Saturated ring-fused dihydropyrimidinone or dihydrotriazinone compounds and pharmaceutical use thereof
阅读说明：本技术 饱和环稠合的二氢嘧啶酮或二氢三嗪酮化合物及其药物用途 (Saturated ring-fused dihydropyrimidinone or dihydrotriazinone compounds and pharmaceutical use thereof ) 是由 横田正宏 关法良 渡边英一 藤冈真悟 于 2019-02-27 设计创作，主要内容包括：本发明涉及具有RORγ拮抗剂活性的饱和环稠合的二氢嘧啶酮或二氢三嗪酮化合物或其药学上可接受的盐、包含它们的药物组合物及其药物用途。提供了式[I]化合物或其药学上可接受的盐、包含它们的药物组合物及其药物用途：<Image he="287" wi="222" file="DEST_PATH_IMAGE002.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>其中各个取代基的限定是如说明书中所限定。(The present invention relates to saturated ring fused dihydropyrimidinone or dihydrotriazinone compounds having ROR γ antagonist activity or pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising the same, and pharmaceutical uses thereof. Provides formula [ I]Compounds or pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising them and their pharmaceutical uses: wherein the definitions of the various substituents are as defined in the specification.)
1. A compound of the formula [ I ]:
wherein R is1Is that
(1)C1-8An alkyl group, a carboxyl group,
(2) halogen substituted C1-8An alkyl group, a carboxyl group,
(3)C3-8cycloalkyl, optionally identical or different 1 to 3 selected from group A1Is substituted by a substituent of (a), or
(4)C3-8cycloalkyl-C1-4Alkyl radical, wherein C3-8The cycloalkyl radicals may optionally be identical or different from 1 to 31The substituent (b) of (a) is substituted,
group A1Is that
(1) The halogen(s) are selected from the group consisting of,
(2)C1-4alkyl, and
(3) halogen substituted C1-4An alkyl group, a carboxyl group,
X1is that
(1) A key, or
(2)-O-，
R2Is that
(1) Hydrogen, or
(2) The halogen(s) are selected from the group consisting of,
R3is that
(1) Hydrogen, or
(2)-Y3-COO-R30，
Y3Is that
(1)C1-8An alkylene group or a substituted alkylene group,
(2)C3-8a cycloalkylene group,
(3) bridged C5-8Cycloalkylene, or
(4)C6-14An arylene group, a cyclic or cyclic alkylene group,
R30is that
(1) Hydrogen, or
(2)C1-4An alkyl group, a carboxyl group,
X2is that
(1) =C(R4) -, or
(2) =N-，
R4Is that
(1) Hydrogen, or
(2)C1-4An alkyl group, a carboxyl group,
X3is that
(1)-C(R5)(R6)-，
X4Is that
(1) A key, or
(2)-C(R7)(R8)-，
X5Is that
(1)-C(R9)(R10)-，
(2)-N(R11) -, or
(3)-O-，
R5And R6Each independently is
(1) The presence of hydrogen in the presence of hydrogen,
(2)C1-4an alkyl group, a carboxyl group,
(3) halogen substituted C1-4An alkyl group, a carboxyl group,
(4) cyano-C1-4Alkyl, or
(5) Is one selected from-O-R51、-CO-R61、-COO-R52、-N(R71)(R72)、-CO-N(R73)(R74)、-N(R75)-CO-R62、-N(R76)-COO-R53and-O-S (O)2-R63C substituted by a substituent of1-4An alkyl group, a carboxyl group,
R7、R8、R9and R10Each independently is
(1) The presence of hydrogen in the presence of hydrogen,
(2) the halogen(s) are selected from the group consisting of,
(3) the cyano group(s),
(4) a hydroxyl group(s),
(5)C1-4an alkyl group, a carboxyl group,
(6) halogen substituted C1-4An alkyl group, a carboxyl group,
(7) cyano-C1-4An alkyl group, a carboxyl group,
(8)C1-4alkoxy radical, or
(9) Is one selected from-O-R51、-CO-R61、-COO-R52、-N(R71)(R72)、-CO-N(R73)(R74)、-N(R75)-CO-R62、-N(R76)-COO-R53and-O-S (O)2-R63C substituted by a substituent of1-4An alkyl group, a carboxyl group,
R51、R52and R53Each independently is
(1) The presence of hydrogen in the presence of hydrogen,
(2)C1-4alkyl, or
(3)C6-14aryl-C1-4An alkyl group, a carboxyl group,
R61、R62and R63Each independently is
(1)C1-4An alkyl group, a carboxyl group,
R71、R72、R73、R74、R75and R76Each independently is
(1) Hydrogen, or
(2)C1-4An alkyl group, a carboxyl group,
R11is that
(1)-CO-R111Or is or
(2)-COO-R112，
R111Is that
(1)C1-4An alkyl group, a carboxyl group,
R112is that
(1)C1-4An alkyl group, a carboxyl group,
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1, having the structure of formula [ II ]:
wherein the variables are defined as in claim 1, or a pharmaceutically acceptable salt thereof.
3. A compound according to claim 1 or 2, wherein X2Is = N-, or a pharmaceutically acceptable salt thereof.
4. A compound according to claim 1 or 2, wherein X2Is = C (R)4) -and R4Is hydrogen, or a pharmaceutically acceptable salt thereof.
5. A compound according to any one of claims 1 to 4, wherein R3Is hydrogen, or a pharmaceutically acceptable salt thereof.
6. A compound according to any one of claims 1 to 4, which isIn R3is-Y3-COO-R30，
Y3Is that
(1)C1-8An alkylene group or a substituted alkylene group,
(2)C3-8cycloalkylene, or
(3) Bridged C5-8A cycloalkylene group,
R30is hydrogen or C1-4An alkyl group, a carboxyl group,
or a pharmaceutically acceptable salt thereof.
7. A compound according to any one of claims 1 to 6, wherein R2Is halogen, or a pharmaceutically acceptable salt thereof.
8. A compound according to any one of claims 1 to 7, wherein R1Is C1-8Alkyl and X1Is a bond, or a pharmaceutically acceptable salt thereof.
9. A compound according to any one of claims 1 to 8, wherein R5And R6Each independently is hydrogen or C1-4Alkyl, or a pharmaceutically acceptable salt thereof.
10. A compound according to any one of claims 1 to 9, wherein X4Is a bond or-C (R)7)(R8) -and R7And R8Are both hydrogen, or a pharmaceutically acceptable salt thereof.
11. A compound according to any one of claims 1 to 10, wherein X5is-C (R)9)(R10) -or-O-and R9And R10Are both hydrogen, or a pharmaceutically acceptable salt thereof.
12. The compound according to claim 1, selected from the following group of compounds:
or a pharmaceutically acceptable salt thereof.
13. A pharmaceutical composition comprising a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
A ROR γ antagonist comprising a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof.
15. A therapeutic or prophylactic agent for a disease selected from an autoimmune disease, an allergic disease, dry eye, fibrosis, cancer, a metabolic disease, ischemia, cardiomyopathy, hypertension, and periodontal disease, comprising a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof.
16. A method of antagonizing rory comprising administering to a mammal a therapeutically effective amount of a compound of any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof.
17. A method of treating or preventing a disease selected from the group consisting of autoimmune diseases, allergic diseases, dry eye, fibrosis, cancer, metabolic diseases, ischemia, cardiomyopathy, hypertension, and periodontal disease comprising administering to a mammal a therapeutically effective amount of a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof.
18. Use of a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, in the preparation of a ROR γ antagonist.
19. Use of a compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof in the preparation of a therapeutic or prophylactic agent for a disease selected from the group consisting of an autoimmune disease, an allergic disease, dry eye, fibrosis, cancer, a metabolic disease, ischemia, cardiomyopathy, hypertension and periodontal disease.
20. A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, for use in a ROR γ antagonist.
21. A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a disease selected from autoimmune diseases, allergic diseases, dry eye, fibrosis, cancer, metabolic diseases, ischemia, cardiomyopathy, hypertension and periodontal disease.
Technical Field
The present invention relates to saturated ring fused dihydropyrimidinone or dihydrotriazinone compounds having ROR γ antagonist activity or pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising the same, and pharmaceutical uses thereof.
Background
ROR γ (i.e., retinoid-related orphan receptor γ) is a nuclear receptor that is important for differentiation and activation of Th17 cells. ROR γ t is also known as a splice variant of ROR γ (non-patent document 1). ROR γ and ROR γ t differ only in their N-terminal domains and share the same ligand binding domain and DNA binding domain. ROR γ is reported to be expressed in other tissues besides Th17cells (non-patent document 1).
Inhibition of ROR γ may inhibit differentiation and activation of Th17 cells. IL-17 produced in Th17cells is involved in the induction of various chemokines, cytokines, metalloproteinases and other inflammatory mediators and migration of neutrophils, and therefore inhibition of IL-17 can lead to inhibition of such induction and migration (non-patent documents 2 and 3). Th17cells are known to be involved in autoimmune diseases (e.g., rheumatoid arthritis, psoriasis, inflammatory bowel disease (e.g., crohn's disease and ulcerative colitis), multiple sclerosis, Systemic Lupus Erythematosus (SLE), behcet's disease, sarcoidosis, madder disease, ankylosing spondylitis, uveitis, polymyalgia rheumatica, type I diabetes, graft-versus-host disease, alopecia areata, and vitiligo), allergic diseases, dry eye, fibrosis (e.g., pulmonary fibrosis and primary biliary cirrhosis), and cancer (e.g., malignant melanoma and prostate cancer).
ROR γ in adipose tissue is involved in regulation of adipogenesis, and inhibition of ROR γ can improve insulin resistance (non-patent document 4). Adipose tissue is known to be involved in metabolic diseases (e.g., hepatic steatosis).
IL-17 and Th17cells are also known to be involved in ischemia, cardiomyopathy, hypertension, and periodontitis.
For example, in the case of rheumatoid arthritis, it is reported that administration of an anti-IL-17 antibody can improve swelling and joint destruction associated with collagen-induced arthritis (non-patent document 5). It has also been reported that swelling and joint destruction associated with collagen-induced arthritis can be improved in an experiment using IL-17 deficient mice (non-patent document 6).
For psoriasis, it is reported that administration of an anti-IL-17 antibody in a clinical trial is effective in treating psoriasis (non-patent document 7). anti-IL-17 antibodies have been marketed for psoriasis (non-patent document 8).
In inflammatory bowel diseases such as crohn's disease and ulcerative colitis, adaptive transfer of T cells derived from ROR γ -KO mice does not increase IL-17 in the mucosa in a colitis model induced by adaptive transfer of T cells, and thus the onset of colitis can be suppressed (non-patent document 9). It has also been reported that an anti-IL-23 antibody, i.e., an antibody against IL-23 which activates Th17cells, is effective in treating Crohn's disease in clinical trials (non-patent document 20).
For multiple sclerosis, the disease state of a mouse experimental autoimmune encephalomyelitis model, which is an animal model of multiple sclerosis, can be suppressed in ROR γ -KO mice (non-patent document 10). It has also been reported that an anti-IL-17A antibody can improve MRI observation in relapsing-remitting multiple sclerosis in a clinical trial (non-patent document 21).
Regarding systemic lupus erythematosus, it has been reported that the administration of an anti-IL-17 antibody to ROR γ t-KO mice, which are an animal model of glomerulonephritis, can suppress the onset of GBM nephritis model (non-patent document 11). Administration of an anti-IL-17 antibody also potentially inhibits SLE-associated nephritis (non-patent document 12).
In ankylosing spondylitis, it has been reported that administration of an anti-IL-17 antibody is effective in treating ankylosing spondylitis (non-patent document 13).
For uveitis, it is reported that administration of an anti-IL-17 antibody is effective in treating uveitis associated with behcet's disease, sarcoidosis, and madreporters disease (non-patent document 7).
For polymyalgia rheumatica, the efficacy of anti-IL-17 antibodies is currently being evaluated in clinical trials directed at polymyalgia rheumatica.
