Polycyclic compounds as soluble epoxide hydrolase inhibitors
阅读说明：本技术 多环化合物作为可溶性环氧化物水解酶抑制剂 (Polycyclic compounds as soluble epoxide hydrolase inhibitors ) 是由 S·科多尼·伊·吉斯伯特 C·加尔迪亚诺·坎塔多尔 R·莱瓦·马特内兹 A·拉里萨·图尔库 于 2019-06-19 设计创作，主要内容包括：本发明涉及式(I)的可溶性环氧化物水解酶(sEH)抑制剂,其获得过程和其治疗适应征。(The present invention relates to soluble epoxide hydrolase (sEH) inhibitors of formula (I), processes for their obtainment and therapeutic indications thereof.)
1. A compound of formula (I)
Or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
G1represents an oxygen atom or a methylene group or a single bond;
G2represents an oxygen atom or a sulfur atom;
G3represents a group selected from-NH- (CH)2)m–、–O–(CH2)m-and- (CH)2)n-a group of the group consisting of;
m is an integer of 0 to 6;
n is an integer from 1 to 7;
R1is a group selected from the group consisting of:
a)C6-C10aryl, which may be optionally substituted with 1 to 4 substituents selected from the group consisting of: halogen atom, C1-C6Acyl radicalNitro (NO)2) Cyano (C.ident.N), trifluoromethyl (CF)3) Trifluoromethoxy group (OCF)3) Pentafluorosulfanyl (SF)5) Sulfonyl (SO)3H) Fluorosulfonyl (SO)2F) Carboxyl (COOH), amino (NH)2) mono-C1-C6Alkylamino radical, di-C1-C6Alkylamino radical, C1-C6Alkoxy radical, C1-C6Alkyl radical, C1-C6Alkoxycarbonylmethyl and methylaminocarbonylpyridyloxy;
b) heteroaryl having 2 to 11 carbon atoms and 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S and which may be optionally substituted with 1 to 4 substituents selected from the group consisting of: halogen atom, C1-C6Acyl, Nitro (NO)2) Cyano (C.ident.N), trifluoromethyl (CF)3) Trifluoromethoxy group (OCF)3) Pentafluorosulfanyl (SF)5) Sulfonyl (SO)3H) Fluorosulfonyl (SO)2F) Carboxyl (COOH), amino (NH)2) mono-C1-C6Alkylamino radical, di-C1-C6Alkylamino radical, C1-C6Alkoxy radical, C1-C6Alkyl and C1-C6An alkoxycarbonylmethyl group;
c) a saturated or partially unsaturated monocyclic or bicyclic heterocyclic group having 5 to 11 carbon atoms and 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S and which may be optionally substituted with 1 to 4 substituents selected from the group consisting of: halogen atom, C1-C6Acyl radical, C3-C6cycloalkyl-C (═ O), Nitro (NO)2) Cyano (C.ident.N), trifluoromethyl (CF)3) Trifluoromethyl Carbonyl (CF)3CO), pentafluorosulfanyl (SF)5) Sulfonyl (SO)3H) Carboxyl (COOH), amino (NH)2) mono-C1-C6Alkylamino radical, di-C1-C6Alkylamino radical, C1-C6Alkoxy radical, C1-C6Alkyl radical, C1-C6Alkoxycarbonylmethyl, C1-C6Alkylsulfonyl radical, C3-C6Cycloalkylsulfonyl, benzyl, heteroarylmethyl, pyridylcarbonyl, phenylcarbonyl, tetrahydropyranocarbonyl, C, possibly optionally substituted with 1 to2 substituents selected from the group consisting of6-C10Arylsulfonyl: halogen atom, nitro group (NO)2) Cyano (C.ident.N), trifluoromethyl (CF)3) Trifluoromethoxy group (OCF)3) Pentafluorosulfanyl (SF)5) Sulfonyl (SO)3H) Carboxyl (COOH), amino (NH)2) mono-C1-C6Alkylamino radical, di-C1-C6Alkylamino radical, C1-C6Alkoxy radical, C1-C6Alkyl radical, C1-C6Alkoxycarbonylmethyl, and phenyl which may be optionally substituted with 1 to 4 substituents selected from the group consisting of: halogen atom, C1-C6Acyl, Nitro (NO)2) Cyano (C.ident.N), trifluoromethyl (CF)3) Trifluoromethoxy group (OCF)3) Pentafluorosulfanyl (SF)5) Sulfonyl (SO)3H) Fluorosulfonyl (SO)2F) Carboxyl (COOH), amino (NH)2) mono-C1-C6Alkylamino radical, di-C1-C6Alkylamino radical, C1-C6Alkoxy radical, C1-C6Alkyl radical, C3-C6Cycloalkyl and C1-C6An alkoxycarbonylmethyl group;
d)C6-C10cycloalkyl, which may be optionally substituted with 1 to 4 substituents selected from the group consisting of: halogen atom, C1-C6Acyl, Nitro (NO)2) Cyano (C.ident.N), trifluoromethyl (CF)3) Trifluoro-methoxy (OCF)3) Pentafluorosulfanyl (SF)5) Sulfonyl (SO)3H) Carboxyl (COOH), amino (NH)2) mono-C1-C6Alkylamino radical, di-C1-C6Alkylamino radical, C1-C6Alkoxy radical, C1-C6Alkyl radical, C1-C6Alkoxycarbonylmethyl, possibly unsubstituted or selected from COOH and CONHCH3By substitution of a group ofAnd possibly unsubstituted or COOH, COOR5、CONH2CN or OH substituted phenoxy;
R2is a group selected from the group consisting of: hydrogen or deuterium atoms, halogen atoms, methyl, hydroxy and C1-C6An alkoxy group;
R3and R4Are the following groups, which may be the same or different and are independently selected from the group consisting of: hydrogen atom, halogen atom, C1-C6Acyl, Nitro (NO)2) Cyano (C.ident.N), Carboxyl (COOH), hydroxyl (OH), trifluoromethyl (CF)3) Trifluoromethoxy group (OCF)3) Pentafluorosulfanyl (SF)5) Sulfonyl (SO)3H) Fluorosulfonyl (SO)2F) Amino (NH)2) mono-C1-C6Alkylamino radical, di-C1-C6Alkylamino radical, C1-C6Alkoxy radical, C1-C6Alkyl and C1-C6An alkoxycarbonylmethyl group;
or R3And R4Possibly together forming a group-O- (CH)2)p-O-, wherein p is an integer from 1 to 3;
R5is selected from C1-C6Alkyl and C3-C6A group of cycloalkyl groups.
2. The compound of claim 1, wherein G1Represents a methylene group.
3. The compound of any one of claims 1-2, wherein G2Represents an oxygen atom.
4. A compound according to any one of claims 1 to 3, wherein G3Represents a group selected from-NH- (CH)2)m-and- (CH)2)n-a group of the group consisting of m is an integer from 0 to 6 and n is an integer from 1 to 7.
5. The compound of claim 4, wherein G3Represents the group-NH- (CH)2)m-and m is an integer from 0 to 6.
6. The compound according to any one of claims 1 to 5, wherein when G is3Selected from the group consisting of-NH- (CH)2)m-and-O- (CH)2)m-when in the group, m has a value of 0, and wherein when G is3Is- (CH)2)nWhen-is, n has a value of 1.
7. A compound according to any one of claims 1 to 6, wherein R1Selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted cyclohexyl, and substituted or unsubstituted piperidinyl.
8. A compound according to any one of claims 1 to 7, wherein R2Selected from the group consisting of: hydrogen atom, fluorine atom, chlorine atom, methyl group, hydroxyl group and C1-C3An alkoxy group.
9. The compound according to any one of claims 1 to 8, wherein R3And R4Are the following groups, which may be the same or different and are independently selected from the group consisting of: hydrogen atom, halogen atom, C1-C6Acyl, trifluoromethyl (CF)3) Trifluoromethoxy group (OCF)3) Nitro (NO)2) Amino (NH)2) And C1-C6An alkoxy group.
10. The compound according to any one of claims 1 to 9, wherein R3Is hydrogen and R4Is a group selected from the group consisting of: hydrogen atom, halogen atom, C1-C6Acyl, trifluoromethyl (CF)3) Trifluoromethoxy group (OCF)3) Nitro (NO)2) Amino (NH)2) And C1-C6An alkoxy group.
11. The compound according to any one of claims 1 to 10, selected from the group consisting of:
p-tolyl (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethanobenzo [9] annulen-7-yl) carbamate
ii.1- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-bis-methanobenzo [9] annulen-7-yl) -3- (4- (trifluoromethyl) phenyl) thiourea
1- (1-acetylpiperidin-4-yl) -3- (5-methyl-1, 5,6, 7-tetrahydro-1, 5:3, 7-dimethanobenzo [ e ] oxazeonotetraen-3 (2H) -yl) urea
1- (1-acetylpiperidin-4-yl) -3- (1,5,6, 7-tetrahydro-1, 5:3, 7-dimethanomethyl-benzo [ e ] oxazeonotetraen-3 (2H) -yl) urea
1- (1-acetylpiperidin-4-yl) -3- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] annulen-7-yl) urea
vi.1- (1-acetylpiperidin-4-yl) -3- (9-hydroxy-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] annulen-7-yl) urea
1- (1-acetylpiperidin-4-yl) -3- (9-methoxy-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] annulen-7-yl) urea
1- (1-Acetylpiperidin-4-yl) -3- (9-fluoro-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] annulen-7-yl) urea
ix.1- (1-acetylpiperidin-4-yl) -3- (9-chloro-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-di-methanobenzo [9] annulen-7-yl) urea
x.4- (((1r,4r) -4- (3- (5-methyl-1, 5,6, 7-tetrahydro-1, 5:3, 7-dimethanobenzo [ e ] oxazeonotetraen-3 (2H) -yl) ureido) cyclohexyl) oxy) benzoic acid
xi.4- (((1r,4r) -4- (3- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-di-methanobenzo [9] annulen-7-yl) ureido) cyclohexyl) oxy) benzoic acid
xii.1- [1- (isopropylsulfonyl) piperidin-4-yl ] -3- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] annulen-7-yl) urea
xiii.1- (1-benzylpiperidin-4-yl) -3- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] annulen-7-yl) urea
xiv.1- (2-acetyl-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-bis-methanobenzo [9] annulen-7-yl) -3- (1-acetylpiperidin-4-yl) urea
xv.1- (1-acetylpiperidin-4-yl) -3- (9-methyl-2-nitro-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] annulen-7-yl) urea
1- (1-acetylpiperidin-4-yl) -3- (2-amino-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] annulen-7-yl) urea
xvii.4- (tert-butyl 2- ((9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-di-methanobenzo [9] annulen-7-yl) amino) -2-oxoethyl) piperidine-1-carboxylate
xviii.N- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-bis (methanobenzo [9] annulen-7-yl) -2- (piperidin-4-yl) acetamide
xix.2- [1- (isopropylsulfonyl) piperidin-4-yl ] -N- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] annulen-7-yl) acetamide
xx.2- (1-acetylpiperidin-4-yl) -N- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] annulen-7-yl) acetamide
xxi.1- (9-methyl-6, 7,8,9,10, 11-hexahydro-5H-5, 9:7, 11-bis-methanobenzo [9] annulen-7-yl) -3- (2,3, 4-trifluorophenyl) urea
xxii.1- (5-methyl-1, 5,6, 7-tetrahydro-1, 5:3, 7-dimethanembenzo [ e ] oxazeonotetraen-3 (2H) -yl) -3- (2,3, 4-trifluorophenyl) urea
xxiii.2- (1-Benzylpiperidin-4-yl) -N- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] annulen-7-yl) acetamide
xxiv.1- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-bis-methanobenzo [9] annulen-7-yl) -3- (1-propionylpiperidin-4-yl) urea
xxv.1- (1- (4-acetylphenyl) piperidin-4-yl) -3- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] annulen-7-yl) urea
xxvi.1- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-bis-methanobenzo [9] annulen-7-yl) -3- (1- (tetrahydro-2H-pyran-4-carbonyl) piperidin-4-yl) urea
xxvii.1- (1- (2-fluorobenzoyl) piperidin-4-yl) -3- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] annulen-7-yl) urea
xxviii.1- ((1R,3S,5S) -8-benzyl-8-azabicyclo [3.2.1] oct-3-yl) -3- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethanobenzo [9] annulen-7-yl) urea
xxix.1- (1-acetylpiperidin-4-yl) -3- (2-fluoro-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-di-methanobenzo [9] annulen-7-yl) urea
xxx.1- (1-acetylpiperidin-4-yl) -3- (2-methoxy-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] annulen-7-yl) urea
xxxi.1- (1-acetylpiperidin-4-yl) -3- (1-fluoro-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] annulen-7-yl) urea
xxxii.1- (1-acetylpiperidin-4-yl) -3- (2, 3-dimethoxy-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-bis-methanobenzo [9] annulen-7-yl) urea
xxxiii.1- (1-acetylpiperidin-4-yl) -3- (5,8,9, 10-tetrahydro-5, 8:7, 10-dimethanobenzo [8] annulen-7 (6H) -yl) urea
xxxiv.1- (benzo [ d ] thiazol-2-yl) -3- (9-methoxy-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] annulen-7-yl) urea
xxxv.1- (1-acetylpiperidin-4-yl) -3- (1, 9-difluoro-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] annulen-7-yl) urea
xxxvi.1- (1-acetylpiperidin-4-yl) -3- (1,5,6, 7-tetrahydro-1, 5:3, 7-dimethanobenzo [ e ] oxazeonotetraen-3 (2H) -yl-5-d) urea.
12. A pharmaceutical or veterinary composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 11.
13. A compound according to any one of claims 1 to 11 or a composition according to claim 12 for use as a medicament.
14. A compound according to any one of claims 1 to 11 or a composition according to claim 12 for use in the treatment or prevention of a disease or condition susceptible to amelioration by inhibition of soluble epoxide hydrolase in an animal, including a human.
15. The compound or composition for use according to claim 14, wherein the disease or condition is selected from the group consisting of: hypertension; atherosclerosis; pulmonary diseases, such as chronic obstructive pulmonary disease, asthma, sarcoidosis, and cystic fibrosis; kidney diseases such as acute kidney injury, diabetic nephropathy, chronic kidney disease, hypertension-mediated kidney disorders, and high fat diet-mediated kidney injury; stroke; pain; neuropathic pain; inflammation; pancreatitis, particularly acute pancreatitis; immunological disorders; neurodevelopmental disorders such as schizophrenia and autism spectrum disorders; eye diseases, in particular diabetic keratopathy, wet age-related macular degeneration and retinopathies, such as retinopathy of prematurity and diabetic retinopathy; cancer; obesity, including obesity-induced colonic inflammation; diabetes mellitus; metabolic syndrome; pre-eclampsia; anorexia nervosa; depression; male sexual dysfunction, such as erectile dysfunction; healing of the wound; NSAID-induced ulcers; emphysema; pruritus; parkinson's disease; arthritis; cardiac arrhythmia; cardiac fibrosis; alzheimer's disease; raynaud's syndrome; nemann-Pick type C disease (Niemann-Pick-type C disease); cardiomyopathy; vascular cognitive disorders; mild cognitive impairment; inflammatory bowel disease; cirrhosis of the liver; non-alcoholic fatty liver disease; non-alcoholic steatohepatitis; liver fibrosis; osteoporosis; chronic periodontitis; sepsis; epilepsy, such as epilepsy; dementia; edema, such as cerebral edema; attention deficit hyperactivity disorder; schizophrenia; drug dependence; social anxiety; colitis; amyotrophic lateral sclerosis; chemotherapy-induced side effects; laminitis; inflammatory joint pain and synovitis; endothelial dysfunction; subarachnoid hemorrhage, including aneurysmal subarachnoid hemorrhage; traumatic brain injury; cerebral ischemia; and diabetes-induced learning and memory disorders.
16. Use of a compound according to any one of claims 1 to 11 or a composition according to claim 12 in the manufacture of a medicament.
17. Use of a compound according to any one of claims 1 to 11 or a composition according to claim 12 in the manufacture of a medicament for the treatment or prevention of a disease or condition susceptible to amelioration by inhibition of soluble epoxide hydrolase in an animal, including a human.
18. The use of claim 17, wherein the disease or condition is selected from the group consisting of: hypertension; atherosclerosis; pulmonary diseases, such as chronic obstructive pulmonary disease, asthma, sarcoidosis, and cystic fibrosis; kidney diseases such as acute kidney injury, diabetic nephropathy, chronic kidney disease, hypertension-mediated kidney disorders, and high fat diet-mediated kidney injury; stroke; pain; neuropathic pain; inflammation; pancreatitis, particularly acute pancreatitis; immunological disorders; neurodevelopmental disorders such as schizophrenia and autism spectrum disorders; eye diseases, in particular diabetic keratopathy, wet age-related macular degeneration and retinopathies, such as retinopathy of prematurity and diabetic retinopathy; cancer; obesity, including obesity-induced colonic inflammation; diabetes mellitus; metabolic syndrome; pre-eclampsia; anorexia nervosa; depression; male sexual dysfunction, such as erectile dysfunction; healing of the wound; NSAID-induced ulcers; emphysema; pruritus; parkinson's disease; arthritis; cardiac arrhythmia; cardiac fibrosis; alzheimer's disease; raynaud's syndrome; neman-pick type C disease; cardiomyopathy; vascular cognitive disorders; mild cognitive impairment; inflammatory bowel disease; cirrhosis of the liver; non-alcoholic fatty liver disease; non-alcoholic steatohepatitis; liver fibrosis; osteoporosis; chronic periodontitis; sepsis; epilepsy, such as epilepsy; dementia; edema, such as cerebral edema; attention deficit hyperactivity disorder; schizophrenia; drug dependence; social anxiety; colitis; amyotrophic lateral sclerosis; chemotherapy-induced side effects; laminitis; inflammatory joint pain and synovitis; endothelial dysfunction; subarachnoid hemorrhage, including aneurysmal subarachnoid hemorrhage; traumatic brain injury; cerebral ischemia; and diabetes-induced learning and memory disorders.
19. A method for treating or preventing a disease or condition susceptible to amelioration by inhibition of soluble epoxide hydrolase, comprising administering to an animal in need thereof, including a human, an effective amount of a compound of claim 1 or a composition of claim 12.
20. The method for treatment according to claim 19, wherein the disease or condition susceptible to amelioration by inhibition of soluble epoxide hydrolase is selected from the group consisting of: hypertension; atherosclerosis; pulmonary diseases, such as chronic obstructive pulmonary disease, asthma, sarcoidosis, and cystic fibrosis; kidney diseases such as acute kidney injury, diabetic nephropathy, chronic kidney disease, hypertension-mediated kidney disorders, and high fat diet-mediated kidney injury; stroke; pain; neuropathic pain; inflammation; pancreatitis, particularly acute pancreatitis; immunological disorders; neurodevelopmental disorders such as schizophrenia and autism spectrum disorders; eye diseases, in particular diabetic keratopathy, wet age-related macular degeneration and retinopathies, such as retinopathy of prematurity and diabetic retinopathy; cancer; obesity, including obesity-induced colonic inflammation; diabetes mellitus; metabolic syndrome; pre-eclampsia; anorexia nervosa; depression; male sexual dysfunction, such as erectile dysfunction; healing of the wound; NSAID-induced ulcers; emphysema; pruritus; parkinson's disease; arthritis; cardiac arrhythmia; cardiac fibrosis; alzheimer's disease; raynaud's syndrome; neman-pick type C disease; cardiomyopathy; vascular cognitive disorders; mild cognitive impairment; inflammatory bowel disease; cirrhosis of the liver; non-alcoholic fatty liver disease; non-alcoholic steatohepatitis; liver fibrosis; osteoporosis; chronic periodontitis; sepsis; epilepsy, such as epilepsy; dementia; edema, such as cerebral edema; attention deficit hyperactivity disorder; schizophrenia; drug dependence; social anxiety; colitis; amyotrophic lateral sclerosis; chemotherapy-induced side effects; laminitis; inflammatory joint pain and synovitis; endothelial dysfunction; subarachnoid hemorrhage, including aneurysmal subarachnoid hemorrhage; traumatic brain injury; cerebral ischemia; and diabetes-induced learning and memory disorders.
Background
A total of more than 100 patent publications have described several classes of sEH inhibitors based on different chemical structures (e.g., amides, thioamides, ureas, thioureas, carbamates, acylhydrazones, and chalcone oxides) (see, e.g., h.c. shen, "Soluble epoxide hydrolase inhibitors: a patent reviews," reviews of therapeutic Patents (Expert Opin patent reviews) 2010, volume 20, page 941-956, review citation 149).
sEH inhibition has been associated with various beneficial biological effects that can be translated into various therapeutic treatments (see, e.g., h.c. shen and b.d. hammock, "finding Soluble epoxide hydrolase inhibitors: targets with multiple potential therapeutic indications (Discovery of Soluble epoxide hydrolase: a target with multiple potential therapeutic indications)", "journal of pharmaceutical chemistry (J Med Chem) 2012, vol.55, page 1789 and 1808, citation 117, k.m. wagner et al," Soluble epoxide hydrolase as a therapeutic target for pain, inflammatory and neurodegenerative diseases "(therapeutic as a therapeutic target for diseases), and" pharmacological and neurodegenerative diseases "(review by pharma 20176, review at 186).
