Novel ACC inhibitor

Abstract

TIFF2025524984000197.tif61152 [Chemical 2] A compound having the structure of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt [wherein, R is H, C1-C6 alkyl, C1-C6 alkoxy and -(CH2) m Selected from the group consisting of -W, where W is C3-C8 cycloalkyl, bicycloalkyl, bridged bicycloalkyl, phenyl, naphthyl, a 5- or 6-membered heteroaryl or heterocyclic containing 1, 2 or 3 heteroatoms selected from the group consisting of N, S and O atoms, and each of said alkyl, cycloalkyl, alkoxy, heterocyclic, phenyl, naphthyl or heteroaryl may be unsubstituted or phenyl, halo, cyano, deuterium, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, -SO2-R’, -CONR’R’’, NR’COR’’, -NR’CONR’R’’, -NR’CO2R’’, -(CH2) n -SO2-R’, -NHSO2-R’, -NR’’SO2-R’, -SO2NR’R’’, NR’R’’ or SR’ and may be substituted, and R’ and R’’ are independently H, C1-C6 alkyl or C3-C8 cycloalkyl, and R1 is phenyl, naphthyl, a 5- or 6-membered heteroaryl or heterocyclic containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of N, S and O atoms, and a 9- or 10-membered bicyclic aryl, a heteroaryl or heterocyclic containing 1, 2 or 3 heteroatoms selected from the group consisting of N, S and O atoms, and each of said phenyl, naphthyl, aryl, heterocyclic, or heteroaryl may be unsubstituted or halo, cyano, deuterium, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, phenyl, -SO2-R’, -CONR’R’’, NR’COR’’, -NR’CONR’R’’, -NR’CO2R’’, -(CH2) n-SO2-R’, -NHSO2-R’, -NR’’SO2-R, -SO2NR’R’’, -P(O)R’R’’, may be substituted by formula (Ic) or NR’R’’’ or SR’, R’ and R’’ are independently H, C1-C6 alkyl or C3-C8 cycloalkyl, and m and n are independently 0, 1, 2 or 3]. The present invention also relates to pharmaceutically acceptable salts of these compounds and their pharmaceutically acceptable solvates, compositions containing such compounds, and the use of such compounds in the treatment of various diseases, particularly acne.

Description

Technical Field

[0001] The present invention relates to novel acetyl-CoA carboxylase (ACC) inhibitors, pharmaceutical compositions containing such compounds, and their use as medicaments. More specifically, the present invention provides novel ACC inhibitors useful for the treatment and prevention of acne.

Background Art

[0002] Acne vulgaris consists of a series of skin lesions including comedones, inflammatory papules, pustules, nodules and cysts. This disease is classified as mild, moderate or severe depending on the severity of the lesions and the anatomical lesion distribution. The onset of the disease typically occurs during puberty due to an increase in sebum production caused by an increase in androgen levels. Approximately 90% of adolescents are troubled by acne, and 15% seek medical treatment. Furthermore, this disease continues to spread to 23 - 35% of young adults (18 - 28 years old). Biologically, acne is considered an inflammatory disease of the pilosebaceous duct, and has several prominent features including (a) excessive sebum production, (b) duct occlusion due to abnormal keratinocyte proliferation and exfoliation, (c) proliferation of Cutibacterium acnes (formerly known as Propionibacterium acnes), and (d) inflammation. These factors often depend on each other. For example, an increase in androgen levels causes epithelial exfoliation and follicular occlusion, as well as excessive sebum production, and the occluded follicle is filled with lipids to form comedones. Next, this excessive sebum acts as a substrate for acne bacteria, resulting in the metabolism of sebum and the release of free fatty acids, which promote further replication of the bacteria and inflammation. Although multiple factors are involved in the etiology of this disorder, sebum acts as a nutrient source for acne bacteria, so acne cannot occur without sebum (Smith and Thiboutot, J Lipid Research, 49, 271 - 281 (2008)).

[0003] Current standard care for acne includes topical treatment for mild to moderate disease and systemic treatment for moderate to severe disease. These current treatments are either of limited efficacy or lack a favorable safety profile for widespread use. Topical acne treatments include retinoids, topical antibiotics, benzoyl peroxide, and combinations thereof. Systemic treatments include hormonal therapy, oral antibiotics, and isotretinoin (Dawson et al., BMJ 2013;346:12634). Hormonal therapy, including oral contraceptives and androgen receptor blockers, is used in the treatment of moderate to severe acne in female patients and has moderate efficacy. Oral antibiotics, including doxycycline, minocycline, tetracycline, and erythromycin, are also moderately effective in the treatment of acne, especially when compared to the resistance patterns of Propionibacterium acnes. However, their use is limited by photosensitivity and gastrointestinal disturbances (Gannon et al., Family Pract. 2011;60:290 - 92). Isotretinoin is highly effective but has several serious side effects. This drug is highly teratogenic and requires special care when prescribing, with regular pregnancy testing required. In addition, isotretinoin causes severe mucocutaneous tolerance problems (dry skin, eyes, nasal passages, lips, etc.) and can lead to dose limitations if not properly managed with supportive care. Isotretinoin treatment is associated with adverse changes in plasma lipids (increased TG, LDL) and hepatotoxicity (requiring pre-treatment liver function tests due to elevated ALT / AST). In addition, isotretinoin treatment has also been associated with myalgia (elevated CK levels in 50% of patients), ligament calcification, and adverse effects on the eyes (loss of night vision, loss of color vision, and dry eyes). In extreme cases, isotretinoin has been associated with neurological / psychological adverse effects, including the potential for depression, psychosis, and suicide.

[0004] ACC catalyzes the conversion from acetyl-CoA to malonyl-CoA and plays a very important role in the regulation of lipid metabolism. ACC is an essential rate-limiting step in de novo fatty acid synthesis and regulates the oxidation of long-chain fatty acids. The terms "de novo lipidogenesis", "DNL", and "de novo fatty acid synthesis" are used to refer to the synthesis of fatty acids from sources other than lipids. There are two closely related isoforms, ACC1 and ACC2. ACC inhibition has attracted attention as a potential mechanism for treating type 2 diabetes and obesity (WO2009144554).

[0005] During preclinical in vivo studies in rats and dogs, it was discovered that multiple ACC inhibitors induce microscopic morphological changes in sebaceous gland cells that correlate with a decrease in the lipid / sebum content of the sebaceous glands. Based on these observations, the hypothesis was put forward that ACC inhibitors may reduce sebum lipid production in rats and dogs by inhibiting de novo fatty acid synthesis. Sebum is a complex mixture of lipids, composed of triglycerides (30 - 50%), wax esters (26% - 30%), free fatty acids (15 - 30%), squalene (12 - 20%), cholesterol esters (3% - 6%) and free cholesterol (1.5 - 2.5%) (Ottaviani et al., Lipid mediators in acne. Mediators of Inflammation, 2010. doi:10.1155 / 2010 / 858176).

[0006] Of these lipid classes, triglycerides, wax esters, free fatty acids, and cholesterol esters all contain or are composed of fatty acids. An increase in sebum production rate is associated with both the onset and severity of acne (Janiczek-Dolphin et al., Br J. Dermatol. 2010;163:683 - 688). Human sebaceous glands are known to be able to de novo synthesize fatty acids (Downie and Kealey, J Invest. Dermatol. 1998;111:199 - 205), but the relative importance of this pathway within sebaceous gland cells for the use of exogenous circulating fatty acids for sebum biosynthesis was unknown.

[0007] Therefore, there is a need for a new approach to acne treatment with a favorable efficacy / safety profile. The present invention provides a new treatment method for treating acne, including the use of ACC inhibitors. Therefore, there is a need to provide new compounds that are potent and selective inhibitors of sebum secretion with suitable pharmacokinetic properties, particularly compounds that can be administered by topical administration and are effective for the treatment of acne.

Summary of the Invention

Problems to be Solved by the Invention

[0008]

Means for Solving the Problems

[0009] The present invention relates to

[0010]

Chemical Formula

[0011] [Chemical formula] Or may be substituted by SR’, and R’ and R’’ are independently H, C1-C6 alkyl or C3-C8 cycloalkyl, m and n are each, independently, 0, 1, 2, or 3.

[0012] In other aspects, the invention also provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula I or a pharmaceutically acceptable salt thereof, as well as a method for treating a condition or disorder comprising: arthritis, including rheumatoid arthritis, juvenile arthritis, and psoriatic arthritis, Hashimoto's thyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritis due to pernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis, Goodpasture's disease, autoimmune thrombocytopenia, sympathetic ophthalmia, myasthenia gravis, Graves' disease, primary biliary cirrhosis, autoimmune hepatitis, primary sclerosing cholangitis, chronic aggressive hepatitis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, ulcerative colitis and membranous glomerulopathy, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, Sjogren's syndrome, Reiter's syndrome, polymyositis, dermatomyositis, Aicardi-Goutieres syndrome and other Mendelian genetic diseases due to overexpression of type I interferon, type I interferonopathy, systemic sclerosis, polyarteritis nodosa, multiple sclerosis, relapsing-remitting multiple sclerosis, primary progressive multiple sclerosis, secondary progressive multiple sclerosis, and bullous pemphigoid, as well as Cogan's syndrome, ankylosing spondylitis, Wegener's granulomatosis, alopecia areata, type I or juvenile-onset diabetes, or thyroiditis, including additional autoimmune diseases that may be based on O cells (humoral) or T cells, autoimmune or inflammatory diseases or disorders, cancer or tumor, including gastrointestinal / gastrointestinal tract cancer, colon cancer, liver cancer, skin cancer including mast cell tumor and squamous cell carcinoma, breast cancer and mammary gland cancer, ovarian cancer, prostate cancer, lymphoma, leukemia including acute myeloid leukemia and chronic myeloid leukemia, kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer, brain tumor, melanoma including intraoral and metastatic melanoma, Kaposi's sarcoma, myeloma including multiple myeloma, myeloproliferative diseases, proliferative diabetic retinopathy, or angiogenesis-related diseases including solid tumors, diabetes, including type I diabetes or complications from diabetes, Eye diseases, disorders or conditions including autoimmune diseases of the eye, keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's disease and lens-induced uveitis, keratitis, herpes keratitis, keratoconus, corneal epithelial dystrophy, corneal leukoma, pemphigus, Mooren's ulcer, scleritis, Graves' ophthalmopathy, Vogt-Koyanagi-Harada syndrome, dry keratoconjunctivitis (dry eye), phlyctenule, iridocyclitis, sarcoidosis, endocrine ophthalmopathy, sympathetic ophthalmia, allergic conjunctivitis, or ocular angiogenesis, Inflammation of the intestine including Crohn's disease, ulcerative colitis, inflammatory bowel disease, celiac disease, proctitis, eosinophilic gastroenteritis, or mastocytosis, Neurological disorders including motor neuron diseases, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, or neurodegenerative diseases caused by traumatic injury, concussion, glutamate neurotoxicity or hypoxia; stroke, myocardial ischemia, renal ischemia, heart attack, cardiac hypertrophy, atherosclerosis and arteriosclerosis, organ hypoxia, or ischemia / reperfusion injury in platelet aggregation, Atopic dermatitis, hand dermatitis, contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, congestive dermatitis, dyshidrotic eczema, dry dermatitis, nummular dermatitis, seborrheic dermatitis, seborrhea, seborrheic muscle, eyelid dermatitis, diaper dermatitis, dermatomyositis, scleroderma, keloid, hypertrophic scar, morphea, frontal fibrosing alopecia, cicatricial alopecia, lichen planus, lichen sclerosus, alopecia areata, vitiligo, pityriasis versicolor, pityriasis versicolor-like dermatitis, steroid-induced dermatitis, drug eruption (including papulopustular drug eruption), epidermolysis bullosa, porokeratosis, pityriasis alba, pemphigus, vulvovaginitis, acne (although not limited to, acne vulgaris, nodular acne, nodulocystic acne, cystic acne, globular acne, steroid acne, and autoinflammatory syndromes [although not limited to, including PAPA, PAPASH, PASS, PASH, SAPHO, PCO, and SH], including acne scars), chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, Vogt-Koyanagi-Harada disease, Sutton's nevus, postinflammatory hypopigmentation, senile vitiligo, chemical / drug-induced vitiligo, cutaneous lupus erythematosus, discoid lupus erythematosus, palmoplantar pustulosis, pemphigoid, Sweet syndrome, hidradenitis suppurativa, psoriasis, psoriasis vulgaris, pustular psoriasis, nail psoriasis, flexural psoriasis, guttate psoriasis, psoriatic arthritis, erythrodermic psoriasis, inverse psoriasis, refractory wound, sebaceous hyperplasia, Fordyce disease (Fordyce granules, Fordyce spots), Fox-Fordyce disease, bromhidrosis (osmidrosis), hypertrichosis, or skin tumors (sebaceous nevus, sebaceous adenoma, sebaceous epithelioma, simple sebaceous cyst (steatocytoma), multiple sebaceous cysts, Muir-Torre syndrome, sebaceous carcinoma), skin diseases, conditions or disorders.

[0013] The present invention will be further understood from the following description which is merely illustrative. The present invention is directed to a certain class of tricyclic spiropiperidine compounds. In particular, the present invention is directed to certain tricyclic spiropiperidine compounds useful as ACC inhibitors useful for the treatment of acne. The present invention is not limited thereto, and various aspects of the present invention can be understood through the following discussion and examples.

Mode for Carrying Out the Invention

[0014] Detailed Description of the Invention Unless otherwise defined herein, scientific and technical terms used in connection with the present invention shall have the meanings that are commonly understood by those of ordinary skill in the art.

[0015] The phrase "therapeutically effective" is intended to qualify the amount of a compound or pharmaceutical composition, or in the case of a combination therapy, the total amount of active ingredients, which achieves the goal of treating the relevant condition.

[0016] The term "treatment," as used herein to describe the present invention, means, unless otherwise limited, administering a compound, pharmaceutical composition, or combination to provide preventative, symptomatic, supportive, restorative, or curative treatment. The term treatment encompasses any objective or subjective improvement in a subject with respect to the associated condition or disease.

[0017] The term "prophylactic treatment," as used herein to describe the present invention, means administering a compound, pharmaceutical composition, or combination to a subject to inhibit or prevent the occurrence of the relevant condition in the subject, particularly in subjects or members of a population that are significantly susceptible to the relevant condition.

[0018] The term "ACC inhibitor," as used herein, refers to a compound that inhibits ACC1 and potentially ACC2. The ACC1 assay disclosed herein measures the inhibitory activity of a compound against ACC1 (IC 50 ) can be used to establish an IC of less than about 10 μM in the ACC1 assay. 50 Compounds having the following formula are considered to be ACC inhibitors: 50is less than about 1 μM in the assay, and a particularly preferred IC50 is less than about 0.1 μM in the assay. In addition, the ACC inhibitors of the present invention selectively inhibit ACC1 and potentially ACC2 as compared to other enzymes, G protein-coupled receptors or ion channels. Compounds contemplated by the present invention inhibit other enzymes or bind to receptors or ion channels at concentrations higher than the concentration required to inhibit ACC1 (K i ). Preferred ACC inhibitory activity is about 2- to 10-fold higher than the IC50 or K i of other enzymes, receptors or ion channels, more preferably 10- to 100-fold, and particularly preferably more than 100-fold.