For type I diabetes, administration of an anti-IL-17 antibody in an NOD mouse model, which is a type I diabetes model, can inhibit the development of a disease state (non-patent document 14). The efficacy of anti-IL-17A antibodies is currently being evaluated in clinical trials (non-patent document 22).
For graft-versus-host disease, it has been reported that transfection of ROR γ -KO mouse-derived cells can improve survival and rejection in the host in a mouse transplantation model (non-patent document 19).
In the case of alopecia areata, the efficacy of anti-IL-17A antibodies is currently being evaluated in clinical trials (non-patent document 25).
For vitiligo, increases in IL-17 and Th17cells were recognized in the serum and pathological tissues of patients, respectively (non-patent document 34).
For allergic diseases such as asthma, reduced eosinophilic lung inflammation, reduced CD4+ lymphocyte count and a reduction in Th2 cytokine/chemokine levels were shown in ROR γ -KO mice in an OVA-sensitized model, which could then inhibit allergic reactions (non-patent document 15). The efficacy of anti-IL-17A antibodies is currently being evaluated in clinical trials for atopic dermatitis (non-patent document 23). The efficacy of anti-IL-23 antibodies is currently being evaluated in clinical trials for asthma (non-patent document 24).
For dry eye, increase of Th17cells in an animal model of dry eye is reported, and the efficacy of an anti-IL-17 antibody is currently being evaluated in a clinical trial for dry eye patients (non-patent document 16).
For fibrosis, administration of an anti-IL-17 antibody can suppress inflammation and fibrosis in the lung and prolong survival of animals in a bleomycin-induced pulmonary fibrosis model, which is an animal model of pulmonary fibrosis (non-patent document 17).
For primary biliary cirrhosis, increase of Th17cells in the lesion region of a primary biliary cirrhosis patient is reported, and the efficacy of an anti-IL-23 antibody is currently being evaluated in clinical trials (non-patent document 18).
For malignant melanoma, the efficacy of anti-IL-17 antibodies is currently being evaluated in clinical trials (non-patent documents 26 and 27).
For prostate cancer, it is recognized that anti-IL-17 antibody treatment reduces the formation of minimally invasive prostate cancer in Pten-deficient mice (non-patent document 28).
Regarding insulin resistance, insulin resistance induced by feeding a high-fat diet can be suppressed in ROR γ KO mice (non-patent document 4).
Regarding hepatic steatosis, it is recognized that anti-IL-17 antibodies improve steatosis in pathological tissues in an alcoholic liver disease model (non-patent document 29).
For non-alcoholic fatty liver disease, it is recognized that anti-IL-17 antibody treatment improves liver function, attenuates liver lipid accumulation, inhibits kupffer cell activation, and lowers proinflammatory cytokine levels in a high-fat diet-induced non-alcoholic fatty liver disease model (non-patent document 30).
For ischemia and cardiomyopathy, it has been reported that IL-17A contributes to myocardial ischemia/reperfusion injury by modulating cardiomyocyte apoptosis and neutrophil infiltration. It is recognized that anti-IL-17A antibody treatment or IL-17A knock-out (knockout) reduces infarct size, improves cardiac function, and thus improves ischemia/reperfusion injury (non-patent document 31).
For hypertension, it is reported that treatment with an anti-IL-17A or IL-17RA antibody inhibits blood pressure elevation by administration of angiotensin II (non-patent document 32).
For periodontitis, an increase in Th17cells or IL-17 was found in the experimental periodontitis model. It is reported that treatment with ROR γ antagonist, GSK805, or anti-IL-17A antibody reduces bone loss in models (non-patent document 33).
Based on these findings, ROR γ antagonists are considered to be useful for the prevention or treatment of autoimmune diseases, allergic diseases, dry eye, fibrosis, cancer (e.g., malignant melanoma and prostate cancer), metabolic diseases, ischemia, cardiomyopathy, hypertension, and periodontal disease.
[ non-patent document 1] JETTEN, "recording-Related Order Receptors (RORs)" critical lines in reduction, immunity, circadian rhythm, and cellular metabolism ", Nucl. Recept. Signal., 7: e003 (2009).
[ non-patent document 2] KOENDERS et al, "positional new targets in arthritis therapy: (Interleukin (IL) -17 and its relationship to clinical diabetes factor and IL-1 experimental arthritis", Ann. Rheum. Dis., 65: iii29-33 (2006).
[ non-patent document 3] SCHMIDT-WEBER, etc. "Th17 cells in the big picture of immunology", J. Allergy Clin. immunol., 120: 247-54 (2007).
[ non-patent document 4] MeissPurger et al, "adaptive and inductance sensitivity associated with related alpha-receptor gamma", EMBO mol. Med., 3: 637-51 (2011).
[ non-patent document 5] KELCHTERMANS, etc. "effects mechanisms of interleukin-17in collagen-induced imaging in the absence of interferon- γ and correlation by interferon- γ", Arthritis Res.
[ non-patent document 6] NAKAE et al, "Suppression of Immune indication of Collagen-Induced Arthritis in IL-17-deficiency Rice", J. Immunol., 171: 6173-.
[ non-patent document 7] HUEBER et al, "Effects of AIN457, a full Human Antibody to Interleukin-17A, on Psoriasis, Rheumatoid Arthritis, and Uveitis", Sci.Transl. Med., 2(52): 52ra72 (2010).
[ non-patent document 8] SANFORD, etc. "Secukinumab: first global apurval", Drugs,75(3): 329) -338 (2015).
[ non-patent document 9] LEPPKES et al, "ROR γ -Expressing Th17Cells InduceMeurineChronic expression of heavy Effects of IL-17A and IL-17F", Gastroenterology, 136(1): 257- "267 (2009).
[ non-patent document 10] IVANOV et al, "The orange Nuclear Receptor ROR γ T Directthe Differentiation Program of fluorescence IL-17+ T Helper Cells", Cell,126(6): 1121-1133 (2006).
[ non-patent document 11] STEINMETZ et al, "The Th17-Defining transformation factor γ t proteins Glomulonecterisis", J. Am. Soc. Nephrol, 22(3): 472-483 (2011).
[ non-patent document 12] CRISPIN et al, "Interleukin-17-producing T cells in pumps", curr, Opin Rheumatol, 22(5): 499-.
[ non-patent document 13] BAETEN et al, "Anti-intercalary Anti-systemicukumab in molecular of alkenyl specific is: a random, double-blind, placbo-controlled trial", Lancet, 382(9906): 1705 and 1713 (2013).
[ non-patent document 14] EMAMULLEE et al, "Inhibition of Th17Cells regulated animals Diabetes in NOD Mice", Diabetes, 58: 1302-.
[ non-patent document 15] TILLEY et al, "truncated-Related alpha Receptor gamma control immunoglobulin Production and Th1/Th2 Cytokine Balance in the Adaptive immune response to Allergen", J. Immunol., 178: 3208-.
Non-patent document 16 U.S. NATIONAL INSTITUTES OF HEALTH, "The Effects OF The interfacial Administration OF Secukinumab (AIN457) or Canakiumab (ACZ885) in Dry Eye Patients", and clinical Trials. gov information for clinical Trials Identifier NCT01250171 (December 4, 2012).
[ non-patent document 17] MI et al, "Blocking IL-17A proteins the Resolution of purification infection and Fibrosis Via TGF-. beta.1-Dependent and-independentMechanisms", J.Immunol., 187: 3003-3014 (2011).
[ non-patent document 18] U.S. NATIONAL INSTITUTES OF HEALTH, "A Study OF efficiency and Safety OF Ustekinumab in Patients With Primary Biliary Cirrhosis (PBC) O Had an ingredient Response to an ingredient Acid", and Clinical Trials for Clinical Trials Identifier NCT01389973(April 2, 2015).
[ non-patent document 19] FULTON et al, "introduction of Acute Graft-summary-HostDisase in the Absence of the transformation Factor ROR γ t", J. Immunol., 189(4): 1765-1772 (2012).
[ non-patent document 20] Brian G Feagan et al, "analysis therapy with The selective interference in-23 inhibition or risanuzumab in tissues with modulation-to-severeCarohn's disease, a random, double-bed, placebo-controlled phase 2study", The Lancet, 389(10080): 1699-.
[ non-patent document 21] Eva Havrova et al, "Activity of secukinuab, an anti-IL-17A antibody, on bridge versions in RRMS: results from a random, proof-of-concept study", J. neuron, 263(7): 1287-1295 (2016).
[ non-patent document 22] U.S. NATIONAL INSTITUTES OF HEALTH, "Study OF Secukinumab in Patients With New Newly-labeled Type 1 Diabetes Mellitis", Clinical Trials.gov information for Clinical Trials Identifier NCT 02044848.
[ non-patent document 23] U.S. NATIONAL INSTITUTES OF HEALTH, "Secukinumab for treatment OF anatomical Dermatitis", clinical Trials. gov information for clinical Trials Identifier NCT 02594098.
[ non-patent document 24] U.S. NATIONAL INSTITUTES OF HEALTH, "effectiveness and safety OF BI 655066/ABBV-066 (Risankizumab) in Patients With Vertepersistent asset", Clinical variants. gov information for Clinical variants identifier NCT 02443298.
[ non-patent document 25] U.S. NATIONAL INSTITUTES OF HEALTH, "A Study OF Secukinumab for the Treatment OF Alopecia Areata," Clinical Trials. visual formation for Clinical Trials Identifier NCT 02599129.
[ non-patent document 26] U.S. NATIONAL INSTITUTES OF HEALTH, "An Open-Label, Proof-OF-Concept Study OF Ixekizumab in the Treatment OF Pythermagangrenosum", Clinical Trials. gov information for Clinical Trials IdentifierNCT 03137160.
Non-patent document 27 U.S. NATIONAL INSTITUTES OF HEALTH, "Single-arm student assay a positional Effect OF Anti-IL-17 (Secukinumab) in the Treatment OF Pythroma Gangrenosum", and Clinical Trials. gov information for Clinical Trials identifier NCT 02733094.
[ non-patent document 28] Q Zhang et al, "Targeting Th17-IL-17 Pathway in advance of Micro-inactive Start Cancer in a Mouse Model", Start, 77(8): 888-.
[ non-patent document 29] W Shi et al, "Anti-IL-17 Antibody Improves hepatotic catalysts by presenting interstitial Acid Synthesis and metabolism", Clin. Dev. Immunol., Volume 2013, and aromatic ID 253046 (2013).
[ non-patent document 30] R Xu et al, "Neutralization of interleukin-17 incision-induced non-alcoholic facial skin disease in mice", actaBiochim. Biophys. sin. (Shanghai), 45(9): 726-.
[ non-patent document 31] Y.H. Lial et al, "Interleukin-17A controls to myocarpial Ischemia/playback injection by Regulating Cardiocytocyte Apoptosis and neutrophilic injection", J. Am. Coll. Cardiol. 59(4): 420) 429 (2012).
[ non-patent document 32] M.A. Saleh et al, "Inhibition of Interleukin 17-A but not Interleukin-17F signalling powers Blood Pressure and recovery End-organic in fluorescence in antibiotic-induced Hypertension", JACC Basic transfer. Sci.1(7): 606) 616 (2016).
[ non-patent document 33] N, Dutzan et al, "A dynamic microbial triggerers TH17cells to medium organic biochemical immunopathology in microorganisms and humans", Sci. Transl. Med. 10(463) eaat0797 (2018).
[ non-patent document 34] R Speeckaert et al, "The management faces of interleukin-17 in-fluidic skins", Br. J. Dermatol. 175(5): 892-.
Disclosure of Invention
The present invention provides saturated ring fused dihydropyrimidinone or dihydrotriazinone compounds having ROR γ antagonist activity or pharmaceutically acceptable salts thereof, pharmaceutical compositions comprising the same, and medical uses thereof. One aspect of the present invention includes the following illustrative embodiments.