More specifically, the references cited below have described the usefulness of sEH inhibition in the treatment of: hypertension (Recent patent of cardiovascular Drug discovery (Recent Pat cardiovascular Drug disease) in 2006, month 1; 1(1): 67-72); atherosclerosis (J cardiovascular Pharmacol, 2008, 10 months; 52(4): 314-23); lung diseases, such as chronic obstructive pulmonary disease, asthma, sarcoidosis and cystic fibrosis (J. USA journal of respiratory Cell and molecular biology (Am J. Respir Cell Mol Biol.) -2012 for 5 months; 46(5): 614-22/. US journal of respiratory and Risk Care medicine (Am J. Respir Crit Care Med.) -2014 for 10 months and 15 days; 190(8): 848-50/. Res.) -2014 for 15 months; 2018,19: 236/. Free radical biology and medicine (Free Rad. Biol. Med.) -2012, 53, 160); renal diseases, such as acute kidney injury, diabetic nephropathy, chronic kidney disease, hypertension-mediated kidney disorders and high-fat diet-mediated kidney injury (journal of bio-organic chemistry and medicinal chemistry (Bioorg Med Chem Lett.) -2014 1-15 days; 24(2): 565-70/< journal of american physiology: Renal physiology (Am J physiologic journal of Physiol.) -2013 1-15 days; 304(2): F168-76/< journal of american physiology: Renal physiology-2014 10-15 days; 307(8): F971-80/< front of pharmacology (Frontiers Pharmacol) > 2019: 9: 1/< journal of american national academy of sciences > (Proc Natl Acad Sci.) 2019,116: 5154: 5159); stroke (26/12/2014 in journal of biochemistry (J Biol Chem.); 289(52):35826-38/, (13/5/2014 in public library of science and synthesis (PLoS One); 9(5): e 97529); pain (journal of agricultural and Food chemistry (J agricultural Food Chem.) 2011, 4/13/2011, (59 (7):2816-24/, (inflammation and Allergy Drug Targets) 2012, 4/11 (2): 143-58); neuropathic pain (journal of agricultural and food chemistry 2011.4.13; 59(7) 2816-24/[ Drug discovery Today (Drug discovery 2015.11.11.; 20 (11)): 1382-90/[ 21.7.2015 ] 2015 of national academy of sciences ] 112(29): 9082-7); inflammation (inflammatory and allergic drug targets, month 4 2012; 11(2): 143-58/[ journal of the national academy of sciences, U.S. 7, month 12 2005; 102(28): 9772-7); pancreatitis, in particular acute pancreatitis (in 2015, 8 months; 88(2):281-90), molecular pharmacy (Mol Pharmacol); immunological disorders (WO 00/23060 a 2); neurodevelopmental disorders, such as schizophrenia and autism spectrum disorder (Proc. Natl. Acad. Sci. USA, 2019,116: 7083-; eye diseases (WO 2007/009001A 1/"Pharmacology fronts" 2019,10:95), in particular diabetic keratopathy (Diabetes mellitus) 2018, 6 months; 67(6): 1162-; cancer (progression of Lipid research (Prog Lipid Res.), (1 month 2014; 53: 108-23); obesity (Nutr Metab cardiovascular disease, 2012, 7 months; 22(7): 598-; diabetes mellitus (journal of American national academy of sciences, 2011, 5, 31; 108(22): 9038-43); metabolic syndrome (Experimental Diabetes research (Exp Diabetes Res.) 2012; 2012: 758614); preeclampsia (Chinese medicinal hypothesis (Med. Hypotheses), 10 months 2017; 108: 81-5); anorexia nervosa ("Pharmacokinetic optimization of six soluble epoxide hydrolase inhibitors for therapeutic use in an anorexia mice model for the therapeutic use in the dietary use in a multiple of animals)" paper abstract, 241st ACS National Meeting and exhibition (241st ACS National Meeting & exhibition), Annam, Calif., 3.2011.27-31.2011, MEDI-92); depression (journal of neuroscience research (J Neurosci Res.) (12 months 2017; 95(12): 2483-2492); male sexual dysfunction (Biomed. pharmacotherapy) 2019,115:108897, such as erectile dysfunction (phytotherapy research 2016 (Phytother Res.) 7/7; 30(7): 1119-27); wound healing (journal of surgical research (J Surg Res.) in 2013, 6/15/year; 182(2):362-7/, journal of Biopreprint (BioRxiv.) in 2019, 3/8/year, doi: 10.1101/571984); NSAID-induced ulcers (J Pharmacol Exp Ther.) 2016, 6 months; 357(3): 529-36); emphysema (J. Res. cell & molecular biology, 2012,5 months; 46(5): 614-22); pruritus (Life science (Life Sci.) in 2013, 6 and 21 days in 2013; 92(23): 1145-50); parkinson's disease (Mol Neurobiol. 2015 8/month; 52; 187-95/[ Proc. Natl. Acad. Sci. USA ] 2018,115: E5815-E5823); arthritis (Drug metabolism and disposition 2015, 5 months; 43(5): 788-; arrhythmia (cardiovascular therapy (heart disease), in 2011, 4 months; 29(2): 99-111); fibrosis of the heart (Alcoholism 2018,42, 1970); alzheimer's disease (pharmacological & therapeutic science, 12.2017; 180: 62-76/[ journal of BioPrep. Express, 10.2019, doi: 10.1101/605055); raynaud's syndrome (WO 2003/002555 a 1); Niemann-Pick-type C disease (Niemann-Pick-type C disease) 2018,50:149, Experimental Molecular Medicine; cardiomyopathy (J. International Cardiol., 2012; 3, 8; 155(2): 181-7); vascular cognitive disorders (Prostaglandins and Other Lipid mediators; 2014 10; 113: 115: 30-7); mild cognitive impairment (Pharmacology and therapeutics, 12 months 2017; 180: 62-76); inflammatory bowel disease (scientific digestive tract disease (Dig Dis Sci.) -10 months 2012; 57(10): 2580-91/' public science library & synthesis 2019-19 months 4, 14(4): e 0215033); cirrhosis (toxicology and pharmacology applied (Toxicol Appl Pharmacol) 2015, 7, 15 days, 286(2): 102-11); nonalcoholic fatty liver disease (public science library, integrated 2014 10, 13, 9(10): e 110162); nonalcoholic steatohepatitis (Am J Physiol gastroenteritic Liver physiology 2019,316, G527-G538); liver fibrosis (clinic and research in hepatology and gastroenterology (Clinics Res Hepatol Gastroenterol) 2018,42, 118-; osteoporosis (journal of the Association of the American society for laboratory and biology (FASEB J.) 2015, 3 months; 29(3): 1092-; chronic periodontitis (J. Pharmacology and Experimental therapeutics, 6.2017; 361(3): 408-416); septicemia (journal of the association of the american society for experimental biology, 2008, 22 months 3 and 2008 (journal of conference abstract) 479.17); epilepsy, such as epilepsy (public science library, complex, 12.11.2013; 8(12): e 80922); dementia (prostaglandin and other lipid mediators; 10 months 2014; 113-; edema, such as cerebral edema (Stroke 2015, 7 months; 46(7): 1916-22.); attention deficit hyperactivity disorder (WO 2017/120012 a 1); schizophrenia (journal of the national academy of sciences of the United states, 2016, 3, 29; 113, 13; E1944-52); drug dependence (WO 2017/120012 a 1); social anxiety (WO 2017/120012 a 1); colitis (Anticancer Res.) 12.2013, 33(12): 5261-5271); amyotrophic lateral sclerosis (WO 2016/133788a 1); chemotherapy-induced side effects (Toxicology, 2017, 8, 15; 389: 31-41); laminitis (horse veterinary journal (Equise Vet J.) in 5 months 2017; 49(3): 345-; inflammatory joint pain and synovitis (J Vet Pharmacol The.) in 4.2018; 41(2): 230-238); endothelial dysfunction (prostaglandin and other lipid mediators; 7 months in 2017; 131: 67-74); subarachnoid hemorrhage (stroke 2015, 7 months; 46(7):1916-22) including aneurysmal subarachnoid hemorrhage (2015, 7 months; 27(3): 222-240); traumatic brain injury (tumor target (Oncotarget) in 2017, 9, 21, 8(61): 103236-60); cerebral ischemia (2018, 8:5279 in Scientific Reports); and diabetes-induced learning and memory disorders ("prostaglandins and other lipid mediators" 5 months 2018; 136: 84-89).
Although many of the reported sEH inhibitory compounds have high inhibitory activity, to date, no sEH inhibitors have entered the market. Therefore, there is a need to develop new sEH inhibitors.
The inventors have now found a new family of polycyclic compounds with high inhibitory activity against soluble epoxide hydrolases.
Disclosure of Invention
One aspect of the present invention relates to the provision of compounds of formula (I)
Or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:
G1represents an oxygen atom or a methylene group or a single bond;
G2represents an oxygen atom or a sulfur atom;
G3represents a group selected from-NH- (CH)2)m–、–O–(CH2)m-and- (CH)2)n-a group of the group consisting of;
m is an integer of 0 to 6;
n is an integer from 1 to 7;
R1is a group selected from the group consisting of:
a)C6-C10aryl, which may be optionally substituted with 1 to 4 substituents selected from the group consisting of: halogen atom, C1-C6Acyl, Nitro (NO)2) Cyano (C.ident.N), trifluoromethyl (CF)3) Trifluoromethoxy group (OCF)3) Pentafluorosulfanyl (SF)5) Sulfonyl (SO)3H) Fluorosulfonyl (SO)2F) Carboxyl (COOH), amino (NH)2) mono-C1-C6Alkylamino radical, di-C1-C6Alkylamino radical, C1-C6Alkoxy radical, C1-C6Alkyl radical, C1-C6Alkoxycarbonylmethyl and methylaminocarbonylpyridyloxy;
b) (ii) heteroaryl having 2 to 11 carbon atoms and 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S and which may be optionally substituted with 1 to 4 substituents selected from the group consisting of: halogen atom, C1-C6Acyl, Nitro (NO)2) Cyano (C.ident.N), trifluoromethyl (CF)3) Trifluoromethoxy group (OCF)3) Pentafluorosulfanyl (SF)5) Sulfonyl (SO)3H) Fluorosulfonyl (SO)2F) Carboxyl (COOH), amino (NH)2) mono-C1-C6Alkylamino radical, di-C1-C6Alkylamino radical, C1-C6Alkoxy radical, C1-C6Alkyl and C1-C6An alkoxycarbonylmethyl group;
c) a saturated or partially unsaturated monocyclic or bicyclic heterocyclic group having 5 to 11 carbon atoms and 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S and which may be optionally substituted with 1 to 4 substituents selected from the group consisting of: halogen atom, C1-C6Acyl radical, C3-C6cycloalkyl-C (═ O), Nitro (NO)2) Cyano (C.ident.N), trifluoromethyl (CF)3) Trifluoromethyl Carbonyl (CF)3CO), pentafluorosulfanyl (SF)5) Sulfonyl (SO)3H) Carboxyl (COOH), amino (NH)2) mono-C1-C6Alkylamino radical, di-C1-C6Alkylamino radical, C1-C6Alkoxy radical, C1-C6Alkyl radical, C1-C6Alkoxycarbonylmethyl, C1-C6Alkylsulfonyl radical, C3-C6Cycloalkylsulfonyl, benzyl, heteroarylmethyl, pyridylcarbonyl, phenylcarbonyl, tetrahydropyranocarbonyl, C which may be optionally substituted by 1 to2 substituents selected from the group consisting of6-C10Arylsulfonyl: halogen atom, nitro group (NO)2) Cyano (C.ident.N), trifluoromethyl (CF)3) Trifluoromethoxy group (OCF)3) Pentafluorosulfanyl (SF)5) Sulfonyl (SO)3H) Carboxyl (COOH), amino (NH)2) mono-C1-C6Alkylamino radical, di-C1-C6Alkylamino radical, C1-C6Alkoxy radical, C1-C6Alkyl radical, C1-C6Alkoxycarbonylmethyl, and phenyl which may be optionally substituted with 1 to 4 substituents selected from the group consisting of: halogen atom, C1-C6Acyl, Nitro (NO)2) Cyano (C.ident.N), trifluoromethyl (CF)3) Trifluoromethoxy group (OCF)3) Pentafluorosulfanyl (SF)5) Sulfonyl (SO)3H) Fluorosulfonyl (SO)2F) Carboxyl (COOH), amino (NH)2) mono-C1-C6Alkylamino radical, di-C1-C6Alkylamino radical, C1-C6Alkoxy radical, C1-C6Alkyl radical, C3-C6Cycloalkyl and C1-C6An alkoxycarbonylmethyl group;
d)C6-C10cycloalkyl, which may be optionally substituted with 1 to 4 substituents selected from the group consisting of: halogen atom, C1-C6Acyl, Nitro (NO)2) Cyano (C.ident.N), trifluoromethyl (CF)3) Trifluoro-methoxy (OCF)3) Pentafluorosulfanyl (SF)5) Sulfonyl (SO)3H) Carboxyl (COOH), amino (NH)2) mono-C1-C6Alkylamino radical, di-C1-C6Alkylamino radical, C1-C6Alkoxy radical, C1-C6Alkyl radical, C1-C6Alkoxycarbonylmethyl, unsubstituted or selected from COOH and CONHCH3Pyridyloxy which is substituted by the radicals of (A), and may be unsubstituted or COOH, COOR5、CONH2CN or OH substituted phenoxy;
R2is a group selected from the group consisting of: hydrogenOr deuterium atom, halogen atom, methyl group, hydroxyl group and C1-C6An alkoxy group;
R3and R4Are the following groups, which may be the same or different and are independently selected from the group consisting of: hydrogen atom, halogen atom, C1-C6Acyl, Nitro (NO)2) Cyano (C.ident.N), Carboxyl (COOH), hydroxyl (OH), trifluoromethyl (CF)3) Trifluoromethoxy group (OCF)3) Pentafluorosulfanyl (SF)5) Sulfonyl (SO)3H) Fluorosulfonyl (SO)2F) Amino (NH)2) mono-C1-C6Alkylamino radical, di-C1-C6Alkylamino radical, C1-C6Alkoxy radical, C1-C6Alkyl and C1-C6An alkoxycarbonylmethyl group;
or R3And R4May together form a group-O- (CH)2)p-O-, wherein p is an integer from 1 to 3;
R5is selected from C1-C6Alkyl and C3-C6A group of cycloalkyl groups.
In a particular embodiment, G1Represents a methylene group.
In a particular embodiment, G1Represents an oxygen atom.
In a particular embodiment, G1Represents a single bond.
In a particular embodiment, G2Represents an oxygen atom.
In a particular embodiment, G3Represents a group selected from the group consisting of: -NH- (CH)2)m-, where m is an integer of 0 to 6; and- (CH)2)m-, where n is an integer of 1 to 7; more specifically, G3Represents the group-NH- (CH)2)m-, where m is an integer of 0 to 6.
In a particular embodiment, when G3Selected from the group consisting of-NH- (CH)2)m-and-O- (CH)2)m-wherein m has a value of 0.
In a particular embodiment, when G3Is- (CH)2)n-where n has the value 1.
In particular embodiments, R1Selected from the group consisting of: substituted or unsubstituted phenyl, substituted or unsubstituted cyclohexyl, and substituted or unsubstituted piperidinyl. In more specific embodiments, the substituents are selected from the group consisting of: methyl, trifluoromethyl, acetyl, 4-carboxy-phenoxy, isopropylsulfonyl, benzyl, tert-butoxycarbonyl, trifluorophenyl, propionyl, tetrahydropyran-4-carbonyl, 2-fluorobenzoyl, acetylphenyl and 8-benzyl.
In particular embodiments, R2Selected from the group consisting of: hydrogen atom, fluorine atom, chlorine atom, methyl group, hydroxyl group and C1-C3An alkoxy group. When G is1When represents an oxygen atom, R2Preferably selected from the group consisting of hydrogen and deuterium atoms and methyl groups.
In another specific embodiment, R2Preferably selected from the group consisting of: hydrogen, methyl, hydroxy, methoxy, fluoro and chloro, more specifically methyl.
In particular embodiments, R3And R4Are the following groups, which may be the same or different and are independently selected from the group consisting of: hydrogen atom, halogen atom, C1-C6Acyl, trifluoromethyl (CF)3) Trifluoromethoxy group (OCF)3) Nitro (NO)2) Amino (NH)2) And C1-C6An alkoxy group. In particular embodiments, R3And R4May be selected from the group consisting of: hydrogen, fluorine, acetyl, nitro, amino and methoxy. In particular embodiments, R3Is hydrogen and R4Is a group selected from the group consisting of: hydrogen atom, halogen atom, C1-C6Acyl, trifluoromethyl (CF)3) Trifluoromethoxy group (OCF)3) Nitro (NO)2) Amino (NH)2) And C1-C6An alkoxy group.
In particular embodiments, the compound is selected from the group consisting of:
p-tolyl (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethanobenzo [9] annulen-7-yl) carbamate
ii.1- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-bis-methanobenzo [9] annulen-7-yl) -3- (4- (trifluoromethyl) phenyl) thiourea
1- (1-acetylpiperidin-4-yl) -3- (5-methyl-1, 5,6, 7-tetrahydro-1, 5:3, 7-dimethanobenzo [ e ] oxazeonotetraen-3 (2H) -yl) urea
1- (1-acetylpiperidin-4-yl) -3- (1,5,6, 7-tetrahydro-1, 5:3, 7-dimethanomethyl-benzo [ e ] oxazeonotetraen-3 (2H) -yl) urea
1- (1-acetylpiperidin-4-yl) -3- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] annulen-7-yl) urea
vi.1- (1-acetylpiperidin-4-yl) -3- (9-hydroxy-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] annulen-7-yl) urea
1- (1-acetylpiperidin-4-yl) -3- (9-methoxy-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] annulen-7-yl) urea
1- (1-Acetylpiperidin-4-yl) -3- (9-fluoro-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] annulen-7-yl) urea
ix.1- (1-acetylpiperidin-4-yl) -3- (9-chloro-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-di-methanobenzo [9] annulen-7-yl) urea
x.4- (((1r,4r) -4- (3- (5-methyl-1, 5,6, 7-tetrahydro-1, 5:3, 7-dimethanobenzo [ e ] oxazeonotetraen-3 (2H) -yl) ureido) cyclohexyl) oxy) benzoic acid
xi.4- (((1r,4r) -4- (3- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-di-methanobenzo [9] annulen-7-yl) ureido) cyclohexyl) oxy) benzoic acid
xii.1- [1- (isopropylsulfonyl) piperidin-4-yl ] -3- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] annulen-7-yl) urea
xiii.1- (1-benzylpiperidin-4-yl) -3- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] annulen-7-yl) urea
xiv.1- (2-acetyl-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-bis-methanobenzo [9] annulen-7-yl) -3- (1-acetylpiperidin-4-yl) urea
xv.1- (1-acetylpiperidin-4-yl) -3- (9-methyl-2-nitro-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] annulen-7-yl) urea
1- (1-acetylpiperidin-4-yl) -3- (2-amino-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] annulen-7-yl) urea
xvii.4- (tert-butyl 2- ((9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethanobenzo [9] annulen-7-yl) amino) -2-oxyethyl) piperidine-1-carboxylate
xviii.N- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-bis (methanobenzo [9] annulen-7-yl) -2- (piperidin-4-yl) acetamide
xix.2- [1- (isopropylsulfonyl) piperidin-4-yl ] -N- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] annulen-7-yl) acetamide
xx.2- (1-acetylpiperidin-4-yl) -N- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] annulen-7-yl) acetamide
xxi.1- (9-methyl-6, 7,8,9,10, 11-hexahydro-5H-5, 9:7, 11-bis-methanobenzo [9] annulen-7-yl) -3- (2,3, 4-trifluorophenyl) urea
xxii.1- (5-methyl-1, 5,6, 7-tetrahydro-1, 5:3, 7-dimethanembenzo [ e ] oxazeonotetraen-3 (2H) -yl) -3- (2,3, 4-trifluorophenyl) urea
xxiii.2- (1-Benzylpiperidin-4-yl) -N- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] annulen-7-yl) acetamide
xxiv.1- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-bis-methanobenzo [9] annulen-7-yl) -3- (1-propionylpiperidin-4-yl) urea
xxv.1- (1- (4-acetylphenyl) piperidin-4-yl) -3- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] annulen-7-yl) urea
xxvi.1- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-bis-methanobenzo [9] annulen-7-yl) -3- (1- (tetrahydro-2H-pyran-4-carbonyl) piperidin-4-yl) urea
xxvii.1- (1- (2-fluorobenzoyl) piperidin-4-yl) -3- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] annulen-7-yl) urea
xxviii.1- ((1R,3S,5S) -8-benzyl-8-azabicyclo [3.2.1] oct-3-yl) -3- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethanobenzo [9] annulen-7-yl) urea
xxix.1- (1-acetylpiperidin-4-yl) -3- (2-fluoro-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-di-methanobenzo [9] annulen-7-yl) urea
xxx.1- (1-acetylpiperidin-4-yl) -3- (2-methoxy-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] annulen-7-yl) urea
xxxi.1- (1-acetylpiperidin-4-yl) -3- (1-fluoro-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] annulen-7-yl) urea
xxxii.1- (1-acetylpiperidin-4-yl) -3- (2, 3-dimethoxy-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-bis-methanobenzo [9] annulen-7-yl) urea
xxxiii.1- (1-acetylpiperidin-4-yl) -3- (5,8,9, 10-tetrahydro-5, 8:7, 10-dimethanobenzo [8] annulen-7 (6H) -yl) urea
xxxiv.1- (benzo [ d ] thiazol-2-yl) -3- (9-methoxy-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] annulen-7-yl) urea
xxxv.1- (1-acetylpiperidin-4-yl) -3- (1, 9-difluoro-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] annulen-7-yl) urea
xxxvi.1- (1-acetylpiperidin-4-yl) -3- (1,5,6, 7-tetrahydro-1, 5:3, 7-dioxamethylenebenzo [ e ] oxazeonotetraen-3 (2H) -yl-5-d) urea
Another aspect of the invention relates to a pharmaceutical or veterinary composition comprising a therapeutically effective amount of a compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof, and preferably a sufficient amount of a pharmaceutically acceptable excipient. In the context of the present invention, pharmacy relates to both human and veterinary medicine.
