hematological malignancies such as ibrutinib-resistant CLL and ibrutinib-resistant Waldenstrom's macroglobulinemia.

Examples of allergic diseases treatable using the disclosed compound, combinations of the disclosed compounds, or pharmaceutical compositions containing them include, but are not limited to, asthma (e.g., atopic asthma, allergic asthma, IgE-mediated atopic bronchial asthma, non-atopic asthma, bronchial asthma, non-allergic asthma, essential asthma, true asthma, congenital asthma caused by pathophysiological disorders, essential asthma of unknown or unclear etiology, emphysematous asthma, exercise-induced asthma, asthma caused by an emotional state, acquired asthma caused by environmental factors, cold-induced asthma, occupational asthma, infectious asthma caused by or associated with a bacterial, fungal, protozoal or viral infection, early-stage asthma, syndrome wheezing in infancy, bronchiolitis, cough-variant asthma, or drug-induced asthma), allergic bronchopulmonary aspergillosis (ABPA), allergic rhinitis, perennial allergic rhinitis, perennial rhinitis, vasomotor rhinitis, postnasal drip, purulent or non-purulent sinusitis, acute or chronic sinusitis, and sinusitis of the ethmoid, frontal, maxillary, or sphenoid sinuses.

As another example, rheumatoid arthritis (RA) typically results in swelling, pain, loss of motion, and tenderness of affected joints throughout the body. RA is characterized by a chronically inflamed synovial membrane with a high density of lymphocytes. The synovial membrane, which is normally one cell layer thick, undergoes intense cellular infiltration and takes on a form similar to lymphoid tissue, including dendritic cells, T, B, and NK cells, macrophages, and plasma cell aggregates. This process, as well as a variety of immunopathological mechanisms, including the formation of antigen-immunoglobulin complexes, ultimately leads to a breakdown of joint integrity, resulting in deformity, irreversible loss of function, and/or bone erosion in or near the joint. The disclosed compound, combinations of the disclosed compounds, or pharmaceutical compositions containing them can be used to treat, alleviate, or prevent any one, more, or all of these symptoms of RA. Thus, in the context of RA, compounds are considered to provide a therapeutic effect when a reduction or alleviation of any of the symptoms commonly associated with RA is achieved, regardless of whether the therapy being administered provides concomitant treatment of the underlying RA and/or a reduction in the amount of circulating rheumatoid factor (RF).

The American College of Rheumatology (ACR) has developed criteria to define improvement and clinical remission in RA. One such parameter, ACR20 (ACR criterion for 20% clinical improvement), requires a 20% improvement in the number of tender and swollen joints, as well as a 20% improvement in 3 of the following 5 parameters: patient global assessment, physician global assessment, patient pain assessment, degree of disability, and acute phase reactant protein level. These criteria have been expanded to 50% and 70% improvement in ACR50 and ACR70, respectively. Other criteria include the Paulus criteria and radiographic progression (eg, Sharp score).

In some embodiments, a therapeutic effect in patients suffering from RA is achieved when the patient has an ACR20. In specific embodiments, improvements in ACR at the level of ACRC50 or even ACR70 can be achieved.

In one embodiment, the compounds disclosed herein can be used to slow the onset of the effects of aging. For example, the present compounds reduce the severe chronic inflammation associated with old age (inflamaging). Inflamaging is associated with a variety of symptoms and conditions, such as conditions that are

- 38 047 748 treatment with the compounds of the present invention include neurodegenerative disorders such as Parkinson's and Alzheimer's diseases, hematopoietic neoplasms and myeloproliferative disorders. Additional conditions to be treated or ameliorated with the present compounds include those described in 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 present compounds can be used to reduce the effects of aging on the reproductive system. For example, Li et al. eLife 2017;6:e27692 and Chaudhary et al. Journal of Biomedical Science (2019) 26:11 found that RIP1 signaling-induced necroptosis is involved in reproductive organ aging, thus the present compounds may be used to treat aging-related symptoms such as decreased testosterone levels, decreased fertility, and prostate hyperplasia.

Additional diseases or disorders treatable and/or preventable with the compounds and compositions of the present invention include amyotrophic lateral sclerosis (ALS), autoimmune syndrome, rheumatoid arthritis, type I diabetes mellitus, inflammatory bowel diseases including Crohn's disease and ulcerative colitis, biliary cirrhosis, multiple sclerosis, Wegener's granulomatosis, ichthyosis, asthma, pollen allergies, reversible obstructive airway disease, bronchial asthma, allergic asthma, congenital asthma, acquired asthma, dust asthma, chronic or intractable asthma, late asthma and airway hyperreactivity, allergic rhinitis, spondylitis, ankylosing spondylitis, autoimmune hepatitis, autoimmune diseases of the hepatobiliary system, cerebrovascular accident, allergic diseases, chronic obstructive pulmonary disease, pulmonary emphysema, Friedreich's ataxia, Lewy body disease, diabetic neuropathy, polyglutamine (poly Q) diseases, Fahr's disease, Menkes disease, Wilson's disease, prion disease, destructive bone disorders such as bone resorption disease, multiple myeloma-associated bone disease; benign tumor, proliferative disorders, inflammatory and hyperproliferative skin disorders, epidermal hyperproliferation, psoriasis, atopic dermatitis, contact dermatitis, eczematous dermatitis, seborrheic dermatitis, pustular psoriasis, bullous dermatitis, dermatitis, erythema multiforme, linear IgA-mediated bullous dermatosis, cement dermatitis, gingivitis, periodontitis, gingival lesion, periodontium, alveolar bone, dental cementum, sepsis, pancreatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia, obesity, eosinophilic fasciitis, acne, alopecia areata, male pattern alopecia, senile alopecia, keratoconjunctivitis, vernal conjunctivitis, corneal alkali burn, Behcet's disease, Behcet's disease uveitis, keratitis, herpetic keratitis, keratoconus, corneal epithelial dystrophy, corneal leukoma, conjunctival pemphigus, Mooren's ulcer, scleritis, Vogt-Koyanagi-Harada syndrome, hematological disorders, hemoblastoses, lymphomas, Hodgkin's lymphoma, non-Hodgkin's lymphoma, breast carcinoma, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, diffuse large B cell lymphoma (DLBCL) ABC-type, Waldenstrom's macroglobulinemia, primary cutaneous T-cell lymphoma, smoldering or indolent multiple myeloma, leukemia, acute myeloid leukemia (AML), DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt's lymphoma/leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, myelodysplastic syndromes (MDS), myelofibrosis, polycythemia vera, Kaposi's sarcoma, splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, intravascular large B-cell lymphoma, IL-1-mediated disorders, MyD88-mediated disorders, drug-resistant malignancies neoplasms such as JAK inhibitor-resistant malignancies and ibrutinib-resistant malignancies such as ibrutinib-resistant hematological malignancies, ibrutinib-resistant CLL and ibrutinib-resistant Waldenstrom's macroglobulinemia, acute myelogenous leukemia, chronic myelogenous 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 lesions associated with thermal burns, celiac disease, proctitis, eosinophilic gastroenteritis, mastocytosis, interleukin-1-converting enzyme-associated fever syndrome, tumor necrosis factor receptor-associated periodic syndrome, NEMO deficiency syndrome, HOIL-1 deficiency, linear ubiquitin chain assembly complex deficiency syndrome, lysosomal storage disease, Gaucher disease, GM2 gangliosidosis, alpha-mannosidosis, aspartylglucosaminuria, cholesteryl ester storage disease, chronic hexosaminidase A deficiency, cystinosis, Danon disease, Fabry disease, Farber disease, fucosidosis, galactosialidosis, GM1 gangliosidosis, mucolipidosis, infantile form of the disease accumulation of free sialic acid, juvenile hexosaminidase A deficiency, Krabbe disease, lysosomal acid lipase deficiency, metachromatic leukodystrophy, mucopolysaccharidosis disorders