[0019] The term "selective", when used to describe a functionally defined receptor ligand or enzyme inhibitor, means selective for a defined receptor or enzyme subtype as compared to other receptor or enzyme subtypes of the same family. For example, a selective ACC inhibitor is a compound that inhibits the ACC enzyme subtype more potently than any other enzyme subtype. Such selectivity is preferably at least 2-fold (as measured using conventional binding assays), more preferably at least 10-fold, and most preferably at least 100-fold.

[0020] The term "alkyl", alone or in combination, means an acyclic saturated hydrocarbon group of the formula C n H 2n+1 , which group may be straight-chain or branched. Examples of such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl and hexyl. Unless otherwise specified, alkyl groups contain from 1 to 6 carbon atoms.

[0021] The carbon atom content of alkyl and various other hydrocarbon-containing moieties is indicated by a prefix indicating the lower and upper numbers of carbon atoms in the moiety, i.e., the prefix C i ~C jrepresents a moiety having from integer "i" to integer "j" carbon atoms including both ends. Thus, for example, C1-C6 alkyl refers to an alkyl having from 1 to 6 carbon atoms including both ends.

[0022] The term "hydroxy", as used herein, means an OH radical.

[0023] The term "heterocyclic" refers to a saturated or partially saturated (i.e., non-aromatic) ring system that can be attached via a ring nitrogen atom (when the heterocycle is attached to a carbon atom) or a ring carbon atom (in all cases). Similarly, when substituted, the substituent can be located on a ring nitrogen atom (when the substituent is attached via a carbon atom) or a ring carbon atom (in all cases). Specific examples include oxiranyl, aziridinyl, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, piperazinyl, azepanyl, oxepanyl, oxazepanyl, and diazepinyl.

[0024] The term "heteroaryl" is an aromatic heterocycle that can be attached via a ring carbon atom or a ring nitrogen atom having an appropriate valence (when the heterocycle is attached to a carbon atom). Similarly, when substituted, the substituent can be located on a ring carbon atom having an appropriate valence (in all cases) or a ring nitrogen atom (when the substituent is attached via a carbon atom). Specific examples include thienyl, furanyl, pyrrolyl, pyrazolyl, imidazoyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

[0025] The term "bicyclic" refers to a ring system containing two rings fused together. Specific examples include naphthyl, imidazo[2,1-b][1,3]thiazolyl, benzofuranyl, benzothienyl, indolyl, benzimidazolyl, indazolyl, benzotriazolyl, pyrrolo[2,3-b]pyridyl, pyrrolo[2,3-c]pyridyl, pyrrolo[3,2-c]pyridyl, pyrrolo[3,2-b]pyridyl, imidazo[4,5-b]pyridyl, imidazo[4,5-c]pyridyl, pyrazolo[4,3-d]pyridyl, pyrazolo[4,3-c]pyridyl, pyrazolo[3,4-c]pyridyl, pyrazolo[3,4-b]pyridyl, isoindolyl, indazolyl, purinyl, indolizinyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrrolo[1,2-b]pyridazinyl, imidazo[1,2-c]pyrimidinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl, 1,8-naphthyridinyl, 1,5-naphthyridinyl, 2,6-naphthyridinyl, 2,7-naphthyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, pyrido[2,3-d]pyrazinyl, pyrido[3,4-b]pyrazinyl, pyrimido[5,4-d]pyrimidinyl, pyrazino[2,3-b]pyrazinyl and pyrimido[4,5-d]pyrimidine.

[0026] The term "cycloalkyl" means a monocyclic or bicyclic saturated hydrocarbon group of the formula C n H 2n-1 Examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Bicyclic compounds include bridged ring compounds such as bicyclo[1.1.1]pentanyl. Unless otherwise specified, cycloalkyl groups contain 3 to 8 carbon atoms.

[0027] The term "alkoxy" means a radical containing an alkyl radical bonded to an oxygen atom, such as a methoxy radical. Examples of such radicals include methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert-butoxy. The term "halo" means fluoro, chloro, bromo or iodo.

[0028] As used herein, the terms "co-administration", "co-administered" and "administered in combination" refer to a combination of a compound of formula I and one or more other therapeutic agents and include the following. · Co-administration of such components to a patient when such a combination of a compound of formula I and a further therapeutic agent is formulated together in a single dosage form and such components are released substantially simultaneously to a patient in need of treatment, · Substantial co-administration of such components to a patient when such a combination of a compound of formula I and a further therapeutic agent is formulated separately into separate dosage forms that are substantially simultaneously ingested by a patient and, moreover, such components are released substantially simultaneously to a patient in need of treatment, · Sequential administration of such components to a patient when such a combination of a compound of formula I and a further therapeutic agent is formulated separately into separate dosage forms that are sequentially ingested by a patient in need of treatment with a significant time interval between each administration and, moreover, such components are released to the patient at substantially different times, as well as · Sequential administration of such components to a patient in need of treatment when such a combination of a compound of formula I and a further therapeutic agent is formulated together in a single dosage form that releases such components in a controlled manner.

[0029] As used herein, the term "excipient" is used to describe any component other than a compound of formula I. The choice of excipient varies widely depending on factors such as the particular method of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. The term "excipient" includes diluents, carriers or adjuvants.

[0030] The present invention relates to novel compounds that are ACC regulators useful for the treatment of diseases and conditions associated with dysregulation of ACC. The present invention further provides pharmaceutical compositions comprising such ACC enzyme regulators, as well as methods for treating and / or preventing such diseases and conditions. Accordingly, the present invention provides a compound of formula I as represented above, or a pharmaceutically acceptable salt thereof.

[0031] Some embodiments (E) of the first aspect of the present invention (for convenience, E1 is the same as it) are described below.

[0032] E1. A compound of formula I as defined above, or a pharmaceutically acceptable salt thereof.

[0033] E2. R is selected from the group consisting of H, C1-C6 alkyl and -(CH2) m -W, where W is C3-C8 cycloalkyl, and each of the alkyl, cycloalkyl, bicycloalkyl, and bridged bicycloalkyl may be unsubstituted or substituted by halo, cyano, deuterium, hydroxy, C1-C6 alkyl, and C1-C6 alkoxy, and m and n are independently 0, 1, 2, or 3, the compound according to E1.

[0034] E3. The compound according to E1, wherein R is t-butyl.

[0035] E4. R1 is phenyl, pyridyl, indolyl, indazolyl, pyrrolopyridinyl, quinolinyl, isoquinolinyl, or naphthyl, and each of the phenyl, pyridyl, indolyl, indazolyl, pyrrolopyridinyl, quinolinyl, isoquinolinyl, or naphthyl may be unsubstituted or substituted by halo, cyano, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, phenyl, -CONR’R’’, NR’R’’, or SR’, where R’ and R’’ are independently H, C1-C6 alkyl, or C3-C8 cycloalkyl, and m and n are independently 0, 1, 2, or 3, the compound according to E1.

[0036] E5. 2-(tert-Butyl)-1'-(7-methoxy-1,3-dimethyl-1H-indazole-5-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one; 2-(tert-Butyl)-1'-(7-methyl-1H-indole-5-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one; 2-(tert-Butyl)-1'-(8-methyl-3-(methylamino)quinoline-6-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one; 2-(tert-Butyl)-1'-(7-ethoxy-1,3-dimethyl-1H-indazole-5-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one; 2-(tert-Butyl)-1'-(4-methyl-2-naphthoyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one; The compound according to E1 selected from the group consisting of, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt.

[0037] E6. The compound according to E1 which is 2-(tert-butyl)-1'-(7-methoxy-1,3-dimethyl-1H-indazole-5-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt.

[0038] The compound described in E1 which is E7. 2-(tert-butyl)-1'-(7-methyl-1H-indole-5-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the said compound or pharmaceutically acceptable salt.

[0039] The compound described in E1 which is E8. 2-(tert-butyl)-1'-(8-methyl-3-(methylamino)quinoline-6-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the said compound or pharmaceutically acceptable salt.

[0040] The compound described in E1 which is E9. 2-(tert-butyl)-1'-(7-ethoxy-1,3-dimethyl-1H-indazole-5-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the said compound or pharmaceutically acceptable salt.

[0041] The compound described in E1 which is E10. 2-(tert-butyl)-1'-(4-methyl-2-naphthoyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the said compound or pharmaceutically acceptable salt.

[0042] A pharmaceutical composition comprising the compound described in any one of E1 to E10 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the said compound or salt, and a pharmaceutically acceptable excipient.

[0043] E12. Inflammation, autoimmune diseases, neuroinflammation, arthritis, rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, lupus nephritis, osteoarthritis, gouty arthritis, pain, fever, pulmonary sarcoidosis, silicosis, cardiovascular diseases, atherosclerosis, myocardial infarction, thrombosis, congestive heart failure and cardiac reperfusion injury, cardiomyopathy, stroke, ischemia, reperfusion injury, brain edema, traumatic brain injury, neurodegeneration, liver diseases, inflammatory bowel diseases, Crohn's disease, ulcerative colitis, nephritis, retinitis, retinopathy, macular degeneration, glaucoma, diabetes (type 1 and type 2), diabetic neuropathy, viral and bacterial infections, myalgia, endotoxin shock, toxic shock syndrome, osteoporosis, multiple sclerosis, endometriosis, dysmenorrhea, vaginitis, candidiasis, cancer, fibrosis, obesity, muscular dystrophy, polymyositis, dermatomyositis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, vitiligo, Alzheimer's disease, flushing of the skin, eczema, psoriasis, atopic dermatitis, sunburn, keloid, hypertrophic scar, rheumatic diseases, urticaria, discoid lupus erythematosus, cutaneous lupus, central nervous system lupus, psoriatic arthritis, asthma, allergic asthma, Aicardi-Goutières syndrome and other Mendelian genetic diseases with overexpression of type I interferon including type I interferonopathy, primary progressive multiple sclerosis, relapsing-remitting multiple sclerosis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, scleroderma, alopecia areata, cicatricial alopecia, prurigo, nodular prurigo, CPUO, lichenoid diseases, lichen planus, Stevens-Johnson syndrome, spondylosis, myositis, vasculitis, pemphigus, lupus, major depressive disorder, allergy, dry eye syndrome, graft rejection, cancer, septic shock, cardiopulmonary dysfunction, acute respiratory diseases, ankylosing spondylitis, cachexia, chronic graft-versus-host disease, acute graft-versus-host disease, celiac sprue, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, myasthenia gravis, Sjögren's syndrome, epidermal hyperplasia, cartilage inflammation, bone resorption, juvenile arthritis, juvenile rheumatoid arthritis, oligoarticular juvenile rheumatoid arthritis, polyarticular juvenile rheumatoid arthritis, systemic-onset juvenile rheumatoid arthritis, juvenile ankylosing spondylitis, juvenile enteropathic arthritis, juvenile Reiter syndrome, SEA syndrome, juvenile dermatomyositis, juvenile psoriatic arthritis, juvenile scleroderma, juvenile systemic lupus erythematosus, juvenile vasculitis, oligoarticular rheumatoid arthritis, polyarticular rheumatoid arthritis, systemic-onset rheumatoid arthritis,A method for treating a disease or condition selected from inflammatory arthritis, reactive arthritis, Reiter's syndrome, myolitis, polymyolitis, dermatomyolitis, polyarteritis nodosa, Wegener's granulomatosis, arteritis, rheumatoid polymyalgia, sarcoidosis, sclerosis, primary biliary sclerosis, sclerosing cholangitis, dermatitis, Still's disease, chronic obstructive pulmonary disease, Guillain - Barré disease, Graves' disease, Addison's disease, Raynaud's phenomenon, psoriatic epidermal hyperplasia, psoriasis vulgaris, guttate psoriasis, inverse psoriasis, pustular psoriasis, psoriatic erythroderma, an immune disorder associated with or resulting from the activity of pathogenic lymphocytes, non - infectious uveitis, Behçet's disease, and Vogt - Koyanagi - Harada syndrome, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound described in E1 to E10 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt.

[0044] The method according to E12, wherein the compound is administered topically.

[0045] The method according to E12 or E13, wherein the compound is administered as a cream, ointment, lotion, gel, solution, suspension, foam, aerosol, spray, shampoo, patch or tape.

[0046] A method for treating acne, the method comprising administering to a subject a therapeutically effective amount of a compound described in E1 to E10 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt.

[0047] The method according to E15, wherein the compound is administered topically.

[0048] The method according to E15 or E16, wherein the compound is administered as a cream, ointment, lotion, gel, solution, suspension, foam, aerosol, spray, shampoo, patch or tape.

[0049] Use of a compound as described in any one of E1 to E10 for the manufacture of a medicament for the treatment of a disorder for which an ACC inhibitor is applicable.

[0050] Use of a compound as described in any one of E1 to E10 for the manufacture of a medicament for the treatment of acne.

[0051] A compound as described in any one of E1 to E10 for use in the treatment of a disorder for which an ACC inhibitor is applicable.

[0052] Compounds of the present invention that have the same molecular formula but differ in the nature or order of the bonds of their atoms, or in the arrangement of those atoms in space, are called "isomers". Isomers that differ in the arrangement of their atoms in space are called "stereoisomers". These stereoisomers are either "R" or "S" depending on the configuration of the substituents around the chiral carbon atom. The terms "R" and "S" as used herein are the configurations defined in Section E, Recommendations on Fundamental Stereochemistry, of IUPAC 1974, Pure Appl. Chem., 1976, 45: 13 - 30. The enantiomers of the present invention represented by (R), (S), or * substantially do not contain other enantiomers. "Substantially do not contain" means that the enantiomeric excess is greater than about 90%, preferably greater than about 95%, more preferably greater than about 99%. In the context of enantiomeric excess, the term "about" means ±1.0%. The symbol *The chiral carbon atoms are designated as either (R) or (S) stereochemistry according to the configuration of the substituents around the chiral carbon atoms. The present invention contemplates various stereoisomers and mixtures thereof that are specifically included within the scope of the present invention. Stereoisomers include enantiomers and mixtures of enantiomers. The individual stereoisomers of the compounds of the present invention can be prepared synthetically from commercially available starting materials containing asymmetric or chiral centers, or by preparing a racemic mixture followed by resolution, which is well known to those skilled in the art. These resolution methods include, but are not limited to, (1) the attachment of a chiral auxiliary to a mixture of enantiomers, the recrystallization or chromatographic separation of the resulting mixture of diastereomers, and the liberation of the optically pure product from the auxiliary, or (2) the direct separation of a mixture of optical enantiomers on a chiral chromatography column. The compounds of the present invention designated as (R), (S), or * not specified can exist as a racemate (i.e., 50% (R) and 50% (S)) or as a mixture of two enantiomers in which one enantiomer is in excess. For example, a mixture of enantiomers can include any combination of (R) and (S) other than a 51% (R) enantiomer and 49% (S) enantiomer or vice versa, or a 50% (R) and 50% (S) racemic mixture.