Another aspect of the invention relates to a compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof, and to a composition comprising a therapeutically effective amount of a compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof, for use as a medicament.
In particular embodiments, the present invention relates to compounds of formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof, and to compositions comprising a therapeutically effective amount of a compound of formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease or condition susceptible to amelioration by inhibition of soluble epoxide hydrolase in an animal, including a human.
Another aspect of the invention relates to the use of a compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof, or a composition comprising a therapeutically effective amount of a compound of formula (I) or a stereoisomer or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament.
In a particular embodiment, the present invention relates to the use of a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, or a composition comprising a therapeutically effective amount of a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of a disease or condition susceptible to amelioration by inhibition of soluble epoxide hydrolase in an animal, including a human.
In particular embodiments, the disease or disorder susceptible to amelioration by inhibition of soluble epoxide hydrolase is selected from the group consisting of: hypertension; atherosclerosis; pulmonary diseases, such as chronic obstructive pulmonary disease, asthma, sarcoidosis, and cystic fibrosis; kidney diseases such as acute kidney injury, diabetic nephropathy, chronic kidney disease, hypertension-mediated kidney disorders, and high fat diet-mediated kidney injury; stroke; pain; neuropathic pain; inflammation; pancreatitis, particularly acute pancreatitis; immunological disorders; neurodevelopmental disorders such as schizophrenia and autism spectrum disorders; eye diseases, in particular diabetic keratopathy, wet age-related macular degeneration and retinopathies, such as retinopathy of prematurity and diabetic retinopathy; cancer; obesity, including obesity-induced colonic inflammation; diabetes mellitus; metabolic syndrome; pre-eclampsia; anorexia nervosa; depression; male sexual dysfunction, such as erectile dysfunction; healing of the wound; NSAID-induced ulcers; emphysema; pruritus; parkinson's disease; arthritis; cardiac arrhythmia; cardiac fibrosis; alzheimer's disease; raynaud's syndrome; neman-pick type C disease; cardiomyopathy; vascular cognitive disorders; mild cognitive impairment; inflammatory bowel disease; cirrhosis of the liver; non-alcoholic fatty liver disease; non-alcoholic steatohepatitis; liver fibrosis; osteoporosis; chronic periodontitis; sepsis; epilepsy, such as epilepsy; dementia; edema, such as cerebral edema; attention deficit hyperactivity disorder; schizophrenia; drug dependence; social anxiety; colitis; amyotrophic lateral sclerosis; chemotherapy-induced side effects; laminitis; inflammatory joint pain and synovitis; endothelial dysfunction; subarachnoid hemorrhage, including aneurysmal subarachnoid hemorrhage; traumatic brain injury; cerebral ischemia; and diabetes-induced learning and memory disorders.
In another aspect, the invention relates to a method of treating or preventing a disease or condition susceptible to amelioration by inhibition of soluble epoxide hydrolase in an animal, including a human, by administering a pharmaceutical or veterinary composition comprising a compound of formula (I). Methods for treating the specific diseases and conditions mentioned above are particular embodiments of the present invention.
According to another aspect of the invention, compounds of formula (Ia) (wherein G2Is oxygen, G3is-NH- (CH)2)m-) can be prepared by reacting an amine of formula (II), preferably in the form of a salt such as the hydrochloride salt, with an isocyanate of formula (III) in an inert solvent such as Dichloromethane (DCM) and in the presence of a base such as triethylamine.
According to another aspect of the invention, compounds of formula (Ia) (wherein G2Is oxygen, G3is-NH- (CH)2)m-) can also be prepared by reacting an amine of the formula (II), preferably in the form of a salt, with (NH) in a first step2→ NCO) converting reagents (e.g. triphosgene) in an inert solvent (e.g. DCM) to form the isocyanate of formula (IV). In a second step, the amine of formula (V) is reacted with an isocyanate of formula (IV) to produce a compound of formula (Ia). The coupling reaction can be carried out without a catalyst and conveniently takes place at room temperature in the presence of an organic solvent, typically DCM, Tetrahydrofuran (THF) or N, N-Dimethylformamide (DMF).
According to another aspect of the invention, compounds of formula (Ib) (wherein G2Is sulfur, G3is-NH- (CH)2)m-) can be prepared by converting an amine of formula (II), preferably in the form of a salt, into a dithiocarbamate of formula (VI) in a first step by reaction with carbon disulfide in an inert solvent such as THF in the presence of a base such as triethylamine. In a second step, the dithiocarbamate is decomposed in the presence of tosyl chloride to give an isothiocyanate of formula (VII), which is subsequently reacted with formula R of formula (V)1-(CH2)m-NH2To yield a compound of formula (Ib).
According to another aspect of the invention, compounds of formula (Ib) (wherein G2Is sulfur, G3is-NH- (CH)2)m-) can also be prepared by reacting an amine of formula (II), preferably in the form of a salt (e.g., hydrochloride salt), with an amine of formula SCN- (CH)2)m-R1(VIII) in an inert solvent such as DCM and in the presence of a base such as triethylamine.
According to another aspect of the invention, the compound of formula (Ic) (wherein G2And G3Both oxygen) can be prepared by reacting an amine of formula (II) with a chloroformate of formula (IX) in the presence of a base such as triethylamine.
According to another aspect of the invention, the compound of formula (Id) (wherein G2Is oxygen and G3Is- (CH)2)n-) can be prepared by reacting an amine of formula (II), preferably in the form of a salt (e.g. hydrochloride salt), with a carboxylic acid of formula (X) in the presence of a coupling agent (e.g. EDCI or HOBt) or in the presence of a base (e.g. triethylamine) using an acid chloride in an organic solvent (e.g. ethyl acetate).
Depending on the substituent G1、R2、R3And R4The amines of formula (II) can be obtained using a series of different reactions, and some amines of formula (II) are disclosed in the art (see, e.g., bioorganic and pharmaceutical chemistry (Bioorg Med Chem.) 2010,18, 46; "bioorganic and pharmaceutical chemistry" 2012,20, 942; "bioorganic and pharmaceutical chemistry" 2014,22, 2678; "bioorganic and pharmaceutical chemistry" 2015,23, 290).
When G is1Is CH2And R is2In the case of OH, the amine of formula (IIa) can be prepared according to the reaction scheme shown below:
the deprotection step of chloroacetamide to give the final amine (IIa) can be performed by refluxing compound (XIII) in ethanol overnight in the presence of thiourea and acetic acid.
When R is3＝R4Diketones (XI) are known compounds when H (1973; 1839-1850). In general, the substituted diketones of formula (XI) can be prepared from substituted phthalaldehydes (XIV) according to the reaction scheme shown below.
Starting from appropriately substituted phthalaldehyde derivatives of formula (XIV) and following the reaction scheme shown above, diketones (XI) having different substituents can also be prepared, as shown below for the substituents:
when G is1Is CH2And R is2Is C1-C6When alkoxy, the amine of formula (IIb) may be prepared according to the reaction scheme shown below:
wherein R is C1-6Alkyl radical
The deprotection step of chloroacetamide can be performed by refluxing compound (XVII) in ethanol overnight in the presence of thiourea and acetic acid to yield the final amine (IIb).
When G is1Is CH2And R is2In the case of methyl, the amine of formula (IIc) may be prepared according to the reaction scheme shown below:
the deprotection step of chloroacetamide can be performed by refluxing compound (XIX) in ethanol overnight in the presence of thiourea and acetic acid to yield the final amine (IIc).
When G is1Is CH2And R is2When bromo or fluoro, the amines of formulae (IId) and (IIe) may be prepared according to the reaction schemes shown below:
alternatively, the amine (IIe) can be obtained starting from compound (XIII) according to the following scheme:
the deprotection step of chloroacetamide to give the final amine (IIe) can be performed by refluxing compound (XX) in ethanol overnight in the presence of thiourea and acetic acid.
When G is1Is CH2And R is2In the case of chlorine, the amine of formula (IIf) can be prepared according to the reaction scheme shown below:
the deprotection step of chloroacetamide can be performed by refluxing compound (XXI) in ethanol overnight in the presence of thiourea and acetic acid to give the final amine (IIf).
When G is1Is CH2And R is2In the case of hydrogen, the amine of formula (IIg) can be prepared according to the reaction scheme shown below:
when G is1Is CH2And R is2In the case of deuterium, the amine of formula (IIh) may be prepared according to the reaction scheme shown below:
when G is1Is O and R2In the case of methyl, the amine of formula (IIi) can be prepared according to the reaction scheme shown below:
compounds (XXIII) can be targeted to R by the presence of compounds as in Bioorganic and pharmaceutical chemistry 2010,18,46-573＝R4The deprotection step of acetamide was performed under reflux overnight with concentrated HCl as reported for H to give the final amine (IIi).
Alternatively, when G1Is O and R2In the case of methyl, the amine of formula (IIi) can be prepared according to the reaction scheme shown below:
when G is1Is O and R2When hydrogen, the amine of formula (IIj) may be prepared according to the reaction scheme shown below:
when G is1Is O and R2In the case of deuterium, the amine of formula (IIk) may be prepared according to the reaction scheme shown below:
when G is1Is O and R2In the case of halogen or hydroxy, the compounds of formulae (Ie) and (If) can be prepared according to the reaction schemes shown below:
in a second step, compound (XXX) is converted to compound (XXXI) using (diethylamino) sulfur trifluoride (DAST) as halogenating agent when X is fluorine and SOCl when X is chlorine2And when X is bromine, the halogenating agent is SOBr2。
The synthesis of compound (XI) (for R) is described in patent application DE 2210799A 13＝R4H) compound (XXVIII) was prepared. The synthetic procedures described therein may also be used to prepare compounds in which R is3And/or R4A compound other than hydrogen.
When G is1Is a bond and R2When fluorine, the compounds of formula (IIn) may be prepared according to the reaction scheme shown below:
preparation of Compound (IIm) (for R)3＝R4H) is described in liberi chemical faculty 1995, 523-535. The synthetic procedures described therein may also be used to prepare compounds in which R is3And/or R4A compound other than hydrogen.
Compounds of formulae (IIo) and (IIp) may be prepared from compounds (XXXII) and (XXXIII), respectively, by one or more well-known reactions. Compounds (XXXII) and (XXXIII) are according to the literature for R3＝R4The method described by H (Leibishi chemical Co., 1973; 1839-1850 and Australian journal of chemistry 1983,36,2465-2472) which is synthesized from compounds of the formula (XI) can also be used for the preparation of compounds in which R is3And/or R4A compound other than hydrogen.
By aligning the radicals R by conventional methods known to those skilled in the art3And R4Can also be converted into other compounds of formula (II). As an example, the compound of formula (IIq) may be converted to the compound of formula (IIr) by catalytic hydrogenation.
It is worth mentioning that the group R can be prepared by reacting the radicals R by conventional methods known to the person skilled in the art3And R4Can be converted into other compounds of formula (I) by modifying some of the compounds of formula (I) of the present invention. As an example, wherein R3And R4Compounds of formula (I) which are hydrogen atoms can be converted into one of the R's by Friedel-Craft reaction3And R4Is hydrogen and the other is C1-6A compound of an acyl group. As another example, wherein R3And/or R4Compounds of formula (I) which are nitro groups may be converted to compounds in which R is the same as R by catalytic hydrogenation3And/or R4A compound which is an amino group.
Finally, it is worth mentioning that the compounds of the invention can also be prepared from precursors of formula (XXXIV) according to the process explained above, wherein the remainder (rest) R6Is the remainder R1Is converted into said remainder R by one or more well-known reactions1). The remainder R6May also already be a radical R1(which is converted to another group R by one or more well-known reactions1)。
Hereinafter, the followingExamples of such synthetic strategies are provided, wherein the group R6Is the remainder of the unsubstituted piperidinyl radical and R1Is a piperidinyl residue bearing substituents as defined in the claims:
using K2CO3And anhydrous DMSO with heat applied to carry out the reaction of compound (Ig) to produce compound (Ih). As shown (RCO)2H. EDCI, HOBt, EtOAc) or using a solution containing RCOCl and Et3N DCM of compound (Ig) to give compound (Ij).
In addition to the three derivatives shown in the above schemes, it is also possible to change from unsubstituted piperidine in (Ig) to benzylpiperidine. The procedure involved the reaction of piperidine (Ig) with benzaldehyde and sodium cyanoborohydride in acetic acid/methanol.
As used herein, the term methylene refers to the group- (CH)2)-。
As used herein, the term aryl refers to an aromatic carbocyclic ring that may be unsubstituted or substituted. Non-limiting examples of unsubstituted aryl groups are phenyl and anthracenyl.
As used herein, the term halogen atom refers to an atom selected from the group consisting of: chlorine, fluorine, bromine and iodine atoms, preferably fluorine, chlorine or bromine atoms. The term halo has the same meaning when used as a prefix.
As used herein, the term CpAcyl means a linkage to a carbonyl group (CH)3-(CH2)p-2-alkyl having p-1 carbon atoms of CO-. Non-limiting examples of acyl groups are acetyl, propionyl, butyryl, pentanoyl and hexanoyl.
As used herein, the term CqAlkyl means a straight or branched chain hydrocarbon group (C)qH2q+1-). Non-limiting examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, and n-pentylAnd hexyl.
As used herein, the term mono-CrAlkylamino means a linkage to the group NH (C)r-alkyl-NH-) CrAn alkyl group. A non-limiting example of a monoalkylamino group is methylamino (CH)3-NH-), ethylamino (CH)3-CH2-NH-) and n-propylamino (CH)3-CH2-CH2-NH-)。
As used herein, the term di-CsAlkylamino means a linkage to the group N ((C)s-alkyl groups)2-N-) wherein the two alkyl residues may have the same or different number of carbon atoms. A non-limiting example of a dialkylamino group is dimethylamino ((CH)3)2NH-), diethylamino ((CH)3-CH2)2N-, ethylmethylamino ((CH))3)(CH3-CH2) N-) and di-N-propylamino ((CH)3-CH2-CH2)2N-)。
As used herein, the term CtAlkoxy means a linkage to an oxygen atom (CH)3-(CH2)t-1-O-) linear or branched alkyl. Non-limiting examples of alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, and n-hexoxy.
As used herein, the term CuAlkoxycarbonylmethyl means a linkage to the group-CO-CH2-((CH3-(CH2)u-1)-O-CO-CH2-) CuAlkoxy residue. Non-limiting examples of alkoxycarbonylmethyl groups are methoxycarbonylmethyl and ethoxycarbonylmethyl.
As used herein, the term methylaminocarbonylpyridyloxy is used to refer to the group:
as used herein, the term heteroaryl refers to a heteroaromatic ring containing as part of the ring carbon, hydrogen, and one or more heteroatoms selected from N, O and S. The groups may be unsubstituted or substituted with one or more substituents. Non-limiting examples of heteroaryl groups are pyridyl, pyrimidinyl, furanyl, thienyl, pyrazolyl, oxazolyl, and thiazolyl.
As used herein, the term saturated or partially unsaturated heterocyclyl is used to refer to a non-aromatic ring containing carbon, hydrogen, and one or more heteroatoms selected from N, O and S as part of the ring. In particular, the heterocyclic group may be monocyclic or bicyclic. Non-limiting examples of saturated heterocyclyl groups are piperidinyl, morpholinyl, tetrahydropyranyl and piperazinyl.
As used herein, the term cycloalkyl refers to hydrocarbon ring groups. The cycloalkyl group may have a monocyclic ring or a polycyclic ring. Non-limiting examples of cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
The term alkylsulfonyl as used herein refers to a linkage to a sulfonyl (CH)3-(CH2)v-1-SO2-) linear or branched alkyl. A non-limiting example of an alkylsulfonyl group is methylsulfonyl (CH)3-SO2-), ethylsulfonyl (CH)3-CH2-SO2-) and n-propylsulfonyl (CH)3-CH2-CH2-SO2-)。
As used herein, the term cycloalkylsulfonyl refers to a cycloalkyl group attached to a sulfonyl group. Non-limiting examples of cycloalkylsulfonyl groups are cyclopropylsulfonyl, cyclobutylsulfonyl, cyclopentylsulfonyl and cyclohexylsulfonyl.
The term arylsulfonyl, as used herein, refers to an aryl group attached to a sulfonyl group. Non-limiting examples of alkylsulfonyl groups are phenylsulfonyl and naphthylsulfonyl.
As used herein, the term pyridylcarbonyl refers to a linkage to a carbonyl (C)5H4Pyridyl group of N-CO-).
As used herein, the term phenylcarbonyl refers to a linkage to a carbonyl group (C)6H5-CO- — phenyl.
The term tetrahydropyranyl carbonyl, as used herein, refers to a linkage to a carbonyl group (C)5H9O-CO-) is used.
As used herein, the term pharmaceutically acceptable salt refers to any salt that is capable of providing (directly or indirectly) a compound as described herein when administered to a patient. For example, pharmaceutically acceptable salts of the compounds provided herein are synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. Typically, such salts are prepared, for example, by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of the two. Generally, non-aqueous media like ether, ethyl acetate, ethanol, 2-propanol or acetonitrile are preferred. Examples of the acid addition salts include inorganic acid addition salts (e.g., hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate) and organic acid addition salts (e.g., acetate, trifluoroacetate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, and p-toluenesulfonate). Examples of base addition salts include inorganic salts (e.g., sodium, potassium, calcium, and ammonium salts) and organic base salts (e.g., ethylenediamine, ethanolamine, N-dialkyleneethanolamine, triethanolamine, and basic amino acid salts).
As used herein, the term stereoisomer refers to a molecule having the same molecular formula and sequence (composition) of bonded atoms, but differing in the three-dimensional orientation of its atoms in space. The compounds of formula (I) have at least two chiral carbon atoms (labeled 1 and 3 in the formulae depicted below), and thus, several stereoisomers of the compounds may exist. Formula (I) encompasses the stereoisomers.
Throughout the description and claims the word "comprise" and variations of the word are not intended to exclude other technical features, additives, components or steps. Furthermore, the word "comprising" encompasses the case where "consists of … …". Additional objects, advantages and features of the invention will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention. The following examples are provided by way of illustration and are not intended to limit the present invention. Moreover, the present invention encompasses all possible combinations of the specific and preferred embodiments described herein.
Abbreviations:
the following abbreviations have been used throughout this application:
an h.: without water
AcOH: acetic acid
AcCl: acetyl chloride
AIBN: azobisisobutyronitrile
Bis/Tris: 2-bis (2-hydroxyethyl) amino-2- (hydroxymethyl) -1, 3-propanediol
BSA: bovine serum albumin
Bu3SnD: tributyl (deuterium) stannane
Calculated (Calcd): calculated value (calculated)
d: double peak
DAST: diethylaminosulfur trifluoride
And Dec: decomposition of
DCM: methylene dichloride
DMF: n, N-dimethylformamide
DMSO, DMSO: dimethyl sulfoxide
doublet of dq quartets
dt trimodal doublet
EDCI: 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide
ESI: electrospray ionization
Et2O: ether (A)
Et3N: triethylamine
EtOAc: ethyl acetate
EtOH: ethanol
HOBt: hydroxybenzotriazoles
h: hour(s)
Hz
HRMS: high resolution mass spectrometry
IR: infrared ray
m: multiple peaks
MeOH: methanol
mp: melting Point
n-Bu: n-butyl
NMR: nuclear magnetic resonance
NSAID: non-steroidal anti-inflammatory drugs
p-TSA: p-toluenesulfonic acid
PHOME: 2- (3-PhenylOxiran-2-yl) acetic acid cyano (6-methoxynaphthalen-2-yl) methyl ester
s: single peak
sEH: soluble epoxide hydrolases
t: three peaks
THF: tetrahydrofuran (THF)
TPPU (thermoplastic polyurethane): n- [1- (1-oxopropyl) -4-piperidinyl ] -N' - [4- (trifluoromethoxy) phenyl ] urea
UV: ultraviolet ray
Examples of the invention
Analytical method
Melting points were determined in open capillaries with MFB 595010M Gallenkamp melting point apparatus.
-running Infrared (IR) spectra on a Perkin-Elmer Spectrum RX I spectrophotometer (using attenuated total reflection technique) or on a spectrophotometer Nicolet Avatar 320 FT-IR. The absorbance was expressed as wave number (cm)-1) (ii) a Giving only a significant absorption band.
Elemental analysis was performed with a Carlo Erba 1106 type analyzer at the microanalysis service of IIQAB (CSIC, Barcelona, Spain).
Preparative normal phase chromatography on CombiFlash Rf 150(Teledyne Isco) with a pre-packed RediSep Rf silica gel column. With silica gel 60F254 (Merck)Thin layer chromatography on aluminum backing plates from 1.05554 or Sigma Aldrich (Sigma-Aldrich), 60805) using UV light, 1% KMnO4The aqueous solution and/or iodine visualizes the spots.
High Resolution Mass Spectrometry (HRMS) analysis with LC/MSD TOF Agilent Technologies spectrometer.
Analytical grade solvents were used for crystallization and purified synthetic solvents were used for reaction, extraction and column chromatography.
The purity of the analytical samples of all novel compounds assessed pharmacologically was > 95% by their elemental analysis.
Reference example 1: 2-fluoro-5, 6,8, 9-tetrahydro-7H-5, 9-propanebenzo [7]]Rotalene-7, 11-dione.