[ item 1]
A compound of the formula [ I ]:
wherein R is1Is that
(1)C1-8An alkyl group, a carboxyl group,
(2) halogen substituted C1-8An alkyl group, a carboxyl group,
(3)C3-8cycloalkyl, optionally identical or different 1 to 3 selected from group A1Is substituted by a substituent of (a), or
(4)C3-8cycloalkyl-C1-4Alkyl radical, wherein C3-8The cycloalkyl radicals may optionally be identical or different from 1 to 31The substituent (b) of (a) is substituted,
group A1Is that
(1) The halogen(s) are selected from the group consisting of,
(2)C1-4alkyl radicalAnd are and
(3) halogen substituted C1-4An alkyl group, a carboxyl group,
X1is that
(1) A key, or
(2)-O-，
R2Is that
(1) Hydrogen, or
(2) The halogen(s) are selected from the group consisting of,
R3is that
(1) Hydrogen, or
(2)-Y3-COO-R30，
Y3Is that
(1)C1-8An alkylene group or a substituted alkylene group,
(2)C3-8a cycloalkylene group,
(3) bridged C5-8Cycloalkylene, or
(4)C6-14An arylene group, a cyclic or cyclic alkylene group,
R30is that
(1) Hydrogen, or
(2)C1-4An alkyl group, a carboxyl group,
X2is that
(1) =C(R4) -, or
(2) =N-，
R4Is that
(1) Hydrogen, or
(2)C1-4An alkyl group, a carboxyl group,
X3is that
(1)-C(R5)(R6)-，
X4Is that
(1) A key, or
(2)-C(R7)(R8)-，
X5Is that
(1)-C(R9)(R10)-，
(2)-N(R11) -, or
(3)-O-，
R5And R6Each independently is
(1) The presence of hydrogen in the presence of hydrogen,
(2)C1-4an alkyl group, a carboxyl group,
(3) halogen substituted C1-4An alkyl group, a carboxyl group,
(4) cyano-C1-4Alkyl, or
(5) Is one selected from-O-R51、-CO-R61、-COO-R52、-N(R71)(R72)、-CO-N(R73)(R74)、-N(R75)-CO-R62、-N(R76)-COO-R53and-O-S (O)2-R63C substituted by a substituent of1-4An alkyl group, a carboxyl group,
R7、R8、R9and R10Each independently is
(1) The presence of hydrogen in the presence of hydrogen,
(2) the halogen(s) are selected from the group consisting of,
(3) the cyano group(s),
(4) a hydroxyl group(s),
(5)C1-4an alkyl group, a carboxyl group,
(6) halogen substituted C1-4An alkyl group, a carboxyl group,
(7) cyano-C1-4An alkyl group, a carboxyl group,
(8)C1-4alkoxy radical, or
(9) Is one selected from-O-R51、-CO-R61、-COO-R52、-N(R71)(R72)、-CO-N(R73)(R74)、-N(R75)-CO-R62、-N(R76)-COO-R53and-O-S (O)2-R63C substituted by a substituent of1-4An alkyl group, a carboxyl group,
R51、R52and R53Each independently is
(1) The presence of hydrogen in the presence of hydrogen,
(2)C1-4alkyl, or
(3)C6-14aryl-C1-4An alkyl group, a carboxyl group,
R61、R62and R63Each independently is
(1)C1-4An alkyl group, a carboxyl group,
R71、R72、R73、R74、R75and R76Each independently is
(1) Hydrogen, or
(2)C1-4An alkyl group, a carboxyl group,
R11is that
(1)-CO-R111Or is or
(2)-COO-R112，
R111Is that
(1)C1-4An alkyl group, a carboxyl group,
R112is that
(1)C1-4An alkyl group, a carboxyl group,
or a pharmaceutically acceptable salt thereof.
[ item 2]
The compound of item 1, having the structure of formula [ II ]:
wherein the variables are defined as in item 1, or a pharmaceutically acceptable salt thereof.
[ item 3]
The compound according to item 1 or 2, wherein X2Is = N-, or a pharmaceutically acceptable salt thereof.
[ item 4]
The compound according to item 1 or 2, wherein X2Is = C (R)4) -and R4Is hydrogen, or a pharmaceutically acceptable salt thereof.
[ item 5]
The compound according to any one of items 1 to 4, wherein R3Is hydrogen, or a pharmaceutically acceptable salt thereof.
[ item 6]
The compound according to any one of items 1 to 4, wherein R3is-Y3-COO-R30，
Y3Is that
(1)C1-8An alkylene group or a substituted alkylene group,
(2)C3-8cycloalkylene, or
(3) Bridged C5-8A cycloalkylene group,
R30is hydrogen or C1-4An alkyl group, a carboxyl group,
or a pharmaceutically acceptable salt thereof.
[ item 7]
The compound according to any one of items 1 to 6, wherein R2Is halogen, or a pharmaceutically acceptable salt thereof.
[ item 8]
The compound according to any one of items 1 to 7, wherein R1Is C1-8Alkyl and X1Is a bond, or a pharmaceutically acceptable salt thereof.
[ item 9]
The compound according to any one of items 1 to 8, wherein R5And R6Each independently is hydrogen or C1-4Alkyl, or a pharmaceutically acceptable salt thereof.
[ item 10]
The compound according to any one of items 1 to 9, wherein X4Is a bond or-C (R)7)(R8) -and R7And R8Are both hydrogen, or a pharmaceutically acceptable salt thereof.
[ item 11]
The compound according to any one of items 1 to 10, wherein X5is-C (R)9)(R10) -or-O-and R9And R10Are both hydrogen, or a pharmaceutically acceptable salt thereof.
[ item 12]
The compound according to item 1, selected from the following group of compounds:
or a pharmaceutically acceptable salt thereof.
[ item 13]
A pharmaceutical composition comprising a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
[ item 14]
A ROR γ antagonist comprising a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof.
[ item 15]
A therapeutic or prophylactic agent for a disease selected from the group consisting of an autoimmune disease, an allergic disease, dry eye, fibrosis, cancer, a metabolic disease, ischemia, cardiomyopathy, hypertension and periodontal disease, comprising a compound according to any one of items 1 to 12, or a pharmaceutically acceptable salt thereof.
[ item 16]
A method of antagonizing rory comprising administering to a mammal a therapeutically effective amount of a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof.
[ item 17]
A method for treating or preventing a disease selected from the group consisting of an autoimmune disease, an allergic disease, dry eye, fibrosis, cancer, a metabolic disease, ischemia, cardiomyopathy, hypertension, and periodontal disease, comprising administering to a mammal a therapeutically effective amount of a compound according to any one of items 1 to 12, or a pharmaceutically acceptable salt thereof.
[ item 18]
Use of a compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, in the preparation of a ROR γ antagonist.
[ item 19]
Use of the compound according to any one of items 1 to 12 or a pharmaceutically acceptable salt thereof in the preparation of a therapeutic or prophylactic agent for a disease selected from the group consisting of an autoimmune disease, an allergic disease, dry eye, fibrosis, cancer, a metabolic disease, ischemia, cardiomyopathy, hypertension and periodontal disease.
[ item 20]
A compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, for use in a ROR γ antagonist.
[ item 21]
A compound according to any one of items 1 to 12 or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of a disease selected from autoimmune diseases, allergic diseases, dry eye, fibrosis, cancer, metabolic diseases, ischemia, cardiomyopathy, hypertension and periodontal disease.
[ item 22]
A commercial package comprising the pharmaceutical composition according to item 13 and a package insert (package insert) describing that the pharmaceutical composition is useful for treating or preventing a disease selected from the group consisting of autoimmune diseases, allergic diseases, dry eye, fibrosis, cancer, metabolic diseases, ischemia, cardiomyopathy, hypertension, and periodontal disease.
[ item 23]
A kit comprising the pharmaceutical composition according to item 13 and a package insert describing that the pharmaceutical composition is useful for treating or preventing a disease selected from the group consisting of autoimmune diseases, allergic diseases, dry eye, fibrosis, cancer, metabolic diseases, ischemia, cardiomyopathy, hypertension, and periodontal disease.
Detailed Description
The definitions of terms used herein are as shown below.
The wavy lines shown below in the incomplete structure show binding sites:
the term "halogen" includes fluorine, chlorine, bromine and iodine. Preferred "halogen" is fluorine, chlorine or bromine.
The term "C1-4Alkyl "refers to a straight or branched chain saturated hydrocarbon group having 1-4 carbon atoms. "C1-4Alkyl "groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.
The term "C1-8Alkyl radical"refers to a straight or branched chain saturated hydrocarbon group having 1 to 8 carbon atoms. "C1-8Alkyl "groups include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 1-dimethylpropyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 2-ethylbutyl, n-heptyl, 5-methylhexyl, 4-dimethylpentyl, 3-dimethylpentyl, 3, 4-dimethylpentyl, 2, 3-dimethylpentyl, 3-ethylpentyl, 2-ethylpentyl, hept-4-yl, n-octyl, 6-methylheptyl, 5-dimethylhexyl, 4, 5-dimethylhexyl, 2-dimethylbutyl, 1-dimethylbutyl, 2-ethylbutyl, 5-dimethyl, 4-ethylhexyl, 3-ethylhexyl, 2-propylpentyl and oct-4-yl.
The term "C1-8Alkylene "refers to a divalent group derived from a straight or branched chain saturated hydrocarbon having from 1 to 8 carbon atoms. "C1-8Alkylene "groups include, for example, the following:
the term "halo C1-4Alkyl "refers to" C "substituted with 1-5 halogen atoms independently selected from the group of the term" halogen1-4An alkyl "group. "halo C1-4Alkyl "groups include, for example, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 1-difluoroethyl, 2,2, 2-trifluoroethyl, pentafluoroethyl, 3-fluoropropyl, 3-chloropropyl, 1-difluoropropyl, 3,3, 3-trifluoropropyl, 4-fluorobutyl and 4,4, 4-trifluorobutyl.
The term "halo C1-8Alkyl "refers to" C "substituted with 1-9 halogen atoms independently selected from the group of the term" halogen1-8An alkyl "group. "halo C1-8Alkyl "groups include, for example, monofluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2-chloroethyl, 2-bromoethyl, 1-difluoroethyl, 2,2, 2-trifluoroethyl, pentafluoroethyl, 3-fluoropropyl, 3-chloropropyl, 1-difluoropropyl, 3,3, 3-trifluoropropyl, 4-fluorobutyl, 4,4, 4-trifluorobutyl, 5-fluoropentyl, 5,5, 5-trifluoropentyl,4,4,5,5, 5-pentafluoropentyl, 3,4,4,5,5, 5-heptafluoropentyl, 6-fluorohexyl, 6,6, 6-trifluorohexyl, 7-fluoroheptyl, 7,7, 7-trifluoroheptyl, 8-fluorooctyl, 8,8, 8-trifluorooctyl and 7,7,8, 8-pentafluorooctyl.
The term "cyano-C1-4Alkyl "means" C "substituted by one cyano group1-4An alkyl "group. "cyano-C1-4Alkyl "groups include, for example, cyanomethyl, 1-cyanoethyl, 2-cyanopropyl, 3-cyanopropyl, 4-cyanobutyl and 2-cyano-2-methylpropyl.
The term "C1-4Alkoxy "means" C1-4Alkyl "groups are those in which an oxygen atom is bonded to an alkyl group and the group is bonded to another group through the oxygen atom. "C1-4Alkoxy "groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy and tert-butoxy.
The term "C3-8Cycloalkyl "refers to a monocyclic saturated hydrocarbon group having 3-8 carbon atoms. "C3-8Cycloalkyl "groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
The term "C3-8cycloalkyl-C1-4Alkyl is defined as being substituted by one selected from "C3-8Cycloalkyl-substituted "C" of the group of cycloalkyl1-4An alkyl "group. "C3-8cycloalkyl-C1-4Alkyl "groups include, for example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, 2-cyclopropylethyl, 2-cyclobutylethyl, 2-cyclopentylethyl, 2-cyclohexylethyl, 2-cycloheptylethyl, 2-cyclooctylethyl, 1-cyclopropylethyl, 1-cyclobutylethyl, 1-cyclopentylethyl, 1-cyclohexylethyl, 1-cycloheptylethyl, 1-cyclooctylethyl, 3-cyclopropylpropyl, 3-cyclobutylpropyl, 3-cyclopentylpropyl, 3-cyclohexylpropyl and 3-cyclooctylpropyl.