- 39 047748 diseases, multiple sulfatase deficiency, Niemann-Pick disease, neuronal ceroid lipofuscinosis, Pompe disease, pycnodysostosis, Sandhoff disease, Schindler disease, sialic acid storage disease, Tay-Sachs disease, Wolman disease, Huntington disease, Parkinson's disease, neurodegenerative diseases, Huntington's disease, Parkinson's disease, metastatic melanoma, neurodegeneration associated with HIV infection and cytomegalovirus retinitis, such as associated neurocognitive disorders or dementia, fibrotic conditions such as non-alcoholic steatohepatitis, and cardiac diseases such as ischemia-reperfusion; allergies, adult respiratory distress syndrome, chronic obstructive pulmonary disease, glomerulonephritis, erythematosus, chronic thyroiditis, Graves' disease, autoimmune gastritis, autoimmune neutropenia, thrombocytopenia, graft-versus-host disease, endotoxin-induced inflammatory reaction, tuberculosis, atherosclerosis, muscular degeneration, cachexia, Reiter's syndrome, rubella arthritis, acute synovitis, pancreatic β-cell disease; diseases characterized by marked neutrophilic infiltration; rheumatoid spondylitis, gouty arthritis, psoriatic arthritis and other arthritic conditions, cerebral malaria, chronic inflammatory lung disease, silicosis, pulmonary sarcoidosis, pulmonary fibrosis, idiopathic interstitial pneumonia, allograft rejection, rejection bone marrow, fever and myalgia due to infection, keloid formation, scar tissue formation, fever, influenza, chronic myelogenous leukemia; angiogenic disorders including solid tumors; viral diseases including acute hepatitis virus infection (including hepatitis A, hepatitis B and hepatitis C), AIDS, SAH (AIDS-associated complex) or malignancy, herpes; stroke, myocardial infarction, arteriosclerosis, atherosclerosis, aortitis, polyarteritis nodosa, myocardial ischemia, ischemic stroke, organ hypoxia, vascular hyperplasia, reperfusion injury of the heart and kidneys, ischemia-reperfusion injury of organs occurring during organ preservation, transplantation, or ischemic disease, cardiac hypertrophy, thrombin-induced platelet aggregation, endotoxemia and/or toxic shock syndrome, prostaglandin-endoperoxide synthase-2-related conditions, pemphigus vulgaris, autoimmune/multiple myositis, dermatomyositis, leukoderma vulgaris, photoallergic reaction, ischemia-reperfusion injury, ischemia-reperfusion injury of the heart following myocardial infarction, multiple systemic atrophy, parkinsonism-plus related syndromes, frontotemporal dementia, intracranial hemorrhage, cerebral hemorrhage, progressive muscular atrophy, pseudobulbar syndrome, progressive bulbar palsy, spinal muscular atrophy, hereditary muscular atrophy, peripheral neuropathies, progressive supranuclear palsy, corticobasal degeneration, demyelinating diseases, systemic juvenile idiopathic arthritis (sJIA) or Still's disease, systemic lupus erythematosus (SLE), Sjogren's syndrome, antiphospholipid syndrome (APS), primary sclerosing cholangitis (PSC), kidney transplant, surgery, acute renal failure (ARF), systemic inflammatory response syndrome (SIRS), cytokine release syndrome (CRS), acute respiratory distress syndrome (ARDS), COVID-19 ARDS, post-infectious autoimmune diseases, rheumatic fever, post-infectious glomerulonephritis, systemic sclerosis, cerebrovascular accident (CVA), chronic obstructive pulmonary disease (COPD), NEMO deficiency syndrome (essential F-kappa-B modulator gene deficiency syndrome (also known as IKK-gamma or IKKG)), solid organ malignancies, lysosomal storage diseases, glaucoma, retinal degenerative disease, retinal ischemia-reperfusion injury, renal ischemia-reperfusion injury, cataract, siderosis, retinitis pigmentosa, retinal degeneration, retinal detachment, age-related macular degeneration, vitreous scarring, lethal anthrax toxin-induced septic shock, LPS-induced cell death (lipopolysaccharide), infectious encephalopathy, encephalitis, allergic encephalomyelitis, autoimmune uveoretinitis, giant cell arteritis, regional enteritis, granulomatous enteritis, distal ileitis, regional ileitis, terminal ileitis, insulin-dependent diabetes mellitus, scleroderma, systemic scleroderma, macular edema, diabetic retinopathy, central areolar choroidal dystrophy, BEST disease, adult vitelliform macular degeneration, pattern dystrophy, myopic degeneration, central serous retinopathy, Stargardt disease, cone-rod dystrophy, North Carolina dystrophy, infectious retinitis, inflammatory retinitis, uveitis, posterior uveitis, toxic retinitis, and light-induced toxicity, macular edema, central areolar choroidal dystrophy, BEST disease, adult vitelliform macular degeneration, pattern dystrophy, optic nerve injury, optic neuritis, optic neuropathies, central retinal artery occlusion, ischemic optic neuropathy (e.g., arteritic and nonarteritic anterior ischemic neuropathy and posterior ischemic optic neuropathy), compressive optic neuropathy, infiltrative optic neuropathy, traumatic optic neuropathy, mitochondrial optic neuropathy (e.g., Leber optic neuropathy), nutritional optic neuropathy, toxic optic neuropathy, and hereditary optic neuropathy.

- 40 047748 (neuropathy, dominant optic atrophy, Beer syndrome, Creutzfeldt-Jakob disease), progressive supranuclear palsy, hereditary spastic paresis, subarachnoid hemorrhage, perinatal brain injury, subclinical brain injury, spinal cord injury, hypoxic-ischemic brain injury, cerebral ischemia, focal cerebral ischemia, global cerebral ischemia and hypoxic hypoxia, peritoneal dialysis (PD) solution-induced peritoneal injury and PD-related side effects, glomerular diseases, tubulointerstitial diseases, interstitial nephritis, occlusion, polycystic kidney disease), focal glomerulosclerosis, immune complex deposition nephropathy, diabetic nephropathy, Goodpasture's syndrome, hepatocellular carcinoma, pancreatic cancer, genitourinary cancer, bladder cancer, colorectal cancer, colon cancer, breast cancer, prostate cancer, prostatic hyperplasia, renal cancer, renal carcinoma, liver carcinoma, adrenal carcinoma, thyroid cancer, gallbladder cancer, peritoneal cancer, ovarian cancer, cervical cancer, gastric cancer, endometrial cancer, esophageal cancer, stomach cancer, head and neck cancer, neuroendocrine cancer, CNS cancer, brain tumors (e.g., brain carcinoma, glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma), bone cancer, soft tissue sarcoma, retinoblastoma, neuroblastoma, peritoneal effusion, malignant pleural effusion, mesotheliomas, tumors Wilms, trophoblastic neoplasms, epithelial neoplasia, gastric carcinoma, ovarian carcinoma, rectal carcinoma, prostate carcinoma, pancreatic carcinoma, lung carcinoma, vaginal carcinoma, cervical carcinoma, testicular carcinoma, genitourinary tract carcinoma, esophageal carcinoma, laryngeal carcinoma, skin carcinoma, bone carcinoma, thyroid carcinoma, sarcoma, glioblastomas, neuroblastomas, gastrointestinal cancer, adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung carcinoma, lymphomas, colon carcinoma, colorectal adenoma, hemangiopericytomas, myxoid carcinoma, round cell carcinoma, squamous cell carcinomas, squamous cell carcinomas of the esophagus, carcinomas of the oral cavity, vulvar cancer, cancers of the adrenal cortex, ACTH (adrenocorticotropic hormone)-producing tumors and leukemia, respiratory viral infections such as influenza virus, rhinovirus, coronavirus, parainfluenza virus, RS (respiratory syncytial 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, MRSA (methicillin-resistant Staphylococcus aureus), Salmonella, Botulinus, Candida, Paget's disease, chondrodysplasia, osteochondritis, hyperparathyroidism, osteogenesis imperfecta, partial liver resection, acute liver necrosis, toxin-induced necrosis, viral hepatitis-induced necrosis, shock-induced necrosis, hypoxia-induced necrosis, viral hepatitis B, non-A, non-B hepatitis, cirrhosis, alcoholic liver disease, alcoholic cirrhosis, alcoholic steatohepatitis, non-alcoholic steatohepatitis (NASH), acetaminophen toxicity, hepatotoxicity, liver failure, fulminant liver failure, late-onset liver failure, exacerbation of chronic liver failure, chronic kidney disease, kidney injury/damage, kidney injury/damage due to nephritis, kidney transplantation-induced kidney injury/damage, kidney surgery-induced kidney injury/damage intervention, renal injury/damage caused by administration of nephrotoxic drugs, enhancement of chemotherapeutic effect, cytomegalovirus infection, HCMV (human cytomegalovirus) infection, AIDS, cancer, senile dementia, trauma, chronic bacterial infection, diseases caused by environmental pollution, aging, hypobaropathy, histamine or leukotriene C4 release disease, muscular dystrophy, pyoderma and Sezary syndrome, Addison's disease, pseudomembranous colitis, drug- or radiation-induced colitis, ischemic acute renal failure, chronic renal failure, oxygen or drug-induced toxicosis, congenital hypophosphatasia, fibromatous lesions, fibrous dysplasia, bone resorption, osteolytic bone lesion, treatment after traumatic bone surgery, treatment after joint replacement surgery, treatment after bone grafting, treatment after dental surgery, chemotherapy to bone or radiation therapy to bone, bone cancer, unstable atherosclerotic plaque, disorder, occlusive disease, stenosis, coronary artery disease, peripheral arterial disease, arterial occlusion, aneurysm formation, posttraumatic aneurysm formation, restenosis, postoperative graft occlusion, Guillain-Barré syndrome, Meniere's disease, polyneuritis, multiple neuritis, mononeuritis, radiculopathy, hyperthyroidism, Graves' disease, autoimmune idiopathic thrombocytopenic purpura (autoimmune ITP), membranous nephritis, autoimmune thyroiditis, Hashimoto's thyroiditis, myasthenia gravis, cold and heat diseases agglutinins, Evans syndrome, hemolytic uremic syndrome/thrombotic thrombocytopenic purpura (HUS/TTP), autoimmune

- 41 047748 hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, anerythroplasia and their combinations.

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

B. Composition and introduction.

Pharmaceutical compositions containing one or more active compounds according to the invention can be prepared by any suitable method, such as mixing, dissolving, granulating, drageeing, trituration, emulsifying, encapsulating, entrapping or lyophilizing. The pharmaceutical compositions can be formulated using one or more physiologically acceptable auxiliary substances (e.g. diluents, carriers or auxiliary ingredients), one or more adjuvants or combinations thereof to obtain formulations that can be used for pharmaceutical purposes.