In a round bottom flask equipped with a condenser and magnetic stirring, a solution of 4-fluoro-phthalaldehyde (3.08g, 20mmol) and dimethyl 3-oxoheterocyclosuccinate (6.98g, 40mmol) in MeOH (60mL) was prepared. Four drops of diethylamine were added and the reaction was heated at reflux for 1.5 hours, the reaction was cooled, and 7 more drops of diethylamine were added and the reaction was stored overnight at 4 ℃. The precipitate was filtered off under vacuum and washed with cold MeOH (4mL) to give 2-fluoro-7, 11-dioxo-6, 7,8, 9-tetrahydro-5H-5, 9-propanebenzo [7] annulene-6, 8,10, 12-tetracarboxylic acid tetramethyl ester (3.05g) as white needles. A solution of this solid in glacial acetic acid (18mL) and concentrated HCl (5mL) was heated at reflux for 12 h. The solvent was removed under vacuum to obtain a solid. A solution of this solid in toluene (50mL) was heated at reflux in a Dean-Stark apparatus for 16 hours. Toluene was removed in vacuo to give pure 2-fluoro-5, 6,8, 9-tetrahydro-7H-5, 9-propanebenzo [7] annulene-7, 11-dione as a light brown solid (1.53g, 33% overall yield).
mp 105-. IR (NaCl dish): 2923. 2848, 1710, 1607, 1593, 1490, 1428, 1380, 1346, 1253, 1208, 1119, 1074, 985, 944, 865, 806cm-1。HRMS-ESI+m/z[M+H]+[C14H13FO2+H]+The calculated value of (a): 233.0972, found: 233.0967.
reference example 2: 2-methoxy-5, 6,8, 9-tetrahydro-7H-5, 9-propanebenzo [7]]Rotalene-7, 11-dione:
from a solution of 4-methoxy-phthalaldehyde (10.2g, 61.9mmol), dimethyl 3-oxoheterocyclosuccinate (21.5g, 124mmol), and diethylamine (28 drops) in MeOH (380mL) and following the procedure described in reference example 1, tetramethyl 2-methoxy-7, 11-dioxo-6, 7,8, 9-tetrahydro-5H-5, 9-propanebenzo [7] annulene-6, 8,10, 12-tetracarboxylic acid (19.4g, 66% yield) was obtained. 2-methoxy-5, 6,8, 9-tetrahydro-7H-5, 9-propbenzo [7] annulene-7, 11-dione (125mg, 98% yield) was obtained from the aforementioned tetracarboxylic acid (250mg, 0.5mmol), concentrated HCl (0.4mL) and glacial acetic acid (1.4mL) and following the procedure described in reference example 1.
mp 157 and 158 ℃. IR (NaCl dish): 2941. 2910, 2837, 1701, 1610, 1585, 1504, 1431, 1414, 1370, 1321, 1300, 1266, 1166, 1094, 1033, 989cm-1。HRMS-ESI+m/z[M+H]+[C15H16O3+H]+The calculated value of (a): 245.1172, found: 245.1180.
reference example 3: 2, 3-dimethoxy-5, 6,8, 9-tetrahydro-7H-5, 9-propanebenzo [7]]Rotalene-7, 11-dione:
from a solution of 4, 5-dimethoxyphthalaldehyde (6.54g, 33.7mmol), dimethyl 3-oxoheterocyclosuccinate (11.7g, 67.4mmol) and diethylamine (19 drops) in MeOH (130mL) and following the procedure described in reference example 1, tetramethyl 2, 3-dimethoxy-7, 11-dioxo-6, 7,8, 9-tetrahydro-5H-5, 9-propanebenzo [7] annulene-6, 8,10, 12-tetracarboxylic acid (6.84g, 40% yield) was obtained. 2, 3-dimethoxy-5, 6,8, 9-tetrahydro-7H-5, 9-propiobenzo [7] annulene-7, 11-dione (2.8g, 76% yield) was obtained from the aforementioned tetracarboxylic acid (6.84g, 13.5mmol), concentrated HCl (10mL) and glacial acetic acid (35mL) and following the procedure described in reference example 1.
mp 236-237 ℃. IR (NaCl dish): 2952. 2840, 1698, 1605, 1516, 1467, 1451, 1416, 1355, 1336, 1254, 1221, 1192, 1162, 1025, 1002, 880, 811cm-1。HRMS-ESI+m/z[M+H]+[C16H18O4+H]+The calculated value of (a): 275.1278, trueMeasuring: 275.1279.
reference example 4: 1-fluoro-5, 6,8, 9-tetrahydro-7H-5, 9-propanebenzo [7]]Rotalene-7, 11-dione.
1-fluoro-7, 11-dioxo-6, 7,8, 9-tetrahydro-5H-5, 9-propanebenzo [7] annulene-6, 8,10, 12-tetracarboxylic acid tetramethyl ester (18.5g, 54% yield) was obtained from a solution of 3-fluoro-phthalaldehyde (11.2g, 73.6mmol), dimethyl 3-oxoheterocyclic succinate (25.6g, 147mmol) and diethylamine (33 drops) in MeOH (220mL) and following the procedure described in reference example 1. 1-fluoro-5, 6,8, 9-tetrahydro-7H-5, 9-propanebenzo [7] annulene-7, 11-dione (8.73g, 94% yield) was obtained from the aforementioned tetracarboxylic acid (18.5g, 39.9mmol), concentrated HCl (31mL) and glacial acetic acid (103mL) and following the procedure described in reference example 1.
mp>150 ℃ (dec.). IR (NaCl dish): 2940. 2908, 1701, 1619, 1585, 1468, 1421, 1370, 1303, 1245, 1222, 1203, 1072, 1052, 988, 931, 897, 789, 746cm-1。HRMS-ESI+m/z[M+H]+[C14H13FO2+H]+The calculated value of (a): 233.0972, found: 233.0976.
reference example 5: 2-fluoro-7, 11-dimethylene-6, 7,8, 9-tetrahydro-5H-5, 9-propanebenzo [7]]And (4) performing cyclonene.
In a three-neck round-bottom flask equipped with magnetic stirring and an argon atmosphere, a suspension of NaH (1.08g, 60% purity, 27.0mmol) in anhydrous DMSO (13.3mL) was heated at 75 ℃ for 45 minutes. The green suspension was cooled to room temperature and methyltriphenylphosphonium iodide (10.92g, 27.0mmol) diluted in anhydrous DMSO (22mL) and 2-fluoro-5, 6,8, 9-tetrahydro-7H-5, 9-propanebenzo [7] diluted in anhydrous DMSO (50mL) were added in that order]Rotacene-7, 11-dione (1.53g, 6.59 mmol). The resulting mixture was heated at 90 ℃ overnight. The reaction was cooled and poured into water (80 mL). The aqueous layer was extracted with hexane (4X 80 mL). The combined organic extracts are dried over anhydrous Na2SO4Dried, filtered and concentrated under vacuum. Column chromatography (SiO)2Hexane/ethyl acetate mixture) to give 2-fluoro-7, 11-dimethylene-6, 7,8, 9-tetrahydro-5H-5, 9-propanebenzo [7] as a colorless wax]Rotalene (1.09, 73% yield).
mp 108 and 109 ℃. IR (NaCl dish): 3072. 2985, 2921, 2844, 1639, 1612, 1592, 1494, 1451, 1444, 1363, 1246, 1162, 1135, 1095, 1048, 974, 951, 930, 887, 820, 716, 658, 638, 598, 528cm-1。
Reference example 6: 2-methoxy-7, 11-dimethylene-6, 7,8, 9-tetrahydro-5H-5, 9-propanebenzo [7]]And (4) performing cyclonene.
2-methoxy-7, 11-dimethylene-6, 7,8, 9-tetrahydro-5H-5, 9-propbenzo [7] annulene (1.5g, 38% yield) was obtained from 2-methoxy-5, 6,8, 9-tetrahydro-7H-5, 9-propbenzo [7] annulene-7, 11-dione (4g, 16.4mmol) and following the procedure described in reference example 5.
mp 68-69 ℃. IR (NaCl dish): 3068. 2979, 2911, 2833, 1639, 1609, 1580, 1501, 1464, 1449, 1431, 1363, 1313, 1260, 1203, 1172, 1152, 1109, 1034, 955, 929, 889, 851, 809, 661, 613cm-1。HRMS-ESI+m/z[M+H]+[C17H20O+H]+The calculated value of (a): 241.1587, found: 241.1588.
reference example 7: 2, 3-dimethoxy-7, 11-dimethylene-6, 7,8, 9-tetrahydro-5H-5, 9-propanebenzo [7]]Wheel An alkene.
2, 3-dimethoxy-7, 11-dimethylene-6, 7,8, 9-tetrahydro-5H-5, 9-propi-o [7] annulene (633mg, 23% yield) was obtained from 2, 3-dimethoxy-5, 6,8, 9-tetrahydro-7H-5, 9-propi-o [7] annulene-7, 11-dione (2.8g, 10.2mmol) and following the procedure described in reference example 5.
mp 74-75 ℃. IR (NaCl dish): 3068. 2977, 2913, 2832, 1639, 1606, 1515, 1464, 1450, 1429, 1414, 1358, 1342, 1293, 1261, 1240, 1225, 1191, 1173, 1103, 1023, 956, 931, 889, 804, 634cm-1。HRMS-ESI+m/z[M+H]+[C18H22O2+H]+The calculated value of (a): 271.1693, found: 271.1688.
reference example 8: 1-fluoro-7, 11-dimethylene-6, 7,8, 9-tetrahydro-5H-5, 9-propanebenzo [7]]And (4) performing cyclonene.
1-fluoro-7, 11-dimethylene-6, 7,8, 9-tetrahydro-5H-5, 9-propanebenzo [7] annulene (2.69g, 69% yield) was obtained as a colorless oil from 1-fluoro-5, 6,8, 9-tetrahydro-7H-5, 9-propanebenzo [7] annulene-7, 11-dione (4g, 17.2mmol) and following the procedure described in reference example 5.
IR (NaCl dish): 3071. 2981, 2921, 2838, 1639, 1614, 1583, 1464, 1446, 1429, 1365, 1248, 1046, 991, 935, 919, 895cm-1。HRMS-ESI+m/z[M+H]+[C16H17F+H]+The calculated value of (a): 229.1387, found: 229.1392.
reference example 9: 1-fluoro-7-methylene-6, 7,8, 9-tetrahydro-5H-5, 9-propanebenzo [7]Rotalen-11-ones
In a three-neck round-bottom flask equipped with magnetic stirring and an argon atmosphere, a suspension of NaH (1.01g, 60% purity, 25.2mmol) in anhydrous DMSO (50mL) was heated at 75 ℃ for 45 minutes. The green suspension was cooled to room temperature and methyltriphenylphosphonium iodide (10.61g, 25.33mmol) diluted in anhydrous DMSO (58mL) and 1-fluoro-5, 6,8, 9-tetrahydro-7H-5, 9-propanebenzo [7] diluted in anhydrous DMSO (50mL) were added in that order]Rotacene-7, 11-dione (4.72g, 20.3mmol, from reference example 4). The resulting mixture was heated at 90 ℃ overnight. The reaction was cooled and poured into water (80 mL). The aqueous layer was extracted with hexane (5X 80 mL). The combined organic extracts are dried over anhydrous Na2SO4Dried, filtered and concentrated under vacuum. Column chromatography (SiO)2Hexane/ethyl acetate mixture) to obtain 1-fluoro-7-methylene-6, 7,8, 9-tetrahydro-5H-5, 9-propanebenzo [7]Rotalen-11-one (2.16, 55% yield).
mp 96℃。IR(ATR)：2927、2913、2895、1688、1613、1583、1432、1406、1366、1247、1196、1104、1049、1034、1002、970、921、911、883、819、789、749、715、657cm-1。HRMS-ESI+m/z[M+H]+[C15H15FO+H]+The calculated value of (a): 231.1180, found: 231.1180.
reference example 10: 2-chloro-N- (2-fluoro-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dioxalidene) Methyl radicalBenzo [9]]Rotalen-7-yl) acetamide.
2-fluoro-7, 11-dimethylene-6, 7,8, 9-tetrahydro-5H-5, 9-propanebenzo [7]]A suspension of rotalene (1.09g, 4.77mmol), chloroacetonitrile (1.2mL, 19.1mmol) and acetic acid (3.5mL) was cooled to 0 deg.C and concentrated H was added dropwise2SO4(1.53mL，28.6mmol)(T<At 10 deg.C). The mixture was allowed to reach room temperature and stirred overnight. The suspension was added to ice (20g) and after stirring for 10 min, the suspension was extracted with DCM (3 × 15 mL). The combined organic layers were washed with NaOH 10N (1X 25mL) and anhydrous Na2SO4Drying, filtering and concentrating under vacuum to obtain 2-chloro-N- (2-fluoro-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] as a white solid]Rotalen-7-yl) acetamide (1.2g, 78% yield).
mp 141 and 144 ℃. IR (NaCl dish): 3399. 3313, 3067, 2944, 2920, 2851, 1657, 1607, 1591, 1518, 1498, 1451, 1361, 1345, 1252, 1179, 1145, 966, 963, 863, 820cm-1。HRMS-ESI+m/z[M+H]+[C18H21ClFNO+H]+The calculated value of (a): 322.1368, found: 322.1370.
reference example 11: 2-chloro-N- (2-methoxy-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-di Bridged methylene benzo [9]]Rotalen-7-yl) acetamide.
2-chloro-N- (2-methoxy-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-di-methanobenzo [9] annulen-7-yl) acetamide (1.18g, 57% yield) was obtained from 2-methoxy-7, 11-dimethylene-6, 7,8, 9-tetrahydro-5H-5, 9-propen-7-yl) annulen (1.5g, 6.24mmol) and following the procedure described in reference example 10.
mp 144-145 ℃. IR (NaCl dish): 3403. 3304, 3062, 2997, 2945, 2905, 2860, 2838, 1662, 1609, 1582, 1528, 1499, 1454, 1382, 1361, 1311, 1267, 1242, 1198, 1180, 1154, 1043, 1013, 955, 873cm-1。HRMS-ESI+m/z[M+H]+[C19H24ClNO2+H]+The calculated value of (a): 334.1568, found: 334.1569.
reference example 12: 2-chloro-N- (2, 3-dimethoxy-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-bis-methanobenzo [9]]Rotalen-7-yl) acetamide.
2-chloro-N- (2, 3-dimethoxy-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9, 11-dimethano-9-rotanen-7-yl) acetamide (501mg, 75% yield) was obtained from 2, 3-dimethoxy-7, 11-dimethylene-6, 7,8, 9-tetrahydro-5H-5, 9, 11-dimethano-9H-5, 9-propan-7-yl) rotaxane (498mg, 1.84mmol) and following the procedure described in reference example 10.
mp 204-. IR (NaCl dish): 3306. 2941, 2907, 2861, 2838, 1666, 1605, 1516, 1467, 1452, 1415, 1381, 1361, 1345, 1293, 1252, 1231, 1191, 1168, 1092, 1021, 948, 861, 802cm-1。HRMS-ESI+m/z[M+H]+[C20H26ClNO3+H]+The calculated value of (a): 364.1674, found: 364.1674.
reference example 13: 2-chloro-N- (1-fluoro-9-hydroxy-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dioxalidene) Methylbenzo [9]]Rotalen-7-yl) acetamide.
1-fluoro-7-methylene-6, 7,8, 9-tetrahydro-5H-5, 9-propanebenzo [7]]A solution of rotalen-11-one (2.06g, 8.94mmol), chloroacetonitrile (0.6mL, 9.83mmol) in DCM (21mL) was cooled to 0 deg.C and concentrated H was added dropwise2SO4(0.75mL)(T<At 10 deg.C). The mixture was allowed to reach room temperature and stirred overnight. The suspension was added to ice (20g) and after stirring for 10 min, the suspension was extracted with DCM (3 × 15 mL). The combined organic layers were washed with NaOH 10N (1X 25mL) and anhydrous Na2SO4Dried, filtered and concentrated under vacuum. Column chromatography (SiO)2Hexane/ethyl acetate mixture) to obtain 2-chloro-N- (1-fluoro-9-hydrido-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-di-methanobenzo [9] as a white solid]Rotalen-7-yl) acetamide (921mg, 32% yield).
mp 150℃。IR(ATR)：3406、3272、3075、2926、2905、2850、1661、1561、1466、1443、1409、1362、1341、1311、1298、1243、1218、1158、1105、1037、991、974、891、884、791、734、679、625cm-1。HRMS-ESI+m/z[M+H]+[C17H19ClFNO2+H]+The calculated value of (a): 324.1161, found: 324.1162.
reference example 14: 2-chloro-N- (1-fluoro-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dioxalidene) Methylbenzo [9]]Rotalen-7-yl) acetamide.
2-chloro-N- (1-fluoro-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-di-methanobenzo [9] annulen-7-yl) acetamide (2.28g, 68% yield) was obtained from 1-fluoro-7, 11-dimethylene-6, 7,8, 9-tetrahydro-5H-5, 9-propen-7-yl) annulene (2.36g, 10.36mmol) and following the procedure described in reference example 10. Analytical samples were obtained by crystallization from DCM.
mp 154 and 155 ℃. IR (NaCl dish): 3402. 3308, 3073, 2947, 2911, 2863, 2840, 1660, 1613, 1583, 1529, 1463, 1363, 1348, 1312, 1242, 1186, 1155, 979, 798, 748cm-1。HRMS-ESI+m/z[M+H]+[C18H21ClFNO+H]+The calculated value of (a): 322.1368, found: 322.1374.
reference example 15: 2-chloro-N- (1, 9-difluoro-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-methano-biante) Benzo [9]]Rotalen-7-yl) acetamide.
A solution of 2-chloro-N- (1-fluoro-9-hydroxy-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethanobenzo [9] annulen-7-yl) acetamide (611mg, 1.89mmol) in DCM (10mL) was cooled to-30 ℃ with dry ice in an acetone bath. Then, DAST (2.8mL, 1M in DCM, 2.8mmol) was added and the reaction mixture was stirred with dry ice in an acetone bath overnight. To the resulting solution was added water (10mL) and the pH was adjusted to about 12 with NaOH 1N. The two layers were separated, the aqueous phase was further extracted with DCM (2 × 8mL), and the combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Crystallization from DCM/pentane gave 2-chloro-N- (1, 9-difluoro-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dioxamethylenebenzo [9] annulen-7-yl) acetamide (420mg, 68% yield).
mp 180℃。IR(ATR)：3276、3075、2964、2940、2901、2858、1671、1650、1552、1463、1442、1360、1317、1282、1242、1175、1143、1104、1066、1018、1004、979、929、901、887、865、799、746、737、696、662cm-1。HRMS-ESI+m/z[M+H]+[C17H18ClF2NO+H]+The calculated value of (a): 326.1118, found: 326.1116.
reference example 16: 2-fluoro-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-bis (methanobenzo) s [9]Rotalene-7-amine hydrochloride.
Thiourea (25mg, 0.32mmol) and glacial acetic acid (200. mu.L) were added to 2-chloro-N- (2-fluoro-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-di-methanobenzo [9]]A solution of rotalen-7-yl) acetamide (87mg, 0.27mmol) in absolute ethanol (5mL) and the mixture heated at reflux overnight. The resulting suspension was then tempered to room temperature, water (5mL) was added, and the pH was adjusted to 12 with 5N NaOH solution. EtOAc (5mL) was added, the phases were separated, and the aqueous phase was extracted with additional EtOAc (2X 5 mL). The combined organic layers were passed over anhydrous Na2SO4Dried, filtered and concentrated in vacuo to give a light brown oil. The hydrochloride salt thereof was obtained by: excess Et2O/HCl was added to a solution of amine in ethyl acetate, and the resulting beige precipitate was filtered to obtain 2-fluoro-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9]]Rotalene-7-amine hydrochloride (18mg, 24% yield).
mp>300 deg.C (dec.). IR (KBr disk): 3200 + 2500(2983, 2945, 2917, 2867), 2059, 1612, 1595, 1501, 1456, 1444, 1431, 1379, 1364, 1302, 1283, 1256, 1246, 1186, 1157, 1143, 1132, 1030, 1004, 962, 863, 814cm-1. For C16H20FN · 2.6HCl, analytically calculated: c56.50, H6.70, N4.12. Measured value: c56.18, H6.40, N4.01.
Reference example 17: 2-methoxy-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-methano-bis (methylene) s Benzo [9]]Rotalene-7-amine hydrochloride.
2-methoxy-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 11-methanobenzo [9] annulen-7-yl) acetamide (1.10g, 3.95mmol) was obtained from 2-chloro-N- (2-methoxy-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-methanobenzo [9] annulen-7-amine hydrochloride by the procedure described in reference example 16. An analytical sample (779mg, 81% yield) was obtained by crystallization from DCM/pentane.
mp>250 deg.C (dec.). IR (KBr disk): 3200 + 2500(2985, 2942, 2908), 2056, 1735, 1609, 1582, 1499, 1449, 1379, 1364, 1334, 1305, 1268, 1252, 1205, 1170, 1132, 1103, 1040, 1001, 954, 869, 849, 815, 756, 692cm-1。HRMS-ESI+m/z[M+H]+[C17H23NO+H]+The calculated value of (a): 258.1852, found: 258.1862.
reference example 18: 2, 3-dimethoxy-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dioxa Methylbenzo [9]]Rotalene-7-amine hydrochloride.
2, 3-dimethoxy-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethanomebenzo [9] annulen-7-yl) acetamide (436mg, 1.2mmol) was obtained from 2-chloro-N- (2, 3-dimethoxy-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethanomebenzo [9] annulen-7-amine hydrochloride (285mg, 73% yield) following the procedure described in reference example 16.
mp>200 deg.C (dec.). IR (KBr disk): 3200-2500(2993, 2918, 2831), 2047, 1701, 1606, 1517, 1451, 1416, 1386, 1365, 1327, 1310, 1291, 1252, 1237, 1192, 1174, 1131, 1098, 1031, 973, 950, 863, 798, 586, 543cm-1。HRMS-ESI+m/z[M+H]+[C18H25NO2+H]+The calculated value of (a): 288.1958, found: 288.1954.
reference example 19: 1-fluoro-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-bis (methanobenzo) s [9]Rotalene-7-amine hydrochloride.