[0053] The scope of the described compounds includes all isomers (e.g., cis, trans, or diastereomers) of the compounds described herein, alone and in any mixture thereof. All of these forms, including enantiomers, diastereomers, cis, trans, syn, anti, solvates (including hydrates), tautomers, and mixtures thereof, are included in the described compounds. Mixtures of stereoisomers, such as mixtures of diastereomers, can be separated into their corresponding isomers in a known manner by using suitable separation methods. For example, mixtures of diastereomers can be separated into their individual diastereomers by using fractional crystallization, chromatography, solvent distribution, and similar procedures. This separation can be carried out at either one level of the starting compounds or the compounds of formula I themselves. Enantiomers can be separated by formation of diastereomeric salts, for example by formation of salts with enantiomerically pure chiral acids, or by chromatography using a chromatographic substrate having a chiral ligand, such as HPLC. The present invention includes all pharmaceutically acceptable isotopically labeled compounds of formula I or pharmaceutically acceptable salts thereof, wherein one or more atoms are replaced by atoms having the same atomic number but different atomic masses or mass numbers than the predominant atomic mass or mass number found in nature.

[0054] Examples of isotopes suitable for inclusion in the compounds of the present invention include isotopes of hydrogen, such as 2 H and 3 H, isotopes of carbon, such as 11 C, 13 C and 14 C, isotopes of chlorine, such as 36 Cl, isotopes of fluorine, such as 18 F, isotopes of iodine, such as 123 I and 125 I, isotopes of nitrogen, such as 13 N and 15 N, isotopes of oxygen, such as 15 O, 17 O and 18 O, isotopes of phosphorus, such as 32P, as well as isotopes of sulfur, such as 35 S are included.

[0055] Certain isotope-labeled compounds of formula I or pharmaceutically acceptable salts thereof, such as those incorporating radioisotopes, are useful in the study of the tissue distribution of drugs and / or substrates. Tritium, a radioactive isotope, i.e., 3 H and carbon-14, i.e., 14 C are particularly useful for this purpose considering their ease of incorporation and the simplicity of detection means.

[0056] Heavier isotopes, such as deuterium, i.e., 2 H substitution provides certain therapeutic advantages obtained from higher metabolic stability, such as an extended in vivo half-life or a reduced required dosage, and may thus be preferred in some circumstances. Substitution with positron-emitting isotopes, such as 11 C, 18 F, 15 O and 13 N may be useful in positron emission topography (PET) studies to examine the occupancy of substrate receptors. Isotope-labeled compounds of formula I can generally be prepared by the prior art known to those skilled in the art or by a process similar to the processes described in the appended examples and preparations using appropriate isotope-labeled reagents in place of the non-labeled reagents previously used.

[0057] In some embodiments, the present disclosure provides deuterium-labeled (or deuterated) compounds and salts, and the formulas and variables of such compounds and salts are, each independently, as described herein. "Deuterated" means that at least one of the atoms in the compound is deuterium in an abundance greater than the natural abundance of deuterium (typically, approximately 0.015%). Those skilled in the art recognize that in compounds containing hydrogen atoms, the hydrogen atoms are actually a mixture of H and D, with approximately 0.015% being D. The concentration of deuterium incorporated into the deuterium-labeled compounds and salts of the present invention can be defined by a deuterium enrichment factor.

[0058] As used herein, the "deuterium enrichment factor" means the ratio of the deuterium abundance and the natural abundance of deuterium to the hydrogen abundance, respectively. An atomic position designated as having deuterium typically has a deuterium enrichment factor of at least 1000 (15% deuterium incorporation), at least 2000 (30% deuterium incorporation), at least 3000 (45% deuterium incorporation), at least 3500 (52.5% deuterium incorporation), at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) in certain embodiments.

[0059] It is understood that under physiological conditions, one or more deuteriums can be exchanged with hydrogen.

[0060] In some embodiments, the present disclosure provides a deuterium compound of Formula I, or a pharmaceutically acceptable salt thereof, in place of a previously used unlabeled reagent.

[0061] In some embodiments, R1 is selected from CH3, CH2D, CHD2 and CD3.

[0062] In some embodiments, the deuterium compound of Formula I is selected from any one of the compounds described in the Examples section.

[0063] In some embodiments, the metabolically labile sites of the compounds of the present invention are deuterated.

[0064] The isotope-labeled compounds of the present invention can generally be prepared by processes similar to those described in the attached examples and preparations, by the prior art known to those skilled in the art or using appropriate isotope-labeled reagents in place of the unlabeled reagents previously used. In the synthesized compounds, some variation in the natural isotope abundances may occur, which may depend on the origin of the synthetic materials used in the synthesis of the compounds, and this is also well recognized in the art.

[0065] The deuterium enrichment of the compounds provided herein can be determined using conventional analytical methods known to those skilled in the art, including mass spectrometry, nuclear magnetic resonance spectroscopy, and X-ray crystallography.

[0066] Pharmaceutically acceptable solvates according to the present invention include those in which the crystallization solvent can be isotope-substituted, for example, D2O, d6-acetone, d6-DMSO.

[0067] For therapeutic use in treating mammalian disorders, the compounds of the present invention or pharmaceutical compositions thereof can be administered orally, parenterally, topically, rectally, transmucosally, or enterally. Parenteral administration includes indirect injection to produce a systemic effect or direct injection into the affected area. Topical administration includes treatment of the skin or organs that are readily accessible by topical application, such as the eyes or ears. Also included is transdermal delivery to produce a systemic effect. Rectal administration includes the form of suppositories. Preferred routes of administration are oral and parenteral.

[0068] Pharmaceutically acceptable salts of the compound of formula I or a pharmaceutically acceptable salt thereof include its acid addition salts and base salts. Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-naphthylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, saccharinate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xinoformate.

[0069] Suitable base salts are formed from bases that form non-toxic salts. Examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, and zinc salts.

[0070] Hemisalts of acids and bases, such as hemisulfate and hemicalcium salts, may also be formed. For a general review of suitable salts, see Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (Wiley-VCH, 2002).

[0071] The pharmaceutically acceptable salts of the compounds of formula I or the pharmaceutically acceptable salts of such salts can each be prepared by one or more of the following three methods: (i) by reacting a compound of formula I with a desired acid or base, (ii) by removing an acid- or base-labile protecting group from a suitable precursor of a compound of formula I, or by ring-opening a suitable cyclic precursor, such as a lactone or lactam, using the desired acid or base, or (iii) by reacting one salt of a compound of formula I with a suitable acid or base or by converting it to another salt by using a suitable ion-exchange column. All three reactions are typically carried out in solution. The resulting salt can be precipitated and collected by filtration or recovered by evaporation of the solvent. The degree of ionization of the resulting salt can vary from fully ionized to hardly ionized.

[0072] The pharmaceutical compositions of the present invention can be manufactured by methods well known in the art, for example, by using conventional mixing, dissolving, granulating, tablet coating, pulverizing, emulsifying, encapsulating, entrapping, lyophilization processes or spray drying.

[0073] The pharmaceutical compositions for use in accordance with the present invention can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers including excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Suitable formulations depend on the chosen route of administration. Pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are thus included in the present invention. Such excipients and carriers are described, for example, in Remington’s Pharmaceutical Sciences, Mack Pub.Co., New Jersey (1991). The formulations of the present invention can be designed to be of short-acting, rapid-release, long-acting, and sustained-release types. Thus, the pharmaceutical formulations can also be formulated for controlled or sustained release.

[0074] Pharmaceutical compositions suitable for use in the present invention include compositions in which the active ingredient is contained in an amount sufficient to achieve the intended purpose, i.e., the control or treatment of a disorder or disease. More specifically, a therapeutically effective amount means an amount of a compound effective to prevent, alleviate or ameliorate the symptoms / signs of a disease or to prolong the survival period of a subject to be treated.

[0075] The amounts of the active constituent, which is the compound of the present invention, in the pharmaceutical composition and its unit dosage forms can be widely varied or adjusted according to the mode of administration, the potency of the specific compound and the desired concentration. The determination of a therapeutically effective amount is within the ability of those skilled in the art. Generally, the amount of the active constituent ranges between 0.01% and 99% by weight of the composition.

[0076] Generally, the therapeutically effective dosage of the active constituent ranges from about 0.01 to about 100 mg / kg body weight / day, preferably from about 0.1 to about 10 mg / kg body weight / day, more preferably from about 0.3 to 3 mg / kg body weight / day, and still more preferably from about 0.3 to 1.5 mg / kg body weight / day. It should be understood that the dosage may vary depending on the requirements of each subject and the severity of the disorder or disease to be treated.

[0077] The desired dosage may conveniently be presented as a single dose or as divided doses administered at appropriate intervals, for example as two, three, four or more sub-doses per day. The sub-doses themselves may be further divided, for example, into individual administrations at several gentle intervals, such as multiple inhalations from an inhaler or the application of multiple droplets to the eye.

[0078] It should also be understood that, in order to rapidly achieve the desired concentration at the site of action, the initial dosage administered may be increased beyond the upper limit levels described above. On the other hand, the initial dosage may be less than the optimal amount and the daily dosage may be gradually increased during the course of treatment according to specific circumstances. Also, if desired, the daily dosage may be divided into multiple dosages, for example, for administration two to four times a day.

[0079] The present invention also includes the following embodiments. A compound of I or a pharmaceutically acceptable salt thereof as defined in any of the embodiments described herein for use as a medicament, or a pharmaceutically acceptable solvate of said compound or salt, Inflammation, autoimmune diseases, neuroinflammation, arthritis, rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, lupus nephritis, osteoarthritis, gouty arthritis, pain, fever, pulmonary sarcoidosis, silicosis, cardiovascular diseases, atherosclerosis, myocardial infarction, thrombosis, congestive heart failure and cardiac reperfusion injury, cardiomyopathy, stroke, ischemia, reperfusion injury, cerebral edema, traumatic brain injury, neurodegeneration, liver diseases, inflammatory bowel diseases, Crohn's disease, ulcerative colitis, nephritis, retinitis, retinopathy, macular degeneration, glaucoma, diabetes (type 1 and type 2), diabetic neuropathy, viral and bacterial infections, myalgia, endotoxin shock, toxic shock syndrome, osteoporosis, multiple sclerosis, endometriosis, dysmenorrhea, vaginitis, candidiasis, cancer, fibrosis, obesity, muscular dystrophy, polymyositis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, vitiligo, Alzheimer's disease, flushing of the skin, eczema, psoriasis, atopic dermatitis, sunburn, keloid, hand dermatitis, contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, congestive dermatitis, dyshidrotic eczema, xerotic dermatitis, nummular dermatitis, seborrheic dermatitis, seborrhea, seborrheic myosis, eyelid dermatitis, diaper dermatitis, dermatomyositis, scleroderma, hypertrophic scar, morphea, frontal fibrosing alopecia, cicatricial alopecia, lichen planus, lichen sclerosus, alopecia areata, vitiligo, rosacea, rosacea-like dermatitis, steroid-induced dermatitis, drug eruption (including papulopustular drug eruption), epidermolysis bullosa, porokeratosis, pityriasis alba, pemphigus, vulvovaginitis, acne (including but not limited to acne vulgaris, nodular acne, nodulocystic acne, cystic acne, globular acne, steroid acne), and autoinflammatory syndromes (including but not limited to PAPA, PAPASH, PASS, PASH, SAPHO, PCO, and SH), and acne scars, chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, Vogt-Koyanagi-Harada disease, Sutton's nevus, postinflammatory hypopigmentation, senile vitiligo, chemical / drug-induced vitiligo, cutaneous lupus erythematosus, palmoplantar pustulosis, pemphigoid, Sweet's syndrome, hidradenitis suppurativa, onychomycosis, flexural psoriasis, refractory wounds, sebaceous hyperplasia, Fox-Fordyce disease (Fordyce granules, Fordyce spots), Fox-Fordyce disease, bromhidrosis (osmidrosis), hypertrichosis, or skin tumors (sebaceous nevus, sebaceous adenoma, sebaceous epithelioma, simple sebaceous cyst,Type I interferonopathy, including multiple sebaceous cysts, Muir-Torre syndrome, sebaceous adenocarcinoma, hypertrophic scars, rheumatic diseases, urticaria, discoid lupus erythematosus, central nervous system lupus, psoriatic arthritis, asthma, allergic asthma, Aicardi-Goutières syndrome and other Mendelian genetic diseases with overexpression of type I interferon, primary progressive multiple sclerosis, relapsing-remitting multiple sclerosis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, scleroderma, alopecia areata, spondylosis, myositis, vasculitis, pemphigus, lupus, major depressive disorder, allergy, dry eye syndrome, graft rejection, cancer, septic shock, cardiopulmonary dysfunction, acute respiratory diseases, ankylosing spondylitis, cachexia, chronic graft-versus-host disease, acute graft-versus-host disease, celiac sprue, idiopathic thrombocytopenic purpura, myasthenia gravis, Sjögren's syndrome, epidermal hyperplasia, cartilage inflammation, bone resorption, juvenile arthritis, juvenile rheumatoid arthritis, oligoarticular juvenile rheumatoid arthritis, polyarticular juvenile rheumatoid arthritis, systemic-onset juvenile rheumatoid arthritis, juvenile ankylosing spondylitis, juvenile enteropathic arthritis, juvenile Reiter's syndrome, SEA syndrome, juvenile dermatomyositis, juvenile psoriatic arthritis, juvenile scleroderma, juvenile systemic lupus erythematosus, juvenile vasculitis, oligoarticular arthritis, polyarticular arthritis, systemic-onset arthritis, enteropathic arthritis, reactive arthritis, Reiter's syndrome, myositis, polymyositis, dermatomyositis, polyarteritis nodosa, Wegener's granulomatosis, arteritis, polymyalgia rheumatica, sarcoidosis, sclerosis, primary biliary cirrhosis, sclerosing cholangitis, dermatitis, Still's disease, chronic obstructive pulmonary disease, Guillain-Barré disease, Graves' disease, Addison's disease, Raynaud's phenomenon, psoriatic epidermal hyperplasia, psoriasis vulgaris, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, immune disorders associated with or resulting from the activity of pathogenic lymphocytes, for use in the treatment of those selected from non-infectious uveitis, Behçet's disease or Vogt-Koyanagi-Harada syndrome, a compound of I or a pharmaceutically acceptable salt thereof as defined in any of the embodiments described herein, or a pharmaceutically acceptable solvate of said compound or salt, A method of treating a disease for which an ACC inhibitor is indicated in a subject in need of treating said disease, the method comprising administering to the subject a therapeutically effective amount of a compound of formula I as defined in any of the embodiments described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt. Use of a compound of formula I as defined in any of the embodiments described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt, for the manufacture of a medicament for treating a disease or condition for which an ACC inhibitor is indicated, and A pharmaceutical composition for treating a disease or condition for which an ACC inhibitor is indicated, comprising a compound of formula I as defined in any of the embodiments described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt.

