COMPOUNDS AND METHODS FOR KINASE MODULATION, AND INDICATIONS THEREFOR

• US 20080188514A1
• Filed: 12/20/2007
• Published: 08/07/2008
• Est. Priority Date: 12/21/2006
• Status: Active Grant

• Current Assignee: Plexxikon Inc (Daiichi Sankyo Company Limited)
• Original Assignee: Plexxikon Inc (Daiichi Sankyo Company Limited)
• Inventors: Wu, Guoxian, Spevak, Wayne, Zhang, Jiazhong, Shi, Shenghua, Zhang, Chao, Ibrahim, Prabha N., Cho, Hanna, Shi, Songyuan, Artis, Dean, Zhou, Yong
• Granted Patent: US 8,268,858 B2
• Time in Patent Office: Days
• US Class Current: 514/300
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/16 Anti-Parkinson drugs
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/02 specific for leukemia
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 519/00 Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Abstract

Compounds active on protein kinases are described, as well as methods of using such compounds to treat diseases and conditions associated with aberrant activity of protein kinases.

Claims

1. A compound having the chemical structure of Formula I,

2. The compound of claim 1 having the chemical structure of Formula Ie,

3. The compound of claim 1 having the chemical structure of Formula Ij,

4. The compound of claim 1 having the chemical structure of Formula Ip,

5. The compound of claim 4

wherein:

R⁷ is selected from the group consisting of -Cy₁, -alk-Cy₁, -alk-X-(alk)_b-Cy₁, -alk-NR¹²-(alk)_b-Cy₁, -alk-C(X)-(alk)_b-Cy₁, -alk-S(O)-(alk)_b-Cy₁, -alk-S(O)₂-(alk)_b-Cy₁, -alk-OC(X)-(alk)_b-Cy₁, -alk-C(X)O-(alk)_h-Cy₁, -alk-C(X)NR¹²-(alk)_b-Cy₁, -alk-S(O)₂NR¹²-(alk)_b-Cy₁, -alk-NR¹²C(X)-(alk)_b-Cy₁, -alk-NR¹²S(O)₂-(alk)_b-Cy₁, -alk-NR¹²C(X)O-(alk)_b-Cy₁, -alk-OC(X)NR¹²-(alk)_b-Cy₁, -alk-NR¹²C(X)NR¹²-(alk)_b-Cy₁, and -alk-NR¹²S(O)₂NR¹²-(alk)_b-Cy₁;

R⁸ is selected from the group consisting of hydrogen, —

OR⁹, —

SR⁹, —

CR¹⁰R¹¹R⁹, —

NR¹²R⁹, —

C(O)R⁹, —

C(S)R⁹, —

S(O)R⁹, and —

S(O)₂R⁹; and

R⁹ is aryl or heteroaryl, wherein aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of —

OH, —

NH₂, —

CN, —

NO₂, —

C(O)OH, —

S(O)₂NH₂, —

C(O)NH₂, —

C(S)NH₂, —

NHC(O)NH₂, —

NHC(S)NH₂, —

NHS(O)₂NH₂, —

OR¹³, —

SR¹³, —

NR¹²R¹³, —

C(O)R¹³, —

C(S)R¹³, —

C(O)OR¹³, —

C(O)NR¹²R¹³, —

C(S)NR¹²R¹³, —

S(O)₂NR¹²R¹³, —

NR¹²C(O)R¹³, —

NR¹²C(S)R¹³, —

NR¹²S(O)₂R¹³, —

NR¹²C(O)NR¹²R¹³, —

NR¹²C(S)NR¹²R¹³, —

NR¹²S(O)₂NR¹²R¹³, —

S(O)R¹³, —

S(O)₂R¹³, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino.

6. The compound of claim 5 wherein R⁷ is -Cy₁ or -alk-Cy₁.

7. The compound of claim 6

wherein:

Cy₁ is cycloalkyl, heterocycloalkyl, aryl or heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of —

OH, —

NH₂, —

CN, —

NO₂, —

S(O)₂NH₂, —

C(O)NH₂, —

OR¹³, —

NR¹²R¹³, —

C(O)R¹³, —

C(O)NR¹²R¹³, —

S(O)₂NR¹²R¹³, —

NR¹²C(O)R¹³, —

NR¹²S(O)₂R¹³, —

S(O)₂R¹³, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino; and

R⁹ is aryl or heteroaryl, wherein aryl and heteroaryl are optionally substituted with one or more substituents selected from the group consisting of —

OH, —

NH₂, —

CN, —

NO₂, —

S(O)₂NH₂, —

C(O)N₂, —

NHC(O)NH₂, —

NHS(O)₂NH₂, —

OR¹³, —

SR¹³, —

NR¹²R¹³, —

C(O)R¹³, —

C(O)NR¹²R¹³, —

S(O)₂NR¹²R¹³, —

NR¹²C(O)R¹³, —

NR¹²S(O)₂R¹³, —

NR¹²C(O)NR¹²R¹³, —

NR¹²S(O)₂NR¹²R¹³, —

S(O)₂R¹³, halogen, lower alkyl, fluoro substituted lower alkyl, and cycloalkylamino.