The term "C3-8Cycloalkylene "refers to a divalent group derived from a monocyclic saturated hydrocarbon group having 3-8 carbon atoms. "C3-8Cycloalkylene "groups include, for example, the following groups:
the term "bridged C5-8Cycloalkylene "refers to a divalent group derived from a bridged cyclic saturated hydrocarbon group having 5-8 carbon atoms. "bridged C5-8Cycloalkylene "groups include, for example, the following groups:
the term "C6-14Aryl "refers to an aromatic hydrocarbon group having 6-14 carbon atoms. "C6-14Aryl "groups include, for example, phenyl, naphthyl, anthryl, indenyl, azulenyl, fluorenyl, phenanthryl, and pentalenyl.
The term "C6-14aryl-C1-4Alkyl is defined as being substituted by one selected from "C6-14Aryl-substituted "C of the group of aryl1-4An alkyl "group. "C6-14aryl-C1-4Alkyl "groups include, for example, benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, naphthalen-1-ylmethyl, naphthalen-2-ylmethyl, anthracen-1-ylmethyl, anthracen-2-ylmethyl, and anthracen-9-ylmethyl.
The term "C6-14Arylene "refers to a divalent group derived from an aromatic hydrocarbon group having 6 to 14 carbon atoms. "C6-14Arylene "groups include, for example, the following:
for the term "substituted", for example R1The expression "C" in (1)3-8Cycloalkyl, optionally identical or different 1 to 3 selected from group A1By "substituted with" is meant unsubstituted C3-8Cycloalkyl or in which C3-8Any substitutable hydrogen atoms in the cycloalkyl radicals being selected, identically or differently, from 1 to 31A group substituted with a substituent of (1), group A1I.e. a group consisting of: (1) halogen, (2) C1-4Alkyl and (3) halo C1-4An alkyl group. Such substituted C3-8Cycloalkyl groups include, for example, the following groups:
the term "compound of the formula [ I ]" may also be referred to herein as "compound [ I ]". In one embodiment, the compound [ I ] is a compound of formula [ II ]:
wherein the definition of each variable is as defined above. The term "compound of the formula [ II ]" may also be referred to herein as "compound [ II ]".
Embodiments of the incomplete structures and substituents of the compound [ I ] and the compound [ II ] are shown below, but the respective incomplete structures or substituents of the compound [ I ] and the compound [ II ] are not limited to those embodiments; the compound [ I ] and the compound [ II ] include any combination of two or more embodiments optionally selected from embodiments in each incomplete structure or substituent.
The following incomplete structure of compound [ I ]:
refers to any of the following incomplete structures:
one preferred structure is any of the following incomplete structures:
a more preferred structure is any of the following incomplete structures:
a further preferred structure is any of the following incomplete structures:
the following incomplete structure of the compound [ II ]:
refers to any of the following incomplete structures:
。
one preferred structure is any of the following incomplete structures:
a more preferred structure is any of the following incomplete structures:
a further preferred structure is any of the following incomplete structures:
another embodiment of the following incomplete structure of compound [ I ]:
including the following incomplete structures:
such an incomplete structure refers to any of the following incomplete structures:
one preferred structure is any of the following incomplete structures:
a more preferred structure is any of the following incomplete structures:
a further preferred structure is any of the following incomplete structures:
R1preferably C1-8Alkyl, or 1 to 3, which are identical or different, from the group A1C substituted by a substituent of3-8Cycloalkyl, more preferably C1-8An alkyl group.
Group A1Preferably halogen and C1-4An alkyl group.
X1Preferably a bond.
-X1-R1The incomplete structure is preferably any one of the following structures:
R2preferably halogen, more preferably chlorine.
R3Is preferably-Y3-COO-R30。
Y3Preferably C1-8Alkylene radical, C3-8Cycloalkylene or bridged C5-8Cycloalkylene, more preferably C3-8Cycloalkylene or bridged C5-8Cycloalkylene radicals.
Y3C in (1)1-8The alkylene group is preferably any of the following groups:
。
Y3c in (1)3-8Cycloalkylene is preferably the following group:
。
Y3bridged C in (1)5-8The cycloalkylene group is preferably any of the following groups:
。
Y3c in (1)6-14The arylene group is preferably the following group:
。
R30preferably hydrogen or ethyl, more preferably hydrogen.
R4Preferably hydrogen or methyl, more preferably hydrogen.
R5And R6Preferably each independently of the other is hydrogen, C1-4Alkyl, cyano-C1-4Alkyl, or C substituted by one substituent selected from1-4Alkyl groups: -O-R51、-COO-R52、-N(R71)(R72)、-CO-N(R73)(R74)、-N(R75)-CO-R62and-O-S (O)2-R63More preferably each independently of the other hydrogen or C1-4An alkyl group.
In one embodiment, R5And R6Selected from the following options:
(A) both are hydrogen;
(B) one is hydrogen and the other is C1-4Alkyl, preferably methyl;
(C) both are C1-4Alkyl, preferably both methyl;
(D) one is hydrogen and the other is cyano-C1-4Alkyl, preferably cyanomethyl; or
(E) One is hydrogen and the other is C substituted by one substituent selected from1-4Alkyl, preferably methyl or ethyl: -O-R51、-COO-R52、-N(R71)(R72)、-CO-N(R73)(R74)、-N(R75)-CO-R62and-O-S (O)2-R63。
R7And R8Preferably each independently of the others hydrogen, halogen, cyano, C1-4Alkyl, halo C1-4Alkyl radical, C1-4Alkoxy, or by-O-R51Substituted C1-4Alkyl, more preferably both are hydrogen.
In one embodiment, R7And R8Selected from the following options:
(A) both are hydrogen;
(B) both are halogen, preferably both are fluorine;
(C) both are C1-4Alkyl, preferably both methyl; or
(D) One is hydrogen and the other is cyano, C1-4Alkyl (preferably methyl, ethyl or isopropyl), halo C1-4Alkyl (preferably trifluoromethyl), C1-4Alkoxy, preferably methoxy, or by a-O-R group51Substituted C1-4Alkyl (preferably methyl).
R9And R10Preferably each independently hydrogen or C1-4Alkyl, more preferably both are hydrogen.
In one embodiment, R9And R10Selected from the following options：
(A) Both are hydrogen; or
(B) Both are methyl.
In one embodiment, X2Is = N-and R3Is hydrogen.
In another embodiment, X2Is = C (R)4) -and R3is-Y3-COO-R30。
The term "pharmaceutically acceptable salt" can be any salt known in the art that is not unduly toxic. Specifically, it includes, for example, salts with inorganic acids, salts with organic acids, salts with inorganic bases, and salts with organic bases. Various forms of pharmaceutically acceptable salts are well known in the art and are listed, for example, in the following references:
(a) berge et al, j. pharm. sci., 66, p1-19 (1977);
(b) stahl et al, "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, Weinheim, Germany, 2002);
(c) paulekuhn et al, J. Med. chem., 50, p6665-6672 (2007).
The compound [ I ] may be reacted with an inorganic acid, an organic acid, an inorganic base or an organic base according to a known method to obtain various pharmaceutically acceptable salts thereof.
Such salts with inorganic acids include, for example, salts with hydrofluoric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, phosphoric acid, and sulfuric acid. Preferred salts include salts with hydrochloric, nitric, sulfuric, phosphoric and hydrobromic acids.
Such salts with organic acids include, for example, those with acetic acid, adipic acid, alginic acid, 4-aminosalicylic acid, anhydromethylenecitric acid, benzoic acid, benzenesulfonic acid, camphoric acid, camphor-10-sulfonic acid, carbonic acid, citric acid, ethylformic acid, ethane-1, 2-disulfonic acid, dodecylsulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glucuronic acid, glucoheptonic acid, glycolylaspartic acid, hydroxynaphthoic acid, 2-hydroxy-1-ethanesulfonic acid, lactic acid, lactobionic acid, malic acid, maleic acid, mandelic acid, methanesulfonic acid, methylsulfuric acid, methylnitric acid, methylenebis (salicylic acid), galactaric acid, naphthalene-2-sulfonic acid, 2-naphthoic acid, 1, 5-naphthalenedisulfonic acid, oleic acid, oxalic acid, pamoic acid, pantothenic acid, pectic acid, picric acid, citric acid, benzoic acid, benzenesulfonic acid, Salts of propionic acid, polygalacturonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, theanic acid (teoclic acid), thiocyanic acid, trifluoroacetic acid, p-toluenesulfonic acid, undecanoic acid, aspartic acid and glutamic acid. Preferred salts include salts with oxalic acid, maleic acid, citric acid, fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, benzoic acid, glucuronic acid, oleic acid, pamoic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and 2-hydroxy-1-ethanesulfonic acid.
Such salts with inorganic bases include, for example, salts with lithium, sodium, potassium, magnesium, calcium, barium, aluminum, zinc, bismuth, and ammonium. Preferred salts include salts with sodium, potassium, calcium, magnesium and zinc.
Such salts with organic bases include, for example, salts with arecoline, betaine, choline, clemizole, ethylenediamine, N-methylglucamine, N-benzylphenethylamine, tris (hydroxymethyl) methylamine, arginine and lysine. Preferred salts include salts with tris (hydroxymethyl) methylamine, N-methylglucamine and lysine.
Preferred "pharmaceutically acceptable salts" include the hydrochloride and sodium salts.
The compound [ I ] or a pharmaceutically acceptable salt thereof may exist in the form of a solvate.
The term "solvate" means that the compound [ I ] or a pharmaceutically acceptable salt thereof is coordinated to a solvent molecule and includes hydrates. Such solvates are preferably pharmaceutically acceptable solvates, and include hydrates, ethanolates and solvates with dimethyl sulfoxide of the compound [ I ] or a pharmaceutically acceptable salt thereof.
Specifically, such solvates include hemihydrate, monohydrate, dihydrate or monoethanol of compound [ I ], or 2/3 ethoxide of monohydrate of hydrochloride of compound [ I ] or dihydrochloride thereof. Such solvates may be obtained according to known methods.
The compound [ I ] or a pharmaceutically acceptable salt thereof may exist in its tautomeric form. Such compound [ I ] or a pharmaceutically acceptable salt thereof may exist in various tautomeric forms or in a mixture of tautomers thereof.
The compound [ I ] or a pharmaceutically acceptable salt thereof may have a stereoisomer which is considered to be a cis/trans isomer. Such compound [ I ] or a pharmaceutically acceptable salt thereof may exist in its cis or trans form, or in the form of a mixture of its cis and trans isomers.
The compound [ I ] or a pharmaceutically acceptable salt thereof may have one or more asymmetric carbon atoms. Such compound [ I ] or a pharmaceutically acceptable salt thereof may exist in a single enantiomeric form or a single diastereomeric form, or in the form of a mixture of enantiomers or diastereomers thereof.
The compound [ I ] or a pharmaceutically acceptable salt thereof may exist in its atropisomeric form. Such compound [ I ] or a pharmaceutically acceptable salt thereof may exist in various atropisomer forms or in the form of a mixture of atropisomers thereof.
The compound [ I ] or a pharmaceutically acceptable salt thereof may contain a plurality of structural features resulting in the above isomers at the same time. The compound [ I ] or a pharmaceutically acceptable salt thereof may contain the above isomers in any ratio.
Unless otherwise indicated, structural formulae, chemical structures or compound names not specifying stereochemistry herein include any of the above isomers available. For example, the following structure:
unless otherwise indicated, all of the following are included:
(1) the racemate of the following two (i.e., S-and R-) enantiomers:
(2) the S-enantiomer; and
(3) the R-enantiomer.