[0080] The present invention also provides any of the uses, methods or compositions defined above, wherein a compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt, is used in combination with another pharmacologically active compound, in particular one of the functionally defined classes or specific compounds listed below. These agents can be administered according to standard pharmaceutical practice known to those skilled in the art, as part of the same or different dosage forms, via the same or different routes of administration, and at the same or different dosing schedules.

[0081] A compound of formula I or a pharmaceutically acceptable salt thereof, or an agent suitable for use in combination therapy with a pharmaceutically acceptable solvate of said compound or salt, sulfasalazine, mesalazine, prednisone, azathioprine, infliximab, adalimumab, belimumab, becertolizumab, natalizumab, vedolizumab, hydrocortisone, budesonide, cyclosporine, tacrolimus, fexofenadine, 6-mercaptopurine, methotrexate, ursodeoxycholic acid, obeticholic acid, antihistamine, rifampin, prednisone, methotrexate, azathioprine, cyclophosphamide, hydroxychloroquine, mofetil, mycophenolate sodium, tacrolimus, leflunomide, chloroquine and quinacrine, thalidomide, rituxan, NSAID, solumedrol, depomedrol, and dexamethasone.

[0082] For use in combination therapy with a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt, other suitable agents include retinoids, antibiotics, benzoyl peroxide, ITK or TRK inhibitors, 5-lipoxygenase activating protein (FLAP) antagonists; leukotriene antagonists (LTRA), such as antagonists of LTB4, LTC4, LTD4, LTE4, CysLT1 or CysLT2, such as montelukast or zafirlukast; histamine receptor antagonists, such as histamine type 1 receptor antagonists or histamine type 2 receptor antagonists, such as loratidine, fexofenadine, desloratidine, levocetirizine, metapyrilene or cetirizine; α1-adrenergic receptor agonists or α2-adrenergic receptor agonists, such as phenylephrine, methoxamine, oxymetazoline or methylnorepinephrine; muscarinic M3 receptor antagonists, such as tiotropium or ipratropium; muscarinic M3 receptor antagonist / β2 dual agonists; PDE inhibitors, such as PDE3 inhibitors, PDE4 inhibitors or PDE5 inhibitors, such as theophylline, sildenafil, vardenafil, tadalafil, ibudilast, cilomilast or roflumilast; sodium cromoglycate or nedocromil sodium; cyclooxygenase (COX) inhibitors, such as non-selective inhibitors (e.g., aspirin or ibuprofen) or selective inhibitors (e.g., celecoxib or valdecoxib); glucocorticosteroids, such as fluticasone, mometasone, dexamethasone, prednisolone, budesonide, ciclesonide or beclamethasone; anti-inflammatory monoclonal antibodies, such as infliximab, adalimumab, tanezumab, ranibizumab, bevacizumab or mepolizumab; β2 agonists, such as salmeterol, albuterol, salbutamol, fenoterol or formoterol, particularly long-acting β2 agonists; integrin antagonists, such as natalizumab; adhesion molecule inhibitors, such as VLA-4 antagonists;Bradykinin B1 or B2 receptor antagonist; immunosuppressive agent, e.g., inhibitor of the IgE pathway (e.g., omalizumab) or cyclosporine; matrix metalloprotease (MMP) inhibitor, e.g., inhibitor of MMP-9 or MMP-12; tachykinin NK1, NK2 or NK3 receptor antagonist; protease inhibitor, e.g., inhibitor of elastase, chymase or cathepsin G; adenosine A2a receptor agonist; adenosine A2b receptor antagonist; urokinase inhibitor; dopamine receptor agonist (e.g., ropinirole), particularly dopamine D2 receptor agonist (e.g., bromocriptine); regulator of the NFκB pathway, e.g., IKK inhibitor; further regulator of the cytokine signaling pathway, e.g., inhibitor of JAK kinase, syk kinase, p38 kinase, SPHK-1 kinase, Rho kinase, EGF-R or MK-2; mucolytic agent, mucokinetic agent or antitussive; antibiotic; antiviral agent; vaccine; chemokine; epithelial sodium channel (ENaC) blocker or epithelial sodium channel (ENaC) inhibitor; nucleotide receptor agonist, e.g., P2Y2 agonist; thromboxane inhibitor; niacin; 5-lipoxygenase (5-LO) inhibitor, e.g., zileuton; adhesion factor, e.g., VLAM, ICAM or ELAM; CRTH2 receptor (DP2) antagonist; prostaglandin D2 receptor (DP1) antagonist; hematopoietic prostaglandin D2 synthase (HPGDS) inhibitor; interferon-β; soluble human TNF receptor, e.g., etanercept; HDAC inhibitor; phosphoinositotide 3-kinase gamma (PI3Kγ) inhibitor; phosphoinositotide 3-kinase delta (PI3Kδ) inhibitor; CXCR-1 or CXCR-2 receptor antagonist; IRAK-4 inhibitor;Inhibitors of diacylglycerol acyltransferase-1 (DGAT1) or diacylglycerol acyltransferase-2 (DGAT2), and pharmaceutically acceptable salts of the specifically designated compounds, and pharmaceutically acceptable solvates of said specifically designated compounds and salts, are included in a TLR-4 or TLR-9 inhibitor. These agents can be administered together with another active agent, and the second active agent can be administered orally or topically.;

[0083] Accordingly, the present invention provides a method of treating or preventing a disease, condition or disorder associated with ACC in a subject, such as a human or non-human mammal, comprising administering to a subject in need thereof an effective amount of one or more of the compounds described herein.

[0084] One way of practicing the present invention is to administer the compounds of formula I in the form of a prodrug. Accordingly, certain derivatives of the compounds of formula I, which may themselves have little or no pharmacological activity, can be converted to the compounds of formula I having the desired activity when administered in the body or on the body surface, for example by hydrolytic cleavage, particularly hydrolytic cleavage facilitated by esterase or peptidase enzymes. Such derivatives are called "prodrugs". Further information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery Systems", Vol. 14, ACS Symposium Series (T. Higuchi and W. Stella) and "Bioreversible Carriers in Drug Design", Pergamon Press, 1987 (Ed. E. B. Roche, American Pharmaceutical Association). See also Nature Reviews / Drug Discovery, 2008, 7, 355 and Current Opinion in Drug Discovery and Development, 2007, 10, 550.

[0085] The prodrugs according to the present invention can be produced, for example, by replacing appropriate functional groups present in a compound of formula I with a specific moiety known to those skilled in the art as a "pro-moiety", as described in "Design of Prodrugs" by H. Bundgaard (Elsevier, 1985).

[0086] Thus, the prodrugs according to the present invention are (a) ester or amide derivatives of carboxylic acids in a compound of formula I, (b) ester, carbonate, carbamate, phosphate or ether derivatives of hydroxyl groups in a compound of formula I, (c) amide, imine, carbamate or amine derivatives of amino groups in the form of a compound of formula I, (d) thioester, thiocarbonate, thiocarbamate or sulfide derivatives of thiol groups in a compound of formula I, or (e) oxime, enol ester or imine derivatives of carbonyl groups in a compound of formula I.

[0087] Some specific examples of the prodrugs according to the present invention are as follows. (i) When the compound of formula I contains a carboxylic acid functional group (-COOH), its ester, for example, a compound in which the hydrogen of the carboxylic acid functional group of the compound of formula I is replaced by C1-C8 alkyl (e.g., ethyl) or (C1-C8 alkyl)C(=O)OCH2- (e.g., t-BuC(=O)OCH2-), (ii) When the compound of formula I contains an alcohol functional group (-OH), its ester, for example, a compound in which the hydrogen of the alcohol functional group of the compound of formula I is replaced by -CO(C1-C8 alkyl) (e.g., methylcarbonyl), or a compound in which the alcohol is esterified with an amino acid, (iii) When the compound of formula I contains an alcohol functional group (-OH), its ether, for example, a compound in which the hydrogen of the alcohol functional group of the compound of formula I is replaced by (C1-C8 alkyl)C(=O)OCH2- or -CH2OP(=O)(OH)2, (iv) When the compound of formula I contains an alcohol functional group (-OH), its phosphate, for example, the hydrogen of the alcohol functional group of the compound of formula I is replaced by -P(=O)(OH)2 or -P(=O)(ONa)2 or -P(=O)(O-)2Ca 2+ compounds replaced by (v) When the compound of formula I contains a primary or secondary amino functional group (-NH2 or -NHR, where R≠H), its amide, for example, in some cases one or both of the hydrogens of the amino functional group of the compound of formula I are replaced by (C1-C10) alkanoyl, -COCH2NH2, or the amino group is derivatized with an amino acid (vi) When the compound of formula I contains a primary or secondary amino functional group (-NH2 or -NHR, where R≠H), its amine, for example, in some cases one or both of the hydrogens of the amino functional group of the compound of formula I are replaced by -CH2OP(=O)(OH)2 (vii) When the ketone functional group of the compound of formula I is replaced by an oxime, imine or enol ester

[0088] A particular compound of formula I may itself act as a prodrug of another compound of formula I. It is also possible for two compounds of formula I to be linked together in the form of a prodrug. In certain circumstances, the prodrug of a compound of formula I can be produced by internally linking two functional groups of the compound of formula I, for example, by forming a lactone

[0089] References to compounds of formula I are to be construed as including the compounds themselves and their prodrugs. The present invention includes such compounds of formula I, as well as pharmaceutically acceptable salts of such compounds, and pharmaceutically acceptable solvates of said compounds and salts

[0090] Also, the scope of the present invention includes active metabolites of the compounds of formula I, i.e., compounds that are formed in vivo, often by oxidation, reduction or dealkylation, upon administration of the drug. Some examples of metabolites according to the present invention are given below. (i) When the compound of formula I contains a methyl group, its hydroxymethyl derivative (-CH3 → -CH2OH or -CH3 → -COOH), (ii) When the compound of formula I contains an alkoxy group, its hydroxy derivative (-OR → -OH), (iii) When the compound of formula I contains a tertiary amino group, its secondary amino derivative (-NRR’ → -NHR or -NHR’), (iv) When the compound of formula I contains a secondary amino group, its primary derivative (-NHR → -NH2), (v) When the compound of formula I contains a phenyl moiety, its phenol derivative (-Ph → -PhOH), and (vi) When the compound of formula I contains an amide group, its carboxylic acid derivative (-CONH2 → COOH), (vii) When the compound of formula I contains a carbonyl group, its derivative (-C=O(R)) → -CHOH(R)).

[0091] The compounds of formula I can be administered by themselves or, as active ingredients, in the form of a pharmaceutical composition containing an effective dose of at least one compound of the present invention in addition to conventional pharmaceutically innocuous excipients and / or additives.

[0092] Pharmaceutical compositions suitable for the delivery of the compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for preparing them can be found, for example, in Remington’s Pharmaceutical Sciences, 19th Edition (Mack Publishing Company, 1995).

[0093] The compounds of formula I can be administered orally. Oral administration may involve swallowing the compound so that it enters the gastrointestinal tract, or buccal or sublingual administration may be used so that the compound enters the bloodstream directly from the mouth. Formulations suitable for oral administration include solid formulations, such as tablets, granules, capsules containing liquids or powders, lozenges (including liquid-filled), chewable agents, multi-particle and nanoparticle agents, gels, solid solutions, liposome agents, film agents, vaginal ovules, sprays and liquid formulations.

[0094] Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations can be used as fillers for soft or hard capsules and typically contain a carrier, such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, as well as one or more emulsifying agents and / or suspending agents. Liquid formulations can also be prepared, for example, by reconstituting a solid from a sachet.

[0095] The compounds of formula I can also be used in fast-dissolving, fast-disintegrating dosage forms, such as those described by Liang and Chen (2001) in Expert Opinion in Therapeutic Patents, 11(6), 981 - 986.

[0096] In the case of the tablet dosage form, depending on the dosage, the drug may constitute 1% to 80% by weight of the dosage form, more typically 5% to 60% by weight of the dosage form. Tablets generally contain a disintegrant in addition to the drug. Examples of disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch, and sodium alginate. Generally, the disintegrant constitutes 1% to 25% by weight. In one embodiment of the present invention, the disintegrant constitutes 5% to 20% by weight of the dosage form. Binders are generally used to impart adhesive properties to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, saccharides, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose. Tablets may also contain diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch, and calcium hydrogen phosphate dihydrate. Tablets may also contain surfactants such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, the surfactant may constitute 0.2% to 5% by weight of the tablet, and the glidant may constitute 0.2% to 1% by weight of the tablet. Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and a mixture of magnesium stearate and sodium lauryl sulfate. The lubricant generally constitutes 0.25% to 10% by weight. In one embodiment of the present invention, the lubricant constitutes 0.5% to 3% by weight of the tablet. Other possible components include antioxidants, colorants, flavorings, preservatives, and flavoring agents.

[0097] Exemplary tablets contain up to about 80% drug, about 10 wt% to about 90 wt% binder, about 0 wt% to about 85 wt% diluent, about 2 wt% to about 10 wt% disintegrant, and about 0.25 wt% to about 10 wt% lubricant.

[0098] The tablet blend can be compressed directly or by rollers to form tablets. The tablet blend or a portion of the blend can alternatively be wet granulated, dry granulated, melt granulated, melt congealed, or extrusion molded prior to tableting. The final formulation can include one or more layers, can be coated or uncoated, and can further be encapsulated. The formulation of tablets is discussed in H. Lieberman and L. Lachman, Pharmaceutical Dosage Forms: Tablets, Vol. 1 (Marcel Dekker, New York, 1980).

[0099] A consumable oral film for human or veterinary use is typically a flexible water-soluble or water-swellable thin film dosage form that is fast-dissolving or mucoadhesive and typically can include a compound of Formula I, a film-forming polymer, a binder, a solvent, a humectant, a plasticizer, a stabilizer or emulsifier, a viscosity modifier, and a solvent. Some components of the formulation can serve more than one function. The film-forming polymer can be selected from natural polysaccharides, proteins, or synthetic hydrophilic colloids and is typically present in the range of 0.01 to 99 wt%, more typically 30 to 80 wt%. Other possible components include antioxidants, colorants, flavorants and flavor enhancers, preservatives, sialagogues, cooling agents, co-solvents (including oils), emollients, bulking agents, defoamers, surfactants, and taste-masking agents. The films according to the invention are typically prepared by evaporative drying of a thin aqueous film coated on a peelable backing support or paper. This can be done in a drying oven or tunnel, typically a compound coater dryer, or by freeze drying or evacuation.

[0100] Solid formulations for oral administration can be formulated for immediate release and / or modified release. Modified release includes delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release. Modified release formulations suitable for the purposes of the present invention are described in U.S. Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersion, osmotic pressure, and coated particles can be found in Pharmaceutical Technology On-line, 25(2), 1-14 (2001) by Verma et al. The use of chewing gum to achieve controlled release is described in WO-A-00 / 35298.

[0101] The compounds of formula I can also be administered directly to the bloodstream, muscle, or viscera. Such parenteral administrations include intravenous, intraarterial, intraperitoneal, intrathecal, intracerebroventricular, intraurethral, intrasternal, intracranial, intramuscular, intraarticular, and subcutaneous administrations. Devices suitable for parenteral administration include needle (including micro-needle) syringes, needleless syringes, and infusion techniques.