The active compound(s) may be incorporated into pharmaceutical compositions as such or in the form of a pharmaceutically acceptable salt, stereoisomer, N-oxide, tautomer, hydrate, solvate, isotope or prodrug thereof. Typically, such salts are more soluble in aqueous solutions than the corresponding free acids and bases, but salts with lower solubility than the corresponding free acids and bases may also be formed.

The pharmaceutical compositions of the invention may be in a form suitable for virtually any route of administration, including, for example, topical, ocular, oral, buccal, systemic, nasal, injection, such as intravenous or intraperitoneal, transdermal, rectal, vaginal, etc., or a form suitable for administration by inhalation or insufflation.

For topical administration, the active compound(s), pharmaceutically acceptable salt, stereoisomer, N-oxide, tautomer, hydrate, solvate, isotope or prodrug may be prepared as solutions, gels, ointments, creams, suspensions, etc., as is well known in the art.

Systemic formulations include those intended for administration by injection, such as subcutaneous, intravenous, intramuscular, subarachnoid, or intraperitoneal injection, as well as those intended for transdermal, transmucosal, oral, or inhalation administration.

Suitable injectable formulations include sterile suspensions, solutions or emulsions of the active compound(s) in aqueous or oily vehicles. The pharmaceutical compositions may also contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Injectable formulations may be presented in unit dosage form, for example, in ampoules or in multi-dose containers, and may contain added preservatives.

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

In the case of transmucosal administration, the composition uses penetration agents suitable for the barrier to be penetrated. Such penetration agents are known in the art.

For oral administration, the pharmaceutical compositions may take the form of, for example, lozenges, tablets or capsules prepared by conventional methods, with pharmaceutically acceptable excipients such as: binding agents (e.g., pregelatinized corn starch, polyvinylpyrrolidone 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 may be coated by methods well known in the art, for example with sugars, films or enteric coatings.

Liquid preparations for oral administration may take the form of, for example, elixirs, solutions, syrups or suspensions, or they may be presented as a dry product for dilution with water.

- 42 047748 or other suitable vehicle before use. Such liquid formulations can be prepared by conventional means with pharmaceutically acceptable auxiliary substances such as: suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, fatty acid esters, ethyl alcohol, cremophore™ or fractionated vegetable oils); and preservatives (e.g. methyl or propyl p-hydroxybenzoates or sorbic acid). The formulations can also contain buffer salts, preservatives, flavoring agents, coloring agents and sweetening agents as required.

It is well known that formulations for oral administration can be formulated so as to provide controlled release of the active compound.

For transbuccal administration, the pharmaceutical compositions may take the form of tablets or lozenges formulated in the usual manner.

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

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 conveniently be delivered as an aerosol spray from a pressurized container or nebulizer using a suitable propellant, for example, 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 for delivering a metered amount. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound and a suitable powder base, for example, lactose or starch.

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

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

For ocular administration, the active compound(s) may be formulated as a solution, emulsion, suspension, etc., suitable for administration to the eye. Many carrier vehicles suitable for administering compounds to the eye are known in the art. Specific non-limiting examples are described in U.S. Pat. Nos. 6,261,547, 6,197,934, 6,056,950, 5,800,807, 5,776,445, 5,698,219, 5,521,222, 5,403,841, 5,077,033, 4,882,150, and 4,738,851, which are incorporated herein by reference.

For prolonged delivery, the active compound(s) may be formulated as a depot formulation for administration by implantation or intramuscular injection. The active ingredient may be combined with suitable polymeric or hydrophobic materials (e.g. as an emulsion in an acceptable oil) or ion exchange resins, or as poorly soluble derivatives, e.g. as a poorly soluble salt. Alternatively, transdermal delivery systems may be used, formulated as an adhesive disc or patch, which slowly release the active compound(s) for transdermal absorption. For this purpose, permeation enhancers may be used to facilitate transdermal penetration of the active compound(s). Suitable transdermal patches are described, for example, in U.S. Patents 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 hereby incorporated by reference.

Alternatively, other pharmaceutical delivery systems may be used. Liposomes and emulsions are well-known examples of delivery vehicles that may be used to deliver the active compound(s). Some organic solvents, such as dimethyl sulfoxide (DMSO), may also be used, although they generally have the disadvantage of greater toxicity.

The pharmaceutical compositions may, if desired, be presented in a package or a dosing device which may contain one or more unit dosage forms containing the active compound(s). The package may, for example, comprise a metal or plastic foil, such as in the case of a blister pack. The package or dosing device may be accompanied by instructions for use.

There are several approaches to transporting molecules across the blood-brain barrier. To

- 43 047748 These include, but are not limited to, physical methods, lipid-based methods, and receptor- and channel-based methods. Physical methods of transporting a compound across the blood-brain barrier include, but are not limited to, delivery bypassing the blood-brain barrier and/or creating openings in the blood-brain barrier. Bypass delivery 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. U.S.A. 91 :2076-2080, 1994), and implantation of a delivery device into the brain (see, e.g., Gill et al., Nature Med. 9:589-595, 2003). Perforations in the blood-brain barrier include, but are not limited to, ultrasound, osmotic pressure (e.g., by administration of hypertonic mannitol, and permeabilization with, e.g., bradykinin or permeabilizer A-7 (see, e.g., U.S. Pat. 5112596, 5268164, 5506206 and 5686416)). The compounds can also be encapsulated in liposomes with attached binding fragments of antibodies that bind to receptors on the endothelium of the blood-brain barrier vessels.

In certain embodiments, the compounds can be administered continuously by infusion into fluid-containing reservoirs of the CNS or by bolus injection. The compounds can be administered using an indwelling catheter and means for continuous administration, such as a pump, or by implantation of a slow-release carrier. For example, the compounds can be injected through permanently implanted cannulas or continuously infused using osmotic minipumps. Subcutaneous pumps can deliver the compounds to the cerebral ventricles.

C. Dosages.

The disclosed compound, pharmaceutical compositions or combinations of the disclosed compounds will typically be administered in an amount effective to achieve the desired result, such as an amount effective to inhibit RIP1 kinase and/or to treat, prevent or alleviate a particular condition. The disclosed compound(s) or pharmaceutical compositions containing them may be administered therapeutically to achieve a therapeutic effect or prophylactically to achieve a prophylactic effect. A therapeutic effect means eliminating or alleviating the underlying disorder being treated and/or eliminating or alleviating one or more symptoms associated with the underlying disorder, such that the patient reports an improvement in well-being or condition, despite the fact that the patient may still suffer from the underlying disorder. For example, administering a compound to a patient suffering from an allergy provides a therapeutic effect not only when the underlying allergic reaction is eliminated or alleviated, but also when the patient reports a decrease in the severity or duration of the symptoms associated with the allergy after contact with the allergen. As another example, a therapeutic effect in the context of asthma includes improvement in breathing after the onset of an asthma attack or a reduction in the frequency or severity of asthmatic episodes. A therapeutic effect also includes stopping or slowing the progression of the disease, whether or not this results in improvement.

As is known to those skilled in the art, the preferred dosage of the disclosed compounds may depend on various factors, including the age, body weight, general health, and severity of the condition of the patient or subject being treated.

The dosage may also need to be adapted to the sex of the individual and/or the lung capacity of the individual when administered by inhalation. The dosage may also be adapted for individuals suffering from more than one disease, or for individuals having other conditions that affect lung capacity and the ability to breathe normally, such as emphysema, bronchitis, pneumonia, respiratory distress syndrome, chronic obstructive pulmonary disease and respiratory infections. The dosage and frequency of administration of the disclosed compound(s) or pharmaceutical compositions containing them will also depend on whether the disclosed compound(s) is presented as a composition for the treatment of acute episodes of the condition or as a composition for the prophylactic treatment of the disorder. One skilled in the art will be able to determine the optimal dose for a particular individual.

For prophylactic administration, a disclosed compound, combinations of the disclosed compounds, or pharmaceutical compositions containing them may be administered to a patient or subject at risk of developing one of the previously described conditions. For example, if it is unknown whether a patient or subject is allergic to a particular drug, a disclosed compound, combinations of the disclosed compounds, or pharmaceutical compositions containing them may be administered prior to administration of that drug to avoid or reduce an allergic reaction to that drug. Alternatively, prophylactic administration may be used to prevent or alleviate the onset of symptoms in a patient diagnosed with an underlying disorder. For example, a disclosed compound(s) or a pharmaceutical composition containing them may be administered to an allergy sufferer prior to anticipated exposure to an allergen. A disclosed compound, combinations of the disclosed compounds, or pharmaceutical compositions containing them may be administered prior to administration of that drug to avoid or reduce an allergic reaction to that drug.

- 44 047748 maceutical compositions can also be administered prophylactically to healthy individuals who are systematically exposed to agents associated with one of the above-described disorders, in order to prevent the manifestation of the disorder. For example, the disclosed compound, combinations of the disclosed compounds, or pharmaceutical compositions containing them can be administered to a healthy individual who is systematically exposed to an allergen known to cause allergies, such as latex, in order to prevent the development of an allergy in this individual. Alternatively, the disclosed compound, combinations of the disclosed compounds, or pharmaceutical compositions containing them can be administered to a patient suffering from asthma, prior to engaging in activities that cause asthma attacks, in order to reduce the severity of an asthmatic episode or avoid it entirely.