Diastereomeric mixtures can be separated into the individual diastereomers by conventional methods, e.g., chromatography and crystallization. The individual diastereomers can also be prepared using stereochemically pure starting materials or by synthetic methods with stereoselective reactions.
Mixtures of enantiomers can be separated into the individual enantiomers by methods well known in the art.
For example, an enantiomeric mixture can be reacted with a substantially pure enantiomer, known as a chiral auxiliary, to form a diastereomeric mixture, followed by separation from the diastereomeric mixture by conventional methods such as fractional crystallization and chromatography to give the single diastereomer with an increased ratio of isomers or the substantially pure single diastereomer. The separated diastereomer can then be converted into the desired enantiomer by removing the added chiral auxiliary in a cleavage reaction.
Mixtures of enantiomers can also be separated directly into the various enantiomers by chromatographic methods using chiral stationary phases well known in the art. Alternatively, either enantiomer may be obtained using substantially pure optically active starting materials or by stereoselective synthesis, i.e., asymmetric induction, of prochiral intermediates using chiral auxiliaries or asymmetric catalysts.
The absolute configuration can be determined by X-ray crystallography of the crystallized product or intermediate. The crystalline product or intermediate derived from a reagent having a known configuration and asymmetric center can optionally be used in an assay.
Compound [ I]Or pharmaceutically acceptable salts thereof may be substituted with isotopic atoms, e.g.2H、3H、14C and35and (5) marking by S.
For example, the compound [ I]Any hydrogen atom of (1) includes protium1H (H), deuterium2H (D) and tritium3H (T). For example, when R is1C of (A)1-8When alkyl is ethyl, except for-CH2CH3The ethyl group also includes-CD2CD3and-CT2CT3。
The compound [ I ] or a pharmaceutically acceptable salt thereof is preferably a substantially purified compound [ I ] or a pharmaceutically acceptable salt thereof. More preferred is compound [ I ] or a pharmaceutically acceptable salt thereof having a purity of 80% or more.
The pharmaceutical compositions herein can be prepared, for example, by mixing the compound [ I ] or a pharmaceutically acceptable salt thereof with at least one or more pharmaceutically acceptable carriers in an appropriate amount according to a known method in the field of pharmaceutical formulation. The content of the compound [ I ] or a pharmaceutically acceptable salt thereof in the pharmaceutical composition (also referred to herein as "therapeutically effective amount") varies depending on the dosage form and dosage, and is, for example, 0.1 to 100% by weight of the composition.
Dosage forms of the compound [ I ] or a pharmaceutically acceptable salt thereof include oral preparations such as tablets, capsules, granules, powders, lozenges, syrups, emulsions and suspensions, and parenteral preparations such as external preparations, suppositories, injections, eye drops, nasal preparations and pulmonary preparations.
The term "pharmaceutically acceptable carrier" includes various conventional organic or inorganic carrier materials used in formulation materials, such as excipients, disintegrants, binders, fluidizers, and lubricants in solid formulations; solvents, solubilizing agents, suspending agents, tonicity agents, buffers and soothing agents in liquid formulations; and a base (base), an emulsifier, a wetting agent, a stabilizer, a dispersant, a plasticizer, a pH adjuster, an absorption promoter, a gelling agent, a preservative, a filler, a solubilizing agent and a suspending agent in the semisolid preparation. Preservative agents, antioxidants, colorants or sweeteners may also optionally be used as additives.
Such "excipients" include, for example, lactose, soft sugar, D-mannitol, D-sorbitol, corn starch, dextrin, microcrystalline cellulose, crystalline cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, and acacia.
Such "disintegrants" include, for example, carboxymethylcellulose calcium, carboxymethylcellulose sodium, sodium carboxymethyl starch, croscarmellose sodium, crospovidone, low substituted hydroxypropyl cellulose, hydroxypropyl methylcellulose and crystalline cellulose.
Such "binders" include, for example, hydroxypropyl cellulose, hydroxypropyl methylcellulose, povidone, crystalline cellulose, soft sugar, dextrin, starch, gelatin, sodium carboxymethylcellulose, and acacia.
Such "fluidizing agents" include, for example, light anhydrous silicic acid and magnesium stearate.
Such "lubricants" include, for example, magnesium stearate, calcium stearate, and talc.
Such "solvents" include, for example, purified water, ethanol, propylene glycol, polyethylene glycol, sesame oil, corn oil, and olive oil.
Such "solubilizing agents" include, for example, propylene glycol, D-mannitol, benzyl benzoate, ethanol, triethanolamine, sodium carbonate, and sodium citrate.
Such "suspending agents" include, for example, benzalkonium chloride, carboxymethyl cellulose, hydroxypropyl cellulose, propylene glycol, povidone, methyl cellulose, and glyceryl monostearate.
Such "tonicity agents" include, for example, dextrose, D-sorbitol, sodium chloride and D-mannitol.
Such "buffering agents" include, for example, disodium hydrogen phosphate, sodium acetate, sodium carbonate, and sodium citrate.
Such "soothing agents" include, for example, benzyl alcohol.
Such "bases" include, for example, water, animal or vegetable oils such as olive oil, corn oil, peanut oil, sesame oil and castor oil, lower alcohols such as ethanol, propanol, propylene glycol, 1, 3-butylene glycol and phenol, higher fatty acids and esters thereof, waxes, higher alcohols, polyhydric alcohols, hydrocarbons such as white petrolatum, liquid paraffin and paraffin wax, hydrophilic petrolatum, purified lanolin, absorbent ointments, aqueous lanolin, hydrophilic ointments, starch, pullulan, gum arabic, tragacanth, gelatin, dextran, cellulose derivatives such as methyl cellulose, carboxymethyl cellulose, hydroxyethyl cellulose and hydroxypropyl cellulose, synthetic polymers such as carboxyvinyl polymers, sodium polyacrylate, polyvinyl alcohol and polyvinyl pyrrolidone, propylene glycol, polyethylene glycols such as polyethylene glycol 200-600, and combinations of any two or more thereof.
Such "preservative agents" include, for example, ethyl paraben, chlorobutanol, benzyl alcohol, sodium dehydroacetate, and sorbic acid.
Such "antioxidants" include, for example, sodium sulfite and ascorbic acid.
Such "colorants" include, for example, food dyes such as food magenta nos. 2 and 3 and food yellow nos. 4 and 5 and beta-carotene.
Such "sweeteners" include, for example, sodium saccharin, dipotassium glycyrrhizinate, and aspartame.
The pharmaceutical composition herein may be administered orally or parenterally, such as topically, rectally, intravenously, intramuscularly and subcutaneously, to humans and mammals other than humans, such as mice, rats, hamsters, guinea pigs, rabbits, cats, dogs, pigs, cows, horses, sheep and monkeys. The dosage may vary depending on the subject to be administered, the disease, the symptoms, the dosage form, the route of administration, and the like. For example, in oral administration to adult patients, the dose of the active ingredient compound [ I ] is usually about 0.01 mg to about 1 g/day, which may be administered once or in divided number of times.
Kits such as kits for administration, treatment and/or prevention, packages such as packaged goods, and pharmaceutical kits and/or kits are also useful, comprising a pharmaceutical composition containing compound [ I ] or a pharmaceutically acceptable salt thereof as an active ingredient or agent, and written material on the composition indicating that the composition can or should be used for treatment and/or prevention. Such kits, packages and pharmaceutical kits may comprise one or more containers filled with the pharmaceutical composition or one or more active ingredients for the composition and other drugs or drugs (or ingredients). Examples of such kits, packages and kits include commercial kits, commercial packages and commercial kits suitable for treating and/or preventing a desired disease. The written materials contained in such kits, packages, and pharmaceutical kits include notice or package insert in a form designated by a governmental organization that regulates the manufacture, use, or sale of pharmaceuticals or biological products which ensures approval by the governmental organization for the manufacture, use, or sale of products for administration to humans. The kits, packages, and kits may include packaged products and structures configured for appropriate administration steps and configured to enable more preferred medical treatment and/or prevention, including treatment and/or prevention of a desired disease.
The compound [ I ] or a pharmaceutically acceptable salt thereof has a ROR γ antagonistic action and is useful as a ROR γ antagonist.
The term "having ROR γ antagonist activity", "having ROR γ antagonism" or "antagonizing ROR γ" means that the function of ROR γ is antagonized, preferably specifically antagonized, to abolish or reduce its activity, and includes, for example, the function of ROR γ antagonized, preferably specifically antagonized, according to the conditions described in test example 1 below.
The term "ROR γ antagonist" refers to any substance that antagonizes the function of ROR γ, preferably any substance that specifically antagonizes the function of ROR γ.
The term "ROR γ" is preferably "human ROR γ".
The compound [ I ] or a pharmaceutically acceptable salt thereof has a ROR γ antagonistic action, and is expected to be effective for diseases in which the function of ROR γ is involved.
In particular, it is expected that the compound [ I ] or a pharmaceutically acceptable salt thereof can be used for the treatment or prevention of a disease selected from the group consisting of an autoimmune disease, an allergic disease, dry eye, fibrosis, cancer, a metabolic disease, ischemia, cardiomyopathy, hypertension and periodontal disease.
The term "autoimmune disease" refers to the generic term for diseases in which the immune system of a subject overreacts and attacks even normal cells and tissues thereof to cause symptoms, and specifically includes rheumatoid arthritis, psoriasis, inflammatory bowel diseases such as crohn's disease and ulcerative colitis, multiple sclerosis, Systemic Lupus Erythematosus (SLE), behcet's disease, sarcoidosis, madder's disease, ankylosing spondylitis, uveitis, polymyalgia rheumatica, type I diabetes, graft-versus-host disease, alopecia areata, and vitiligo.
The term "allergic disease" refers to a disease derived from a state in which an immunoreaction against a certain antigen excessively occurs, and specifically includes atopic dermatitis, allergic rhinitis such as pollen allergy, allergic conjunctivitis, allergic gastroenteritis, asthma such as bronchial asthma and infantile asthma, food allergy, drug allergy, and urticaria.
The term "fibrosis" refers to a condition with increased fibrous connective tissue, and specifically includes pulmonary fibrosis and primary biliary cirrhosis.
The term "cancer" includes malignant melanoma and prostate cancer.
The term "metabolic disease" refers to a disease caused by abnormal metabolic turnover or a disease including metabolic abnormality as an element constituting pathogenesis, and includes, for example, diabetes such as type I diabetes and type II diabetes, hepatic steatosis and nonalcoholic fatty liver disease.
The term "treating" as used herein also includes ameliorating symptoms, preventing from becoming severe, maintaining remission, preventing exacerbations, and preventing relapse.
The term "prevention" as used herein refers to inhibiting the onset of symptoms.
Combinations of any two or more of the embodiments disclosed herein are also intended to be included in the invention, provided that the embodiments are compatible with another embodiment disclosed in another part of the specification.
General methods for preparing the compound [ I ] or a pharmaceutically acceptable salt thereof are shown below. However, the method for preparing the compound [ I ] or a pharmaceutically acceptable salt thereof is not intended to be limited thereto. Unless otherwise indicated, salts of the various compounds in the general methods may be selected from the "pharmaceutically acceptable salts" described above.
The respective compounds obtained in each step may be separated and/or purified by a known method such as distillation, recrystallization and column chromatography, if necessary, but each reaction may be optionally carried out to the sequential steps without separation and/or purification.
Room temperature herein refers to an uncontrolled temperature and includes, as one embodiment, from 1 ℃ to 40 ℃.
Abbreviations used herein are as defined below.
IPA: isopropanol (I-propanol)
Hex.: n-hexane
DMSO, DMSO: dimethyl sulfoxide
NOE: nuclear ohowhaos effect
DsPhSO3N3: p-dodecyl benzene sulfonyl azide
DMEAD: azodicarboxylic acid di-2-methoxyethyl ester
TBAI: tetrabutylammonium iodide
PPTS: pyridinium p-toluenesulfonate
THF: tetrahydrofuran (THF)
WSC & HCl: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride
DMAP: dimethylaminopyridine compound
LDA: lithium diisopropylamide
DMF: n, N-dimethylformamide
DIBAL-H: diisobutylaluminum hydride
TFA: trifluoroacetic acid
NaHMDS: sodium bis (trimethylsilyl) amide
HMDS: bis (trimethylsilyl) amine
TEMPO: 2,2,6, 6-tetramethylpiperidin-1-oxyl
TBAF: tetrabutylammonium fluoride.