[0102] The compounds of formula I can also be administered topically to the skin or mucosa, i.e., transdermally or transdermally.

[0103] Parenteral formulations of the compounds of the present invention are typically aqueous solutions that can contain excipients such as salts, carbohydrates, and buffers (preferably buffered to pH 3-9). Formulations for parenteral administration may also be in a dry (e.g., lyophilized) form that is reconstituted with a sterile non-aqueous solution or a suitable vehicle, such as sterile water free of pyrogens, for administration.

[0104] Pharmaceutical compositions for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, suppositories, powders, solutions, sprays, drops, inhalants, and patches. The compounds of the present invention are mixed under sterile conditions with a pharmaceutically acceptable topical carrier and any preservatives or buffering agents, if required. Volatile compounds may need to be mixed with a formulation agent or packaging material to ensure delivery of an appropriate dosage. Compounds of the present invention with low skin permeability may require one or more penetration enhancers, while compounds that are rapidly absorbed through the skin may require formulations containing absorption retardants or barriers.

[0105] The term "pharmaceutically acceptable topical carrier" refers to a carrier medium suitable for topical application that appropriately delivers an effective amount of the compound of the present invention, such as an inert liquid or cream vehicle capable of suspending or dissolving the compound. Those skilled in the art will understand that this term also encompasses carrier materials approved for use in topical cosmetics.

[0106] The term "penetration enhancer" is related to increasing the permeability of the skin, nails, hair, hooves, or claws to the compounds of the present invention in order to increase the rate and extent of penetration of the compound. Enhancement of penetration can be observed, for example, by measuring the rate of drug diffusion through animal or human skin, nails, hair, hooves, or claws using a diffusion cell apparatus. Diffusion cells are described by Merritt et al., Diffusion Apparatus for Skin Penetration, J of Controlled Release, 1(1984), pp.161 - 162.

[0107] Ointments, pastes, creams, lotions, gels, suppositories, powders, solutions, sprays, drops, inhalants, and patches for topical administration can contain, in addition to the compounds of the present invention, one or more pharmaceutically acceptable excipients such as animal or vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc, zinc oxide, preservatives, antioxidants, fragrances, emulsifiers, dyes, inert fillers, anti-irritants, tackifiers, flavoring agents, opacifiers, antioxidants, gelling agents, stabilizers, surfactants, emollients, colorants, preservatives, buffers, penetration enhancers, etc. Such excipients should not interfere with the effectiveness of the biological activity of the active drug and should not be harmful to epithelial cells or their functions.

[0108] Transdermal administration can be achieved by using a transdermal patch. The transdermal patch may be of the "reservoir and porous membrane" type or may use a "matrix system".

[0109] The solubility of the compounds of the present invention used in the preparation of pharmaceutical compositions can be increased by using appropriate formulation techniques such as the incorporation of solubility enhancers.

[0110] The compounds of formula I can typically be administered from a dry powder inhaler in the form of a dry powder (alone, as a mixture, e.g., as a dry blend with lactose, or as mixed constituent particles mixed with a phospholipid such as phosphatidylcholine), as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably an atomizer that uses electrohydrodynamics to generate fine mists) or nebulizer, with or without the use of a suitable propellant such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane, or as a nasal drop, intranasally or by inhalation. For intranasal use, the powder can contain a bioadhesive, e.g., chitosan or cyclodextrin. Delivery by inhalation is a preferred route of administration of the compounds of the present invention.

[0111] The pressurized container, pump, spray, atomizer, or nebulizer contains a solution or suspension of a compound of formula I, for example, ethanol, aqueous ethanol, or alternative agents, solvents as propellants, and optional surfactants, such as sorbitan trioleate, oleic acid, or oligolactic acid, suitable for dispersing, solubilizing, or extending the release of the compound.

[0112] The pharmaceutical product is micronized to a size suitable for delivery by inhalation (typically less than 5 microns) before use in dry powder or suspension formulations. This can be achieved by any suitable grinding method, such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.

[0113] Capsules (e.g., made of gelatin or hydroxypropyl methylcellulose), blisters, and cartridges for use in inhalers or insufflators can be formulated to contain a powder mix of the compounds of the present invention, a suitable powder base, such as lactose or starch, and performance modifiers, such as l-leucine, mannitol, or magnesium stearate. Lactose may be in anhydrous or monohydrate form, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.

[0114] Solution formulations suitable for use in atomizers that generate fine mists using electrohydrodynamics can contain from 1 μg to 20 mg of the compounds of the present invention per actuation, and the actuation volume can vary from 1 μl to 100 μl. Typical formulations can include a compound of formula I, propylene glycol, sterile water, ethanol, and sodium chloride. Alternative solvents that can be used in place of propylene glycol include glycerol and polyethylene glycol.

[0115] For the preparation of the present invention intended for intranasal administration, a suitable fragrance such as the fragrance of fruits or flowers can be added. The preparation for intranasal administration can be formulated, for example, using PGLA, to provide immediate release and / or controlled release. Controlled release includes delayed release, sustained release, pulsatile release, controlled release, targeted release, and programmed release.

[0116] The compound of formula I can also be directly administered to the eye or ear, typically in the form of droplets of a micronized suspension or solution in a pH-adjusted isotonic sterile saline.

[0117] When using any of the aforementioned administration methods, the compound of formula I can be combined with soluble macromolecular entities such as cyclodextrin and its suitable derivatives or polyethylene glycol-containing polymers to improve solubility, dissolution rate, taste, bioavailability, and / or stability. For example, drug-cyclodextrin complexes have been found to be generally useful for most dosage forms and administration routes. Both inclusion complexes and non-inclusion complexes can be used. As an alternative to direct complex formation with the drug, cyclodextrin can be used as an adjuvant additive, i.e., as a carrier, diluent, or solubilizing agent. The most commonly used for these purposes are alpha-, beta-, and gamma-cyclodextrin, examples of which can be found in International Patent Publications WO91 / 11172, WO94 / 02518, and WO98 / 55148.

[0118] For example, when it is desirable to administer a combination of active compounds for the purpose of treating a particular disease or condition, it is within the scope of the present invention that two or more pharmaceutical compositions, at least one of which contains a compound of formula I, can be conveniently combined in the form of a kit suitable for co-administration of the compositions. Accordingly, the kits of the present invention include two or more individual pharmaceutical compositions, at least one of which contains a compound of formula I, and means for holding the compositions individually, such as containers, divided bottles, or divided foil packets. Examples of such kits are the familiar blister packs used for packaging tablets, capsules, etc. Such kits are particularly suitable for administering different dosage forms, such as oral and parenteral dosage forms, for administering the individual compositions at different dosing intervals, or for titrating the individual compositions against each other. To assist compliance, the kits typically include instructions for administration and may provide so-called memory aids.

[0119] The compounds of the present invention can be prepared by any method known in the art for preparing compounds of similar structure. In particular, the compounds of the present invention can be prepared by the procedures described with reference to the following schemes, or by the specific methods described in the examples, or by any similar process.

[0120] Those skilled in the art will understand that the experimental conditions described in the following schemes are illustrative of conditions suitable for performing the indicated transformations and that it may be necessary or desirable to vary the exact conditions used in the preparation of the compounds of formula I. Further, it will be understood that it may be necessary or desirable to perform the transformations in an order different from that described in the schemes or to adjust one or more of the transformations in order to obtain the desired compounds of the present invention.

[0121] In addition, those skilled in the art will understand that at any stage of the synthesis of the compounds of the present invention, it may be necessary or desirable to protect one or more sensitive groups in order to prevent unwanted side reactions. In particular, it may be necessary or desirable to protect amino groups or carboxylic acid groups. The protecting groups used in the preparation of the compounds of the present invention can be used in a conventional manner. For example, reference is made to Protective Groups in Organic Synthesis, 3rd Edition (John Wiley and Sons, 1999) by Theodora W Greene and Peter GM Wuts, which is incorporated herein by reference, particularly Chapter 7 ("Protection of Amino Groups") and Chapter 5 ("Protection of Carboxyl Groups"), which also describes methods for removing such groups.

[0122] The compounds of formula I (generally represented as compound G) can be prepared from compounds A - G as shown by Scheme 1 or Scheme 2. The compounds of formulae A - G are either commercially available or can be synthesized by those skilled in the art according to the literature or preparations described herein.

[0123]

Chemical formula

[0124] Compounds prepared according to Scheme 1 The compound of formula B can be prepared from the compound of formula A according to bromination under suitable conditions, which includes process step (a), i.e., treatment with TMS triflate in the presence of an organic base, such as triethylamine, followed by reaction with a brominating agent, such as N - bromosuccinimide. Alternative conditions for step (b) include the use of trimethyl - phenylammonium tribromide in THF at 25°C.

[0125] The compound of formula C can be prepared from the compound of formula B according to process step (b), i.e., an annellation reaction using 2,2-dimethylpropanethioamide under suitable basic conditions. Preferred conditions include pyridine in ethanol at about 80 °C. The compound of formula D can be prepared from the compound of formula C according to process step (c), i.e., bromoalkoxylation which can be carried out using a brominating agent such as N-bromosuccinimide in the presence of an alcohol. This reaction typically proceeds under ambient conditions.

[0126] The compound of formula E can be prepared from the compound of formula D according to process step (d), i.e., an elimination reaction carried out using a non-nucleophilic base such as potassium tert-butoxide under ambient conditions in an inert solvent such as tetrahydrofuran. The compound of formula F can be prepared from the compound of formula E according to process step (e), i.e., deprotection / hydrolysis using a suitable acid such as hydrochloric acid in an aqueous / organic mixed solvent such as dioxane.

[0127] The compound of formula G can be prepared from the compound of formula F according to process step (f), i.e., acylation using a heteroarylcarboxylic acid under suitable basic conditions. Preferred conditions include N-ethyl-N-(propan-2-yl)propan-2-amine (DIPEA) in the presence of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazol[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU). As an alternative condition, the reagents can include propanephosphonic anhydride at 25 °C in the presence of triethylamine in a dipolar solvent such as DMF. Other effective conditions include a water-soluble carbodiimide such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) at 25 °C in the presence of hydroxybenzotriazole (HOBt) and triethylamine in DMF.

[0128] [Chemical Structure]

[0129] Compound prepared by Scheme 2 The compound of formula I can be prepared from the compound of formula H using 9-mesityl-10-methylacridinium perchlorate and irradiation by mini ski coupling with a carboxylic acid.

[0130] Steps (e) and (f) follow the same process as the process described in Scheme 1.

[0131] Therefore, derivatives of formula I can be prepared by the procedures described in the general methods presented below or by their routine modifications. The present invention also includes any novel intermediates used therein, in addition to any one or more of these processes for preparing derivatives of formula I. Those skilled in the art will understand that the following reactions can be heated thermally or under microwave irradiation.

[0132] In the following non-limiting examples and preparations for explaining the present invention, as well as in the foregoing schemes, the following abbreviations, definitions and analytical procedures may be referred to. AcOH: Acetic acid atm: Atmosphere aq: Aqueous BOC2O: BOC anhydride, di-tert-butyl dicarbonate br: Broad ℃: Celsius CBZ: Carboxybenzyl, benzyloxycarbonyl conc. or c.: Concentrated δ: Chemical shift d: Doublet dd: Doublet of doublets ddd: Doublet of doublets of doublets dt: Doublet of triplets DCM: Dichloromethane DHP: Dihydropyran DMAC: N,N-Dimethylacetamide DMAP: 4-Dimethylaminopyridine DMF: Dimethylformamide DMSO: Dimethyl sulfoxide EDCI: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride ESI-MS: Electrospray ionization mass spectrometry EtOAc: Ethyl acetate Et3N: Triethylamine equiv.: Equivalent g: Gram h: Hour HATU: (1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HOPO: 2-Hydroxypyridine 1-oxide HPLC: High performance liquid chromatography iPr2NEt: N,N-Diisopropylethylamine, Hunig's base iPrOH: Isopropanol, 2-Propanol Kg: Kilogram KOtBu: Potassium tert-butoxide L: Liter LAH: Lithium aluminum hydride, LiAlH4 LCMS: Liquid chromatography mass spectrometry LDA: Lithium diisopropylamide LiHMDS: Lithium bis(trimethylsilyl)amide M: Multiplet M: Mole MeCN: Acetonitrile MHz: Megahertz min: Minute mL: Milliliter mm: Millimeter mmol: Millimole μmol: Micromole mol: Mole MS m / z: Mass spectrum peak MTBE: Methyl tert-butyl ether N: Normal n-BuLi: n-Butyllithium NBS: N-Bromosuccinimide NCS: N-Chlorosuccinimide NH4OH: Aqueous ammonia solution NMP: N-Methylpyrrolidine NMR: Nuclear magnetic resonance Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium(0) Pd / C: Palladium on carbon PE: Petroleum ether Prep: Preparative pTSA·H2O: p-Toluenesulfonic acid monohydrate q: Quartet quint: Quintet RT: Room temperature s: Singlet sat.: Saturated SFC: Supercritical fluid chromatography t: Triplet t-BuOH: tert-Butanol TFA: Trifluoroacetic acid THF: Tetrahydrofuran TMSOTf: Trimethylsilyl trifluoromethanesulfonate TTBP·HBF4: Tri-tert-butylphosphonium tetrafluoroborate T3P: Propylphosphonic anhydride X-Phos: 2-Dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl μm: Micrometer μL: Microliter

[0133] General experimental section Unless otherwise stated, all reactions are carried out under a nitrogen atmosphere. The abbreviation RT refers to "room temperature" and is generally interpreted to mean approximately 22 °C (±5 °C). Unless otherwise stated, the term "concentrated" refers to the process of removing volatile compounds such as solvents by using a rotary evaporator under reduced pressure. The term "chromatography" refers to silica gel chromatography using a mobile phase consisting of any mixture or gradient of EtOAc / heptane or methanol / DCM, or a combination of some of them.

[0134] 1 The 1H NMR spectra were consistent with the proposed structures in all cases. 1 The characteristic δ of 1H NMR is reported using the conventional abbreviations for the assignment of the major peaks, compared with the residual solvent signals (δH = 7.27 ppm for CDCl3, δH = 2.50 ppm for DMSO-d6, δH = 3.30 ppm for CD3OD). Those skilled in the art will understand that tautomers may be recorded in the NMR data and some exchangeable protons may not be shown. Similarly, those skilled in the art will understand that a mixture of rotamers may be recorded in the NMR data.

[0135] The mass spectra were recorded using either ESI-MS. Where relevant, unless otherwise stated, the m / z data provided are for 19 F, 35 Cl, 79 Br and / or 81 Br.

[0136] When silica gel chromatography, preparative HPLC or SFC chromatography is used, those skilled in the art will understand that the desired compound can be purified using any suitable solvent or combination of solvents.

[0137] The nomenclature of the compounds in the following preparations and examples was generated using Perkin Elmer's ChemDraw Professional 19.0 according to IUPAC (International Union of Pure and Applied Chemistry).