1-fluoro-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 11-methanobenzo [9] annulen-7-yl) acetamide (1g, 3.11mmol) was obtained from 2-chloro-N- (1-fluoro-9-methyl-5, 6,8,9,10, 11-methanobenzo [9] annulen-7-yl) acetamide and following the procedure described in reference example 16. An analytical sample (521mg, 59% yield) was obtained by crystallization from methanol.
mp>200 deg.C (dec.). IR (KBr disk): 3200-2500(2945, 2717), 2060, 1677, 1608, 1584, 1511, 1464, 1390, 1380, 1366, 1317, 1303, 1248, 1214, 1199, 1165, 1132, 1071, 1052, 1032, 1000, 977, 946, 885, 877, 854, 798, 747, 623cm-1。HRMS-ESI+m/z[M+H]+[C16H20FN+H]+The calculated value of (a): 246.1653, found: 246.1649.
reference example 20: 2-chloro-N- (9-methyl-2-nitro-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-di-bridge Methylenebenzo [9]]Rotalen-7-yl) acetamide.
To the known 2-chloro-N- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-di-methanobenzo [9]]Roylen-7-yl) acetamide (Bio-organic and pharmaceutical chemistry 2012,20,942) (3g, 9.87mmol) in acetic anhydride (10.5mL) in a cold (0 ℃) solution was carefully added glacial acetic acid (1.6mL) and fuming nitric acid (1.85 mL). The mixture was allowed to reach room temperature and stirred overnight. The resulting yellow solution was poured into ice water (20mL) and extracted with DCM (3X 40 mL). The combined organic extracts were washed with aqueous 2N NaOH (1X 40mL), water (1X 40mL) and brine (1X 40 mL). Subjecting the organic layer to anhydrous Na2SO4Dried, filtered and concentrated under vacuum to give a yellow residue. Purification column chromatography (SiO)2Hexane/ethyl acetate mixture) to obtain 2-chloro-N- (9-methyl-2-nitro-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] as a white solid]Rotalen-7-yl) acetamide (2.92g, 85% yield).
mp 174 ℃. IR (KBr disk): 3403. 3288, 3077, 2946, 2922, 2847, 1667, 1607, 1588, 1520, 1456, 1409, 1348, 1229, 1166, 1136, 1082, 1051, 1009, 972, 945, 896, 865, 841, 797, 740, 764, 704, 666cm-1。HRMS-ESI+m/z[M+H]+[C18H21ClN2O3+H]+The calculated value of (a): 349.1313, found: 349.1313.
reference example 21: 9-methyl-2-nitro-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-di (methano) benzene And [9]]Rotalene-7-amine hydrochloride.
9-methyl-2-nitro-5, 6,8,9,10, 11-hexahydro-7H-5, 11-di-methanobenzo [9] annulen-7-yl) acetamide (677mg, 1.94mmol) was obtained from 2-chloro-N- (9-methyl-2-nitro-5, 6,8,9,10, 11-di-methanobenzo [9] annulen-7-yl) acetamide (677mg, 1.94mmol) and following the procedure described in reference example 16 (443mg, 74% yield).
mp>225 ℃ (dec.). IR (KBr disk): 3200--1。HRMS-ESI+m/z[M+H]+[C16H20N2O2+H]+The calculated value of (a): 273.1598, found: 273.1604.
reference example 22: 1, 9-difluoro-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9]] Rotalene-7-amine hydrochloride.
1, 9-difluoro-5, 6,8,9,10, 11-hexahydro-7H-5, 11-di-methanobenzo [9] annulen-7-yl) acetamide (382mg, 1.17mmol) was obtained from 2-chloro-N- (1, 9-difluoro-5, 6,8,9,10, 11-di-methanobenzo [9] annulen-7-yl) acetamide (218mg, 65% yield) and following the procedure described in reference example 16. Analytical samples were obtained by crystallization from methanol.
mp>200℃(dec.)。IR(ATR)：2980-2831(2950、2911、2867)、2703、2676、2559、2063、1611、1588、1509、1465、1445、1363、1321、1246、1194、1105、1095、1008、1002、988、967、903、888、860、801、743、673cm-1。HRMS-ESI+m/z[M+H]+[C15H17F2N+H]+The calculated value of (a): 250.1402, found: 250.1401.
reference example 23: 9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-di-methanobenzo [9]]Wheel Alkene-2, 7-diamine dihydrochloride.
To amine 9-methyl-2-nitro-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-di-methanobenzo [9]]A solution of rotalen-7-amine (201mg, 0.738mmol) in methanol (25mL) was added Pd on charcoal (68.6mg, Cat. No. 10% Pd) and the resulting suspension was placed under 1atm of H at room temperature2Hydrogenation was carried out for 48 hours. The black suspension was filtered and the solvent was removed by concentration under vacuum to give 9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethanobenzo [9] as a brown solid]Rotalene-2, 7-diamine (130mg, 89% yield). Its dihydrochloride salt was obtained by: to a solution of diamine in methanol was added excess Et2O/HCl and the resulting brown precipitate was filtered.
mp 294-. IR (KBr disk): 3200 + 2500(3024, 2912, 2847, 2588), 1994, 1598, 1502, 1454, 1381, 1365, 1303, 1261, 1173, 1131, 1021, 957, 877, 827, 576, 473cm-1. For C16H22N23.4HCl, analytically calculated: c52.46, H6.99, N7.65. Measured value: c52.64, H7.18, N7.43.
Reference example 24: 2-chloro-N- (2-hydroxy-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-di-bridge Methylenebenzo [9]]Rotalen-7-yl) acetamide.
To N- (2-amino-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] at 0 deg.C]Rotalen-7-yl) -2-chloroacetamide (999mg,3.10mmol) in H2A solution of O (5mL) and concentrated HCl (5mL) was added sodium nitrite (427mg, 6.21mmol) dropwise to H2Solution in O (2 mL). To the resulting solution was added concentrated HCl (3mL) containing CuCl (652mg, 6.56mmol) and the gas evolution was observed over 10 minutes. The resulting solution was heated to 60 ℃ for 90 minutes and then cooled to room temperature in H2Diluted in O (60mL) and extracted with DCM (4X 90 mL). The combined organic extracts were washed with saturated NaHCO3Washed with brine and over anhydrous Na2SO4Dried, filtered and concentrated under vacuum to give a dark green solid. Purification column chromatography (SiO)2Hexane/ethyl acetate mixture) to obtain 2-chloro-N- (2-hydroxy-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] as a white solid]Rotalen-7-yl) acetamide (78mg, 9% yield).
mp 98-100 ℃. IR (NaCl dish): 3300--1。HRMS-ESI-m/z[M-H]-[C18H22ClNO2-H]-The calculated value of (a): 318.1266, found: 318.1272.
reference example 25: 2-hydroxy-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-lbenzene And [9]]Rotalene-7-amine hydrochloride.
2-hydroxy-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 11-methanobenzo [9] annulen-7-yl) acetamide (72mg, 0.23mmol) was obtained from 2-chloro-N- (2-hydroxy-9-methyl-5, 6,8,9,10, 11-methanobenzo [9] annulen-7-yl) acetamide (42mg, 67% yield) and following the procedure described in reference example 16. Analytical samples were obtained by crystallization from methanol/diethyl ether.
mp 183-185 ℃. For C16H21NO·1.7HCl·1H2O, analytical calculation: c59.43, H7.70, N4.33. Measured value: c59.63, H7.44, N4.77.
Reference example 26: n- (9-methyl-2-nitro-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-bis (methylene) bridged Benzo [9]]Rotalen-7-yl) acetamide.
To the known Tetrahedron letters (1987, 28, 1585) -1588N-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] amine]A cold solution (0 ℃ C.) of rotalen-7-yl) acetamide (2.68g, 9.93mmol) in acetic anhydride (10.6mL) was carefully added glacial acetic acid (1.6mL) and fuming nitric acid (1.86 mL). The mixture was allowed to reach room temperature and stirred overnight. Will obtainThe yellow solution was poured into ice water (20mL) and extracted with DCM (3X 40 mL). The combined organic extracts were washed with aqueous 2N NaOH (1X 40mL), water (1X 40mL) and brine (1X 40 mL). Subjecting the organic layer to anhydrous Na2SO4Dried, filtered and concentrated under vacuum to give a yellow residue. Purification column chromatography (SiO)2Hexane/ethyl acetate mixture) to obtain N- (9-methyl-2-nitro-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] as a white solid]Rotalen-7-yl) acetamide (1.88g, 60% yield).
mp 174-. IR (NaCl dish): 3398. 3301, 3201, 3063, 2943, 2917, 2863, 1653, 1588, 1523, 1455, 1346, 1322, 1304, 1268, 1245, 1217, 1166, 1141, 1124, 1081, 1037, 1010, 945, 893, 865, 838, 798, 763, 740, 701cm-1。HRMS-ESI+m/z[M+H]+[C18H22N2O3+H]+The calculated value of (a): 315.1703, found: 315.1714.
reference example 27: n- (2-amino-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-methano-biante Benzo [9]]Rotalen-7-yl) acetamide.
In a purification column chromatography (SiO)2Hexane/ethyl acetate mixture) followed by N- (9-methyl-2-nitro-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-di-methanobenzo [9]]Rotalen-7-yl) acetamide (2.64g, 8.41mmol), PtO-containing2(258mg) of anhydrous EtOH and following the procedure described in reference example 23N- (2-amino-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-di-methanobenzo [9]]Rotalen-7-yl) acetamide (1.9g, 80% yield).
mp 112 and 113 ℃. IR (NaCl dish): 3432. 3324, 3224, 3056, 3004, 2938, 2903, 2856, 2835, 1651, 1618, 1546, 1507, 1447, 1362, 1344, 1300, 1262, 1194, 1164, 1136, 1065, 862, 735, 701cm-1。HRMS-ESI+m/z[M+H]+[C18H24N2O+H]+The calculated value of (a): 285.1961, found: 285.1972.
reference example 28: n- (2-chloro-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5,9:7, 11-bis (methylene) benzene And [9]]Rotalen-7-yl) acetamide.
From N- (2-amino-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-di-methanobenzo [9]]Rotalen-7-yl) acetamide hydrochloride (1.04g, 3.25mmol) in H2O (6mL) and concentrated HCl (6mL), H containing sodium nitrite (448mg, 6.5mmol)2O (2mL), CuCl (691mg, 6.99mmol) dissolved in concentrated HCl solution (3mL) and following the procedure described in reference example 24N- (2-chloro-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-di-methanobenzo [9] ne]Rotalen-7-yl) acetamide (210mg, 21% yield).
mp 190 and 191 ℃. IR (NaCl dish): 3301. 3196, 3071, 2921, 2855, 1651, 1594, 1549, 1487, 1454, 1414, 1364, 1343, 1308, 1281, 1263, 1211, 1139, 1109, 1012, 950, 875, 820cm-1。HRMS-ESI+m/z[M+H]+[C18H22ClNO+H]+The calculated value of (a): 304.1463, found: 304.1460.
reference example 29: 2-chloro-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-bis (methanobenzo) s [9]Rotalene-7-amine hydrochloride.
N- (2-chloro-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-di-methanobenzo [9]]Rotalen-7-yl) acetamide (190mg, 0.63mmol), concentrated HCl (4mL), H2A mixture of O (8mL) and isopropanol (6mL) was stirred at reflux for 4 days. The solution was cooled and the isopropanol was concentrated under vacuum. The aqueous phase was extracted with EtOAc (3 × 8mL) and then basified with a solution of 5N NaOH. The aqueous base was extracted with additional EtOAc (3X 10mL) over anhydrous Na2SO4Dried, filtered and concentrated under vacuum to obtain a yellow oil. Purification column chromatography (SiO)2Hexane/ethyl acetate mixture) to obtain 2-chloro-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-di-methanobenzo [9]]Rotalen-7-amine. The hydrochloride salt thereof was obtained by: to the amine in EtOAc was added excess Et2O/HCl (10mg, 5.5% yield).
mp>At 250 ℃ to obtain a mixture. IR (KBr disk): 3200-16、2861)、2058、1597、1570、1509、1488、1454、1416、1380、1365、1302、1217、1155、1133、1093、1032、1000、948、875、820、771、673cm-1. For C16H20ClN 1.35HCl, analytically calculated: c61.79, H6.95, N4.50. Measured value: c61.70, H6.78, N4.93.
Reference example 30: 5,8,9, 10-tetrahydro-5, 8:7, 10-di-methanobenzo [8]]Rotalen-7 (6H) -ylmethanesulfone An acid ester.
To 5,8,9, 10-tetrahydro-5, 8:7, 10-di-methanobenzo [8]]A solution of rotalen-7 (6H) -ol (1.19g, 5.97mmol) in pyridine (9mL) (prepared as reported in Ribis chem. 1973; 1839-1850) was added methanesulfonyl chloride (2.32mL, 29.28mmol) slowly and stirred at room temperature. The mixture was then heated at 120 ℃ for 5 hours. After cooling, crushed ice (100g) was added and the mixture was extracted with DCM (5X 40 mL). The combined organic phases were washed with 2N HCl (2X 40mL), H2O (2X 40mL), saturated aqueous NaHCO3(2X 40mL) and washed with anhydrous Na2SO4And (5) drying. After filtration and removal of the solvent under reduced pressure, 5,8,9, 10-tetrahydro-5, 8:7, 10-dimethanobenzo [8] was isolated as a dark oil]Rotalen-7 (6H) -yl methanesulfonate (1.32g, 80% yield), which was used in the next step without further purification.
IR (NaCl dish): 3060. 3010, 2934, 2857, 1488, 1451, 1341, 1232, 1175, 1145, 1102, 1046, 1012, 992, 966, 923, 853, 800, 753cm-1。HRMS-ESI+m/z[M+H]+[C15H18O3S+NH4]+The calculated value of (a): 296.1315, found: 296.1318.
reference example 31: 7-iodo-5, 6,7,8,9, 10-hexahydro-5, 8:7, 10-di-methanobenzo [8]]And (4) performing cyclonene.
H is to be3PO4(99%, 135g), 5,8,9, 10-tetrahydro-5, 8:7, 10-di-methanobenzo [8]]A mixture of rotalen-7 (6H) -yl methanesulfonate (1.32g, 4.75mmol) and NaI (63g, 420mmol) was stirred at 150 ℃ for 6 hours. After cooling, H is2O (150mL) was added slowlyTo a mixture. The resulting purple solution was extracted with DCM (4X 80mL) and the combined organic phases were washed with 10% aqueous sodium thiosulfate (1X 100mL) over anhydrous Na2SO4Drying and removing the solvent under vacuum to obtain 7-iodo-5, 6,7,8,9, 10-hexahydro-5, 8:7, 10-dimethano-benzo [8] as a white solid]Rotalene (1.39g, 95%).
mp 132-. IR (NaCl dish): 3052. 3013, 2950, 2892, 2852, 1490, 1447, 1304, 1278, 1232, 1215, 1095, 1046, 1032, 967, 830, 778, 755cm-1。GC-MS(EI):310[(M)·+,2],183[(M-I)+,100],141(73),129(23),128(15).
Reference example 32: 5,8,9, 10-tetrahydro-5, 8:7, 10-di-methanobenzo [8]]Rotalene-7 (6H) -carboxylic acid.
To 7-iodo-5, 8,9, 10-tetrahydro-5, 8:7, 10-di-methanobenzo [8]]To a solution of rotalene (2.03g, 6.5mmol) in dry and degassed toluene (20mL) was added methyl oxalyl chloride (2.39g, 19.5mmol) and bis (tributyltin) (4.5g, 7.8 mmol). The mixture was irradiated in a quartz reactor under an argon atmosphere with a lamp of 125W Hg for 20 hours. Then, DCM (15mL), methanol (0.6mL) and triethylamine (1.2mL) were added to the reaction mixture in order at 0 ℃ and concentrated in vacuo to obtain a dark oil (3.99 g). This oil in 40% methanol solution of KOH (50mL) was heated to reflux for 2 hours. Water (50mL) was added and the reaction refluxed for 3 hours. The reaction mixture was cooled to room temperature and the methanol was removed in vacuo. Water (40mL) was added to the residue, and the aqueous layer was washed with DCM (4X 50 mL). After this time, the aqueous phase was acidified with concentrated HCl until pH 1 and extracted with DCM (4 × 50 mL). Subjecting the organic extract to anhydrous Na2SO4Dried, filtered and concentrated under reduced pressure to give 5,8,9, 10-tetrahydro-5, 8:7, 10-dimethanembenzo [8] as a brown solid]Rotacene-7 (6H) -carboxylic acid (555mg, 37% overall yield). An analytical sample of the acid was obtained by crystallization from DCM/pentane.
mp 188-. IR (NaCl dish): 3300--1。HRMS-ESI-m/z[M-H]-[C15H16O2-H]-The calculated value of (a): 227.1078, found: 227.1078.
reference example 33: 5,8,9, 10-tetrahydro-5, 8:7, 10-di-methanobenzo [8]]Rotalen-7 (6H) -amine hydrochloride And (3) salt.
To 5,8,9, 10-tetrahydro-5, 8:7, 10-di-methanobenzo [8]]Et was added to a solution of rotacene-7 (6H) -carboxylic acid (90mg, 0.39mmol) in toluene (1.2mL)3N (73. mu.L, 0.53mmol) and diphenylphosphorylazide (159mg, 0.58mmol), and heated under reflux for 3 hours. The mixture was cooled and washed with 1N HCl (10X 2 mL). Thereafter, 6N HCl (1.6mL) was added to the organic layer, and the suspension was heated at reflux for 24 hours. The reaction mixture was then cooled to room temperature and the two phases were separated. The aqueous phase was extracted with ethyl acetate (3X 3 mL). The combined organic phases were washed with 5N NaOH (3X 10mL) and over anhydrous Na2SO4Dried, filtered and concentrated under vacuum to give 5,8,9, 10-tetrahydro-5, 8:7, 10-dioxamethylenebenzo [8]]Rotalen-7 (6H) -amine. The hydrochloride salt thereof was obtained by: to the amine in methanol solution was added an excess of methanol containing HCl. Methanol was removed under reduced pressure to obtain 5,8,9, 10-tetrahydro-5, 8:7, 10-dioxamethylenebenzo [8] as a brown solid]Rotalene-7 (6H) -amine hydrochloride (35mg, 45% yield). Analytical samples were obtained by crystallization from methanol/diethyl ether.
mp>250 deg.C (dec). IR (KBr disk): 3100--1。HRMS-ESI+m/z[M+H]+[C14H17N+H]+The calculated value of (a): 200.1434, found: 200.1432.
example 34: (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-di-methanobenzo [9]]Annulene- 7-yl) p-tolyl carbamate.
To 9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-di-methanobenzo [9]]A solution of rotan-7-amine hydrochloride (250mg, 0.95mmol) in DCM (2mL) was added p-tolyl chloroformate (19)4mg, 1.14mmol) and Et3N (287mg, 2.84 mmol). The reaction mixture was stirred at room temperature overnight, and then the solvent was evaporated under vacuum. The residue was dissolved in EtOAc (30mL) and water (20mL) and the phases were separated. The aqueous phase was extracted with additional EtOAc (2X 30 mL). The combined organic phases were passed over anhydrous Na2SO4Dried, filtered and concentrated under vacuum to obtain 300mg of a yellow gum. Column chromatography (SiO)2Hexane/ethyl acetate mixture) to give (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] as a white solid]Rotalen-7-yl) carbamic acid p-tolyl ester (46mg, 14% yield).
mp 114-. IR (NaCl dish): 3330. 3018, 2944, 2919, 2854, 1744, 1591, 1531, 1502, 1452, 1379, 1362, 1345, 1255, 1214, 1198, 1167, 1137, 1069, 1042, 1014, 987, 948, 900, 825, 757cm-1. For C24H27NO2·0.3C5H12·0.05CH2Cl2Analysis calculated value: c79.22, H7.99, N3.62. Measured value: c79.23, H7.88, N3.45.
Example 35: 1- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9]]Wheel En-7-yl) -3- (4- (trifluoromethyl) phenyl) thiourea.
To 9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-di-methanobenzo [9]]A solution of rotalen-7-amine hydrochloride (250mg, 0.95mmol) in DCM (2mL) was added 1-isothiocyanato-4- (trifluoromethyl) benzene (193mg, 0.95mmol) and Et3N (287mg, 2.84 mmol). The reaction mixture was stirred at room temperature overnight, and then the solvent was evaporated under vacuum. The residue was dissolved in EtOAc (30mL) and water (20mL) and the phases were separated. The aqueous phase was extracted with additional EtOAc (2X 30 mL). The combined organic phases were passed over anhydrous Na2SO4Dried, filtered and concentrated under vacuum to give 369mg of a yellow solid. The product is taken up in Et2O washing to obtain 1- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] as a white solid]Rotanen-7-yl) -3- (4- (trifluoromethyl) phenyl) thiourea (188mg, 46% yield).
mp 158-. IR (NaCl dish): 3283. 2911, 2834, 1615, 1532, 1493, 1454, 1422, 1324, 120, 1166, 1124, 1067, 1015, 948, 909, 837, 759, 732, 697, 665cm-1. For C24H25F3N2S, analysis and calculation value: c66.96, H5.85, N6.51. Measured value: c66.79, H5.95, N6.37.
Example 36: 1- (1-acetylpiperidin-4-yl) -3- (5-methyl-1, 5,6, 7-tetrahydro-1, 5:3, 7-methanone Radical benzo [ e ]]Oxacyclononanten-3 (2H) -yl) urea.