[ production method 1 ]: preparation of Compound [ I-1] or a salt thereof
Wherein X2Is = C (R)4) Compound of (a) or (b) [ I ]]Or a salt thereof can be obtained by, for example, the following production method 1.
In this scheme, R1、R2、R3、R4、X1、X3、X4And X5Is as defined above, and
L1is halogen, for example selected from chlorine, bromine and iodine.
(step 1-1)
The compound [13] or a salt thereof can be produced by reacting the compound [11] with the compound [12] or a salt thereof in a solvent in the presence of an organometallic reagent and a Lewis acid.
Such solvents include, for example, ether solvents such as tetrahydrofuran; hydrocarbon solvents such as toluene; and a mixed solvent of any of them. The preferred solvent herein is tetrahydrofuran.
Such organometallic reagents include, for example, n-butyllithium and t-butyllithium. The preferred organometallic reagent herein is n-butyllithium.
Such lewis acids include boron trifluoride-diethyl ether complex.
The reaction temperature is here, for example, -102 ℃ to-69 ℃, preferably-78 ℃ to-70 ℃.
The compound [11] is commercially available or can be prepared from a commercially available product by a known method.
The compound [12] or a salt thereof can be produced, for example, by any of the following production methods 1A to 1R.
(step 1-2)
The compound [14] or a salt thereof can be produced by reduction of the compound [13] or a salt thereof in a solvent in the presence of a metal reagent and an acid.
Such metal agents include, for example, zinc and iron. The preferred metal agent herein is zinc.
Such acids include, for example, acetic acid, trifluoroacetic acid, hydrochloric acid, and sulfuric acid. Preferred acids here are acetic acid or hydrochloric acid.
Such solvents include, for example, ether solvents such as tetrahydrofuran; alcohol solvents such as methanol; water; and a mixed solvent of any of them. Preferred solvents here are tetrahydrofuran, methanol or water.
The reaction temperature is here, for example, from 0 ℃ to 80 ℃, preferably from room temperature to 80 ℃.
Compound [14] or a salt thereof can also be produced by hydrogenation of compound [13] or a salt thereof in a solvent in the presence of a catalytic amount of palladium. Such solvents include, for example, ether solvents such as tetrahydrofuran; alcohol solvents such as ethanol; ester solvents such as ethyl acetate; and a mixed solvent of any of them. Preferred solvents here are tetrahydrofuran, ethanol or ethyl acetate. The reaction temperature is here room temperature.
(Steps 1-3)
The compound [16] or a salt thereof can be produced by reacting the compound [14] or a salt thereof with the compound [15] or a salt thereof in a solvent.
Such solvents include, for example, hydrocarbon solvents such as toluene; ether solvents such as tetrahydrofuran; halogenated solvents such as dichloromethane; and a mixed solvent of any of them. Preferred solvents here are toluene, tetrahydrofuran or dichloromethane.
The reaction temperature is here, for example, from 0 ℃ to 80 ℃, preferably from 0 ℃ to room temperature.
The reaction can also be carried out with the optional addition of triethylamine.
(Steps 1-4)
The compound [ I-1] or a salt thereof can be produced by oxidation of the compound [16] or a salt thereof in a solvent in the presence of an oxidizing agent, followed by cyclization.
Such solvents include, for example, halogenated solvents such as chloroform; ester solvents such as ethyl acetate; nitrile solvents such as acetonitrile; ether solvents such as cyclopentyl methyl ether; carboxylic acid solvents such as acetic acid; and a mixed solvent of any of them. Preferred solvents here are dichloromethane, chloroform, cyclopentyl methyl ether or acetic acid.
Such oxidizing agents include, for example, 2-azaadamantan-N-oxyl, 2,6, 6-tetramethylpiperidin-1-oxyl radical and Dess-Martin reagent. The reaction can also be carried out with the optional addition of auxiliary oxidants such as (diacetoxyiodo) benzene and sodium hypochlorite. The preferred oxidizing agent here is a mixture of 2,2,6, 6-tetramethylpiperidin-1-oxyl radical and (diacetoxyiodo) benzene.
Acids in the cyclization include hydrochloric acid, trifluoroacetic acid and p-toluenesulfonic acid. The preferred acid here is trifluoroacetic acid.
The reaction temperature is here, for example, from 0 ℃ to 80 ℃, preferably from 0 ℃ to room temperature.
[ production method 1A ]: preparation of Compound [ I-1A ] or salt thereof
Compound [ I]Wherein X is2Is = C (R)4) -and R4Is hydrogen (compound [ I-1A ]])：
Wherein R is1、R2、R3、X1、X3、X4And X5Is as defined above, or a salt thereof, and can be produced by, for example, using in production Process 1 the compound [12a ] obtained in production Process 1A below]Or a salt thereof in place of Compound [12]]Or a salt thereof.
In this scheme, X3、X4And X5Is as defined above.
(step 1A-1)
The compound [ a2] or a salt thereof can be produced by oxidation of the compound [ a1] or a salt thereof in a solvent.
Such solvents include, for example, ester solvents such as ethyl acetate; hydrocarbon solvents such as toluene; sulfoxide solvents such as dimethyl sulfoxide; ether solvents such as tetrahydrofuran; and halogenated solvents such as chloroform. Preferred solvents here are chloroform or dichloromethane.
Oxidizing agents here include, for example, 2,6, 6-tetramethylpiperidin-1-oxyl radical, dimethyl sulfoxide, sulfur trioxide-pyridine complex, iodoxybenzoic acid, pyridinium chlorochromate and Dess-Martin reagent. The preferred oxidizing agent here is a2, 2,6, 6-tetramethylpiperidin-1-oxyl radical.
The reaction temperature is here, for example, -78 ℃ to room temperature, preferably 0 ℃ to room temperature.
The reaction can also be carried out with the optional addition of (diacetoxyiodo) benzene.
(step 1A-2)
The compound [ A3] or a salt thereof can be prepared by reacting the compound [ a2] or a salt thereof with hydroxylamine hydrochloride in a solvent.
Such solvents include, for example, alcoholic solvents such as ethanol; hydrocarbon solvents such as toluene; halogenated solvents such as dichloromethane; ether solvents such as tetrahydrofuran; amide solvents such as dimethylformamide; nitrile solvents such as acetonitrile; water; and a mixed solvent of any of them. Preferred solvents here are ethanol, toluene, tetrahydrofuran or water.
The reaction temperature here is from room temperature to 120 ℃.
The reaction can also be carried out with optional addition of sodium acetate.
(step 1A-3)
The compound [12a ] or a salt thereof can be produced by cyclization of the compound [ a3] or a salt thereof in a solvent in the presence of an oxidizing agent.
Such oxidizing agents include, for example, (diacetoxy-iodine) benzene, sodium hypochlorite, chloramine T, and N-chlorosuccinimide. Preferred oxidizing agents here are (diacetoxyiodo) benzene or sodium hypochlorite.
When (diacetoxyiodo) benzene is used as the oxidant, an acid is used as the additive. Such acids include trifluoroacetic acid. Solvents useful herein include, for example, alcoholic solvents such as methanol; halogenated solvents such as dichloromethane; and a mixed solvent of any of them. Preferred solvents here are methanol or dichloromethane. The reaction temperature here is from 0 ℃ to room temperature.
When aqueous sodium hypochlorite is used as the oxidizing agent, a base is used as the additive. Such bases include, for example, triethylamine and pyridine. The preferred base herein is triethylamine. Solvents useful herein include, for example, halogenated solvents such as dichloromethane; alcohol solvents such as ethanol; nitrile solvents such as acetonitrile; ether solvents such as t-butyl methyl ether; and a mixed solvent of any of them. The preferred solvent here is dichloromethane. The reaction temperature here is, for example, 0 ℃ to room temperature, and preferably room temperature.
[ production method 1B ]: preparation of Compound [ I-1B ] or a salt thereof
Compound [ I]Wherein X is2Is = C (R)4)-，R4Is hydrogen, X4Is a bond, and X5is-O- (Compound [ I-1B ]])：
Wherein R is1、R2、R3、X1And X3Is as defined above, or a salt thereof, and can be produced, for example, by using the compound [12B ] obtained in the following production Process 1B in the above production Process 1]Or a salt thereof in place of Compound [12]]Or a salt thereof.
In this scheme, X3Is as defined above, and
G1a protecting group for a carboxyl group, for example selected from methyl, ethyl, isopropyl, tert-butyl or benzyl.
(step 1B-1)
The compound [ B3] or a salt thereof can be prepared by reacting the compound [ B1] with the compound [ B2] or a salt thereof in a solvent in the presence of a catalyst or without any solvent.
Such solvents include, for example, halogenated solvents such as dichloromethane; ester solvents such as ethyl acetate; ether solvents such as diethyl ether; hydrocarbon solvents such as benzene; and a mixed solvent of any of them. Here, no solvent or dichloromethane is preferred.
Such catalysts include, for example, rhodium (II) acetate dimer dihydrate, indium (III) chloride, and iron (III) chloride. The preferred catalyst herein is rhodium (II) acetate dimer dihydrate.
The reaction temperature is here room temperature.
(step 1B-2)
The compound [ B4] or a salt thereof can be produced by reduction of the compound [ B3] or a salt thereof in a solvent.
Such solvents include, for example, ether solvents such as tetrahydrofuran; halogenated solvents such as dichloromethane; hydrocarbon solvents such as toluene; and a mixed solvent of any of them. Preferred solvents here are tetrahydrofuran, dichloromethane or toluene.
The reducing agent used herein includes, for example, diisobutylaluminum hydride and lithium aluminum hydride. The preferred reducing agent herein is diisobutylaluminum hydride.
The reaction temperature is here, for example, -78 ℃ to room temperature, preferably-78 ℃ to 0 ℃.
(step 1B-3)
Compound [ B5] or a salt thereof can be prepared from compound [ B4] or a salt thereof in a similar manner to step 1A-2.
(step 1B-4)
Compound [12B ] or a salt thereof can be produced from compound [ B5] or a salt thereof in a similar manner to step 1A-3.
[ production method 1C ]: preparation of Compound [ I-1C ] or a salt thereof
Compound [ I]Wherein X is2Is = C (R)4)-，R4Is hydrogen, X4Is a bond, X5is-C (R)9)(R10) -, and R9And R10Are each hydrogen (compound [ I-1C ]])：
Wherein R is1、R2、R3、X1And X3Is as defined above, or a salt thereof, and can be produced, for example, by using the compound [12C ] obtained in the following production Process 1C in the above production Process 1]Or a salt thereof in place of Compound [12]]Or a salt thereof.
In this scheme, X3And G1Is as defined above.
[ production method 1D ]: preparation of Compound [ I-1D ] or a salt thereof
Compound [ I]Wherein X is2Is = C (R)4)-，R4Is hydrogen, X3is-C (R)5)(R6)-，R5Is hydrogen, R6Is C1-4Alkyl radical, X4is-C (R)7)(R8)-，R7And R8Each independently is hydrogen or C1-4Alkyl radical, X5is-C (R)9)(R10) -, and R9And R10Are each hydrogen (compound [ I-1D ]])：
Wherein R is6DIs C1-4An alkyl group, a carboxyl group,
R7Dand R8DEach independently is hydrogen or C1-4Alkyl, and
R1、R2、R3and X1Is as defined above, or a salt thereof, and can be produced, for example, by using the compound [12D ] obtained in the following production method 1D in the above production method 1]Or a salt thereof in place of Compound [12]]Or a salt thereof.
In this scheme, G1、R6D、R7DAnd R8DIs as defined above.