[0138] Amidation method A) To a mixture of carboxylic acid (1.0 equiv), DIPEA (4.0 equiv) in DMF (c = 0.14 M) was added, followed by the addition of HATU (1.5 equiv). The resulting mixture was stirred at about 15 °C for about 10 minutes, and then amine (1.0 equiv) was added to the mixture. The reaction was stirred at about 15 °C for about 16 hours. The reaction was filtered and the filtrate was purified by preparative HPLC.

[0139] B) To carboxylic acid (1.0 equiv) was added a TPTU stock solution (1.5 equiv, 0.30 M in DMF), followed by the addition of amine (1.0 equiv, 0.20 M stock solution in DMF) together with 2 equiv of DIPEA (2.20 mmol, 383 μl). The mixture was stirred at about 65 °C for about 14 hours. The solvent was evaporated under a stream of N2 gas. The resulting residue was dissolved in DMSO, filtered, and purified by preparative HPLC.

[0140] C) A mixture of amine (1.0 equiv), acid (1.0 equiv), and EDCI (1.5 equiv) in pyridine (final concentration = 65 mM) was heated at about 110 °C for about 30 minutes using a microwave reactor. The solvent was evaporated and it was further purified by preparative HPLC.

[0141] D) To a mixture of carboxylic acid (1.0 equiv), under N2, a solution of amine (1.0 equiv) in DMF (c = 0.25 M) and triethylamine (6.0 equiv) were added. The resulting mixture was stirred at about 23 °C for about 5 minutes and then further cooled in an ice / water bath for 5 minutes. T3P (50% in DMF) was slowly added dropwise to the reaction mixture over 10 minutes (2.0 equiv). The reaction was slowly warmed to about 15 °C over about 1.5 hours, and then H2O (3 times the volume of the reaction mixture) was added. The workup mixture was filtered, the precipitate was collected, dried, and purified by preparative HPLC.

[0142] Formulation 1: 2-(tert-Butyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one hydrochloride (P1)

[0143]

Chem.

[0144]

Chem.

[0145] Step 2: Synthesis of 2-(tert-butyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one hydrochloride (P1)

[0146]

Chemical Structure

[0147] Preparation 2: 5-Methyl-2-(methylamino)quinoline-7-carboxylic acid (P2)

[0148]

Chemical Structure

[0149]

Chem.

[0150] Step 2: Methyl 5-methyl-2-(methylamino)quinoline-7-carboxylate (C3)

[0151]

Chem.

[0152] Step 3: 5-Methyl-2-(methylamino)quinoline-7-carboxylic acid (P2)

[0153]

Chem.

[0154] Preparation 3: 2-(tert-Butyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one hydrochloride (P3)

[0155]

Chem.

[0156]

Chemical Structure

[0157] Step 2: Synthesis of ethyl 7-acetoxy-1,3-dimethyl-1H-indazole-5-carboxylate (C5)

[0158]

Chemical Structure

[0159] Step 3: Synthesis of Ethyl 7-hydroxy-1,3-dimethyl-1H-indazole-5-carboxylate (C6)

[0160]

Chemical Structure

[0161] Step 4: Synthesis of Ethyl 7-methoxy-1,3-dimethyl-1H-indazole-5-carboxylate (C7)

[0162]

Chem.

[0163] Step 5: Synthesis of 7-methoxy-1,3-dimethyl-1H-indazole-5-carboxylic acid (P3)

[0164]

Chem.

Example

[0165] (Example 1) 1'-(3,7-Dimethyl-2H-indazole-5-carbonyl)-2-(1-methylcyclopropyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one

[0166]

Chemical formula

[0167] (Example 2) 1'-(3,7-Dimethyl-1H-indazole-5-carbonyl)-2-(1-methylcyclobutyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one

[0168]

Chemical Structure

[0169] (Example 3) 1'-(3,7-Dimethyl-1H-indazole-5-carbonyl)-2-(2,3-dimethylbutan-2-yl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one

[0170] [Chemical formula] Step 1: Synthesis of tert-butyl 2-(2,3-dimethylbutan-2-yl)-4-oxo-4,7-dihydro-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-1'-carboxylate (C8)

[0171] [Chemical formula] In acetonitrile (1.5 mL) and water (1.5 mL), to a solution of tert-butyl 4-oxo-4,7-dihydro-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-1'-carboxylate (0.1 g, 0.31 mmol), prepared as in Compound P1, were added 2,2,3-trimethylbutanoic acid (0.121 g, 0.93 mmol), Na2HPO4 (0.132 g, 0.93 mmol) and 9-mesityl-10-methylacridinium perchlorate (3.83 g, 0.0093 mmol). The reaction mixture was irradiated with a 72 W blue LED strip for about 60 h. The resulting mixture was filtered and the residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18, 50×250 mm, 10 μm); mobile phase A: water (0.05 v / v% concentrated NH4OH); mobile phase B: MeCN; gradient of 63 - 83% B for 9 min, holding at 100% B for 2 min; flow rate 25 mL / min to give the title compound (30 mg, 23.8%). 1 H NMR (400 MHz, methanol-d4) δ 3.52 - 3.44 (m, 4H), 3.20 (s, 2H), 2.68 (s, 2H), 2.12 (h, 1H), 1.60 (m, 4H), 1.47 (s, 9H), 1.38 (s, 6H), 0.88 (s, 3H), 0.87 (s, 3H); LC / MS m / z (M+H) + = 407.4.

[0172] Step 2: Synthesis of 2-(2,3-dimethylbutan-2-yl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one (C9)

[0173]

Chemical Structure

[0174] Step 3: Synthesis of 1'-(3,7-dimethyl-1H-indazole-5-carbonyl)-2-(2,3-dimethylbutan-2-yl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one

[0175] [Chemical formula] A solution of 2-(2,3-dimethylbutan-2-yl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one (0.015 g, 0.08 mmol), 3,7-dimethyl-1H-indazole-5-carboxylic acid (0.025 g, 0.07 mmol), EDCI·HCl (0.027 g, 0.146 mmol), and pyridine (2 mL) was microwave-treated at about 110 °C for about 30 minutes. The resulting mixture was concentrated, and the residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18, 40 × 80 mm, 3 μm); mobile phase A: water (0.05 v / v% concentrated NH4OH); mobile phase B: MeCN; gradient of 31 - 71% B for 9 minutes, holding at 100% B for 2 minutes; flow rate 25 mL / min to give the title compound (5.56 mg, 16%). 1 H NMR (400 MHz, methanol-d4) δ 7.67 (dd, 1H), 7.23 (t, 1H), 3.82 (m, 2H), 3.58 (m, 2H), 3.27 (s, 2H), 2.76 (s, 2H), 2.55 (s, 3H), 2.54 (s, 3H), 2.12 (h, 1H), 1.53 (m, 4H), 1.37 (s, 6H), 0.88 (s, 3H), 0.87 (s, 3H); LC / MS m / z (M+H) + = 479.4.

[0176] (Example 4) 1'-(3,7-Dimethyl-1H-indazole-5-carbonyl)-2-(1-methylcyclopentyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one

[0177] [Chemical formula] A solution of 2-(1-methylcyclopentyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one (0.024 g, 0.07 mmol), 3,7-dimethyl-1H-indazole-5-carboxylic acid (0.015 g, 0.07 mmol), EDCI·HCl (0.027 g, 0.141 mmol), and pyridine (2 mL), which was prepared in the same manner as Compound C9, was microwave-treated at about 110 °C for about 30 minutes. The resulting mixture was filtered, and the residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18, 40×80 mm, 3 μm); mobile phase A: water (0.05 v / v% concentrated NH4OH); mobile phase B: MeCN; gradient of 29~69% B for 9 minutes, holding 100% B for 2 minutes; flow rate 25 mL / min to obtain the title compound (7.2 mg, 21%). 1 H NMR (400 MHz, methanol-d4) δ 7.66 (s, 1H), 7.22 (s, 1H), 3.82 (m, 2H), 3.59 (m, 2H), 3.27 (s, 2H), 2.75 (s, 2H), 2.58 (m, 6H), 2.19 (m, 2H), 1.86 - 1.75 (m, 7H), 1.68 (s, 3H), 1.46 (s, 3H); LC / MS m / z (M+H) + = 477.3.

[0178] (Example 5) 1'-(3,7-Dimethyl-1H-indazole-5-carbonyl)-2-(tert-pentyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one

[0179] [Chemical formula] Using 2,2-dimethylbutanoic acid instead of 2,2,3-trimethylbutanoic acid in Step 1, the title compound (8.3 mg) was prepared in the same manner as in Example 3. LC / MS m / z (M+H) + = 465.3

[0180] (Example 6) 1'-(3,7-Dimethyl-1H-indazole-5-carbonyl)-2-ethyl-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one

[0181] [Chemical formula] According to amidation method A, 2-ethyl-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one (0.08 g, 0.28 mmol) prepared in the same manner as compound P1 was coupled with 3,7-dimethyl-1H-indazole-5-carboxylic acid (0.056 g, 0.28 mmol). The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18, 40×80 mm, 3 μm); mobile phase A: water (0.05 v / v% concentrated NH4OH); mobile phase B: MeCN; gradient of 9 - 60% B for 9 minutes, holding at 100% B for 2 minutes; flow rate 25 mL / min to obtain the title compound (45 mg, 38%). 1 H NMR (400 MHz, methanol-d4) δ 7.67 (d, 1H), 7.22 (d, 1H), 3.83 (m, 2H), 3.55 (m, 2H), 3.26 (s, 2H), 3.03 (q, 2H), 2.75 (s, 2H), 2.58 (s, 3H), 2.57 (s, 3H), 1.75 (m, 2H), 1.65 (m, 2H), 1.38 (t, 3H); LC / MS m / z (M+H) + = 423.1.

[0182] (Example 7) 2-(Bicyclo[1.1.1]pentan-1-yl)-1'-(3,7-dimethyl-1H-indazole-5-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one

[0183] [Chemical Structure Diagram] According to amidation method A, 2-(bicyclo[1.1.1]pentan-1-yl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one (0.08 g, 0.28 mmol), prepared in the same manner as compound P1, was coupled with 3,7-dimethyl-1H-indazole-5-carboxylic acid (0.056 g, 0.28 mmol). The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18, 40×80 mm, 3 μm); mobile phase A: water (0.225 v / v% formic acid); mobile phase B: MeCN; gradient of 19 - 59% B for 9 minutes, holding at 100% B for 2 minutes; flow rate 25 mL / min to obtain the title compound (28.5 mg, 40%). 1 H NMR (400 MHz, methanol-d4) δ 7.66 (dd, 1H), 7.22 (t, 1H), 3.81 (s, 2H), 3.57 (s, 2H), 3.26 (s, 2H), 2.75 (s, 2H), 2.57 (s, 3H) 2.56 (s, 3H), 2.27 (s, 7H), 1.74 (s, 2H), 1.65 (s, 2H); LC / MS m / z (M+H)+ = 461.4.

[0184] (Example 8) 2-Isopropyl-1'-(5-methyl-2-(methylamino)quinoline-7-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one

[0185] [Chemical Structure] According to amidation method A, 2-Isopropyl-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one (0.034 g, 0.116 mmol), prepared in the same manner as compound P1, was coupled with 5-methyl-2-(methylamino)quinoline-7-carboxylic acid (0.03 g, 0.14 mmol). The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18, 40×80 mm, 3 μm); mobile phase A: water (0.225 v / v% formic acid); mobile phase B: MeCN; gradient of 20 - 50% B for 9 minutes, holding at 100% B for 2 minutes; flow rate 25 mL / min to obtain the title compound (23.2 mg, 36%). 1 H NMR (400 MHz, methanol-d4) δ 8.06 (dd, 1H), 7.57 - 7.50 (m, 1H), 7.05 (dd, 1H), 6.83 (d, 1H), 3.85 (m, 2H), 3.55 (m, 2H), 3.31 (h, 1H), 3.27 (s, 2H), 3.03 (s, 3H), 2.75 (d, 2H), 2.61 (s, 3H), 1.78 (m, 2H), 1.66 (m, 2H), 1.40 (d, 6H); LC / MS m / z (M+H) + = 463.4.

[0186] (Example 9) 1'-(5-Methyl-2-(methylamino)quinoline-7-carbonyl)-2-(1-methylcyclopropyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one

[0187]

Chem.

[0188] (Example 10) 2-Isopropyl-1'-(7-methoxy-1,3-dimethyl-1H-indazole-5-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one

[0189]

Chem.

[0190] (Example 11) 1'-(7-Methoxy-1,3-dimethyl-1H-indazole-5-carbonyl)-2-(1-methylcyclopropyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one

[0191]

Chem.

[0192] (Example 12) 1'-(7-methoxy-1,3-dimethyl-1H-indazole-5-carbonyl)-2-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one

[0193]

Chemical Structure

[0194] (Example 13) 2-(tert-Butyl)-1'-(7-methoxy-1,3-dimethyl-1H-indazole-5-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one

[0195] [Chemical formula] In DMF (25.8 mL), to a solution of Preparation P1 (0.97 g, 3.1 mmol), Preparation P3 (0.68 g, 3.1 mmol), EDCI·HCl (0.89 g, 4.65 mmol), and HOBt (0.73 g, 4.65 mmol) at about 25 °C i Pr2NEt (2.97 mL, 17.0 mmol) was added. The mixture was stirred at about 25 °C for about 16 h and then diluted with EtOAc (50 mL). The mixture was washed successively with 5% aqueous LiCl (25 mL), 0.5 N HCl (25 mL), saturated aqueous NaHCO3 (20 mL), and 1:1 brine - water (30 mL). The organic phase was dried over MgSO4, filtered, concentrated, heptane (2×25 mL) was added, and the resulting mixture was concentrated under reduced pressure. The residual product was purified by chromatography (silica, EtOAc / hexane, 0 - 100%, then MeOH:EtOAc, 0 - 10%) to give the title compound (1.05 g, 70.4% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.23 (s, 1H), 6.74 (s, 1H), 4.22 (s, 3H), 3.96 (s, 3H), 3.73 (m, 2H), 3.62 (m, 2H), 3.10 (s, 2H), 2.71 (s, 2H), 2.50 (s, 3H), 1.68 (m, 4H), 1.45 (s, 9H); LC / MS m / z (M + H) + = 481.3.

[0196] (Example 14) 2-(tert-Butyl)-1'-(7-ethoxy-1,3-dimethyl-1H-indazole-5-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one

[0197]

Chemical Structure

[0198]

Chem.

[0199] Step 2: Synthesis of 7 - ethoxy - 1,3 - dimethyl - 1H - indazole - 5 - carboxylic acid (C11)

[0200]

Chem.

[0201] Step 3: 2-(tert-Butyl)-1'-(7-ethoxy-1,3-dimethyl-1H-indazole-5-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one (Example 14)

[0202]

Chem.

[0203] (Example 15) 2-(tert-Butyl)-1'-(8-methyl-3-(methylamino)quinoline-6-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one

[0204]

Chemical formula

[0205]

Chem.