Effective dosages may be initially estimated from in vitro assay data. For example, the initial dosage for administration to subjects may be selected to achieve a circulating blood or serum concentration of the active compound equal to or greater than the IC50 or EC50 of the particular compound as measured in an in vitro assay. Dosages may be calculated to achieve such circulating blood or serum concentrations while taking into account the bioavailability of the particular compound. Fingl & Woodbury, General Principles, In: Goodman and Gilman's The Pharmaceutical Basis of Therapeutics, Chapter 1, pp. 1-46, Pergamon Press, and references cited therein, provide additional information regarding effective dosages.

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.

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

In some embodiments, assays suitable for determining RIP1 activity may be used. Such assays may be used to evaluate the efficacy of embodiments of the compounds disclosed herein and/or they may be used to determine amounts/dosages of embodiments of the compounds that may provide the desired efficacy. In some embodiments, the assay may be an ADP-Glo™ assay, which evaluates the ability of an embodiment compound to inhibit RIP1. In other embodiments, whole cell assays may be conducted using mouse and/or human cells, such as U937 and/or L929 cell necroptosis assays, to determine safe and effective doses of compounds that may be used in in vivo studies in humans. These whole cell assays may evaluate the activity of a compound against human and/or mouse RIP1 in an in vitro context, which then allows one of skill in the art to determine safe and effective doses for in vivo use. Another assay that can be used to evaluate the activity of embodiments of the compounds described herein for treating a disease or condition associated with RIP1 is a mouse model of acute hypothermia that evaluates the ability of a compound to inhibit TNF-alpha-induced hypothermia. Each of these assays and the various results obtained using these assays are described in detail in the Examples section of this disclosure.

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

The dosage size and frequency of dosing can be adjusted for individuals to provide plasma levels of the disclosed compound sufficient to maintain a therapeutic or prophylactic effect. For example, the compounds can be administered once daily, several times daily, once weekly, several times weekly (e.g., every other day), once monthly, several times monthly, or once annually, depending on, among other things, the route of administration, the particular condition being treated, and the judgment of the treating physician. Those skilled in the art will be able to optimize effective topical dosages without undue experimentation.

Pharmaceutical compositions comprising one or more of the disclosed compounds typically comprise from greater than 0 to 99% by weight of the disclosed compound or compounds and/or another therapeutic agent based on total weight. Typically, pharmaceutical compositions comprising one or more of the disclosed compounds comprise from about 1 to about 20% by weight of the disclosed compound and another therapeutic agent and from about 80 to about 99% by weight of a pharmaceutically acceptable excipient based on total weight. In some embodiments, the pharmaceutical composition may further comprise an adjuvant.

Preferably, the disclosed compound, combinations of the disclosed compounds, or pharmaceutical compositions containing them will provide a therapeutic or prophylactic effect without causing significant toxicity. The toxicity of a disclosed compound can be determined using standard pharmaceutical procedures. The ratio of doses providing a toxic and therapeutic (or prophylactic) effect is the therapeutic index. Disclosed compounds that exhibit high therapeutic indices are preferred.

V. Examples.

Example 1.

The compounds of the present invention can be prepared using a suitable starting compound, such as compound 200 or compound 206, shown in the schemes above. A representative method for preparing compound 200 is shown in scheme 4A, and a representative method for preparing compound 206 is shown in scheme 4B.

Scheme 4A.

Br

200

NHTr Cs ₂ CO ₃ , DMF Br

D 50 °C, 1.5 d

NHTr

HE

TrCI, _Et3N ,

CHCI ₃ , 0 0 °C, 4h

Scheme 4B.

NHBoc .OH

NHBoc

NaH, DMF, RT, 4h

EtOH- _H2O °C, 1h

NHBoc

Fe, NH4CI,

HATU, iPr ₂ NEt, DMSO, k.t., 18h

Spectral characteristics for 3-^)-N-trityl-amino-7-bromo-5-methyl-4-oxobenzoxazapine (200): ¹ H NMR (400 MHz, CDCl ₃ ) δ 7.41-7.38 (6H, m, 6H resp. C(C ₆ H ₅ ) ₃ ), 7.25-7.15 (10H, m, H-8 oxobenzoxazapine, 9H resp. C (C ₆ H ₅ ) ₃ ), 7.00 (1H , d, J 2.5 Hz, H-6 oxobenzoxazapine), 6.91 (1H, d, J 8.5 Hz, H-9 oxobenzoxazapine), 4.50 (1H, dd, J 10.0, 7, 5 Hz, 1H corresponding to H-2 oxobenzoxazapine), 4.37 (1H, dd, J 11.5, 10.0 Hz, 1H corresponding to H-2 oxobenzoxazapine), 3.53 (1H, dd, J 11.5, 7 ,5 Hz, H-3 oxobenzoxazapine), 3.30 (1H, br s, NH), 2.87 (3H, s, NCH3).

Example 2.

Scheme 5 shows a method for obtaining 4-phenoxypicolinonitrile and 4-phenoxypyridine-2-carboxylic acid.

- 46 047748

Scheme 5.

As shown in Scheme 5, cesium carbonate (20.58 g, 63.1 mmol, 1.1 equiv) was added to a solution of 4-fluoropicolinonitrile 90 (7.00 g, 57.4 mmol, 1.0 equiv) and phenol 92 (5.66 g, 60.2 mmol, 1.05 equiv) in dimethylformamide (90 mL). The reaction mixture was heated to 80 °C for 8 h and cooled. The reaction mixture was poured into ice water (1 L). A precipitate formed, which was isolated by filtration to give 4-phenoxypicolinonitrile 94 (10.7 g, 95%) as a white solid; ^1H NMR (400 MHz, CDCl ₃ ) δ 8.52 (1H, d, J 6.0 Hz, ruH-6), 7.50-7.45 (2H, m, 2H belongs to C6H5), 7.33 (1H, tt, J 7.5, 1.0 Hz, 1H belongs to C ₆ H ₅ ), 7.20 (1H, d, J 2 ,0 Hz, ruH-3), 7.11-7.08 (2H, m, 2H belongs to C ₆ H ₅ ), 7.02 (1H, dd, J 5.5, 2.5 Hz, ruH-5); m/z: 197 [M+H]+.

Example 3.

This example relates to a method for the preparation of 4-phenoxypyridine-2-carboxylic acid 96 from 4-phenoxypicolinonitrile 94. A suspension of picolinonitrile 94 (10.7 g, 54.6 mmol) in hydrochloric acid (6 M, 100 mL) was heated to 100 °C for 8 h. The reaction mixture was cooled to room temperature to form a precipitate, which was isolated by filtration. The filtrate was cooled to give an additional solid, which was isolated by filtration and added to the first crop of product. The solid was dried in vacuo to give a white solid of 4-phenoxypyridine-2-carboxylic acid 96 (12.6 g, 92%); ¹ H NMR (400 MHz, D^MTO) δ 8.64 (1H, d, J 6.0 Hz, pH-6), 7.57-7.53 (3H, m, pH-3, 2H belongs to C ₆ H ₅ ), 7.38 (1H, tt, J 7.5, 1.0 Hz, 1H belongs to C ₆ H ₅ ), 7.33 (1H, dd, J 6.0 2.5 Hz, pH-5), 7.28-7.26 (2H, m, 2H belongs to C ₆ H ₅ ); m/z: 216 [M+H] ⁺ .

Example 4.

This example pertains to methods for the preparation of 5-(4-fluorophenoxy)pyridine-2-carboxylic acid. N-methylpyrrolidinone (5 mL) was added to a mixture of methyl fluoropicolinate (0.400 g, 2.58 mmol, 1.0 equiv), 4-fluorophenol (0.318 g, 2.84 mmol, 1.1 equiv), and cesium carbonate (0.925 g, 2.84 mmol, 1.1 equiv). The reaction mixture was stirred at 95 °C for 75 min. The reaction mixture was cooled and added to ice water (150 mL) to form a precipitate. After stirring for 15 min, the precipitate was isolated by filtration (0.540 g, 85%) as a white solid; 1H NMR (400 MHz, CDCl ₃ ) δ 8.46 (1H, dd, J 3.0, 0.5 Hz, ruH-6), 8.09 (1H, dd, J 9.0 0.5 Hz, ruH-2), 7.24 (1H, dd, J 9.0, 3.0 Hz, ruH-4), 7.14-7, 04 (4H, m, C6H4F), 3.99 (3H, s, OCH3); 19F NMR (380 MHz, CDCl ₃ ) δ -117.0; m/z: 248 [M+H]+.

An aqueous solution of lithium hydroxide (0.14 g in 5 mL water, 3.28 mmol, 1.5 equiv) was added to a solution of the methyl ester (0.54 g, 2.19 mmol, 1.0 equiv) in tetrahydrofuran (12 mL). The reaction mixture was stirred at room temperature for 35 min and concentrated to remove organics. The solution was diluted with water (5 mL) and hydrochloric acid (3 M, ~1 mL) was added to pH ~3. A white precipitate formed which was isolated by filtration. Additional hydrochloric acid (3 M, 10 drops) was added to the filtrate forming an additional precipitate which was isolated by filtration. The precipitates were combined and dried in vacuo to give the title compound (0.49 g, 75%) as a white solid; 1H NMR (400 MHz, D6-H,MCO) δ 8.43 (1H, dd, J 3.0, 0.5 Hz, ruH-6), 8.02 (1H, dd, J 8.5 0.5 Hz, ruH-2), 7.39 (1H, dd, J 8.5, 3.0 Hz, ruH-4), 7.33- 7.22 (4H, m, C6H4F); 19F NMR (380 MHz, D6^MTO) δ -117.7; m/z: 234 [M+H]+.