[ production method 1E ]: preparation of Compound [ I-1E ] or a salt thereof
Compound [ I]Wherein X is2Is = C (R)4)-，R4Is hydrogen, and X5is-O- (Compound [ I-1E)])：
Wherein R is1、R2、R3、X1、X3And X4Is as defined above, or a salt thereof, and can be produced, for example, by using the compound [12E ] obtained in the following production Process 1E in the above production Process 1]Or a salt thereof in place of Compound [12]]Or a salt thereof.
In this scheme, X3And X4Is as defined above.
(step 1E-1)
The compound [ E3] can be prepared by reacting the compound [ E1] with the compound [ E2] in a solvent in the presence of a base.
Such solvents include, for example, ether solvents such as tetrahydrofuran; hydrocarbon solvents such as toluene; alcohol solvents such as methanol; amide solvents such as dimethylformamide; sulfoxide solvents such as dimethyl sulfoxide; and a mixed solvent of any of them. The preferred solvent herein is tetrahydrofuran.
Such bases include, for example, sodium hydride, sodium hydroxide, sodium tert-butoxide, sodium bis (trimethylsilyl) amide, lithium diisopropylamide, and n-butyllithium. The preferred base herein is sodium hydride.
The reaction temperature is here, for example, from 0 ℃ to 140 ℃, preferably from 0 ℃ to room temperature.
(step 1E-2)
The compound [ E4] can be prepared by treating the compound [ E3] in a solvent in the presence of an acid.
Such solvents include, for example, ether solvents such as tetrahydrofuran; halogen solvents such as dichloromethane; alcohol solvents such as methanol; water; and a mixed solvent of any of them. Preferred solvents here are tetrahydrofuran or water.
Such acids include, for example, hydrochloric acid, sulfuric acid, acetic acid, phosphoric acid, boron trifluoride-diethyl ether complex, trimethylsilyl iodide, iodine, and ion exchange resins. The preferred acid here is hydrochloric acid.
The reaction temperature is here, for example, from 0 ℃ to 120 ℃, preferably 60 ℃.
(step 1E-3)
Compound [ E5] or a salt thereof can be prepared from compound [ E4] in a similar manner to step 1A-2.
(step 1E-4)
Compound [12E ] or a salt thereof can be produced from compound [ E5] or a salt thereof in a similar manner to step 1A-3.
[ production method 1F ]: preparation of Compound [ I-1F ] or salt thereof
Compound [ I]Wherein X is2Is = C (R)4)-，R4Is hydrogen, X3is-C (R)5)(R6)-，R5Is hydrogen, R6Is C1-4Alkyl radical, X4Is a bond, X5is-C (R)9)(R10) -, and R9And R10Each independently is hydrogen or C1-4Alkyl (Compound [ I-1F ]])：
Wherein R is9FAnd R10FEach independently is hydrogen or C1-4Alkyl, and
R1、R2、R3、R6Dand X1Is as defined above, or a salt thereof, and can be produced, for example, by using the compound [12F ] obtained in the following production Process 1F in the above production Process 1]Or a salt thereof in place of Compound [12]]Or a salt thereof.
In this scheme, R6D、R9FAnd R10FIs as defined above.
[ production method 1G ]: alternative preparation of Compound [ I-1A ] or salt thereof
Compound [ I]Wherein X is2Is = C (R)4) -and R4Is hydrogen (compound [ I-1A ]])：
Wherein R is1、R2、R3、X1、X3、X4And X5Is as defined above, or a salt thereof, and can be produced, for example, by using the compound [12a ] obtained in the following production Process 1G in the above production Process 1]Or a salt thereof in place of Compound [12]]Or a salt thereof.
In this scheme, RG1And RG2Each independently is C1-4Alkyl, and X3、X4And X5Is as defined above.
(step 1G-1)
The compound [ G3] or a salt thereof can be prepared by reacting the compound [ G1] or a salt thereof with the compound [ G2] in a solvent in the presence of a base.
Such solvents include, for example, ether solvents such as tetrahydrofuran; hydrocarbon solvents such as toluene; sulfoxide solvents such as dimethyl sulfoxide; and a mixed solvent of any of them. The preferred solvent herein is tetrahydrofuran.
Such bases include sodium hydride and lithium diisopropylamide.
The reaction temperature is here, for example, -78 ℃ to 110 ℃, preferably-78 ℃ to 65 ℃.
The reaction can also be carried out with optional addition of 18-crown-6-ether.
(step 1G-2)
The compound [ G5] or a salt thereof can be produced by protecting the carbonyl group of the compound [ G3] or a salt thereof with the compound [ G4] in a solvent in the presence of an acid.
Such solvents include, for example, hydrocarbon solvents such as toluene; halogenated solvents such as dichloromethane; nitrile solvents such as acetonitrile; and a mixed solvent of any of them. The preferred solvent herein is toluene.
Such acids include, for example, p-toluenesulfonic acid and pyridinium p-toluenesulfonate. The preferred acid herein is p-toluenesulfonic acid.
The reaction temperature is here, for example, from room temperature to 120 ℃, preferably from 100 ℃ to 120 ℃.
(step 1G-3)
The compound [ G6] or a salt thereof can be produced by reduction of the compound [ G5] or a salt thereof in a solvent.
Such solvents include, for example, ether solvents such as tetrahydrofuran; hydrocarbon solvents such as toluene; halogenated solvents such as dichloromethane; and a mixed solvent of any of them. Preferred solvents here are tetrahydrofuran or toluene.
The reducing agent used herein includes, for example, lithium aluminum hydride and diisobutylaluminum hydride. The preferred reducing agent herein is diisobutylaluminum hydride.
The reaction temperature is here, for example, -78 ℃ to 65 ℃, preferably-78 ℃ to room temperature.
(step 1G-4)
The compound [ G8] or a salt thereof can be produced by Mitsunobu reaction of the compound [ G6] or a salt thereof with the compound [ G7] in a solvent.
Such solvents include, for example, ether solvents such as tetrahydrofuran; halogenated solvents such as dichloromethane; hydrocarbon solvents such as toluene; and a mixed solvent of any of them. Preferred solvents here are tetrahydrofuran or dichloromethane.
Reagents used in the Mitsunobu reaction include, for example, mixtures of triphenylphosphine or tributylphosphine with diethyl azodicarboxylate or dipiperidinamide. The preferred reagent used in the Mitsunobu reaction is a mixture of triphenylphosphine and diethyl azodicarboxylate.
The reaction temperature is here, for example, from 0 ℃ to 80 ℃, preferably from 0 ℃ to room temperature.
(step 1G-5)
The compound [ G9] or a salt thereof can be produced by removing the phthaloyl group of the compound [ G8] or a salt thereof in a solvent.
Such solvents include, for example, alcoholic solvents such as ethanol; halogenated solvents such as dichloromethane; ether solvents such as diethyl ether; and a mixed solvent of any of them. Preferred solvents here are ethanol or dichloromethane.
Reagents for removing phthaloyl groups include, for example, methylhydrazine, hydrazine, and ethanolamine. The preferred reagent for removal of phthaloyl groups is methylhydrazine or hydrazine.
The reaction temperature is here, for example, from 0 ℃ to 100 ℃, preferably from room temperature to 100 ℃.
(step 1G-6)
The compound [12a ] or a salt thereof can be produced by removing the acetal group of the compound [ G9] or a salt thereof in a solvent in the presence of an acid, followed by intramolecular cyclization in the presence of a base.
Such solvents include, for example, alcoholic solvents such as methanol; ether solvents such as tetrahydrofuran; halogenated solvents such as dichloromethane; and a mixed solvent of any of them. Preferred solvents here are methanol or tetrahydrofuran.
Such acids include, for example, hydrochloric acid, acetic acid, and p-toluenesulfonic acid. Preferred acids here are hydrochloric acid or p-toluenesulfonic acid.
Such bases include, for example, potassium carbonate, sodium acetate and triethylamine. The preferred base herein is potassium carbonate.
The reaction temperature is here, for example, from 0 ℃ to 120 ℃, preferably from 0 ℃ to room temperature.
[ production method 1H ]: preparation of Compound [ I-1H ] or salt thereof
Compound [ I]Wherein X is2Is = C (R)4)-，R4Is hydrogen, X3is-C (R)5)(R6)-，R5Is hydrogen, R6Is C1-4Alkyl radical, X4is-C (R)7)(R8)-，R7Is C1-4Alkyl radical, R8Is hydrogen, X5is-C (R)9)(R10) -, and R9And R10Are each hydrogen (compound [ I-1H ]])：
Wherein R is7HIs C1-4Alkyl, and
R1、R2、R3、R6Dand X1Is as defined above, or a salt thereof, and can be produced, for example, by using the compound [12H ] obtained in the following production Process 1H in the above production Process 1]Or a salt thereof in place of Compound [12]]Or a salt thereof.
In this scheme, R6D、R7HAnd G1Is as defined above.
[ production method 1I ]: preparation of Compound [ I-1I ] or a salt thereof
Compound [ I]Wherein X is2Is = C (R)4)-，R4Is hydrogen, X3is-C (R)5)(R6)-，R5Is hydrogen, R6Is C1-4Alkyl radical, X4is-C (R)7)(R8)-，R7Is C1-4Alkyl radical, R8Is hydrogen, X5is-C (R)9)(R10) -, and R9And R10Are each hydrogen (compound [ I-1I ]])：
Wherein R is1、R2、R3、R6D、R7HAnd X1Is as defined above, or a salt thereof, and can be produced, for example, by using, in the above production process 1, the compound [12I ] obtained in the following production process 1I]Or a salt thereof in place of Compound [12]]Or a salt thereof.
In this scheme, R6D、R7HAnd G1Is as defined above.
[ production method 1J ]: preparation of Compound [ I-1J ] or a salt thereof
Compound [ I]Wherein X is2Is = C (R)4) -and R4Is C1-4Alkyl (Compound [ I-1J)])：
Wherein R is4JIs C1-4Alkyl, and
R1、R2、R3、X1、X3、X4and X5Is as defined above, or a salt thereof, and can be produced, for example, by using the compound [12J ] obtained in the following production Process 1J in the above production Process 1]Or a salt thereof in place of Compound [12]]Or a salt thereof.
In this scheme, X3、X4、X5And R4JIs as defined above.
[ production method 1K ]: preparation of Compound [ I-1K ] or salt thereof
Compound [ I]Wherein X is2Is = C (R)4)-，R4Is hydrogen, X3is-C (R)5)(R6)-，R5Is hydrogen, and R6The method comprises the following steps:
(1) halogen substituted C1-4An alkyl group, a carboxyl group,
(2) cyano-C1-4Alkyl, or
(3)C1-4Alkyl substituted by one radical selected from the group consisting of-O-R51、-CO-R61、-COO-R52、-N(R71)(R72)、-CO-N(R73)(R74)、-N(R75)-CO-R62、-N(R76)-COO-R53and-O-S (O)2-R63Substituent (Compound [ I-1K ]])：
Wherein R is6KThe method comprises the following steps:
(1) halogen substituted C1-4An alkyl group, a carboxyl group,
(2) cyano-C1-4Alkyl, or
(3)C1-4Alkyl substituted by one radical selected from the group consisting of-O-R51、-CO-R61、-COO-R52、-N(R71)(R72)、-CO-N(R73)(R74)、-N(R75)-CO-R62、-N(R76)-COO-R53and-O-S (O)2-R63Is substituted with a substituent of (a), and
R1、R2、R3、X1、X4and X5Is as defined above, or a partial salt thereof, and can be produced, for example, by using the compound [12K ] obtained in the following production method 1K in the above production method 1]Or a salt thereof in place of Compound [12]]Or a salt thereof, or by converting the benzyl ether group of the resulting compound into various substituents.
In this scheme, X4、X5And G1Is as defined above.