To 5-methyl-1, 5,6, 7-tetrahydro-1, 5:3, 7-di-methanobenzo [ e ]]A solution of oxacyclononatetraen-3 (2H) -amine hydrochloride (180mg, 0.69mmol) in DCM (3mL) and saturated aqueous NaHCO3Triphosgene (102mg, 0.34mmol) was added to the solution (2 mL). The biphasic mixture was stirred at room temperature for 30 min, and then the two phases were separated and the organic phase was washed with brine (5mL), over anhydrous Na2SO4Dried, filtered and evaporated under vacuum to obtain 1-2mL of a solution of isocyanate in DCM. To this solution was added 1- (4-aminopiperidin-1-yl) eth-1-one hydrochloride (122mg, 0.68mmol) and Et3N (139mg, 1.37 mmol). The mixture was stirred at room temperature overnight, diluted with additional DCM (10mL), and washed with 2N NaOH solution (2X 10 mL). Subjecting the organic layer to anhydrous Na2SO4Dried, filtered and concentrated in vacuo to afford a yellow residue (206 mg). Column chromatography (SiO)2DCM/methanol mixture) to give 1- (1-acetylpiperidin-4-yl) -3- (5-methyl-1, 5,6, 7-tetrahydro-1, 5:3, 7-dimethanomethylbenzo [ e ] as a white solid]Oxacyclononanten-3 (2H) -yl) urea (135mg, 49% yield). An analytical sample was obtained by crystallization from hot EtOAc (112 mg).
mp 208-. IR (NaCl dish): 3357. 3054, 3012, 2969, 2926, 2853, 1646, 1611, 1546, 1492, 1450, 1358, 1324, 1268, 1222, 1156, 1101, 1088, 1035, 1212, 991, 947, 918, 900, 866, 829, 760, 733, 699cm-1. For C23H31N3O3Analysis calculated value:c69.49, H7.86, N10.57. Measured value: c69.47, H7.92, N10.38.
Example 37: 1- (1-acetylpiperidin-4-yl) -3- (1,5,6, 7-tetrahydro-1, 5:3, 7-methanobenzo [e]Oxacyclononanten-3 (2H) -yl) urea.
To 1,5,6, 7-tetrahydro-1, 5:3, 7-dimethanolbenzo [ e ]]A solution of Oxacyclononantene-3 (2H) -amine hydrochloride (300mg, 1.19mmol) in DCM (7mL) and saturated aqueous NaHCO3Triphosgene (130mg, 0.44mmol) was added to the solution (7 mL). The biphasic mixture was stirred at room temperature for 30 min, and then the two phases were separated and the organic phase was washed with brine (10mL), over anhydrous Na2SO4Dried, filtered and evaporated under vacuum to obtain 1-2mL of a solution of isocyanate in DCM. To this solution was added 1- (4-aminopiperidin-1-yl) eth-1-one hydrochloride (203mg, 1.43mmol) and Et3N (292mg, 2.88 mmol). The mixture was stirred at room temperature overnight, diluted with additional DCM (10mL), and washed with 2N NaOH solution (2X 10 mL). Subjecting the organic layer to anhydrous Na2SO4Dried, filtered and concentrated in vacuo to afford a yellow residue (400 mg). Column chromatography (SiO)2DCM/methanol mixture) to give 1- (1-acetylpiperidin-4-yl) -3- (1,5,6, 7-tetrahydro-1, 5:3, 7-dimethanomenzo [ e ] as a white solid]Oxacyclononanten-3 (2H) -yl) urea (50mg, 49% yield).
mp 200-. IR (NaCl dish): 3347. 3065, 3016, 2922, 1645, 1624, 1548, 1492, 1451, 1436, 1362, 1323, 1268, 1230, 1211, 1196, 1109, 1073, 1022, 980, 967cm-1。HRMS-ESI+m/z[M+H]+[C22H29N3O3+H]+The calculated value of (a): 384.2282, found: 384.2285.
example 38: 1- (1-acetylpiperidin-4-yl) -3- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-bis-methanobenzo [9]]Rotalen-7-yl) urea.
To 5-methyl-1, 5,6, 7-tetrahydro-1, 5:3, 7-di-methanobenzo [ e ]]Oxacyclononatetraen-3 (2H) -amine hydrochloride (180mg,0.69mmol) in DCM (3mL) and saturated aqueous NaHCO3Triphosgene (102mg, 0.34mmol) was added to the solution (2 mL). The biphasic mixture was stirred at room temperature for 30 min, and then the two phases were separated and the organic layer was washed with brine (5mL), over anhydrous Na2SO4Dried, filtered and evaporated under vacuum to obtain 1-2mL of a solution of isocyanate in DCM. To this solution was added 1- (4-aminopiperidin-1-yl) eth-1-one hydrochloride (122mg, 0.68mmol) and Et3N (138mg, 1.36 mmol). The mixture was stirred at room temperature overnight, diluted with additional DCM (10mL), and washed with 2N NaOH solution (2X 10 mL). Subjecting the organic matter to anhydrous Na2SO4Dried, filtered and concentrated in vacuo to afford a yellow oil (232 mg). Column chromatography (SiO)2DCM/methanol mixture) 1- (1-acetylpiperidin-4-yl) -3- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] was obtained as a white solid]Rotalen-7-yl) urea (143mg, 53% yield). Analytical samples were obtained by crystallization from hot EtOAc (113 mg).
mp 206-. IR (NaCl dish): 3359. 3065, 3016, 2938, 2906, 2860, 1644, 1620, 1555, 1493, 1452, 1360, 1344, 1319, 1267, 1228, 1212, 1136, 1090, 1049cm-1. For C24H33N3O20.21 ethyl acetate, analytically calculated: c71.91, H8.45, N10.06. Measured value: c71.73, H8.43, N10.27.
Example 39: 1- (1-acetylpiperidin-4-yl) -3- (9-hydroxy-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-bis-methanobenzo [9]]Rotalen-7-yl) urea.
To a solution of 1- (4-aminopiperidin-1-yl) ethan-1-one (192mg, 1.35mmol) in DCM (4mL) and saturated aqueous NaHCO3Triphosgene (200mg, 0.68mmol) was added to the solution (3 mL). The biphasic mixture was stirred at room temperature for 30 min, and then the two phases were separated and the organic phase was washed with brine (5mL), over anhydrous Na2SO4Dried, filtered and evaporated under vacuum to obtain 1-2mL of a solution of isocyanate in DCM. To this solution was added 9-amino-5, 6,8,9,10, 11-hexahydro-7H-5,9:7, 11-bis-methanobenzo [9]]Rotacene-7-ol hydrochloride (300mg, 1.14mmol) and Et was added3N (228mg, 2.25 mmol). The reaction mixture was stirred at room temperature overnight and the solvent was evaporated under vacuum. Column chromatography (SiO)2DCM/methanol mixture) to give 1- (1- (isopropylsulfonyl) piperidin-4-yl) -3- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] as a grey solid]Rotalen-7-yl) urea (19mg, 4.2% yield).
mp 222-. IR (NaCl dish): 3313. 2921, 2852, 1733, 1716, 1646, 1621, 1557, 1542, 1506, 1490, 1472, 1455, 1358, 1336, 1318, 1300, 1265, 1231, 1204, 1134, 1104, 1053cm-1. For C23H31N3O3·0.2C5H12·0.9H2O, analytical calculation: c67.33, H8.29, N9.81. Measured value: c67.25, H8.15, N9.72.
Example 40: 1- (1-acetylpiperidin-4-yl) -3- (9-methoxy-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-bis-methanobenzo [9]]Rotalen-7-yl) urea.
To 9-methoxy-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-di-methanobenzo [9]]A solution of rotalen-7-amine (300mg, 1.23mmol) in DCM (4.5mL) and saturated aqueous NaHCO3Triphosgene (183mg, 0.61mmol) was added to the solution (3 mL). The biphasic mixture was stirred at room temperature for 30 min, and then the two phases were separated and the organics were washed with brine (5mL), over anhydrous Na2SO4Dried, filtered and evaporated under vacuum to obtain 1-2mL of a solution of isocyanate in DCM. To this solution was added 1- (4-aminopiperidin-1-yl) ethan-1-one (210mg, 1.47 mmol). The reaction mixture was stirred at room temperature overnight, and the solvent was evaporated under vacuum to give a white gum (521 mg). Column chromatography (SiO)2DCM/methanol mixture) 1- (1-acetylpiperidin-4-yl) -3- (9-methoxy-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] was obtained as a white solid]Rotalen-7-yl) urea (148mg, 30% yield). Analytical samples were obtained by crystallization from hot EtOAc (119 mg).
mp 212-213 ℃. IR (NaCl dish): 3358. 2930, 2847, 1646, 1617, 1555, 1495, 1451, 1356, 1319, 1266, 1228, 1094, 1075, 972, 849, 755, 735cm-1. For C24H33N3O30.15EtOAc, calculated analytically: c69.56, H8.12, N9.89. Measured value: c69.63, H8.28, N8.86.
Example 41: 1- (1-acetylpiperidin-4-yl) -3- (9-fluoro-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7,11- Bis-methanobenzo [9]]Rotalen-7-yl) urea.
To 9-fluoro-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-di-methanobenzo [9]]A solution of rotalen-7-amine (143mg, 0.53mmol) in DCM (4mL) and saturated aqueous NaHCO3Triphosgene (78mg, 0.26mmol) was added to the solution (2 mL). The biphasic mixture was stirred at room temperature for 30 min, and then the two phases were separated and the organic layer was washed with brine (5mL), over anhydrous Na2SO4Dried, filtered and evaporated under vacuum to obtain 1-2mL of a solution of isocyanate in DCM. To this solution was added 1- (4-aminopiperidin-1-yl) ethan-1-one (90mg, 0.63 mmol). The reaction mixture was stirred at room temperature overnight, and the solvent was evaporated under vacuum to give a yellow gum (259 mg). Column chromatography (SiO)2DCM/methanol mixture) to give 1- (1-acetylpiperidin-4-yl) -3- (9-fluoro-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9]]Rotalen-7-yl) urea (180mg, 85% yield). Analytical samples were obtained by crystallization from hot DCM (57 mg).
mp 228-. IR (NaCl dish): 3357. 2927, 2856, 1643, 1618, 1553, 1494, 1451, 1358, 1340, 1316, 1267, 1227, 1207, 1134, 1097, 1042, 1004cm-1. For C23H30FN3O2·0.15C5H12·0.62H2O, analytical calculation: c67.59, H7.91, N9.96. Measured value: c67.61, H7.93, N8.94.
Example 42: 1- (1-acetylpiperidin-4-yl) -3- (9-chloro-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7,11- Bis-methanobenzo [9]]Rotalen-7-yl) urea.
To 9-chloro-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-di-methanobenzo [9]]A solution of rotalen-7-amine hydrochloride (150mg, 0.53mmol) in DCM (3mL) was added saturated aqueous NaHCO3Solution (3mL) and triphosgene (58mg, 0.20 mmol). The biphasic mixture was stirred at room temperature for 30 min, and then the two phases were separated and the organic layer was washed with brine (3mL), over anhydrous Na2SO4Dried, filtered and concentrated in vacuo to obtain a solution of 1-2mL of isocyanate in DCM. To this solution was added 1- (4-aminopiperidin-1-yl) ethan-1-one (90mg, 0.63 mmol). The reaction mixture was stirred at room temperature overnight, and the solvent was evaporated under vacuum to obtain a white solid (204 mg). Column chromatography (SiO)2DCM/methanol mixture) 1- (1-acetylpiperidin-4-yl) -3- (9-chloro-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] was obtained as a white solid]Rotalen-7-yl) urea (115mg, 55% yield).
mp 209-. IR (NaCl dish): 3358. 3019, 2926, 2855, 1644, 1619, 1556, 1494, 1452, 1358, 1319, 1301, 1268, 1228, 1206, 1135, 1090, 1050, 991, 969, 947, 802, 761, 735cm-1。HRMS-ESI+m/z[M+H]+[C23H30ClN3O2+H]+The calculated value of (a): 416.2099, found: 416.2100.
example 43: 4- (((1r,4r) -4- (3- (5-methyl-1, 5,6, 7-tetrahydro-1, 5:3, 7-methanobenzo [ b ])) [e]Oxacyclononatetraen-3 (2H) -yl) ureido) cyclohexyl) oxy) benzoic acid.
To 5-methyl-1, 5,6, 7-tetrahydro-1, 5:3, 7-di-methanobenzo [ e ]]A solution of Oxacyclononantene-3 (2H) -amine hydrochloride (200mg, 0.76mmol) in DCM (3.5mL) and saturated aqueous NaHCO3To the solution (2.2mL) was added triphosgene (113mg, 0.38 mmol). The biphasic mixture was stirred at room temperature for 30 min, and then the two phases were separated and the organic layer was washed with brine (5mL), over anhydrous Na2SO4Dried, filtered and evaporated under vacuum to obtain 1-2mL of a solution of isocyanate in DCM. To this solution is added 4- (((s) ((1r,4r) -4-aminocyclohexyl) oxy) benzoic acid hydrochloride (206mg, 0.76mmol) and Et3N (153mg, 1.52 mmol). The mixture was stirred at room temperature overnight. The resulting suspension was evaporated to obtain a white solid, which was suspended in DCM (20mL) and washed with 2N HCl solution (2 × 10 mL). The resulting organic suspension was filtered to obtain a white solid (200mg, 54% yield).
mp: 220 ℃ and 222 ℃. IR (NaCl dish): 3352. 2626, 1678, 1601, 1558, 1506, 1454, 1373, 1343, 1312, 1288, 1247, 1221, 1161, 1104, 1029, 997, 953, 776cm-1。HRMS-ESI+m/z[M+H]+[C29H34N2O5+H]+The calculated value of (a): 491.254, found: 491.254.
example 44: 4- (((1r,4r) -4- (3- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dioxa-ylidene) Methylbenzo [9]]Annulen-7-yl) ureido) cyclohexyl) oxy) benzoic acid.
To 5-methyl-1, 5,6, 7-tetrahydro-1, 5:3, 7-di-methanobenzo [ e ]]A solution of oxacyclononatetraen-3 (2H) -amine hydrochloride (180mg, 0.69mmol) in DCM (3mL) and saturated aqueous NaHCO3Triphosgene (102mg, 0.34mmol) was added to the solution (2 mL). The biphasic mixture was stirred at room temperature for 30 min, and then the two phases were separated and the organic layer was washed with brine (5mL), over anhydrous Na2SO4Dried, filtered and evaporated under vacuum to obtain 1-2mL of a solution of isocyanate in DCM. To this solution was added 4- (((1r,4r) -4-aminocyclohexyl) oxy) benzoic acid hydrochloride (206mg, 0.76mmol) and Et3N (153mg, 1.52 mmol). The mixture was stirred at room temperature overnight. The resulting suspension was evaporated and the residue was suspended in DCM (20mL) and washed with 2N HCl solution (2 × 10 mL). The resulting organic suspension was filtered, and the filtrate was taken over anhydrous Na2SO4Dried, filtered and concentrated under vacuum to obtain a white gum. Crystallization from hot EtOAc afforded 4- (((1r,4r) -4- (3- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-di-methanobenzo [9] methyl) benzene as a white solid]Rotalen-7-yl) ureido) cyclohexyl) oxy) benzoic acid (55mg, 16% yield).
mp 182-. IR (NaCl dish): 3335. 2921, 2855, 1692, 1681, 1642, 1632, 1602, 1564, 1537, 1504, 1494, 1469, 1453, 1419, 1360, 1307, 1248, 1163, 1122, 1096, 1969cm-1. For C30H36N2O4·1,5H2O, analytical calculation: c69.88, H7.62, N5.43. Measured value: c69.53, H7.37, N5.10.
Reference example 45: [1- (isopropylsulfonyl) piperidin-4-yl](iii) carbamic acid tert-butyl ester.
To a solution of tert-butyl (piperidin-4-yl) carbamate (850mg, 4.24mmol) in DCM (7mL) was added Et3N (858mg, 8.48 mmol). The mixture was cooled to 0 ℃ with an ice bath and then propane-2-sulfonyl chloride (725mg, 5.09mmol) was added dropwise. The reaction mixture was stirred at room temperature overnight. The suspension was washed with 2N NaOH solution (2X 5mL) and the organic phase was washed with anhydrous Na2SO4Dried, filtered and concentrated in vacuo to give [1- (isopropylsulfonyl) piperidin-4-yl]Tert-butyl carbamate (1.15g, 89% yield).
Reference example 46: 1- (isopropylsulfonyl) piperidin-4-amine.
To a solution of tert-butyl (1- (isopropylsulfonyl) piperidin-4-yl) carbamate (1.15g, 3.75mmol) dissolved in DCM (5mL) was added 1, 4-dioxane (2mL) containing 4M HCl. The mixture was stirred at room temperature for 2 days, and the solvent was evaporated under vacuum. The residue was then dissolved in DCM (5mL) and washed with 5N NaOH solution (5 mL). Subjecting the organic layer to anhydrous Na2SO4Dried, filtered and concentrated in vacuo to afford 1- (isopropylsulfonyl) piperidin-4-amine as a yellow oil (704mg, 91% yield).
Example 47: 1- [1- (isopropylsulfonyl) piperidin-4-yl]-3- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H- 5,9:7, 11-bis-methanobenzo [9]]Rotalen-7-yl) urea.
To 5-methyl-1, 5,6, 7-tetrahydro-1, 5:3, 7-di-methanobenzo [ e ]]Oxacyclononantene-3 (2H) -amine hydrochloride (3)00mg, 1.13mmol) in DCM (6mL) and saturated aqueous NaHCO3Triphosgene (169mg, 0.57mmol) was added to the solution (4 mL). The biphasic mixture was stirred at room temperature for 30 min, and then the two phases were separated and the organic layer was washed with brine (5mL), over anhydrous Na2SO4Dried, filtered and evaporated under vacuum to obtain 1-2mL of a solution of isocyanate in DCM.
To a solution of 1- (isopropylsulfonyl) piperidin-4-amine (233mg, 1.13mmol) in anhydrous THF (5mL) at-78 deg.C under an argon atmosphere was added dropwise a solution of n-butyllithium (2.5M in hexane, 0.59mL, 1.47mmol) over a period of 20 minutes. After addition, the mixture was tempered to 0 ℃ using an ice bath. This solution was carefully added to a solution of the isocyanate from the previous step cooled to 0 ℃ under an argon atmosphere. The reaction mixture was stirred at room temperature overnight. Methanol (2mL) was then added to quench any unreacted n-butyllithium. The solvent was evaporated under vacuum to give an orange gum (506 mg). This residue was dissolved in EtOAc (10mL) and washed with 2N HCl solution (2X 5mL), and the organic layer was washed with anhydrous Na2SO4Dried, filtered and concentrated under vacuum to give a white gum (241 mg). Column chromatography (SiO)2DCM/methanol mixture) obtained a white solid. Crystallization from hot DCM/pentane gave pure 1- (1- (isopropylsulfonyl) piperidin-4-yl) -3- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] m-tylenebenzo [9] as a white solid]Rotalen-7-yl) urea (66mg, 13% yield).
mp 218-219 ℃. IR (NaCl dish): 3364. 3061, 3012, 2945, 2919, 2853, 1709, 1638, 1553, 1493, 1453, 1360, 1319, 1305, 1265, 1248, 1232, 1133, 1091, 1045, 943, 880, 841, 759, 732, 665, 592, 555cm-1. For C25H37N3O3S, analysis and calculation value: c65.33, H8.11, N9.14. Measured value: c65.41, H8.31, N8.93.
Example 48: 1- (1-Benzylpiperidin-4-yl) -3- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7,11- Bis-methanobenzo [9]]Rotalen-7-yl) urea.
To 5-methyl-1, 5,6, 7-tetrahydro-1, 5:3, 7-di-methanobenzo [ e ]]A solution of Oxacyclononantene-3 (2H) -amine hydrochloride (250mg, 0.95mmol) in DCM (4.5mL) and saturated aqueous NaHCO3Triphosgene (140mg, 0.47mmol) was added to the solution (3 mL). The biphasic mixture was stirred at room temperature for 30 min, and then the two phases were separated and the organic layer was washed with brine (5mL), over anhydrous Na2SO4Dried, filtered and evaporated under vacuum to obtain 1-2mL of a solution of isocyanate in DCM. To this solution was added 1- (4-aminopiperidin-1-yl) ethan-1-one (216mg, 1.13 mmol). The reaction mixture was stirred at room temperature for 24 hours and the solvent was evaporated under vacuum to obtain a yellow gum. Column chromatography (SiO)2DCM/methanol mixture) the title compound was obtained as a white solid (159mg, 36% yield).
mp 106-. IR (NaCl dish): 3318. 3058, 3025, 2945, 2918, 2838, 2792, 2761, 1632, 1559, 1493, 1453, 1361, 1343, 1321, 1302, 1281, 1234, 1209, 1136, 1120, 1066, 1028, 909, 757, 733, 698cm-1. For C29H37N3O · 0.5 methanol, analytically calculated: c77.09, H8.55, N9.14. Measured value: c77.19, H8.36, N8.98.
Reference example 49: n- (2-acetyl-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dicarbamethylenes Radical benzo [9]]Rotalen-7-yl) -2-chloroacetamide.
To 2-chloro-N- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-di-methanobenzo [9]]A solution of rotalen-7-yl) acetamide (2.0g, 6.58mmol) in DCM (50mL) was added acetyl chloride (5.16g, 65.8 mmol). Then, using AlCl3(4.38g, 32.9mmol) and the resulting orange mixture was stirred at room temperature for 1 hour. This solution was poured onto ice (50g) and saturated aqueous NaHCO was added3Solution (40 mL). After stirring for 20 min, the mixture was extracted with DCM (3X 50mL) and the combined organic phases were purified over anhydrous Na2SO4Dried, filtered and concentrated under vacuum to give a green gum (1.85 g). Column chromatography (SiO)2Hexane/acetic acidEthyl ester mixture) to obtain N- (2-acetyl-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] as a pale yellow solid]Rotalen-7-yl) -2-chloroacetamide (1.27g, 56% yield).
Reference example 50: 1- (7-amino-9-methyl-6, 7,8,9,10, 11-hexahydro-5H-5, 9:7, 11-methano-bis (methylene) s Benzo [9]]Rotalen-2-yl) eth-1-one hydrochloride.