Example 5.

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

Scheme 6.

A solution of cyclobutanol 102 (0.30 mL, 3.84 mmol, 1.2 equiv.) in tetrahydrofuran (20 mL) was cooled to 0 °C. Sodium hydride (0.154 g of 60% suspension, 3.84 mmol, 1.2 equiv.) was added and the reaction mixture was stirred at 0 °C for 25 min. Fluoropicolinonitrile 100 (0.390 g, 3.20 mmol,

- 47 047748

1.0 equiv) and stirred the reaction mixture at room temperature for 2 h. The reaction was quenched by addition of NH4Cl (5 mL). The reaction mixture was diluted with EtOAc (80 mL) and washed with NaHCO3 (80 mL). The aqueous phase was extracted with EtOAc (30 mL). The combined organic layers were washed with brine (60 mL), dried ( _Na2SO4 ), filtered and concentrated under reduced pressure. MPLC (10 >60% EtOAc- _hexane ) afforded 4-cyclobutyloxypicolinonitrile 104 (0.487 g, 88%) as a colorless oil. Ή NMR (400 MHz, CDCl ₃ ) δ 8.46 (1H, d, J 5.5 Hz, ruH-6), 7.10 (1H, d, J 2.5 Hz, ruH-3), 6.88 (1H, dd, J 5.5, 2.5 Hz, ruH-5), 4.72 (1H, pentet, J 7.0 G ts, cBuH-1), 2.53-2.46 (2H, m, 2H belongs to cBuH-2, H-4), 2.26-2.16 (2H, m, 2H belongs to cBuH2, H-4), 1.98-1.89 (1H, m, 1H belongs to cBuH-3), 1.82-1.71 (1H, m, 1H belongs to cBuH-3).

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

Example 6.

This example relates to a method for the preparation of N-substituted-4-[(aryl/heteroaryl)methyl]-1H-pyrazole-1-carboxamides via the formation of a pyrazole-1-carbonyl chloride intermediate according to Scheme 7.

Scheme 7.

Triphosgene g /ss>%7\r/HetAr i-ProNEt /^s/^Ar/HetAr

ΗΝ Ί --- ² ---। _n zj ^N n HCI CH ₂ CI ₂ , 0 0 °C-k.t. Cl N

1400 1402

1406

To a stirred heterogeneous mixture of 4-[(aryl/heteroaryl)methyl]-III-pyrazole hydrochloride 1400 (1 equiv) and triphosgene (1.5 equiv) in _CH2Cl2 (15 mL/mmol) under nitrogen at 0 °C was gradually added i- _Pr2NEt (5-9 equiv) (15 _min /mmol). The red reaction solution was stirred at 0 °C for 1 h, warmed to room temperature (2 h), analyzed for 4-[(aryl/heteroaryl)methyl]-III-pyrazole consumption by LC/MS and concentrated to dryness to afford 1402. The red semi-solid concentrate was added to 1404 or the appropriate amine or salt thereof (1 equiv) and DMAP (0.1 equiv) and cooled in an ice bath under nitrogen. _CH2Cl2 (15 _mL /mmol) was added to the flask, stirred for 15 min, and the red solution was gradually treated with i- _Pr2NEt (5-9 equiv) (15 min/mmol) while stirring. The ice bath was removed after 1 h and the reaction solution was allowed to warm to room temperature. After analyzing the reaction progress, the reaction solution was concentrated to dryness, diluted with water, and extracted with either EtOAc or _CH2Cl2 . Flash column chromatography of the crude concentrate on silica gel provided the desired N-substituted-4-[(aryl/heteroaryl)methyl]-N-pyrazole-1- _carboxamide 1406 (yield: 20-75%).

Example 7.

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

- 48 047748

Scheme 8.

Triphosgene i-Pr ₂ NEt

NH ₂ hci -----------CH ₂ CI ₂ , Yu°N-k

1420

'Ar/HetAr

NH

_{CH2CI2 ,} 0 °CK.T. ⁰

1426 i-Pr ₂ NEt (10-15 equiv) was added gradually (20 min/mmol) to a stirred heterogeneous mixture of compound 1420 or its corresponding amine or salt (1 equiv) and triphosgene (2.3 equiv) in CH ₂ Cl ₂ (15 mL/mmol) under nitrogen atmosphere at 0 °C. The pale yellow reaction solution was stirred at 0 °C for 1 h, warmed to room temperature (2 h), analyzed for consumption of the corresponding amine by LC/MS and concentrated to dryness. To the red semi-solid concentrate containing compound 1422 were added 4-[(aryl/heteroaryl)methyl]-III-pyrazole hydrochloride 1424 (0.9 equiv) and DMAP (0.1 equiv) and cooled in an ice bath under nitrogen. The flask was charged _{with CH2Cl2 (} 15 mL/mmol), stirred for 15 min and gradually treated with stirred red solution of i- _Pr2NEt (10-15 equiv) (15 min/mmol). The ice bath was removed after 1 h and the reaction solution was allowed to warm to room temperature (6-8 h). After analysis of the reaction progress, the reaction solution was concentrated to dryness, diluted _with water and extracted with either EtOAc or _CH2Cl2 . Purification of the resulting crude material by flash column chromatography on silica gel provided the desired \-substituted-4[(aryl/heteroaryl)methyl]-N-pyrazole-1-carboxamide 1426 (Yield: 19-73%).

Example 8.

This example relates to a method for preparing embodiments of the disclosed 4[(aryl/heteroaryl)methyl]-III-pyrazole compounds according to Scheme 9.

Scheme 9.

Cl/^Ar/HetAr 1452

XPhos-Pd-G2 ° _h \ /=ss ₁ /'Ar/HetAr

K ₂ CO ₃

1,4-dioxane:H ₂ 0 °C 1454

Ar/HetAr

4.0 N HCI in 1,4-dioxane HN I __________ _g η HCI

CH ₂ CI ₂ , rt k.t.

^{2 2} 1456

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 K ₂ CO ₃ (3-4 mmol) in 1,4-dioxane:H ₂ O (9:1, 10 mL/mmol) was degassed under high vacuum and back-flushed with argon in a balloon for three cycles over 5-10 min and heated at 70-75 °C for 2-6 h. The reaction mixture was cooled and concentrated to dryness. The crude residue was diluted with EtOAc (or CH ₂ Cl ₂ ), water, and saturated aqueous Na2CO3 (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, stirred over anhydrous _Na2SO4 and filtered through celite®. After concentration of the filtrate, the crude material was purified by silica gel chromatography to afford tert-butyl ₄ -[(aryl/heteroaryl)methyl]-N-pyrazole-1-carboxylate (49-85% yield) 1454. 4.0 N HCl in 1,4-dioxane (5-7 _eq .) was added to a stirred solution of 4[(aryl/heteroaryl)methyl]-N-pyrazole (1 eq.) in _CH2Cl2 (3-6 mL/mmol) at room temperature. The reaction mixture was stirred until tert-butyl 4-[(aryl/heteroaryl)methyl]-N-pyrazole-1-carboxylate was consumed and concentrated to dryness. The crude solid was sonicated in EtOAc (6-7 mL/mmol), filtered, washed with EtOAc on a funnel and sucked dry for a short time. The thus partially dried material collected was further dried under high vacuum and obtained as the hydrochloride salt of 4-[(aryl/heteroaryl)methyl]-N-pyrazole 1456 (80-98%) and used in the next step without further purification (purity >95%).

- 49 047748

Example 9.

(S)-5-benzyl-N-(7-bromo-5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide.

1H NMR (400 MHz, CDCl ₃ ) δ 8.10 (1H, d, J Hz, NH), 7.33 (1H, m, H-6 oxobenzoxazapine), 7.31 (1H, dd, J 8.0 , 2.5 Hz, H-8 oxobenzoxazapine), 7.15 (5H, br s, C ₆ H ₅ ), 7.02 (1H, dd, J 8.0, 1.0 Hz, H-9 oxobenzoxazapine) , 4.10 (2H, s, CH2C6H5), 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] ⁺ (found [M+H] ⁺ , 458.0651, giving C ₂₀ H ₁₈ BrN ₅ O ₃ required [M+H] ⁺ 458.0645).

(S)-5-benzyl-N-(7-bromo-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-1,2,4-triazole-3-carboxamide.

1H NMR (400 MHz, CD3OD) δ 7.32-7.21 (7H, m, C ₆ H ₅ , H-6, H-8 oxobenzoxazapine), 7.06 (1H, d, J 8.0 Hz, H-9 oxobenzoxazapine), 5.00 (1H, dd, J 10.5, 6.5 Hz, H-3 oxobenzoxazapine), 4.61 (1H, dd, J 10.5, 6.5 Hz, 1H belongs to H-2 of oxobenzoxazapine), 4.40 (1H, t, J 9.5 Hz, 1H belongs to H-2 of oxobenzoxazapine), 4.15 (2H, s, CH2C6H5); m/z: 444, 442 [M+H] ⁺ (found [M+H] ⁺ , 444.0492, for SchHshBg^Oz it is necessary [M+H] ⁺ 444.0489).