[ production method 1M ]: preparation of Compound [ I-1M ] or a salt thereof
Compound [ I]Wherein X is2Is = C (R)4)-，R4Is hydrogen, X3is-C (R)5)(R6)-，R5And R6Are each hydrogen, X4Is a bond, and X5is-C (R)9)(R10) - (Compound [ I-1M)])：
Wherein R is1、R2、R3、R9、R10And X1Is as defined above, or a salt thereof, and can be produced, for example, by using, in the above production process 1, the compound [12M ] obtained in the following production process 1M]Or a salt thereof in place of Compound [12]]Or a salt thereof.
In this scheme, R9And R10Is as defined above.
[ production method 1N ]: preparation of Compound [ I-1N ] or salt thereof
Compound [ I]Wherein X is2Is = C (R)4)-，R4Is hydrogen, X3is-C (R)5)(R6)-，R5Is hydrogen, R6The method comprises the following steps:
(1) halogen substituted C1-4An alkyl group, a carboxyl group,
(2) cyano-C1-4Alkyl, or
(3)C1-4Alkyl substituted by one radical selected from the group consisting of-O-R51、-CO-R61、-COO-R52、-N(R71)(R72)、-CO-N(R73)(R74)、-N(R75)-CO-R62、-N(R76)-COO-R53and-O-S (O)2-R63Is substituted with a substituent of (a), and
X4is a bond (Compound [ I-1N ]])：
Wherein R is1、R2、R3、R6K、X1And X5Is as defined above, or a partial salt thereof, and can be produced, for example, by using the compound [12N ] obtained in the following production method 1N in the above production method 1]Or a salt thereof in place of Compound [12]]Or a salt thereof, or by converting the benzyl ether group of the resulting compound into various substituents.
In this scheme, X5And G1Is as defined above.
[ production method 1P ]: preparation of Compound [ I-1P ] or salt thereof
Compound [ I]Wherein X is2Is = C (R)4)-，R4Is hydrogen, X4Is a bond, and X5is-N (R)11) - (Compound [ I-1P)])：
Wherein R is1、R2、R3、R11、X1And X3Is as defined above, or a salt thereof, and can be produced, for example, by using the compound [12P ] obtained in the following production method 1P in the above production method 1]Or a salt thereof in place of Compound [12]]Or a salt thereof.
In this scheme, R11、X3And G1Is as defined above.
(step 1P-1)
Compound [ P2] or a salt thereof can be prepared from compound [ P1] or a salt thereof in a similar manner to step 1B-2.
(step 1P-2)
Compound [ P3] or a salt thereof can be prepared from compound [ P2] or a salt thereof in a similar manner to step 1A-2.
(step 1P-3)
Compound [12P ] or a salt thereof can be produced from compound [ P3] or a salt thereof in a similar manner to step 1A-3.
[ production method 1Q ]: preparation of Compound [ I-1Q ] or salt thereof
Compound [ I]Wherein X is2Is = C (R)4)-，R4Is hydrogen, X3is-C (R)5)(R6)-，R5And R6Each independently is C1-4Alkyl radical, X4Is a bond, X5is-C (R)9)(R10) -, and R9And R10Are each hydrogen (compound [ I-1Q ]])：
Wherein R is5QIs C1-4Alkyl, and
R1、R2、R3、R6Dand X1Is as defined above, or a salt thereof, and can be produced, for example, by using the compound [12Q ] obtained in the following production Process 1Q in the above production Process 1]Or a salt thereof in place of Compound [12]]Or a salt thereof.
In this scheme, R5QAnd R6DIs as defined above.
[ production method 1R ]: preparation of Compound [ I-1R ] or salt thereof
Compound [ I]Wherein X is2Is = C (R)4)-，R4Is hydrogen, X4is-C (R)7)(R8)-，R7And R8Are each hydrogen, X5is-C (R)9)(R10) -, and R9And R10Are each hydrogen (compound [ I-1R ]])：
Wherein R is1、R2、R3、X1And X3Is as defined above, or a salt thereof, and can be produced, for example, by using the compound [12R ] obtained in the following production Process 1R in the above production Process 1]Or a salt thereof in place of Compound [12]]Or a salt thereof.
In this scheme, X3And G1Is as defined above.
[ production method 1S ]: preparation of Compound [11] used in preparation Process 1
The compound [11 ]:
wherein R is1、R2、X1And L1Is as defined above in that,
can be produced by, for example, the following compound [ S1 ]]Is prepared by cross-coupling reaction of (A) when X is1When is a bond, R1Is C1-8Alkyl, optionally substituted C3-8Cycloalkyl, or optionally substituted C3-8cycloalkyl-C1-4Alkyl (i.e. Compound [11s ]]Or [11t])。
In this scheme, R2And L1Is as defined above in that,
L2is halogen (e.g. iodine) or trifluoromethanesulfonyloxy,
R1Sis C1-8Alkyl, optionally substituted C3-8Cycloalkyl or optionally substituted C3-8cycloalkyl-C1-4An alkyl group, a carboxyl group,
RW1is boric acid, boric acid ester or trifluoroborate,
RW2is zinc or zinc halide, and can be used as the zinc halide,
R1Tis C2-8Alkyl, or optionally substituted C3-8cycloalkyl-C2-4Alkyl, and
R100Tis trimethylsilyl or a straight or branched saturated hydrocarbon having 1 to 6 carbon atoms.
Such Cross-coupling Reactions include methods described in literature, e.g., F. Diederich, P.J. Stang (1998). Metal-catalyzed Cross-linking Reactions, Weinheim, Germany, Wiley-VCH, which include Suzuki, Negishi and Sonogashira couplings.
Compound [ S1]Preferably wherein L1Is bromine and L2The compound is iodine, and the following compounds are more preferable.
For the compound [ S2], the compound [ S3] and the compound [ S4], for example, commercially available products such as isobutylboronic acid, 1-hexylboronic acid pinacol ester, (3, 3-dimethylbutyl) trifluoroborate, butyl zinc bromide and cyclohexylacetylene can be used, or these compounds can be prepared according to known methods from corresponding commercially available compounds having chlorine, bromine or iodine such as 1-chloro-3, 3-dimethylbutane and bromomethyl-cyclohexane.
Wherein R isW1Compound being boronic acid [ S2]Can be prepared by using commercially available compounds such as R1Br and magnesium followed by reaction with, for example, trimethyl borate or triisopropyl borate.
Wherein R isW1Being compounds of boronic esters [ S2]Can be prepared, for example, by reacting a boronic acid compound with pinacol.
Wherein R isW1Compound being a trifluoroborate [ S2]Can be prepared, for example, by reacting a boric acid compound with potassium hydrogen fluoride (potassium hydrogen fluoride).
Compound [ S3]Can be prepared, for example, from commercially available compounds such as R1-I and zinc preparation.
Activators for zinc include iodine, trimethylsilyl chloride, and 1, 2-dibromoethane, and these agents may be used alone or in combination of any two or more of them. Preferred activators are trimethylsilyl chloride or 1, 2-dibromoethane.
As the compound [ S4], commercially available products such as 3, 3-dimethyl-1-butyne, cyclohexylacetylene and phenylacetylene can be used.
The compound [11t ] can be obtained by catalytic hydrogenation of an alkynylene compound obtained in Sonogashira reaction with a catalyst such as palladium on carbon, platinum on carbon and rhodium-alumina to convert into an alkyl compound.
The solvent in each step includes tetrahydrofuran, N-dimethylformamide and N, N-dimethylacetamide. Preferred solvents here are tetrahydrofuran or N, N-dimethylacetamide.
The reaction temperature in each step includes room temperature to 80 ℃. The preferred reaction temperature is here room temperature.
[ production method 1Z ]: preparation of Compound [15] or a salt thereof used in preparation Process 1
The compound [15] or a salt thereof may be a commercially available product such as 6-isocyanatoethyl hexanoate, 2-isocyanato-2-methyl-propionic acid methyl ester, 3-isocyanato-propionic acid ethyl ester, 4-isocyanato-cyclohexanecarboxylic acid methyl ester and 4-isocyanatobenzoic acid ethyl ester, or may also be obtained by, for example, the production method 1Z shown below.
In this scheme, R3Is as defined above.
The compound [15] or a salt thereof can be produced by an azidation reaction of the compound [ Z1] such as commercially available products, for example, 3- (methoxycarbonyl) bicyclo [1.1.1] pentane-1-carboxylic acid, 3- (methoxycarbonyl) bicyclo [2.1.1] pentane-1-carboxylic acid, 1- (2-methoxy-2-oxoethyl) -5-oxopyrrolidine-3-carboxylic acid, and 3- [1- (ethoxycarbonyl) cyclopropyl ] propionic acid in a solvent in the presence of a base, followed by Curtius rearrangement.
Such solvents include, for example, benzene, toluene, xylene, tetrahydrofuran, and mixed solvents of any of them. The preferred solvent herein is toluene.
The azidation reagent herein includes, for example, diphenylphosphoryl azide (diphenylphosphoryl azide).
Such bases include, for example, triethylamine and diisopropylethylamine. The preferred base herein is triethylamine.
The reaction temperature is here, for example, from 0 ℃ to 140 ℃, preferably from 100 ℃ to 120 ℃.
When the compound [15] is obtained in the production method 1Z illustrated herein]Or salts thereof R3is-Y3-COO-R30And R is30Is C1-4When alkyl, wherein R30Compound [ I-1] which is hydrogen]Can be prepared by reacting the above-mentioned compound [15] in preparation Process 1]Or a salt thereof wherein R30Is C1-4Alkyl compound [ I-1]Then according to the known methodObtained by hydrolysis.
[ production method 2 ]: preparation of Compound [ I-2A ] or salt thereof
Compound [ I]Wherein X is2Is = N-, X3is-C (R)5)(R6)-，R3Is hydrogen and R5Is hydrogen (compound [ I-2A ]]) Or a salt thereof, can be obtained, for example, by the following production method 2.
In this scheme, R1、R2、R6、X1、X4、X5And L1Is as defined above.
(step 2-1)
The compound [22] or a salt thereof can be produced by oxidation of the compound [21] or a salt thereof in a solvent.
Such solvents include, for example, ether solvents such as tetrahydrofuran; ester solvents such as ethyl acetate; hydrocarbon solvents such as toluene; halogenated solvents such as dichloromethane; nitrile solvents such as acetonitrile; and a mixed solvent of any of them. The preferred solvent here is dichloromethane.
Oxidizing agents useful herein include, for example, sulfur trioxide-pyridine complex, dimethyl sulfoxide, pyridinium chlorochromate, and Dess-Martin reagent. The preferred oxidizing agent herein is a sulfur trioxide-pyridine complex.
The reaction temperature is here, for example, -60 ℃ to 60 ℃, preferably 0 ℃ to room temperature.
(step 2-2)
The compound [24] or a salt thereof can be produced by reacting the compound [22] or a salt thereof with the compound [23] or a salt thereof in a solvent in the presence of a base.
Such solvents include, for example, alcoholic solvents such as ethanol; halogenated solvents such as chloroform; hydrocarbon solvents such as chlorobenzene; and a mixed solvent of any of them. Preferred solvents here are ethanol or water.
Such bases include, for example, sodium bicarbonate and triethylamine. The preferred base herein is sodium bicarbonate.
The reaction temperature is here, for example, -10 ℃ to 100 ℃, preferably 0 ℃ to room temperature.
(step 2-3)
The compound [26] or a salt thereof can be produced by reacting the compound [24] or a salt thereof with the compound [11] or a salt thereof in a solvent.
Such solvents include, for example, ether solvents such as tetrahydrofuran. Preferred solvents here are tetrahydrofuran or diethyl ether.
Reagents useful herein include, for example, organometallic reagents such as n-butyllithium and grignard reagents such as magnesium. The preferred reagent herein is n-butyllithium.
The reaction temperature here is from-78 ℃ to room temperature.
(step 2-4)
The compound [ I-2A ] or a salt thereof can be produced by oxidation of the compound [26] or a salt thereof in a solvent.
Such solvents include halogenated solvents such as dichloromethane. The preferred solvent here is dichloromethane.
The oxidizing agent used herein includes m-chloroperbenzoic acid.
The reaction temperature is here room temperature.