8. A composition comprising:

a pharmaceutically acceptable carrier; and

a compound according to claim 1.

9. A method for treating a subject suffering from or at risk of a kinase mediated disease or condition, comprising administering to the subject an effective amount of a compound of claim 1.

10. The method of claim 9, wherein the disease or condition is selected from the group consisting of ischemic stroke, cerebrovascular ischemia, multi-infarct dementia, head injury, spinal cord injury, Alzheimer'"'"'s disease, Parkinson'"'"'s disease, amyotrophic lateral sclerosis, dementia, senile chorea, Huntington'"'"'s disease, chemotherapy-induced hypoxia, gastrointestinal stromal tumors, prostate tumors, mast cell tumors, acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, multiple myeloma, melanoma, mastocytosis, gliomas, glioblastoma, astrocytoma, neuroblastoma, sarcomas, carcinomas of the lung, breast, pancreas, colon, liver, kidney, female genital tract, squamous cells, or carcinoma in situ, histiocytic lymphoma, non-Hodgkin'"'"'s lymphoma. MEN2 syndromes, neurofibromatosis, myelodysplastic syndrome, leukemia, tumor angiogenesis, cancers of the thyroid, liver, bone, skin, brain, central nervous system, pancreas, lung, breast, colon, bladder, prostate, gastrointestinal tract, endometrium, fallopian tube, testes or ovary, metastasis of tumors to other tissues, neuropathic pain, acute pain, chronic pain, bone pain, cancer related pain, migraine, heart failure, cardiac hypertrophy, thrombosis, atherosclerosis, reperfusion injury, ischemia, age-related macular degeneration, rheumatoid arthritis, allergic rhinitis, inflammatory bowel disease, ulcerative colitis, Crohn'"'"'s disease, systemic lupus erythematosis, Sjogren'"'"'s Syndrome, Wegener'"'"'s granulomatosis, psoriasis, scleroderma, chronic thyroiditis, Grave'"'"'s disease, myasthenia gravis, multiple sclerosis, osteoarthritis, endometriosis, scarring, vascular restenosis, fibrotic disorders, hypereosinophilia, CNS inflammation, pancreatitis, nephritis, atopic dermatitis, hepatitis, severe combined immunodeficiency, organ transplant rejection, graft versus host disease, diabetic nephropathy, polycystic kidney disease, nephrosclerosis, glomerulonephritis, interstitial nephritis, Lupus nephritis, prostate hyperplasia, chronic renal failure, tubular necrosis, diabetes-associated renal complications, hypertrophy, type 1 diabetes, type 2 diabetes, metabolic syndrome, obesity, hepatic steatosis, insulin resistance, hyperglycemia, lipolysis, obesity, Helicobacter pylori infection, Influenza virus infection, Hepatitis virus infection, fever, sepsis, chronic obstructive pulmonary disease, acute respiratory distress syndrome, asthma, allergy, bronchitis, emphysema, pulmonary fibrosis, Noonan'"'"'s syndrome, Crouzon syndrome, acrocephalo-syndactyly type I, Pfeiffer'"'"'s syndrome, Jackson-Weiss syndrome, Costello syndrome, LEOPARD syndrome, cardio-faciocutaneous syndrome, neural crest syndrome abnormalities causing cardiovascular, skeletal, intestinal, skin, hair or endocrine diseases, osteoporosis, increased risk of fracture, Paget'"'"'s disease, hypercalcemia, metastatis of cancer to bone, Grave'"'"'s disease, Hirschsprung'"'"'s disease, lymphoedema, selective T-cell defect, X-linked agammaglobulinemia, diabetic retinopathy, alopecia, erectile dysfunction, tuberous sclerosis, Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, Emery-Dreifuss Muscular Dystrophy, Limb-Girdle Muscular Dystrophy, Facioscapulohumeral Muscular Dystrophy, Myotonic Muscular Dystrophy, Oculopharyngeal Muscular Dystrophy, Distal Muscular Dystrophy, Congenital Muscular Dystrophy, amyotrophic lateral sclerosis, infantile progressive spinal muscular atrophy, intermediate spinal muscular atrophy, juvenile spinal muscular atrophy, spinal bulbar muscular atrophy, adult spinal muscular atrophy, dermatomyositis, polymyositis, inclusion body myositis, Lambert-Eaton syndrome, congenital myasthenic syndrome), hyperthyroid myopathy, hypothyroid myopathy, Charcot-Marie-Tooth disease, Dejerine-Sottas disease, Friedreich'"'"'s ataxia, myotonia congenital paramyotonia congenita, central core disease, nemaline myopathy, myotubular myopathy, periodic paralysis, phosphorylase deficiency, acid maltase deficiency, phosphofructokinase deficiency, debrancher enzyme deficiency, mitochondrial myopathy, carnitine deficiency, carnitine palmatyl transferase deficiency, phosphoglycerate kinase deficiency, phosphoglycerate mutase deficiency, lactate dehydrogenase deficiency, and myoadenylate deaminase deficiency.