The following examples provide a synthetic protocol for preparing embodiments of the pyridine-containing compounds disclosed in the present invention.

^)-1-benzyl-4-fluoro-N-(5-methyl-4-oxo-7-(8-oxa-2-azaspiro[4.5]decan-2-yl)-2,3,4,5- tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1 H-pyrazol-3-carboxamide (I-1).

MS (ESI, m/e) calculated 533.2438; found 534.1 M+H] ⁺ .

(±)-4-benzyl-N-(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1Nabenzo ^azepin-Z-yl^-pyrazole-Ecarboxamide (racemic variant I-2).

1H NMR (400 MHz, methanol^) 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) ⁺ .

^)-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]oxazepin-3-yl)-1 H-pyrazol-1-carboxamide (I-3).

Path 2. 1H 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, 7.5 Hz, 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)+.

^)<Ы~-(5-Methyl-7-(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[Ь][1,4]oxazepin-3-yl)-4-phenoxypicolinamide (I-5).

- 50 047748

1H NMR (400 MHz, methylene chloride^) δ 8.74 (d, J=7.4 Hz, 1H), 8.48 (d,J=5.6 Hz, 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, 7.4 Hz, 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 (arr m, 4H), 2.41-2.34 (arr m, 4H), 2.26 (s, 3H), 1.66-1.54 (m, 8H). LC -MS: purity 98%, MS (m/e) 556 (M+H)+.

( )-5-benzyl-\-(2-hydroxy-8-(7-hydroxy-2-azac11yro[3.5]nonan-2-yl)-2,3,4,5-hexahydro-111-benzo[L]azepin3-yl)-1H-1,2,4-triazole-3-carboxamide (I-11).

LC-MS: purity 95%, MS (m/e) 487 (M+H) ⁺ .

( )-\-(8-(1,4-diazabi11yl[3.2.2]nonan-4-yl)-1-methyl-2-oxo-2,3,4,5-hexahydro-111-benzo[L]azepin3-yl)-5-benzyl-1H-1,2,4-triazole-3-carboxamide (I-12).

1H NMR (400 MHz, methanol^4) δ 7.34-7.17 (m, 5H), 7.10 (d, J=8.4 Hz, 1H), 6.79-6.69 (m, 2H), 4.53 (dd, J=11.4, 7.8 Hz, 1H), 4.13 (s, 2H), 3.62 (t, J=5.6 Hz, 2H), 3, 36 (s, 3H), 3.22-3.11 (m, 7H), 2.72 (td, J=13.3, 7.7 Hz, 1H), 2.57 (dd, J=13, 7, 7.0 Hz, 1H), 2.53-2.38 (m, 1H), 2.18 (s, 2h), 2.07 (td, J=11.9, 7.4 Hz, 1H), 1.88 (dtt, J=14.9, 10.1, 4.9 Hz, 2H). LC-MS: purity 97%, MS (m/e) 500 (M+H) ⁺ .

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

1H NMR (400 MHz, chloroform-d) δ 8.04 (d, J=7.7 Hz, 1H), 7.35-7.24 (m, 5H), 7.01 (d, J=8, 2 Hz, 1H), 6.27 (d, J=8.2 Hz, 1H), 6.20 (s, 1H), 4.62 (dt, J=11.0, 7.7 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). LC-MS: purity 97%, MS (m/e) 499 (M+H) ⁺ .

(±)-5-benzyl-N-(1-methyl-2-oxo-8-(3-oxa-9-azaspiro[5.5]undecan-9-yl)-2,3,4,5-tetrahydro-Sbenzo [b]azepin-3-yl)-1H-1,2,4-triazol-3-carboxamide (I-14).

1H NMR (400 MHz, chloroform-d) δ 11.58 (s, 1H), 8.05 (d, J=7.7 Hz, 1H), 7.33-7.18 (m, 5H), 7 .06 (d, J=8.4 Hz, 1H), 6.76 (dd, J=8.4, 2.5 Hz, 1H), 6.70 (s, 1H), 4.62 (dt, J=11.0, 7.6 Hz, 1H), 4.11 (s, 2H), 3.72-3.64 (m, 4H), 3.37 (s, 3H), 3.15 (t , J=5.8 Hz, 4H), 2.82-2.69 (m, 1H), 2.62 (ddd, J=19.6, 12.6, 7.1 Hz, 1H), 2.52 (dd, J=12.9, 6.6 Hz, 1H), 1.97 (td, J=11.6, 7.3 Hz, 1H), 1.69 (app t, J=5.8 Hz, 4H), 1.62-1.53 (m, 4H). LC-MS: purity 95%, MS (m/e) 529 (M+H) ⁺ .

(±)-5-benzyl-N-(1-(methyl^ ₃ )-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5 -tetrahydro-Nbenzo[ED azepin-3-yl)-1H-1,2,4-triazole-3-carboxamide (I-15).

1H NMR (400 MHz, methanol^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

- 51 047748 (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). LC-MS: purity 948, MS (m/e) 504 (M+H)+.

(^)-5-benzyl-X-(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-IIIbenzo[L]azech ιηι ι-3-yl)-1H-1,2,4-triazole-3-carboxamide (I-16).

¹ H NMR (400 MHz, chloroform-d) δ 11.79 (s, 1H), 8.07 (d, J=7.8 Hz, 1H), 7.32 -7.21 (arp 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 (arp 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). LC-MS: retention time 1.50 min (A), purity 96%, MS (m/e) 501 (MH ⁺ ).

(±)-4-benzyl-X-(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1Hbenzo [b]azepin-3-yl)-1H-pyrazol-1-carboxamide (I-17).

1H NMR (400 MHz, methanol-d4) 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) ⁺ .

(±)-X-(1-Methyl-2-oxo-8-(3-oxa-9-azaspiro[5.5]undecan-9-yl)-2,3,4,5-tetrahydro-III-benzo[L]azepin-3-yl)-4-phenoxypicolinamide (I-18).

1H 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), 3.183.10 (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). LC-MS: purity 98%, MS (m/e) 541 (m+H) ⁺ .

(±)-X-(1-methyl^ ₃ )-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H- benzo[b]azepin-3yl)-4-phenoxypicolinamide (I-19).

1H 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, 7.7 Hz, 1H), 3.69-3.62 (m, 4H), 3.62 (s, 4H), 2.84-2.68 (m, 1H), 2.67-2.53 (m, 1H) , 2.51 (dd, J=13.1, 6.9 Hz, 1H), 2.05-1.93 (m, 1H), 1.87-1.79 (m, 4H). LC-MS: purity 97%, MS (m/e) 516 (M+H) ⁺ .

(±)-X-(1-methyl-2-oxo-8-(2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[L]azepin-3-yl)-4-phenoxypicolinamide (I-20).

1H 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),

- 52 047748

1.68 (t, J=5.7 Hz, 4H), 1.45 (d, J=5.9 Hz, 4H), 1.45-1.35 (m, 2H). LC-MS: purity 98%, MS (m/e) 511 (M+H)+.

(±)-N-(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b azepin3 -yl)-4-phenoxypicolinamide (I-21).

1H 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). LC-MS: purity 96%, MS (m/e) 513 (m+H) ⁺ .

^)-1-benzyl-N-(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-Nbenzo[ b]azepin-3-yl)-1 H-pyrazol-3-carboxamide (I-22).

1H 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). LC-MS: purity 95%, MS (m/e) 500 (M+H)+.

Example 10.

This example provides a general method for the preparation of (I)-N-(8-(6-(3-hydroxy-3-methylbut-1-yn-1yl)pyridin-3-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[L]azepin-3-yl)-4-phenoxypicolinamide (I-10), as shown in Scheme 10.

Scheme 10.

A stirred mixture of (N)-(8-bromo-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[L]azepin-3-yl)4-phenoxypicolinamide (71 mg, 0.152 mmol) (see below), 2-chloropyridine-5-boronic acid pinacol ester (47 mg, 0.196 mmol), Pd( _PPh3 ) ₄ (13 mg, 0.01 mmol), _CS2CO3 (149 mg, 0.456 mmol) in 1,4-dioxane (3 ml):water (0.3 ml) was heated at 75 _° C after three cycles of degassing under vacuum followed by purging with argon. After 6 h, the reaction mixture was cooled to room temperature, diluted with THF (10 mL) and filtered through Celite®. After concentration of the filtrate, the resulting crude material was diluted with water (3 mL) and extracted with EtOAc (3 x 15 mL). After washing the combined organic layers with saturated aqueous NaCl (10 mL), stirred over anhydrous Na ₂ SO ₄ , purified by filtration and concentrated to dryness. The resulting crude material was dissolved in _CH2Cl2 (2 mL), loaded onto hexanes-conditioned silica gel cartridge, and purified by flash chromatography [Combiflash® Teledyne RediSep® column with hexanes-conditioned silica gel (12 _G Gold) and elution with 0-35% EtOAc/hexanes] to afford (N)-(8-(6-chloropyridin-3-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[L]azepin-3-yl)-4-phenoxypicolinamide (35 mg, 46%) as a cream-colored solid.