[0206] Step 2: Synthesis of Ethyl 3-Bromo-8-methylquinoline-6-carboxylate (C13)

[0207]

Chem.

[0208] Step 3: Ethyl 3-((tert-butoxycarbonyl)(methyl)amino)-8-methylquinoline-6-carboxylate (C14)

[0209]

Chem.

[0210] Step 4: 3-((tert-Butoxycarbonyl)(methyl)amino)-8-methylquinoline-6-carboxylic acid (C15)

[0211]

Chem.

[0212] Step 5: 8-Methyl-3-(methylamino)quinoline-6-carboxylic acid hydrochloride (C16)

[0213]

Chem.

[0214] Step 6: Synthesis of 2-(tert-Butyl)-1'-(8-methyl-3-(methylamino)quinoline-6-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one (Example 15)

[0215]

Chem.

[0216] (Example 16) 2-(tert-Butyl)-1'-(4-methyl-2-naphthoyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one

[0217] [Chemical Structure Diagram] Step 1: Synthesis of methyl 4-hydroxy-2-naphthoate (C17)

[0218] [Chemical Structure Diagram] In MeOH (500 mL), concentrated H2SO4 (8.33 mL, 150 mmol) was slowly added to a solution of 4-hydroxy-2-naphthoic acid (18.8 g, 100 mmol), and then the reaction mixture was refluxed for about 48 h. The solvent was concentrated under reduced pressure, the residue was diluted with EtOAc (250 mL), washed successively with water (150 mL) and brine (150 mL), dried over MgSO4, filtered, and concentrated to give a dark brown solid (19.6 g, 96.9%), which was used directly in the next step without further purification. 1 H NMR (400 MHz, chloroform-d) δ 8.28 (d, 1H), 8.23 (s, 1H), 7.94 (d, 1H), 7.67 - 7.54 (m, 4H), 4.02 (s, 3H); LC / MS m / z (M-H) + = 201.1.

[0219] Step 2: Synthesis of methyl 4-(((trifluoromethyl)sulfonyl)oxy)-2-naphthoate (C18)

[0220]

Chemical Structure

[0221] Step 3: Synthesis of methyl 4-methyl-2-naphthoate (C19)

[0222]

Chem.

[0223] Step 4: Synthesis of 4-methyl-2-naphthoic acid (C20)

[0224]

Chemical formula

[0225] Step 5: Synthesis of 2-(tert-butyl)-1'-(4-methyl-2-naphthoyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one (Example 16)

[0226]

Chemical formula

[0227] (Example 17) 2-(tert-Butyl)-1'-(7-methyl-1H-indole-5-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one

[0228]

Chemical Structure

[0229] (Example 18) 2-(tert - Butyl)-1'-(3-(ethylamino)-8 - methylquinoline - 6 - carbonyl)-5H - spiro[benzo[d]thiazole - 6,4'-piperidine]-4(7H)-one

[0230]

Chemical Structure

[0231] (Example 19) 2-(tert-Butyl)-1'-(3-methoxy-8-methylquinoline-6-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one

[0232] [Chemical Structure Diagram] Prepared in the same manner as in Example 15 using methanol instead of tert-butyl methylcarbamate in Step 3 to obtain the title compound (56 mg). 1 H NMR (400 MHz, CD3OD) δ 8.63 (s, 1H), 7.75 (s, 1H), 7.72 (s, 1H), 7.43 (s, 1H), 3.98 (s, 3H), 3.88 - 3.82 (m, 2H), 3.51 (m, 2H), 3.26 (s, 2H), 2.76 (s, 3H), 2.73 (s, 2H), 1.77 - 1.64 (m, 4H), 1.43 (s, 9H); LC / MS m / z (M + H) + = 478.3.

[0233] (Example 20) 2-(tert-Butyl)-1'-(3-ethoxy-8-methylquinoline-6-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one

[0234] [Chemical Structure Diagram] In Step 3, ethanol was used instead of tert-butyl methylcarbamate and the title compound (2.5 mg) was obtained in the same manner as in Example 15. 1 H NMR (400 MHz, CD3OD) δ 8.64 (s, 1H), 7.75 (s, 1H), 7.71 (s, 1H), 7.44 (s, 1H), 4.24 (q, 2H), 3.80 - 3.60 (m, 2H), 3.53 (m, 2H), 3.28 (s, 2H), 2.77 (s, 3H), 2.76 (s, 2H), 1.79 - 1.63 (m, 4H), 1.52 (t, 3H), 1.45 (s, 9H); LC / MS m / z (M+H) + = 492.3.

[0235] (Example 21) 2-(tert-Butyl)-1'-(8-methyl-3-(methylthio)quinoline-6-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one

[0236]

Chemical Structure

[0237] (Example 22) 4-(4-(2-(tert-Butyl)-4-oxo-4,7-dihydro-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-1'-carbonyl)-6-(dimethylamino)pyridin-2-yl)benzamide

[0238] [Chemical formula] Step 1: Synthesis of 2-(4-carbamoylphenyl)-6-(dimethylamino)isonicotinic acid (C21)

[0239] [Chemical formula] In a microwave vial, to methyl 2-chloro-6-(dimethylamino)isonicotinate (104 mg, 0.486 mmol) in dioxane (3.0 mL) and water (1.0 mL) were added Na2CO3 (64 mg, 0.61 mmol), Pd(PPh3)4 (14 mg, 0.012 mmol), and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (100 mg, 0.41 mmol). The mixture was sparged with nitrogen, placed in the microwave, and irradiated at about 100 °C for about 45 minutes. The mixture was cooled to about 25 °C and concentrated under reduced pressure. The aqueous residue was acidified to approximately pH 5 with 2N HCl, and the resulting precipitate was filtered to obtain the title compound (78 mg, 68% yield). 1 H NMR (400 MHz, CD3OD) δ 8.20 (d, 1H), 7.99 (d, 1H), 7.65 (s, 1H), 7.19 (s, 1H), 3.24 (s, 6H); LC / MS m / z (M+H) + = 285.9.

[0240] Step 2: 4-(4-(2-(tert-Butyl)-4-oxo-4,7-dihydro-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-1'-carbonyl)-6-(dimethylamino)pyridin-2-yl)benzamide (Example 22)

[0241]

Chem.

[0242] (Example 23) 4-(4-(2-(tert-Butyl)-4-oxo-4,7-dihydro-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-1'-carbonyl)-6-methoxypyridin-2-yl)benzamide

[0243]

Chem.

[0244] (Example 24) 2-(tert-Butyl)-1'-(5-methyl-1-(methylamino)isoquinoline-7-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one

[0245]

Chemical formula

[0246]

Chemical formula

[0247] Step 2: 7-Bromo-5-methylisoquinolin-1(2H)-one (C23)

[0248]

Chemical formula

[0249] Step 3: Methyl 5-methyl-1-oxo-1,2-dihydroisoquinoline-7-carboxylate (C24)

[0250]

Chemical formula

[0251] Step 4: Methyl 1-chloro-5-methylisoquinoline-7-carboxylate (C25)

[0252]

Chem.

[0253] Step 5: Methyl 5-methyl-1-(methylamino)isoquinoline-7-carboxylate (C26)

[0254]

Chem.

[0255] Step 6: 5-Methyl-1-(methylamino)isoquinoline-7-carboxylic acid (C27)

[0256]

Chem.

[0257] Step 7: 2-(tert-Butyl)-1'-(5-methyl-1-(methylamino)isoquinoline-7-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one

[0258]

Chem.

[0259] (Example 25) 2-(tert-Butyl)-1'-(1-cyclopropyl-5-methylisoquinoline-7-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one

[0260]

Chemical Structure

[0261] (Example 26) 2-(tert-Butyl)-1'-(4-methyl-1-(methylamino)isoquinoline-7-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one

[0262] [Chemical formula] Step 1: Methyl 1-((tert-butoxycarbonyl)(methyl)amino)-4-methylisoquinoline-7-carboxylate (C28)

[0263] [Chemical formula][ / END] To 1-chloro-4-methylisoquinoline-7-carboxylate (140 mg, 0.594 mmol), tert-butyl-N-methylcarbamate (100 mg, 0.594 mmol), Pd2(dba)3 (27 mg, 0.030 mmol), Cs2CO3 (581 mg, 1.78 mmol), and X-Phos (28 mg, 0.059 mmol) was added toluene (5 mL). The mixture was sparged with nitrogen. The mixture was heated at about 110 °C for about 16 hours. The solution was concentrated under reduced pressure and the residue was purified by chromatography (0% - 30% EtOAc in petroleum ether) to give the title compound (15 mg, 8%). LC / MS m / z (M+H - Boc) + = 231.1.

[0264] Step 2: Methyl 4-methyl-1-(methylamino)isoquinoline-7-carboxylate (C29)

[0265] [Chemical formula][ / END] To compound C28 (15 mg, 0.045 mmol) in MeOH (1.0 mL) was added HCl (4 M in dioxane, 1.0 mL). The reaction mixture was stirred at about 50 °C for about 2 hours. The mixture was concentrated under reduced pressure to give the title compound (10 mg, 96%). LC / MS m / z (M+H) + = 231.0

[0266] Step 3: 4-Methyl-1-(methylamino)isoquinoline-7-carboxylic acid (C30)

[0267]

Chemical formula

[0268] Step 3: 2-(tert-Butyl)-1'-(4-methyl-1-(methylamino)isoquinoline-7-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one

[0269]

Chemical formula

[0270] (Example 27) 2-(tert-Butyl)-1'-(1,4-dimethylisoquinoline-7-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one

[0271] [Chemical Structure Diagram] Prepared in the same manner as Example 26 using trimethylboroxine instead of tert-butyl-N-methylcarbamate in Step 1 to obtain the title compound (42 mg). 1 1H NMR (400 MHz, CD3OD) δ 8.31 (s, 1H), 8.20 (s, 1H), 8.15 (d, 1H), 7.84 (d, 1H), 3.91 - 3.86 (m, 2H), 3.53 (m, 2H), 3.27 (s, 2H), 2.93 (s, 3H), 2.75 (s, 2H), 2.63 (s, 3H), 1.85 - 1.65 (m, 4H), 1.43 (s, 9H); LC / MS m / z (M + H) + = 462.3.

[0272] (Example 28) 2-(tert-Butyl)-1'-(5-methoxy-1-methylisoquinoline-7-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one

[0273]

Chem.

[0274]

Chem.

[0275] Step 2: 5-Methoxy-7-(methoxycarbonyl)isoquinoline 2-oxide (C32)

[0276]

Chem.

[0277] Step 3: Methyl 1-chloro-5-methoxyisoquinoline-7-carboxylate (C33)

[0278]

Chem.

[0279] Step 4: Methyl 5-methoxy-1-methylisoquinoline-7-carboxylate (C34)

[0280]

Chem.

[0281] Step 5: 5-Methoxy-1-methylisoquinoline-7-carboxylic acid (C35)

[0282]

Chem.

[0283] Step 6: 2-(tert-Butyl)-1'-(5-methoxy-1-methylisoquinoline-7-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one (Example 28)

[0284]

Chemical formula

[0285] (Example 29) 2-(tert-Butyl)-1'-(1-ethyl-5-methoxyisoquinoline-7-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one

[0286]

Chem.

[0287] (Example 30) 2-(tert-Butyl)-1'-(2-(isopropylamino)quinoline-7-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one

[0288]

Chem.

[0289]

Chem.

[0290] Step 2: 2-(Isopropylamino)quinoline-7-carboxylic acid (C37)

[0291]

Chem.

[0292] Step 3: 2-(tert-Butyl)-1'-(2-(isopropylamino)quinoline-7-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one (Example 30)

[0293]

Chem.

[0294] (Example 31) 2-(tert-Butyl)-1’-(2-(cyclobutylamino)quinoline-7-carbonyl)-5H-spiro[benzo[d]thiazole-6,4’-piperidine]-4(7H)-one

[0295]

Chemical Structure

[0296] (Example 32) 2-(tert-Butyl)-1'-(2-(ethylamino)quinoline-7-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one

[0297] [Chemical Structure Diagram] Prepared in the same manner as in Example 30 using ethylamine instead of isopropylamine in Step 1 to obtain the title compound (27 mg). 1 H NMR (400 MHz, CD3OD) δ 7.82 (d, 1H), 7.66 (d, 1H), 7.63 (s, 1H), 7.17 (d, 1H), 6.78 (d, 1H), 3.87 - 3.81 (m, 2H), 3.52 - 3.46 (m, 4H), 3.26 (s, 2H), 2.73 (s, 2H), 1.76 - 1.64 (m, 4H), 1.43 (s, 9H), 1.28 (t, 3H); LC / MS m / z (M+H) + = 477.4.

[0298] (Example 33) 2-(tert-Butyl)-1'-(5-methoxy-4-methyl-1H-indazole-7-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one

[0299] [Chemical Structure Diagram] Step 1: Synthesis of 6-bromo-4-methoxy-2,3-dimethylaniline (C38)

[0300] [Chemistry] In MeCN (10 mL), NBS (706 mg, 3.97 mmol) was added to 4-methoxy-2,3-dimethylaniline (500 mg, 3.31 mmol). The mixture was stirred at about 25 °C for about 2 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by chromatography (17% EtOAc in petroleum ether, then 20% MeOH in EtOAc) to give the title compound (600 mg, 79%). 1 H NMR (400 MHz, CDCl3) δ = 6.88 (s, 1H), 3.77 (s, 3H), 2.18 (s, 3H), 2.15 (s, 3H); LC / MS m / z (M+H) + = 231.9.

[0301] Step 2: Synthesis of 7-bromo-5-methoxy-4-methyl-1H-indazole (C39)

[0302] [Chemistry] To a solution of compound C38 (600 mg, 2.61 mmol) in H2O (4 mL) was added concentrated HCl (4 mL). The mixture was heated at about 60 °C for about 30 minutes and then cooled to about 0 °C. A solution of NaNO2 (198 mg, 2.87 mmol) in H2O (1 mL) was added dropwise, and the mixture was stirred at about 0 °C for about 1 hour. Saturated aqueous NaOAc was added to the mixture until the pH reached 4 - 5. A solution of 2-methylpropan-2-thiol (259 mg, 2.87 mmol) in EtOH (7 mL) was added. The mixture was slowly warmed to about 25 °C and stirred for about 16 hours. The mixture was diluted with EtOAc (20 mL), washed with water (20 mL), and washed with brine (20 mL). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was dissolved in DMSO (5 mL), and a solution of KOtBu (1.69 g, 15 mmol) in DMSO (10 mL) was added dropwise. The mixture was stirred at about 25 °C for about 2 hours. The mixture was diluted with EtOAc (50 mL), washed with water (50 mL), and washed with brine (50 mL). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography (17% EtOAc in petroleum ether) to give the title compound (170 mg, 27%). 1 H NMR (400 MHz, CDCl3) δ = 8.12 (s, 1H), 7.29 (s, 1H), 3.90 (s, 3H), 2.45 (s, 3H); LC / MS m / z (M+H) + = 242.8.