11. A kit comprising a compound according to claim 1.

12. The kit of claim 11, wherein the compound or composition is approved for a medical indication selected from the group consisting of ischemic stroke, cerebrovascular ischemia, multi-infarct dementia, head injury, spinal cord injury, Alzheimer'"'"'s disease, Parkinson'"'"'s disease, amyotrophic lateral sclerosis, dementia, senile chorea, Huntington'"'"'s disease, chemotherapy-induced hypoxia, gastrointestinal stromal tumors, prostate tumors, mast cell tumors, acute myeloid leukemia, acute lymphocytic leukemia, chronic myeloid leukemia, chronic lymphocytic leukemia, multiple myeloma, melanoma, mastocytosis, gliomas, glioblastoma, astrocytoma, neuroblastoma, sarcomas, carcinomas of the lung, breast, pancreas, colon, liver, kidney, female genital tract, squamous cells, or carcinoma in situ, histiocytic lymphoma, non-Hodgkin'"'"'s lymphoma, MEN2 syndromes, neurofibromatosis, myelodysplastic syndrome, leukemia, tumor angiogenesis, cancers of the thyroid, liver, bone, skin, brain, central nervous system, pancreas, lung, breast, colon, bladder, prostate, gastrointestinal tract, endometrium, fallopian tube, testes or ovary, metastasis of tumors to other tissues, neuropathic pain, acute pain, chronic pain, bone pain, cancer related pain, migraine, heart failure, cardiac hypertrophy, thrombosis, atherosclerosis, reperfusion injury, ischemia, age-related macular degeneration, rheumatoid arthritis, allergic rhinitis, inflammatory bowel disease, ulcerative colitis, Crohn'"'"'s disease, systemic lupus erythematosis, Sjogren'"'"'s Syndrome, Wegener'"'"'s granulomatosis, psoriasis, scleroderma, chronic thyroiditis, Grave'"'"'s disease, myasthenia gravis, multiple sclerosis, osteoarthritis, endometriosis, scarring, vascular restenosis, fibrotic disorders, hypereosinophilia, CNS inflammation, pancreatitis, nephritis, atopic dermatitis, hepatitis, severe combined immunodeficiency, organ transplant rejection, graft versus host disease, diabetic nephropathy, polycystic kidney disease, nephrosclerosis, glomerulonephritis, interstitial nephritis, Lupus nephritis, prostate hyperplasia, chronic renal failure, tubular necrosis, diabetes-associated renal complications, hypertrophy, type 1 diabetes, type 2 diabetes, metabolic syndrome, obesity, hepatic steatosis, insulin resistance, hyperglycemia, lipolysis, obesity, Helicobacter pylori infection, Influenza virus infection, Hepatitis virus infection, fever, sepsis, chronic obstructive pulmonary disease, acute respiratory distress syndrome, asthma, allergy, bronchitis, emphysema, pulmonary fibrosis, Noonan'"'"'s syndrome, Crouzon syndrome, acrocephalo-syndactyly type I, Pfeiffer'"'"'s syndrome, Jackson-Weiss syndrome, Costello syndrome, LEOPARD syndrome, cardio-faciocutaneous syndrome, neural crest syndrome abnormalities causing cardiovascular, skeletal, intestinal, skin, hair or endocrine diseases, osteoporosis, increased risk of fracture, Paget'"'"'s disease, hypercalcemia, metastatis of cancer to bone, Grave'"'"'s disease, Hirschsprung'"'"'s disease, lymphoedema, selective T-cell defect, X-linked agammaglobulinemia, diabetic retinopathy, alopecia, erectile dysfunction, tuberous sclerosis, Duchenne Muscular Dystrophy, Becker Muscular Dystrophy, Emery-Dreifuss Muscular Dystrophy, Limb-Girdle Muscular Dystrophy, Facioscapulohumeral Muscular Dystrophy, Myotonic Muscular Dystrophy, Oculopharyngeal Muscular Dystrophy, Distal Muscular Dystrophy, Congenital Muscular Dystrophy, amyotrophic lateral sclerosis, infantile progressive spinal muscular atrophy, intermediate spinal muscular atrophy, juvenile spinal muscular atrophy, spinal bulbar muscular atrophy, adult spinal muscular atrophy, dermatomyositis, polymyositis, inclusion body myositis, Lambert-Eaton syndrome, congenital myasthenic syndrome), hyperthyroid myopathy, hypothyroid myopathy, Charcot-Marie-Tooth disease, Dejerine-Sottas disease, Friedreich'"'"'s ataxia, myotonia congenita, paramyotonia congenita, central core disease, nemaline myopathy, myotubular myopathy, periodic paralysis, phosphorylase deficiency, acid maltase deficiency, phosphofructokinase deficiency, debrancher enzyme deficiency, mitochondrial myopathy, carnitine deficiency, carnitine palmatyl transferase deficiency, phosphoglycerate kinase deficiency, phosphoglycerate mutase deficiency, lactate dehydrogenase deficiency, and myoadenylate deaminase deficiency.