1H NMR (400 MHz, CDCl ₃ ) 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,

- 53 047748

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). LC-MS: purity 93%, MS (m/e) 500 (M+H)+.

^)-N-(8-(6-(3-Chloro-3-methylbut-1-yn-1-yl)pyridin-3-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-phenoxypicolineamide (11 mg, 28%, white solid) was prepared analogously to the Sonogashira coupling conditions as described in the General Procedure by reacting (S)-N-(8-(6-chloropyrudin-3-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-phenoxypicolinamide (35 mg, 0.07 mmol) and 2-methyl-3-butyn-2-ol (9 mg, 0.01 mL, 0.11 mmol) in the presence of NEt ₃ (70 mg, 0.10 ml, 0.70 mmol) using CuI (2.7 mg, 0.014 mmol) and Pd(PPh ₃ ) ₄ (8.1 mg, 0.007 mmol) in DMF (1 ml) at 90°C. ¹ H NMR (400 MHz, CD ₂ Cl ₂ ) δ 8.80 (dd, J=2.4, 0.9 Hz, 1H), 8.77 (d, J=7.6 Hz, 1H), 8.46 (d, J=5.6 Hz, 1H), 7.87 (dd, J=8.1, 2.4 Hz, 1H), 7.70-7, 59 (m, 2H), 7.59-7.49 (m, 3H), 7.49-7.38 (m, 6H), 7.32-7.24 (m, 1H), 7.14-7.06 (m, 2H), 6.97 (dd, J=5.6, 2.6 Hz, 1H), 4.59 (dt, J=11.1, 7.4 Hz , 1H), 3.47 (s, 3H), 3.03-2.89 (m, 1H), 2.78-2.64 (m, 2H), 2.27 (br s, 1H), 2.11-2.04 (m, 1H), 1.63 (s, 6H). LC-MS: purity 92%, MS (m/e) 547 (M+H)+.

Example 11.

In this example, compounds of the invention were evaluated using a biochemical assay using ADP-Glo™ technology.

ADP-Glo™ reagents (Promega, Madison, WI, USA) were thawed at ambient temperature. The kinase detection reagent was prepared by mixing the kinase detection buffer with the lyophilized kinase detection substrate.

A stock volume of 500 ml of 5X kinase reaction buffer was prepared by mixing 1000 µl _of 1 M MgCl2, 500 µl of 1 M Tris-HCL pH 7.4, 0.5 mg/ml (25 mg) BSA and 3475 µl of distilled H2O. _A 3 ml of 2X working stock volume of kinase reaction buffer containing a final concentration of 100 µM DTT and 4 mM MnCl2 _was prepared.

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

Compounds were serially diluted in DMSO starting at 250 μM by 4-fold dilutions, then diluted 1:5 in 2X reaction buffer in a 96-well plate. 1.0 μL of the diluted compound was added to a 384-well plate in duplicate. 2 μL of diluted active RIPK1 (not added to column 1) was added to the 384-well plate, and 2X kinase reaction buffer was added to column 1. AKT (Anaspec, Fremont, CA, USA) at a concentration of 150 nM was combined with an equal volume of ATP working solution and added to the 384-well plate at 2 μL/well. The final reaction volume was 5.0 μL.

The plate was quickly centrifuged and the reaction mixture was incubated at 30°C for 30 minutes. The addition of 5 μl of ADP-Glo™ stopped the reaction. The plate was quickly centrifuged and the reaction mixture 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 (0.1 s luminescence) using a Wallac Victor2 luminometer (PerkinElmer, Waltham, MA, USA). The IC ₅₀ values obtained in this example are listed in Table 1.

- 54 047748

Table 1

Connection RIPK1 kinase by ADP-Glo (ICso) method 1-4 0,193 1-5 0,0279 1-6 0,0161 1-7 0,0604 1-8 0,0704 1-9 0,0363 1-10 0,0334 1-11 0,4137 1-12 0,8077 1-13 0,4443 1-14 0.3728 1-15 0,1065 1-16 0,0366 1-17 0,0612 1-18 0,0464 1-19 0,0413 1-20 0,6032 1-21 0,054 1-22 0,0388 1-23 0,0621 1-24 0,0559 1-25 0,0612 1-28 0,0239 1-29 0,0488

Example 12.

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

U937 and L929 cells were obtained from the American Type Culture Collection (Manassas, VA, USA). Both cell lines were maintained in logarithmic phase growth in complete RPMI 1640 medium (Sigma, St. Louis, MO, USA) supplemented with 10% fetal bovine serum (Sigma, St. Louis, MO, USA) at 37°C with 5% CO ₂ . For necroptosis assays, L929 cells were seeded for 18 h in 100 μl/well medium at 10,000 cells/well in black 96-well Costar clear-bottom plates (Fisher Scientific, Hampton, NH, USA); U937 cells were seeded on the day of the assay in 50 µl/well of medium containing 60 µM zVAD-fink (Lonza, Basel, Switzerland) at 50,000 cells/well. The L929 cell medium was removed from the 96-well plates and replaced with 50 µl/well of new medium containing 40 µM zVAD-fmk. Each compound of the invention evaluated in this example was serially diluted in DMSO, starting at 2.5 mM, through 4-fold dilutions, and then diluted 1:125 in complete medium. 50 µl/well of the 2x compound solution was then added to the cells in the plates. Cells were pre-incubated with compound for 1 hour at 37°C with 5% _CO2 and before the addition of 10 µl/well 11x TNFa (Peprotech, Rocky Hill, NJ, USA) to give a final TNFa concentration of 2 ng/ml. The relative amount of cells undergoing necroptosis was determined by luminescence using a Wallac Victor2 Luminometer (PerkinElmer, Waltham, MA, USA) and CellTiter-Glo® Luminescence Cell Viability Assay Reagent (Promega, Madison, WI, USA), which was added according to the manufacturer's instructions after 18 hours of TNFa stimulation at 37°C with 5% _CO2 . The results obtained in this example are summarized in Table 2. This example demonstrates that embodiments of the compounds described in

- 55 047748 in this document, have unexpectedly high activity against human RIP 1 and murine RIP1, allowing their evaluation in mouse models of the disease in vivo. These results are useful in determining safe and effective doses for humans.

Table 2

Connection Result for L929 in Ь929-CTC assay, TNFa+zVAD (1C ₅₀ ) Result for U937 in CTG analysis in U937 with Zvad and TNF, TNFa+zVAD (1C ₅₀ ) 1-4 BUT 0,5101 1-5 10.45 0,0633 1-6 2.22 0,0083 1-7 0,1006 0,0234 1-8 0,0016 0,007 1-9 0,6543 0,008 1-10 0,1425 0,002 1-11 30.8 0,0131 1-12 BUT* 1,075 1-13 0,0432 0,0052 1-14 0,0949 0,0021 1-15 0.2566 0,0079 1-16 0.2285 0,0039 1-17 0,2123 0,0017 1-18 0,6415 0,0048 1-19 1,424 0,0063 1-20 1,175 0,0162 1-21 1,683 0,0176 1-22 0,1822 0,0027 1-23 1,071 0,0132 1-24 0.2583 0,0066 1-25 0,2123 0,0017 1-29 5000 0,1436

*HO means that no activity was detected or that the inhibition curve showed artifacts. This value does not necessarily indicate an inactive compound, but does indicate that for some reason no data were obtained in the experiment. For example, an insoluble compound or other experimental artifact could result in a HO value.

Example 13.

In this example, a murine model of acute hypothermia was used to evaluate the ability of the compounds disclosed herein to inhibit TNF-alpha-induced hypothermia.

Female C57BL/6 mice were randomly assigned to groups and weighed at day -1. On the day of the study (day 0), mice were administered vehicle or test drug by oral gavage. Fifteen minutes after oral administration of test agents, each mouse received an intraperitoneal (i.p.) 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 0 h (prior to i.p. injections) and then hourly using a rectal temperature measuring device. Three (3) hours after i.p. injections of TNF-a and zVAD/FMK, mice were sacrificed by CO2 asphyxiation and blood was collected by cardiac puncture. Serum and plasma were collected for cytokine and compound determinations, respectively. Separate groups of mice (satellite mice) were included to determine plasma compound levels during TNFa/zVAD-FMK administration.

- 56 047748

(^)-5-benzyl-N-(5-methyl-4-oxo-2,3,4,5-tetrahydrobenzo[L][1,4]oxazepin-3-yl)-4H-1,2,4-triazole-3-carboxamide (WO 2014/125444), having the structure shown below, was used as a reference compound and tested using a similar protocol as described in WO 2014/125444. According to WO 2014/125444, this reference compound demonstrated 93% inhibition at a dose of 30 mg/kg; however, when tested by the present inventors, the compound only inhibited 70% at 30 mg/kg. In comparison, compound I-30 of the present invention achieved greater than 85% inhibition at a dose of only 5 mg/kg using a similar assay protocol described above.

Comparative connection

In certain embodiments, the invention provides a compound, compounds, or compositions containing them for crossing the blood-brain barrier. The disclosed embodiments of the compounds and compositions exhibit sufficient brain penetration to serve as potential therapeutic agents for neurological diseases. Brain penetration can be assessed by assessing the ratio of free drug in the brain to in plasma (Bu/Pu) measured in in vivo pharmacokinetic studies in rodents. Other methods for assessing brain penetration are known to those skilled in the art. See, for example, Liu, X. et al., J. Pharmacol. Exp. Therap., 325:349-56, 2008.