N- (2-acetyl-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-di-methanobenzo [9]]A mixture of rotalen-7-yl) -2-chloroacetamide (1.18g, 3.43mmol), thiourea (313mg, 4.12mmol), acetic acid (1.3mL) and ethanol (6mL) was stirred at reflux overnight. The mixture was tempered to room temperature and water (40mL) and 10N NaOH solution (14mL) were added. The mixture was extracted with EtOAc (3X 50mL) and the combined organic extracts were taken over anhydrous Na2SO4Dried, filtered and concentrated in vacuo to give a yellow residue (980mg) which was dissolved in EtOAc (5mL) and added excess HCl/Et2And O. The resulting suspension was filtered to obtain a beige solid. This product was dissolved in DCM (50mL) and washed with 5N NaOH solution (40 mL). Subjecting the organic layer to anhydrous Na2SO4Dried, filtered and concentrated in vacuo to give a yellow residue, which was dissolved in EtOAc (5mL) and added excess HCl/Et2And O. The resulting suspension was filtered to obtain 1- (7-amino-9-methyl-6, 7,8,9,10, 11-hexahydro-5H-5, 9:7, 11-dimethano-9-methylbenzo [9] as a beige solid]Rotalen-2-yl) ethan-1-one as its hydrochloride salt (758mg, 73% yield).
Example 51: 1- (2-acetyl-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-di (methano) benzene And [9]]Rotalen-7-yl) -3- (1-acetylpiperidin-4-yl) urea.
To 1- (7-amino-9-methyl-6, 7,8,9,10, 11-hexahydro-5H-5, 9:7, 11-di-methanobenzo [9]]Solution of rotalen-2-yl) eth-1-one hydrochloride (300mg, 0.98mmol) in DCM (5mL) and saturated aqueous NaHCO3To the solution (3.52mL) was added triphosgene (145mg, 0.49 mmol). Stirring the two-phase mixture at room temperatureStirred for 30 min, and then the two phases were separated and the organic layer was washed with brine (5mL), over anhydrous Na2SO4Dried, filtered and evaporated under vacuum to obtain 1-2mL of a solution of isocyanate in DCM. To this solution was added 1- (4-aminopiperidin-1-yl) ethan-1-one (167mg, 1.17 mmol). The reaction mixture was stirred at room temperature overnight, and the solvent was evaporated under vacuum to give a yellow gum (483 mg). Column chromatography (SiO)2DCM/methanol mixture) to obtain 1- (2-acetyl-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9]]Rotanen-7-yl) -3- (1-acetylpiperidin-4-yl) urea (324mg, 76% yield).
mp 144-145 ℃. IR (NaCl dish): 3363. 3005, 2918, 2861, 2239, 1679, 1619, 1552, 1453, 1426, 1361, 1320, 1272, 1229, 1203, 1137, 1106, 1057, 973, 950, 917, 830, 731, 645cm-1. For C26H35N3O3·0.15C5H12·0.6C3H6O, analytical calculation: c70.96, H8.43, N8.70. Measured value: c70.83, H8.60, N8.88.
Example 52: 1- (1-acetylpiperidin-4-yl) -3- (9-methyl-2-nitro-5, 6,8,9,10, 11-hexahydro-7H- 5,9:7, 11-bis-methanobenzo [9]]Rotalen-7-yl) urea.
To 9-methyl-2-nitro-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-di-methanobenzo [9]]A solution of rotalen-7-amine hydrochloride (600mg, 1.94mmol) in DCM (10mL) was added saturated aqueous NaHCO3Solution (10mL) and triphosgene (213mg, 0.718 mmol). The biphasic mixture was stirred at room temperature for 30 min, and then the two phases were separated and the organic layer was washed with brine (5mL), over anhydrous Na2SO4Dried, filtered and evaporated under vacuum to obtain 1-2mL of a solution of isocyanate in DCM. To this solution was added 1- (4-aminopiperidin-1-yl) ethan-1-one (331mg, 2.33 mmol). The reaction mixture was stirred at room temperature overnight, and the solvent was evaporated under vacuum to give a brown solid (840 mg). Column chromatography (SiO)2DCM/methanol mixture) to give 1- (1-acetyl) as a pale yellow solidArylpiperidin-4-yl) -3- (9-methyl-2-nitro-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9]]Rotalen-7-yl) urea (640mg, 75% yield).
mp 155-. IR (NaCl dish): 3360. 2918, 2237, 1619, 1552, 1522, 1454, 1345, 1322, 1266, 1230, 1164, 1137, 1081, 974, 949, 911, 865, 838, 798, 761, 731, 644cm-1. For C24H32N4O4Analysis calculated value: c65.43, H7.32, N12.72. Measured value: c65.22, H7.45, N12.56.
Example 53: 1- (1-acetylpiperidin-4-yl) -3- (2-amino-9-methyl-5, 6,8,9,10, 11-hexahydro-7H- 5,9:7, 11-bis-methanobenzo [9]]Rotalen-7-yl) urea.
To 1- (1-acetylpiperidin-4-yl) -3- (9-methyl-2-nitro-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9]]Addition of PtO to a solution of rotalen-7-yl urea (260mg, 0.59mmol) in EtOH (17ml)2(20 mg). The mixture was hydrogenated at room temperature and atmospheric pressure for 8 days. The resulting suspension was filtered and the filtrate was evaporated in vacuo to give a dark brown solid (223mg) which was dissolved in DCM (10 mL). Et was added to this solution2O, and a white solid (140mg) precipitated. Column chromatography (SiO)2DCM/methanol mixture) obtained as a white solid (82mg, 34% yield).
mp 150-. IR (NaCl dish): 3344. 3006, 2905, 2853, 1614, 1556, 1505, 1454, 1360, 1344, 1320, 1303, 1266, 1229, 1194, 1162, 1136, 1060, 974, 868, 820, 734cm-1。HRMS-ESI+m/z[M+H]+[C24H34N4O2+H]+The calculated value of (a): 411.2755, found: 411.2756.
example 54: 4- (2- ((9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-di-methanobenzo [9]] Rotalen-7-yl) amino) -2-oxyethyl) piperidine-1-carboxylic acid tert-butyl ester.
To 9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-di-methanobenzo [9]]Rotalene-7-aminesSuspension of hydrochloride salt (500mg, 1.89mmol) in EtOAc (5mL) was added 2- (1- (tert-butoxycarbonyl) piperidin-4-yl) acetic acid (461mg, 1.89mmol), HOBt (384mg, 2.84mmol), EDC & HCl (440mg, 2.84mmol) and Et3N (767mg, 7.58 mmol). The mixture was stirred at room temperature for 24 hours. Water (10mL) and DCM (20mL) were added to the resulting suspension and the two phases were separated. The organic phase was washed with saturated aqueous NaHCO3The solution (1X 10mL), brine (1X 10mL), 2N HCl solution (1X 10mL), and 2N NaOH (1X 10mL) were washed and dried over anhydrous Na2SO4Dried, filtered and concentrated in vacuo to afford a yellow solid (515mg, 60% yield).
1H-NMR(400MHz,CDCl3) δ:0.92(s,3H),1.11(dq, J ═ 4.4Hz, J' ═ 11.6Hz,2H),1.4(s,9H),1.54(d, J ═ 13.6Hz,2H),1.63-1.68 (complex signal, 4H),1.84(s,2H),1.91(m,1H),1.97(s,2H),2.0(d, J ═ 12.8Hz,2H),2.14-2.18 (complex signal, 2H),2.69(t, J ═ 13.2Hz,2H),3.06(t, J ═ 6Hz,2H),4.06 (wide signal, 2H),5.14(s,1H),7.02-7.08 (complex signal, 4H).
Example 55: n- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9]]Wheel En-7-yl) -2- (piperidin-4-yl) acetamide.
To 4- (2- ((9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-di-methanobenzo [9]]Rotalen-7-yl) amino) -2-oxyethyl) piperidine-1-carboxylic acid tert-butyl ester (250mg, 0.55mmol) in DCM (4mL) was added 4M HCl in 1, 4-dioxane (0.5 mL). The reaction mixture was stirred at room temperature for 3 days. The solvent was then evaporated in vacuo and the residue was dissolved in DCM (10mL) and washed with 5N NaOH solution, over anhydrous Na2SO4Dried, filtered and concentrated in vacuo to afford a yellow solid (189mg, 97% yield).
1H-NMR(400MHz,CDCl3) δ:0.91(s,3H),1.12(dq, J ═ 4Hz, J ═ 12.0Hz,2H),1.53(d, J ═ 13.2Hz,2H),1.62 to 1.71 (complex signal, 4H),1.84(s,2H),1.88(m,1H),1.95 to 2.01 (complex signal, 4H),2.14 to 2.19 (complex signal, 2H),2.6(dt, J ═ 2.8Hz, J ═ 12.0Hz,2H),3.00 to 3.07 (complex signal, 4H),5.15(s,1H),7.02 to 7.09 (complex signal, 4H).
Example 56: 2- [1- (isopropylsulfonyl) piperidin-4-yl]-N- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H- 5,9:7, 11-bis-methanobenzo [9]]Rotalen-7-yl) acetamide.
To N- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-di-methanobenzo [9]]A solution of rotalen-7-yl) -2- (piperidin-4-yl) acetamide (185mg, 0.52mmol) in DCM (5mL) was added Et3N (63mg, 0.63 mmol). The mixture was cooled to 0 ℃ and propane-2-sulfonyl chloride (74mg, 0.52mmol) was added dropwise. The reaction mixture was then stirred at room temperature overnight and quenched by the addition of 2N HCl solution (3 mL). The two phases were separated and the aqueous phase was extracted with EtOAc (2X 20 mL). The combined organic phases were washed with 5N NaOH solution and over anhydrous Na2SO4Dried, filtered and concentrated under vacuum to give a yellow solid. Column chromatography (SiO)2Hexane/ethyl acetate mixture) to yield a white solid (145mg, 60% yield). Analytical samples were obtained by crystallization from hot EtOAc (76 mg).
mp 172-. IR (NaCl dish): 3365. 3319, 3058, 3017, 2916, 2852, 1648, 1536, 1493, 1451, 1361, 1322, 1308, 1264, 1167, 1137, 1044, 1011, 993, 944, 904, 880, 800, 758, 731, 701, 665cm-1. For C26H38N2O3S · 0.25 methanol, analytically calculated: c67.56, H8.42, N6.00. Measured value: c67.75, H8.62, N5.74.
Example 57: 2- (1-acetylpiperidin-4-yl) -N- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-bis-methanobenzo [9]]Rotalen-7-yl) acetamide.
To N- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-di-methanobenzo [9] under argon atmosphere]A solution of rotalen-7-yl) -2- (piperidin-4-yl) acetamide (200mg, 0.57mmol) in anhydrous DCM (5mL) was added anhydrous Et3N (69mg, 0.68 mmol). The mixture was cooled to 0 ℃ and acetyl chloride (45mg, 0.57mmol) was added dropwise. The reaction mixture was then stirred at room temperature overnight and quenched by the addition of 2N HCl solution (3 mL). Separating the two phasesThe aqueous layer was separated and extracted with EtOAc (2X 20 mL). The combined organic phases were washed with 2N NaOH solution and over anhydrous Na2SO4Dried, filtered and concentrated under vacuum. Column chromatography (SiO)2Hexane/ethyl acetate mixture) to yield a white solid (134mg, 48% yield).
mp 85-86 ℃. IR (NaCl dish): 3314. 3060, 3016, 2915, 2859, 2239, 1630, 1544, 1492, 1450, 1361, 1303, 1273, 1196, 1164, 1137, 1096, 1048cm-1. For C25H34N2O20.15DCM, analytically calculated: c74.17, H8.49, N6.88. Measured value: c74.31, H8.73, N6.72.
Example 58: 1- (9-methyl-6, 7,8,9,10, 11-hexahydro-5H-5, 9:7, 11-dimethano-benzo [9]]Wheel En-7-yl) -3- (2,3, 4-trifluorophenyl) urea.
To 5-methyl-1, 5,6, 7-tetrahydro-1, 5:3, 7-di-methanobenzo [ e ]]A solution of oxacyclononatetraen-3 (2H) -amine (273mg, 1.2mmol) in anhydrous DCM (10mL) was added 2,3, 4-trifluorophenylisocyanate (147mg, 1.0mmol) and triethylamine (0.55mg, 4 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was then removed under vacuum. Subjecting the crude product to column chromatography (SiO)2Hexane/ethyl acetate mixture) and the appropriate fractions were concentrated under vacuum to give urea as a white solid (38mg, 13% yield).
mp 206-207℃。IR(ATR)：3331、2903、2839、1654、1556、1510、1473、1361、1344、1290、1237、1174、1101、1038、1019、1004、800、756、690、669、625cm-1. For C23H23F3N2O, analytical calculation: c68.99, H5.79, N7.00. Measured value: c68.94, H5.92, N6.71.
Example 59: 1- (5-methyl-1, 5,6, 7-tetrahydro-1, 5:3, 7-dimethano-robenzo [ e ]]Oxacyclononatetraene-3 (2H) -yl) -3- (2,3, 4-trifluorophenyl) urea.
To a solution of 5-methyl-1, 5,6, 7-tetrahydro-1, 5:3, 7-dimethanembenzo [ e ] oxazeonotetraen-3 (2H) -amine (275mg, 1.2mmol) in anhydrous DCM (10mL) were added 2,3, 4-trifluorophenylisocyanate (147mg, 1.0mmol) and triethylamine (0.55mg, 4 mmol). The reaction mixture was stirred at room temperature overnight. The solvent was then removed under vacuum. The desired urea was obtained as a white solid (205mg, 54% yield).
mp 257-259℃。IR(ATR)：3295、3241、3118、2916、2173、1693、1620、1564、1510、1493、1468、1462、1356、1345、1320、1302、1286、1273、1254、1229、1210、1181、1167、1111、1091、1074、1049、1035、1008、999、958、906、820、812、763、646cm-1. For C22H21F3N2O2·0.1H2O, analytical calculation: c65.37, H5.29, N6.93. Measured value: c65.18, H5.31, N6.73. HRMS-ESI + M/z [ M + H ]]+[C22H21F3N2O2+H]+The calculated value of (a): 403.1633, found: 403.1631.
example 60: 2- (1-Benzylpiperidin-4-yl) -N- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7,11- Bis-methanobenzo [9]]Rotalen-7-yl) acetamide.
To 9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-di-methanobenzo [9]]Suspension of rotalen-7-amine hydrochloride (250mg, 0.95mmol) in EtOAc (5mL) was added 2- (1-benzylpiperidin-4-yl) acetic acid hydrochloride (255mg, 0.95mmol), HOBt (192mg, 1.42mmol), EDC & HCl (220mg, 1.42mmol) and Et3N (480mg, 4.74 mmol). The mixture was stirred at room temperature for 24 hours. Water (10mL) and DCM (10mL) were added to the resulting suspension and the two phases were separated. The organic phase was washed with saturated aqueous NaHCO3The solution (1X 10mL), brine (1X 10mL) was washed with anhydrous Na2SO4Dried, filtered and concentrated under vacuum to give a yellow gum (479 mg). Column chromatography (SiO)2DCM/methanol mixture) obtained as a white solid (280mg, 67% yield). By stripping from hot EtOAc and Et2O (124mg) was crystallized to obtain an analytical sample.
mp 145-146 ℃. IR (NaCl dish): 3302. 3060, 3024, 2917, 2841, 2798, 2755, 1641, 1544、1493、1452、1361、1342、1309、1279、1211、1184、1143、1077、1008、974、943、916、794、756、737、697cm-1。HRMS-ESI+m/z[M+H]+[C30H38N2O+H]+The calculated value of (a): 443.3057, found: 443.3061.
reference example 61: (1-Propoylpiperidin-4-yl) carbamic acid tert-butyl ester.
To a solution of piperidin-4-ylcarbamic acid tert-butyl ester (500mg, 2.49mmol) in anhydrous THF (5mL) was added Et3N (252mg, 2.49 mmol). The mixture was cooled to 0 ℃ with an ice bath and propionyl chloride (230mg, 2.49mmol) was then added dropwise. The reaction mixture was stirred at room temperature for 2 hours. The suspension was filtered, and the filtrate was evaporated to obtain carbamate as a pale yellow solid (661mg, quantitative yield).
Reference example 62: 1- (4-aminopiperidin-1-yl) propan-1-one.
To a solution of tert-butyl (1-propionylpiperidin-4-yl) carbamate (660g, 2.57mmol) in DCM (3mL) was added 1, 4-dioxane (2mL) containing 4M HCl. The mixture was stirred at room temperature overnight and the solvent was evaporated under vacuum. The residue was then dissolved in DCM (5mL) and washed with 5N NaOH solution (5 mL). Subjecting the organic layer to anhydrous Na2SO4Dried, filtered and concentrated in vacuo to give 1- (4-aminopiperidin-1-yl) propan-1-one (335mg, 83% yield) as a yellow oil.
Example 63: 1- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9]]Wheel En-7-yl) -3- (1-propionylpiperidin-4-yl) urea.
To 9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-di-methanobenzo [9]]A solution of rotalen-7-amine hydrochloride (464mg, 1.76mmol) in DCM (10mL) was added saturated aqueous NaHCO3Solution (10mL) and triphosgene (193mg, 0.65 mmol). The biphasic mixture was stirred at room temperature for 30 min, and then the two phases were separated and the organic layer was washed with brine (5mL), over anhydrous Na2SO4Drying and filteringAnd evaporated under vacuum to obtain a solution of 1-2mL of isocyanate in DCM. To this solution was added 1- (4-aminopiperidin-1-yl) propan-1-one (350mg, 2.11 mmol). The reaction mixture was stirred at room temperature overnight, and the solvent was evaporated under vacuum to obtain a white solid (741 mg). Column chromatography (SiO)2DCM/methanol mixture) 1- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] was obtained as a white solid]Rotanen-7-yl) -3- (1-propionylpiperidin-4-yl) urea (597mg, 83% yield). Analytical samples were obtained by crystallization from hot EtOAc and DCM (300 mg).
mp 207-. IR (NaCl dish): 3357. 2917, 2858, 1644, 1620, 1555, 1493, 1449, 1360, 1344, 1318, 1263, 1221, 1131, 1067, 1023, 971, 948, 758cm-1. For C25H35N3O20.15EtOAc, calculated analytically: c72.73, H8.63, N9.94. Measured value: c72.65, H8.49, N9.82.
Example 64: 1- (1- (4-acetylphenyl) piperidin-4-yl) -3- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H- 5,9:7, 11-bis-methanobenzo [9]]Rotalen-7-yl) urea.
To 9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-di-methanobenzo [9]]A solution of rotalen-7-amine hydrochloride (241mg, 0.95mmol) in DCM (5mL) was added saturated aqueous NaHCO3Solution (5mL) and triphosgene (104mg, 0.35 mmol). The biphasic mixture was stirred at room temperature for 30 min, and then the two phases were separated and the organic layer was washed with brine (5mL), over anhydrous Na2SO4Dried, filtered and evaporated under vacuum to obtain 1-2mL of a solution of isocyanate in DCM. To this solution was added 1- (4- (4-aminopiperidin-1-yl) phenyl) ethan-1-one (250mg, 1.15mmol, prepared according to the procedure reported in WO 2007016496). The reaction mixture was stirred at room temperature overnight, and the solvent was evaporated under vacuum to give an orange solid (475 mg). Column chromatography (SiO)2Hexane/ethyl acetate mixture) to give 1- (1- (4-aminopiperidine) piperidin-4-yl) -3- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] as a pale yellow solid]Rotalen-7-yl) urea (120mg, 27% yield).
mp 211 and 212 ℃. IR (NaCl dish): 3357. 2919, 2844, 1666, 1633, 1596, 1552, 1518, 1493, 1452, 1427, 1389, 1359, 1306, 1281, 1224, 1193, 1128, 1068, 956, 915, 825, 758cm-1。HRMS-ESI+m/z[M+H]+[C30H37N3O2+H]+The calculated value of (a): 472.2959, found: 472.2962.
example 65: 1- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9]]Wheel En-7-yl) -3- (1- (tetrahydro-2H-pyran-4-carbonyl) piperidin-4-yl) urea.
To 9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-di-methanobenzo [9]]A solution of rotalen-7-amine hydrochloride (258mg, 0.98mmol) in DCM (4mL) was added saturated aqueous NaHCO3Solution (4mL) and triphosgene (107mg, 0.36 mmol). The biphasic mixture was stirred at room temperature for 30 min, and then the two phases were separated and the organic layer was washed with brine (2mL), over anhydrous Na2SO4Dried, filtered and evaporated under vacuum to obtain 1-2mL of a solution of isocyanate in DCM. To this solution was added (4-aminopiperidin-1-yl) (tetrahydro-2H-pyran-4-yl) methanone (215mg, 1.10 mmol). The reaction mixture was stirred at room temperature overnight, and the solvent was evaporated under vacuum to give a yellow residue (534 mg). Column chromatography (SiO)2DCM/methanol mixture) 1- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] was obtained as a white solid]Rotanen-7-yl) -3- (1- (tetrahydro-2H-pyran-4-carbonyl) piperidin-4-yl) urea (207mg, 45% yield).
mp 224-. IR (NaCl dish): 3356. 3064, 2945, 2919, 2850, 1639, 1613, 1552, 1493, 1446, 1360, 1344, 1320, 1278, 1261, 1238, 1211, 1126, 1089, 1068, 1018, 983, 941, 874, 818, 758, 733cm-1。HRMS-ESI+m/z[M+H]+[C28H39N3O3+H]+The calculated value of (a): 466.3064, found: 466.3065.
example 66: 1- (1- (2-fluorobenzoyl) piperidin-4-yl) -3- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H- 5,9:7, 11-bis-methanobenzo [9]]Rotalen-7-yl) urea.