Table 3 below provides additional biological data for representative compounds of the present invention.

Table 3

CONNECTION PLASMA BRAIN CI T1/2 Vss AUCo-6 AUCo-6 Ratio (brain/plasma) 1-1 16.4 1,1 1,0 1000 456 0.46 1-2 57.7 1,4 5.2 280 157 0.56 1-3 19,0 2,4 2.6 783 731 0.93

In view of the many possible embodiments to which the principles of the present invention may be applied, it should be noted that the illustrated embodiments are merely preferred examples and should not be considered as limiting. Rather, the scope of the present invention is defined by the following claims. Accordingly, the inventors claim that everything within the scope and spirit of these claims is their invention.

Claims (25)

1. A compound having formula I: Formula I, or a pharmaceutically acceptable salt thereof, wherein ring B is a 5- or 6-membered heteroaryl containing one or more N or O; each R ¹ is independently an 8- to 12-membered spiroheterocyclyl containing one or more N or O, or a bridged non-aromatic heterocyclyl containing one or more N or O, wherein the 8- to 12-membered spiroheterocyclyl containing one or more N or O, or a bridged non-aromatic heterocyclyl containing one or more N or O, is optionally substituted with one or more R ⁶ , wherein each R ⁶ is independently C1. ₆ alkyl; R ² is H, D or _C1.6 alkyl; R ³ is H, D or _C1.6 alkyl, or R ³ together with the -NC(O)- moiety to which it is attached and two ring atoms from ring B may form a 5- or 6-membered heterocyclyl containing one or more N or O that is fused to ring B; - 57 047748 each R ⁴ , if present, independently represents halogen; L is O, _{C1.6 alkyl} or _C3.6 cycloalkyl; Y is _CH2 ; Z represents a C ₁ . ₁₀ aliphatic or C ₆ . ₁₀ aromatic group; m is 1, 2, 3, or 4; and n is 0, 1, or 2. 2. The compound of claim 1, wherein ring B is pyridinyl, pyrazolyl, triazolyl or oxadiazolyl. 3. A compound according to claim 1 or 2, wherein L is O or _C1.6 alkyl. 4. The compound according to claim 3, wherein L is O or _-CH2- . 5. A compound according to any one of claims 1 to 4, wherein one R ¹ is an optionally substituted 812-membered spiroheterocyclyl containing one or more N or O. 6. A compound according to any one of claims 1 to 4, wherein one R ¹ is an optionally substituted bridged non-aromatic heterocyclyl containing one or more N or O. 7. A connection according to any one of claims 1 to 4, where m is equal to 1. 8. The compound according to claim 7, wherein R ¹ is 9. A compound according to any one of claims 1 to 8, wherein R ² is H or _C1.6 alkyl. 10. A compound according to any one of claims 1 to 9, wherein R ³ is H, or R ³ together with the -NC(O)- moiety to which it is attached and two ring atoms from ring B forms a 5- or 6-membered non-aromatic heterocyclyl containing one or more N or O that is fused to ring B. 11. A connection according to any one of claims 1 to 10, where n is 0. 12. A connection according to any one of paragraphs 1-11, where Z is each R ⁵ independently halogen; and p is 0, 1, 2, 3, 4, or 5. 13. The compound according to claim 12, where p is 0. 14. The compound according to claim 12, where p is equal to 1. 15. A compound according to any one of claims 1 to 14, wherein the fragment -L-Z is phenoxy, benzyl, 4-fluorobenzyl or 1-phenylcyclopropyl. 16. 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] azepin3 -yl)-1H-1,2,4-triazol-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[L]azepin3-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[L]azepin3-yl)-1H-1,2,4-triazole-3-carboxamide; I-14: 5-benzyl-N-(1-methyl-2-oxo-8-(3-oxa-9-azaspiro[5.5]undecan-9-yl)-2,3,4,5-tetrahydro-1H-benzo[L]azepin-3-yl)-1H-1,2,4-triazole-3-carboxamide; I-15: 5-benzyl-N(1-(methyl^3)-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5- tetrahydro-1Hbenzo[b]azepin-3-yl)-1H-1,2,4-triazol-3-carboxamide; I-16: ^)-5-benzyl^-(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro1 N-benzo[b]azepin-3-yl)-1H-1,2,4-triazole-3-carboxamide; I-17: 4-benzyl^-(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro1 H-benzo [b]azepin-3-yl)-1 H-pyrazol-1-carboxamide; I-18: Na(1-methyl-2-oxo-8-(3-oxa-9-azaspiro[5.5]undecan-9-yl)-2,3,4,5-tetrahydro-1H-benzo[b] azepin-3yl)-4-phenoxypicolinamide; I-19: N(1-(methyl^3)-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H- benzo[b]azepin3-yl)-4-phenoxypicolinamide; I-20: N-(1-methyl-2-oxo-8-(2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[L]azepin-3-yl)4-phenoxypicolinamide; I-21: Na(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydro-1H-benzo[b] azepin3-yl)-4-phenoxypicolinamide; I-22: (8)-1-benzyl-N(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5- tetrahydro-1H - 58 047748 benzo[b]azepin-3-yl)-1H-pyrazol-3-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-1Hbenzo [b]azepin-3-yl)-1H-pyrazol-1-carboxamide; I-26: (b)-4-benzyl-H-(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5|nonan-2-yl)-2,3,4,5 -tetrahydro-1Hbenzo[b]azepin-3-yl)-1H-pyrazol-1-carboxamide; I-27: (C)-4-benzyl-H-(1-methyl-2-oxo-8-(7-oxa-2-azaspiro[3.5|nonan-2-yl)-2.3.4.5-tetrahydro-1Hbenzo [b]azepin-3-yl)-1H-pyrazol-1-carboxamide. 17. A compound that is I-1: (^)-1-benzyl-4-fluoro-N-(5-methyl-4-oxo-7-(8-oxa-2-azaspiro[4.5]decan-2-yl)-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazole-3-carboxamide; I-2: ^)-1-benzyl-4-fluoro-M-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3, 4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazol-3-carboxamide; I-3: ^)-4-(4-fluorobenzyl)-M-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3, 4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazol-1-carboxamide; I-4: ^)-H-(5-methyl-4-oxo-8-(3-oxa-9-azaspiro[5.5]undecan-9-yl)-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-4-phenoxypicolinamide; I-5: (^)-Ы-(5-methyl-7-(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)-4-oxo-2,3,4,5-tetrahydrobenzo[b][1,4]oxazepin-3-yl)-4-phenoxypicolinamide; I-6: ^)-H-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-4-phenoxypicolinamide; I-7: ^)-3-(2-benzyl-3-chloro-6-oxo-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl)-5-methyl-7- (7-oxa-2azaspiro[3.5]nonan-2-yl)-2,3-dihydrobenzo[b][1,4]oxazepin-4(5H)-one; I-8: ^)-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]oxazepin-4(5H)-one; I-9: ^)-H-(5-methyl-4-oxo-7-(8-oxa-2-azaspiro[4.5]decan-2-yl)-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-4-phenoxypicolinamide; I-10: ^)-N-(8-(6-(3-hydroxy-3-methylbut-1-yn-1-yl)pyridin-3-yl)-1-methyl-2-oxo-2,3,4,5-tetrahydro1H-benzo [b] azepin-3-yl)-4-phenoxypicolinamide; I-23: ^)-H-(5-methyl-4-oxo-7-(7-oxa-2-azaspiro[3.5]nonan-2-yl)-2,3,4,5-tetrahydrobenzo[b] [1,4]oxazepin-3-yl)-5-(1-phenylcyclopropyl)-1,3,4-oxadiazol-2-carboxamide; I-24: ^)-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]oxazepin-3-yl)-1,3,4-oxadiazol-2-carboxamide; I-28: ^)-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]oxazepin-3-yl)-1H-pyrazol-1-carboxamide; or I-29: ^)-4-(4-fluorobenzyl)-N-(5-methyl-7-(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)-4-oxo-2, 3,4,5tetrahydrobenzo[b][1,4]oxazepin-3-yl)-1H-pyrazol-1-carboxamide. 18. A pharmaceutical composition containing a compound according to any one of claims 1 to 17 and an excipient. 19. Use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17 for the treatment of a disease in a subject, wherein said subject has or is suspected of having or developing a disease associated with receptor interacting protein kinase-1 (RIP1). 20. The use of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 17 for the treatment of a disease associated with receptor interacting protein kinase-1 (RIP1), wherein the disease is associated with inflammation, necroptosis, or both. 21. A method for treating a disease associated with receptor-interacting protein kinase-1 (RIP1), comprising administering to a subject a compound according to any one of claims 1-17 or a composition according to claim 18. 22. The method according to claim 21, wherein the disease is an inflammatory or immunoregulatory disorder. 23. The method according to claim 21, wherein the disease is selected from amyotrophic lateral sclerosis (ALS), multiple sclerosis, Parkinson's disease or Alzheimer's disease. 24. The method according to claim 21, wherein the disease is myelodysplastic syndrome. 25. The method according to claim 21, wherein the disease is atopic dermatitis, rheumatoid arthritis or ankylosing spondylitis.