To 9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-di-methanobenzo [9]]A solution of rotalen-7-amine hydrochloride (247mg, 0.93mmol) in DCM (4mL) was added saturated aqueous NaHCO3Solution (4mL) and triphosgene (103mg, 0.36 mmol). The biphasic mixture was stirred at room temperature for 30 min, and then the two phases were separated and the organic layer was washed with brine (3mL), over anhydrous Na2SO4Dried, filtered and evaporated under vacuum to obtain 1-2mL of a solution of isocyanate in DCM. To this solution was added (4-aminopiperidin-1-yl) (2-fluorophenyl) methanone (250mg, 1.12 mmol). The reaction mixture was stirred at room temperature overnight, and the solvent was evaporated under vacuum to obtain a white solid (486 mg). Column chromatography (SiO)2DCM/methanol mixture) 1- (1- (2-fluorobenzoyl) piperidin-4-yl) -3- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] m]Rotalen-7-yl) urea (285mg, 45% yield).
mp 265 and 266 ℃. IR (NaCl dish): 3368. 2920, 2854, 1614, 1549, 1492, 1452, 1364, 1318, 1282, 1222, 1122, 1089, 1029, 974, 948, 817, 755cm-1。HRMS-ESI+m/z[M+H]+[C29H34FN3O2+H]+The calculated value of (a): 476.2708, found: 476.2711.
example 67: 1- ((1R,3S,5S) -8-benzyl-8-azabicyclo [ 3.2.1)]Oct-3-yl) -3- (9-methyl-5, 6, 8,9,10, 11-hexahydro-7H-5, 9:7, 11-di-methanobenzo [9]]Rotalen-7-yl) urea.
To 9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-di-methanobenzo [9]]A solution of rotalen-7-amine hydrochloride (253mg, 0.96mmol) in DCM (4mL) was added saturated aqueous NaHCO3Solution (4mL) and triphosgene (105mg, 0.35 mmol). The biphasic mixture was stirred at room temperature for 30 minutes, and then the two phases were separated and the organic layer was washed with brine (3mL), anhydrousNa2SO4Dried, filtered and evaporated under vacuum to obtain 1-2mL of a solution of isocyanate in DCM. To this solution was added (1R,3S,5S) -8-benzyl-8-azabicyclo [ 3.2.1%]Oct-3-amine (250mg, 1.15 mmol). The reaction mixture was stirred at room temperature overnight and the solvent was evaporated under vacuum to give a yellow gum (498 mg). Column chromatography (SiO)2DCM/methanol mixture) 1- ((1R,3S,5S) -8-benzyl-8-azabicyclo [ 3.2.1) as a white solid was obtained]Oct-3-yl) -3- (9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-di-methanobenzo [9]]Rotalen-7-yl) urea (293mg, 65% yield). By mixing EtOAc: Et from heat2The analytical sample was obtained by crystallization from O (187 mg).
mp 100-. IR (NaCl dish): 3319. 3022, 2944, 2919, 2843, 1632, 1557, 1493, 1452, 1344, 1321, 1304, 1279, 1263, 1235, 1164, 1122, 1056, 1027, 756, 729, 696cm-1。HRMS-ESI+m/z[M+H]+[C31H39N3O+H]+The calculated value of (a): 470.3166, found: 470.3168.
example 68: 1- (1-acetylpiperidin-4-yl) -3- (2-fluoro-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-bis-methanobenzo [9]]Rotalen-7-yl) urea.
To 2-fluoro-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-di-methanobenzo [9]]A solution of rotalen-7-amine hydrochloride (150mg, 0.53mmol) in DCM (3mL) was added saturated aqueous NaHCO3Solution (3mL) and triphosgene (59mg, 0.20 mmol). The biphasic mixture was stirred at room temperature for 30 min, and then the two phases were separated and the organic layer was washed with brine (3mL), over anhydrous Na2SO4Dried, filtered and evaporated under vacuum to obtain 1-2mL of a solution of isocyanate in DCM. To this solution was added 1- (4-aminopiperidin-1-yl) ethan-1-one (91mg, 0.64 mmol). The reaction mixture was stirred at room temperature overnight, and the solvent was evaporated under vacuum to give a pale yellow oil (165 mg). Column chromatography (SiO)2DCM/methanol mixture) 1- (1-acetylpiperidin-4-yl) -3- (2-fluoro-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5,9:7, 11-bis-methanobenzo [9]]Rotalen-7-yl) urea (103mg, 49% yield).
mp 269-270 ℃. IR (NaCl dish): 3357. 2919, 2856, 1644, 1620, 1555, 1499, 1453, 1361, 1342, 1320, 1228, 1153, 1138, 1064, 967, 863, 818cm-1。HRMS-ESI+m/z[M+H]+[C24H32FN3O2+H]+The calculated value of (a): 414.2551, found: 414.2553.
example 69: 1- (1-acetylpiperidin-4-yl) -3- (2-methoxy-9-methyl-5, 6,8,9,10, 11-hexahydro- 7H-5,9:7, 11-bis-methanobenzo [9]]Rotalen-7-yl) urea.
To 2-methoxy-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-di-methanobenzo [9]]A solution of rotalen-7-amine hydrochloride (150mg, 0.51mmol) in DCM (3mL) was added saturated aqueous NaHCO3Solution (3mL) and triphosgene (56mg, 0.19 mmol). The biphasic mixture was stirred at room temperature for 30 min, and then the two phases were separated and the organic layer was washed with brine (3mL), over anhydrous Na2SO4Dried, filtered and evaporated under vacuum to obtain 1-2mL of a solution of isocyanate in DCM. To this solution was added 1- (4-aminopiperidin-1-yl) ethan-1-one (87mg, 0.61 mmol). The reaction mixture was stirred at room temperature overnight, and the solvent was evaporated under vacuum to give a brown oil (256 mg). Column chromatography (SiO)2DCM/methanol mixture) 1- (1-acetylpiperidin-4-yl) -3- (2-methoxy-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] was obtained as a white solid]Rotalen-7-yl) urea (121mg, 56% yield).
mp 116-. IR (NaCl dish): 3359. 2905, 2861, 1644, 1619, 1551, 1501, 1452, 1360, 1343, 1319, 1267, 1227, 1153, 1136, 1042, 973, 807, 736cm-1。HRMS-ESI+m/z[M+H]+[C25H35N3O3+H]+The calculated value of (a): 426.2571, found: 4426.2760.
example 70: 1- (1-acetylpiperidin-4-yl) -3- (1-fluoro-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-bis-methanobenzo [9]]Rotalen-7-yl) urea.
To 1-fluoro-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-di-methanobenzo [9]]A solution of rotalen-7-amine hydrochloride (150mg, 0.53mmol) in DCM (3mL) was added saturated aqueous NaHCO3Solution (3mL) and triphosgene (58mg, 0.20 mmol). The biphasic mixture was stirred at room temperature for 30 min, and then the two phases were separated and the organic layer was washed with brine (3mL), over anhydrous Na2SO4Dried, filtered and evaporated under vacuum to obtain 1-2mL of a solution of isocyanate in DCM. To this solution was added 1- (4-aminopiperidin-1-yl) ethan-1-one (91mg, 0.64 mmol). The reaction mixture was stirred at room temperature overnight, and the solvent was evaporated under vacuum to obtain a yellow oil (320 mg). Column chromatography (SiO)2DCM/methanol mixture) to give 1- (1-acetylpiperidin-4-yl) -3- (1-fluoro-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9] as a white solid]Rotalen-7-yl) urea (160mg, 73% yield).
mp 122-. IR (NaCl dish): 3351. 2944, 2918, 2861, 1642, 1618, 1555, 1462, 1362, 1321, 1238, 1137, 1066, 976, 885, 798, 749cm-1。HRMS-ESI+m/z[M+H]+[C24H32FN3O2+H]+The calculated value of (a): 414.2551, found: 414.2554.
example 71: 1- (1-acetylpiperidin-4-yl) -3- (2, 3-dimethoxy-9-methyl-5, 6,8,9,10, 11-hexa-position Hydrogen-7H-5, 9:7, 11-bis-methanobenzo [9]]Rotalen-7-yl) urea.
To2, 3-dimethoxy-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-di-methanobenzo [9]]A solution of rotalen-7-amine hydrochloride (150mg, 0.46mmol) in DCM (3mL) was added saturated aqueous NaHCO3Solution (3mL) and triphosgene (51mg, 0.17 mmol). The biphasic mixture was stirred at room temperature for 30 min, and then the two phases were separated and the organic layer was washed with brine (3mL), over anhydrous Na2SO4Dried, filtered and evaporated under vacuum to obtain 1-2mL of isocyanideA solution of the acid ester in DCM. To this solution was added 1- (4-aminopiperidin-1-yl) ethan-1-one (79mg, 0.55 mmol). The reaction mixture was stirred at room temperature overnight, and the solvent was evaporated under vacuum to obtain a yellow oil (334 mg). Column chromatography (SiO)2DCM/methanol mixture) to give 1- (1-acetylpiperidin-4-yl) -3- (2, 3-dimethoxy-9-methyl-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-nebenzo [9] as a white solid]Rotalen-7-yl) urea (168mg, 80% yield).
mp 127-. IR (NaCl dish): 3365. 3052, 2913, 2862, 2834, 1643, 1616, 1553, 1516, 1452, 1360, 1343, 1320, 1293, 1252, 1232, 1168, 1137, 1092, 1019, 974, 863, 801, 734cm-1。HRMS-ESI+m/z[M+H]+[C26H37N3O4+H]+The calculated value of (a): 456.2857, found: 456.2859.
example 72: 1- (1-acetylpiperidin-4-yl) -3- (5,8,9, 10-tetrahydro-5, 8:7, 10-methanobenzo [8]Rotalen-7 (6H) -yl) urea.
To 5,8,9, 10-tetrahydro-5, 8:7, 10-di-methanobenzo [8]]A solution of rotalen-7 (6H) -amine hydrochloride (57mg, 0.24mmol) in DCM (1mL) was added saturated aqueous NaHCO3Solution (1mL) and triphosgene (27mg, 0.09 mmol). The biphasic mixture was stirred at room temperature for 30 min, and then the two phases were separated and the organic layer was washed with brine (1mL) over anhydrous Na2SO4Dried, filtered and evaporated under vacuum to obtain 1-2mL of a solution of isocyanate in DCM. To this solution was added 1- (4-aminopiperidin-1-yl) ethan-1-one (41mg, 0.29 mmol). The reaction mixture was stirred at room temperature overnight, and the solvent was evaporated under vacuum to give a brown gum (93 mg). Column chromatography (SiO)2DCM/methanol mixture) to give 1- (1-acetylpiperidin-4-yl) -3- (5,8,9, 10-tetrahydro-5, 8:7, 10-dimethano-benzo [8] as a white solid]Rotalen-7 (6H) -yl) urea (47mg, 53% yield).
mp 98-99 ℃. IR (NaCl dish): 3359. 3013, 2927, 2856, 2239, 1621, 1556, 1449, 1372, 1334, 1318, 1268, 1238, 1225、1192、1153、1107、1081、1048、1041、972、920、756、730cm-1。HRMS-ESI+m/z[M+H]+[C22H29N3O2+H]+The calculated value of (a): 4368.2333, found: 368.2331.
example 73: 1- (benzo [ d ]]Thiazol-2-yl) -3- (9-methoxy-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-bis-methanobenzo [9]]Rotalen-7-yl) urea.
To 9-methoxy-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-di-methanobenzo [9]]A solution of rotalen-7-amine (250mg, 1.03mmol) in DCM (3mL) was added saturated aqueous NaHCO3Solution (3mL) and triphosgene (113mg, 0.38 mmol). The biphasic mixture was stirred at room temperature for 30 min, and then the two phases were separated and the organic layer was washed with brine (3mL), over anhydrous Na2SO4Dried, filtered and evaporated under vacuum to obtain 1-2mL of a solution of isocyanate in DCM.
To a solution of benzo [ d ] thiazol-2-amine (141mg, 0.94mmol) in anhydrous THF (8mL) at-78 deg.C under an argon atmosphere was added dropwise a solution of n-butyllithium (2.5M in hexane, 0.38mL, 0.94mmol) over a period of 20 minutes. After addition, the mixture was tempered to 0 ℃ using an ice bath. This solution was carefully added to a solution of the isocyanate from the previous step cooled to 0 ℃ under an argon atmosphere. The reaction mixture was stirred at room temperature overnight. Methanol (3mL) was then added to quench any unreacted n-butyllithium. The solvent was evaporated under vacuum to give a yellow solid (531 mg). Column chromatography (SiO2, hexane/ethyl acetate mixture) afforded 1- (benzo [ d ] thiazol-2-yl) -3- (9-methoxy-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethanembenzo [9] annulen-7-yl) urea as a white solid (65mg, 15% yield).
mp 247-. IR (NaCl dish): 2926. 2851, 1712, 1675, 1593, 1537, 1445, 1358, 1268, 1217, 1556, 1116, 1080, 1044, 1015, 910, 845cm-1。HRMS-ESI+m/z[M+H]+[C24H25N3O2S+H]+The calculated value of (a): 420.1740, found:368.2331。
example 74: 1- (1-acetylpiperidin-4-yl) -3- (1, 9-difluoro-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-bis-methanobenzo [9]]Rotalen-7-yl) urea.
To 1, 9-difluoro-5, 6,8,9,10, 11-hexahydro-7H-5, 9:7, 11-dimethano-benzo [9]]A solution of rotalen-7-amine hydrochloride (120mg, 0.42mmol) in DCM (3mL) and saturated aqueous NaHCO3Triphosgene (46mg, 0.16mmol) was added to the solution (3 mL). The biphasic mixture was stirred at room temperature for 30 min, and then the two phases were separated and the organic phase was washed with brine (3mL), over anhydrous Na2SO4Dried, filtered and evaporated under vacuum to obtain 1-2mL of a solution of isocyanate in DCM. To this solution was added 1- (4-aminopiperidin-1-yl) ethan-1-one (72mg, 0.51 mmol). The mixture was stirred at room temperature overnight, and then the solvent was evaporated. Column chromatography (SiO)2DCM/methanol mixture) to give urea as a pale yellow solid (84mg, 48% yield). Analytical samples were obtained by crystallization from hot EtOAc/pentane.
mp 248-249℃。IR(ATR)：3382、3266、2923、2164、1645、1622、1562、1503、1464、1454、1425、1362、1341、1325、1318、1304、1244、1232、1185、1135、1099、1059、1036、1015、995、978、952、929、891、868、795、746、717、695、645、625、605、590cm-1。HRMS-ESI+m/z[M+H]+[C23H29F2N3O2+H]+The calculated value of (a): 418.2301, respectively; measured value: 418.2300.
reference example 75: 1,5,6, 7-tetrahydro-1, 5:3, 7-di-methanobenzo [ e]Oxacyclononatetraene-5-d-3 (2H) -an alcohol.
To 5,6,7, 8-tetrahydro-7H-5, 9-propanebenzo [7]]A solution of rotalene-7, 11-dione (3.13g, 14.6mmol) in MeOH (88mL) was added in portions with NaBD4(1g, 23.9mmol) and the suspension was stirred at reflux for 6 h. The solution was cooled and the solvent was removed under vacuum. To the obtained white solid, NaOH 2N (100mL) was added, and the suspension was refluxed for 30 minutes. In-line with the aboveThereafter, the suspension is filtered and washed with H2O (50mL) to obtain 1,5,6, 7-tetrahydro-1, 5:3, 7-dimethanobenzo [ e ] as a white solid]Oxacyclononantene-5-d-3 (2H) -ol (2.88g, 91% yield).
mp 200℃。IR(ATR)：3304、2957、2941、2927、2913、1492、1461、1451、1431、1383、1356、1339、1328、1278、1253、1234、1219、1189、1157、1141、1127、1082、1047、1017、1002、958、935、863、844、773、755、718、673cm-1。HRMS-ESI+m/z[M+H]+[C14H15DO2+H]+The calculated value of (a): 218.1286, found: 218.1297.
reference example 76: (1,5,6, 7-tetrahydro-1, 5:3, 7-di-methanobenzo [ e)]Oxetanonene-3 (2H) - Group-5-d) hydroxylamine hydrochloride.
A solution of 1,5,6, 7-tetrahydro-1, 5:3, 7-dimethanomenzo [ e ] oxazenonatetraen-5-d-3 (2H) -ol (1.2g, 5.52mmol) in hydrazine hydrate (9mL, 64% aqueous sol, 183.98mmol) and concentrated HCl (0.2mL) was heated at reflux overnight. The solution was cooled and the suspension was filtered. The obtained solid was dissolved in methanol, and HCl/MeOH was added to obtain (1,5,6, 7-tetrahydro-1, 5:3, 7-dioxamethylenebenzo [ e ] oxacyclononatetraen-3 (2H) -yl-5-d) hydroxylamine hydrochloride (1.26g, 85% yield).
mp 232-235℃。IR(ATR)：3303、3226、2911、2845、2650、1589、1525、1490、1451、1435、1356、1328、1278、1253、1219、1157、1145、1129、1084、1050、1024、1002、958、936、892、865、830、812、771、750、721cm-1。HRMS-ESI+m/z[M+H]+[C14H17DN2O+H]+The calculated value of (a): 232.1555, found: 232.1554.
reference example 77: 1,5,6, 7-tetrahydro-1, 5:3, 7-di-methanobenzo [ e]Oxacyclononatetraene-5-d-3 (2H) -amine hydrochloride.
1,5,6, 7-tetrahydro-1, 5:3, 7-di-methanobenzo [ e ]]Oxonozetane-3 (2H) -yl-5-d) hydroxylamine hydrochloride (1g, 37mmol) and PtO2(100mg) in ethanol (100mL) were hydrogenated at room temperature under a pressure of 1atm for 5 days. The resulting suspension was filtered, and the residue was washed with methanol. The solvent was removed under vacuum to obtain a white solid. The solid was dissolved in MeOH, and excess HCl/MeOH was added. The solvent was evaporated to obtain 1,5,6, 7-tetrahydro-1, 5:3, 7-dioxamethylenebenzo [ e ] as a white solid]Oxacyclononantene-5-d-3 (2H) -amine hydrochloride (791mg, 85% yield). By reaction from methanol/Et2Crystallizing in O to obtain an analysis sample.
mp 195℃。IR(ATR)：3304、3010、2940、2913、2847、1510、1490、1451、1435、1379、1356、1328、1280、1251、1235、1221、1157、1126、1082、1041、1000、957、937、866、844、773、762、755、720、670cm-1。HRMS-ESI+m/z[M+H]+[C14H16DNO+H]+The calculated value of (a): 217.1446, found: 217.1449.
example 78: 1- (1-acetylpiperidin-4-yl) -3- (1,5,6, 7-tetrahydro-1, 5:3, 7-methanobenzo [e]Oxacyclononanten-3 (2H) -yl-5-d) urea.
1- (1-acetylpiperidin-4-yl) -3- (1,5,6, 7-tetrahydro-1, 5:3, 7-methanobenzo [ e ] oxacyclononatetraen-3 (2H) -yl-5-d) urea was obtained from 1,5,6, 7-tetrahydro-1, 5:3, 7-methanobenzo [ e ] oxacyclononatetraen-5-d-3 (2H) -amine hydrochloride and following the procedure of example 37.
Example 79: in vitro assay for sEH inhibitory activity
The following fluorescence assay was used to determine sEH inhibitory activity (IC)50) Wherein the substrate and comparative control compound (TPPU) are indicated below.
Substrate: cyano (6-methoxynaphthalen-2-yl) 2- (3-phenyloxiran-2-yl) acetate (PHOME; from Karman Chemical, Catman Chemical, Cathan # 10009134; CAS 1028430-42-3); see n.m. wolf et al, "analytical biochemistry (anal. biochem.) 2006, vol 355, pages 71-80.
TPPU (thermoplastic polyurethane): n- [1- (1-oxopropyl) -4-piperidinyl ] -N' - [4- (trifluoromethoxy) phenyl ] urea.
Solution:
-assay buffer: Bis/Tris HCl 25mM pH 7.0 with 0.1mg/mL Bovine Serum Albumin (BSA).
DMSO containing 200. mu.M of PHOME.
Recombinant human seh (hseh) solution diluted with assay buffer (camman chemical, cat # 10011669).
Inhibitors dissolved in DMSO at appropriate concentrations.
The scheme is as follows: in a black 96-well plate (Greiner Bio-One, cat # 655900), the background wells were filled with 90. mu.L of assay buffer and the positive control and inhibitor wells were filled with 85. mu.L of assay buffer. Mu.l of DMSO was added to the background wells and positive control wells, and then 5. mu.l of inhibitor solution was added to the inhibitor wells. mu.L of hsEH solution was added to the positive control wells and inhibitor wells and the mixture was stirred. 1/21 dilutions of the PHOME solution were prepared with assay buffer according to the final volume required, followed by addition of 105. mu.L per well. Plates were carefully shaken for 10 seconds and incubated for 5 minutes at room temperature. The appearance of fluorescence at an excitation wavelength of 337nm and an emission wavelength of 460nm was read (FLUOStar OPTIMA microplate reader, BMG). Fluorescence intensity for analysis and calculation of IC50The value is obtained. Results were obtained from at least three data points in the linear region of the curve by regression analysis. IC (integrated circuit)50The value is the average of a minimum of three independent replicas.
Tables 1 and 2: selected Compound (I)aHuman sEH inhibitory Activity (IC)50，nM)
Examples of the invention
TTPU
35
36
38
39
40
41
42
43
44
47
48
51
52
53
56
IC50
A
D
D
A
D
B
A
A
B
A
A
A
A
A
B
B
Examples of the invention
57
58
59
60
63
64
65
66
67
68
69
70
71
72
73
74
IC50
D
A
B
D
A
A
A
A
A
A
A
A
A
B
D
A
aA means IC50Less than 10nM, B means IC50At least 10nM but less than 50nM, C means IC50Is at least 50nM but less than 100nM, and D means IC50At least 100nM but less than 1000 nM.
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