[0303] Step 3: Synthesis of ethyl 5-methoxy-4-methyl-1H-indazole-7-carboxylate (C40)

[0304]

Chemical Structure

[0305] Step 4: Synthesis of 5-methoxy-4-methyl-1H-indazole-7-carboxylic acid (C41)

[0306]

Chemical Structure

[0307] Step 5: Synthesis of 2-(tert-butyl)-1'-(5-methoxy-4-methyl-1H-indazole-7-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one (Example 33)

[0308]

Chem.

[0309] (Example 34) 2-(tert-Butyl)-1'-(4-chloro-5-methyl-1H-indazole-7-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one

[0310]

Chem.

[0311] (Example 35) 2-(tert-Butyl)-1'-(4,5-dimethyl-1H-indazole-7-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one

[0312] [Chemical Structure Diagram] Prepared in the same manner as in Example 33 using 2,3,4-trimethylaniline instead of 4-methoxy-2,3-dimethylaniline in Step 1 to obtain the title compound (26 mg). 1 1H NMR (400 MHz, CD3OD) δ 8.13 (s, 1H), 7.26 (s, 1H), 3.70 - 3.59 (m, 4H), 3.23 (s 2H), 2.73 (s, 2H), 2.55 (s, 3H), 2.39 (s, 3H), 1.76 - 1.67 (m, 4H), 1.43 (s, 9H); LC / MS m / z (M + H) + = 451.4.

[0313] (Example 36) 2-(tert-Butyl)-1'-(4-methoxy-5-methyl-1H-indazole-7-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one

[0314] [Chemical Structure Diagram] Step 1: Synthesis of 4-methoxy-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (C42)

[0315]

Chemical formula

[0316] Step 2: Synthesis of 7-bromo-4-methoxy-5-methyl-1H-indazole (C43)

[0317]

Chemical formula

[0318] Step 3: Synthesis of ethyl 4-methoxy-5-methyl-1H-indazole-7-carboxylate (C44)

[0319]

Chemical formula

[0320] Step 4: Synthesis of 4-methoxy-5-methyl-1H-indazole-7-carboxylic acid (C45)

[0321]

Chemical formula

[0322] Step 5: Synthesis of 2-(tert-butyl)-1'-(4-methoxy-5-methyl-1H-indazole-7-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one

[0323]

Chemical formula

[0324] (Example 37) 2-(tert-Butyl)-1'-(4-chloro-5-methoxy-1H-indole-7-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one

[0325]

Chemical Structure

[0326]

Chemical Structure

[0327] Step 2: Synthesis of 7-bromo-4-chloro-5-methoxy-1H-indole (C47)

[0328]

Chemical formula

[0329] Step 3: Synthesis of Ethyl 4-chloro-5-methoxy-1H-indole-7-carboxylate (C48)

[0330]

Chem.

[0331] Step 4: Synthesis of 4-chloro-5-methoxy-1H-indole-7-carboxylic acid (C49)

[0332]

Chem.

[0333] Step 5: Synthesis of 2-(tert-butyl)-1'-(4-chloro-5-methoxy-1H-indole-7-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one

[0334]

Chem.

[0335] (Example 38) 2-(tert-Butyl)-1'-(5-methyl-2-(methylamino)quinoline-7-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one

[0336]

Chemical Structure

[0337] (Example 39) 2-(tert-Butyl)-1'-(2-(ethylamino)-5-methylquinoline-7-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one

[0338] [Chemical Structure Diagram] Step 1: Synthesis of 7-Bromo-N-ethyl-5-methylquinolin-2-amine (C50)

[0339] [Chemical Structure Diagram] 7-Bromo-2-chloro-5-methylquinoline (50 mg, 0.19 mmol, prepared as described in patent application WO2013185103A1) was added to iPr2NEt (67 μL, 0.39 mmol), ethylamine (70% aqueous solution, 0.234 mmol), and NMP (0.2 mL). The mixture was heated at about 110 °C for about 18 h, then at about 140 °C for about 24 h. The mixture was cooled to about 25 °C and diluted with water. The mixture was extracted with diethyl ether (3 times). The combined ether extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (0% - 60% EtOAc in heptane) to afford the title compound (14 mg, 27%). LC / MS m / z (M+H) + = 265.2.

[0340] Step 2: Synthesis of 2-(tert-butyl)-1'-(2-(ethylamino)-5-methylquinoline-7-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one

[0341]

Chemical Structure

[0342] (Example 40) 2-(tert-Butyl)-1'-(5-methoxy-2-(methylamino)quinoline-7-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one

[0343] [Chemical formula] Step 1: Synthesis of 5-methoxy-7-(methoxycarbonyl)quinoline 1-oxide (C51)

[0344] [Chemical formula] The following reaction was carried out in parallel in two batches. To methyl 5-methoxyquinoline-7-carboxylate (1.20 g, 4.70 mmol) in DCM (25 mL), m-CPBA (972 mg, 5.63 mmol) was added. The mixture was stirred at about 20 °C for about 16 h. The two batches were combined and saturated aqueous Na2S2O3 was added. Saturated aqueous Na2CO3 was added until the pH exceeded 8, and then the mixture was stirred for about 30 min. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with DCM (50 mL) and washed with water (3 × 20 mL). The DCM extract was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (0% - 15% MeOH in EtOAc) to give the title compound (1.90 g, average yield 95%). LC / MS m / z (M+H) + = 233.9。

[0345] Step 2: Synthesis of methyl 5-methoxy-2-(methylamino)quinoline-7-carboxylate (C52)

[0346]

Chemical formula

[0347] Step 3: Synthesis of 5-methoxy-2-(methylamino)quinoline-7-carboxylic acid (C53)

[0348]

Chem.

[0349] Step 4: Synthesis of 2-(tert-butyl)-1'-(5-methoxy-2-(methylamino)quinoline-7-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one

[0350]

Chem.

[0351] (Example 41) 2-(tert-Butyl)-1’-(4-methoxy-8-methylquinoline-6-carbonyl)-5H-spiro[benzo[d]thiazole-6,4’-piperidine]-4(7H)-one

[0352]

Chemical formula

[0353]

Chemical formula

[0354] Step 2: Synthesis of methyl 4-methoxy-8-methylquinoline-6-carboxylate (C55)

[0355]

Chemical formula

[0356] Step 3: Synthesis of 4-methoxy-8-methylquinoline-6-carboxylic acid (C56)

[0357]

Chemical Structure

[0358] Step 4: Synthesis of 2-(tert-butyl)-1'-(4-methoxy-8-methylquinoline-6-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one

[0359]

Chemical Structure

[0360] (Example 42) 2-(tert-Butyl)-1'-(3-chloro-7-methyl-1H-indole-5-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one

[0361]

Chem.

[0362] [Chemistry] To a solution of ethyl 7-methyl-1H-indole-5-carboxylate (commercially available, 0.45 g, 2.21 mmol) in THF (22 mL) was added NCS (0.5 g, 3.76 mmol). The reaction mixture was stirred at about 25 °C for about 3 hours and then diluted with EtOAc (20 mL) and water (20 mL). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2 × 20 mL). The combined EtOAc extracts were dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound (380 mg, 72%) as a yellow solid. 1 1H NMR (400 MHz, chloroform-d) δ 8.36 (s, 0.5H), 8.31 - 8.26 (m, 0.5H), 8.24 (s, 0.5H), 8.18 (d, 0.5H), 7.79 (d, 1H), 7.24 (d, 1H), 4.43 (q, 2H), 2.53 (s, 3H), 1.45 (t, 3H).

[0363] Step 2: Synthesis of 3-chloro-7-methyl-1H-indole-5-carboxylic acid (C62)

[0364] [Chemistry] To a solution of compound ethyl 3-chloro-7-methyl-1H-indole-5-carboxylate C61 (0.38 g, 1.6 mmol) in MeOH (9 mL) and H2O (3 mL) was added LiOH·H2O (0.2 g, 4.80 mmol). The mixture was heated at about 25 °C for about 4 hours and then concentrated. The mixture was diluted with water (6 mL), extracted with EtOAc (2 × 20 mL), and the EtOAc extracts were discarded. The pH of the aqueous layer was adjusted to 3 - 4 with 1N HCl and then extracted with EtOAc (2 × 20 mL). The combined EtOAc extracts were dried over MgSO4, filtered, and concentrated under reduced pressure to give the title compound (210 mg, 63%) as a yellow solid. 11H NMR (400 MHz, DMSO-d6) δ 12.60 (s, 1H), 11.77 (s, 1H), 8.04 (s, 1H), 7.74 - 7.67 (m, 1H), 7.66 (s, 1H), 2.56 (s, 3H, overlapping with d-DMSO).

[0365] Step 3: Synthesis of 2-(tert-butyl)-1'-(3-chloro-7-methyl-1H-indole-5-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one

[0366]

Chemical Structure

[0367] (Example 43) 2-(tert-Butyl)-1’-(4,8-dimethoxyisoquinoline-6-carbonyl)-5H-spiro[benzo[d]thiazole-6,4’-piperidine]-4(7H)-one

[0368]

Chem.

[0369]

Chem.

[0370] Step 2: Synthesis of Ethyl 8-bromo-4-chloroisoquinoline-6-carboxylate (C64)

[0371] [Chemical formula] To a solution of ethyl 8-bromoisoquinoline-6-carboxylate C63 (0.25 g, 0.89 mmol) in AcOH (5 mL) was added NCS (0.143 g, 1.07 mmol). The reaction mixture was stirred at about 50 °C for about 16 h, and then the temperature was raised to about 60 °C for an additional 16 h. The reaction was concentrated and then diluted with EtOAc (50 mL) and aqueous saturated NaHCO3 (20 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3 × 50 mL). The combined EtOAc layers were washed with brine (2 × 30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography (0% - 20% EtOAc in petroleum ether) to give the title compound (0.2 g, 71.2%). 1 H NMR (400 MHz, chloroform-d) δ 9.51 (d, 1H), 8.82 (t, 1H), 8.67 (s, 1H), 8.42 (d, 1H), 4.43 (q, 2H), 1.41 (t, 3H); LC / MS m / z (M+H) + = 315.9.

[0372] Step 3: Synthesis of methyl 4,8-dimethoxyisoquinoline-6-carboxylate (C65)

[0373] [Chemical formula] To a solution of ethyl 8-bromo-4-chloroisoquinoline-6-carboxylate (0.2 g, 0.636 mmol) in dioxane (5 mL) were added Rockphos-Pd-G3 (0.053 g, 0.0636 mmol), Cs2CO3 (0.414 g, 1.27 mmol) and MeOH (0.102 g, 3.18 mmol). The reaction mixture was stirred at about 80 °C for about 16 h, cooled to room temperature, filtered and concentrated. The residue was purified by chromatography (0% - 40% EtOAc in petroleum ether) to give the title compound (0.09 g, 57%) as a yellow solid. 1 H NMR (400 MHz, chloroform-d) δ 9.22 (d, 1H), 8.42 (dt, 1H), 8.11 (s, 1H), 7.43 (d, 1H), 4.10 - 3.99 (m, 6H), 3.93 (s, 3H); LC / MS m / z (M+H) + = 248.1.

[0374] Step 4: Synthesis of 4,8-dimethoxyisoquinoline-6-carboxylic acid (C66)

[0375]

Chemical formula

[0376] Step 5: Synthesis of 2-(tert-butyl)-1'-(4,8-dimethoxyisoquinoline-6-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one (Example 43)

[0377]

Chemical Structure

[0378] The following compounds of the present invention were prepared in the same manner using the amidation methods described above. For those examples characterized by HPLC retention time, the following HPLC conditions were used.

[0379] Method 1 Column: ACQUITY UPLC BEH C18 50×2.1 mm, 1.7 μm Mobile phase A: 10 mM ammonium acetate in water / acetonitrile - 95 / 5 v / v Mobile phase B: 10 mM ammonium acetate in acetonitrile / water - 95 / 5 v / v Gradient: Increase from 5% D to 100% D within 1 minute, hold at 100% D for 0.2 minutes, then return to 0% D at 1.21 minutes and hold for 0.29 minutes. Flow rate: 1.0 mL / min.

[0380] Method 2 Column: Atlantis dC18 4.6×50 mm 5 μm Mobile phase A: 0.05% TFA (v / v) in water Mobile phase B: 0.05% TFA (v / v) in acetonitrile Gradient: Increase linearly from 95% water / 5% acetonitrile to 5% water / 95% acetonitrile in 4.0 minutes and hold at 5% water / 95% acetonitrile for 5 minutes Flow rate: 2 mL / min.

[0381] Method 3 Column: Xbridge C18 2.1×50 mm 5 μm Mobile phase A: 0.0375% TFA in water Mobile phase B: 0.01875% TFA in acetonitrile Gradient: Hold 10% B for 0.5 minutes, then increase linearly to 100% B in 4 minutes and decrease to 10% B from 4.30 minutes to 4.70 minutes Flow rate: 0.8 mL / min.

[0382] Method 4 Column: Xbridge C18 2.1×50 mm 5 μm Mobile phase A: 0.0375% TFA in water Mobile phase B: 0.01875% TFA in acetonitrile Gradient: Hold 1% B for 0.6 minutes, then increase linearly to 100% B in 4 minutes and decrease to 1% B from 4.30 minutes to 4.70 minutes Flow rate: 0.8 mL / min.

[0383] Method 5 Column: Waters Acquity HSS T3, 2.1 mm × 50 mm, 1.7 μm Mobile phase A: 0.1% formic acid in water (v / v) Mobile phase B: 0.1% formic acid in acetonitrile (v / v) Gradient: Initial conditions A - 95%: B - 5%; Hold the initial conditions for 0.0 - 0.1 minutes, linearly increase to A - 5%: B - 95% over 0.1 - 1.0 minutes, hold A - 5%: B - 95% for 1.0 - 1.1 minutes, and return to the initial conditions at 1.1 - 1.5 minutes Flow rate: 1.25 mL / min

[0384]

Table 1 - 1

[0385]

Table 1 - 2

[0386]

Table 1 - 3

[0387]

Table 1 - 4

[0388]

Table 1 - 5

[0389]

Table 1 - 6

[0390]

Table 1 - 7

[0391]

Table 1 - 8

[0392]

Table 1-9

[0393]

Table 1-10

[0394]

Table 1-11

[0395]

Table 1-12

[0396]

Table 1-13

[0397]

Table 1-14

[0398]

Table 1-15

[0399]

Table 1-16

[0400]

Table 1-17

[0401] (Example 109) rac-(R)-(2-(tert-Butyl)-4-hydroxy-4,7-dihydro-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-1'-yl)(7-ethoxy-1,3-dimethyl-1H-indazol-5-yl)methanone

[0402]

Chem.

[0403] Deuterated analog of the compound of Example 14 The metabolite profiles of the compounds of Example 14 were evaluated in liver microsomes and hepatocytes (mouse, rat, rabbit, dog, monkey, and human), recombinant human cytochrome P450 enzymes, recombinant human UGT enzymes, and plasma of animals (mouse, rat, and dog). The metabolite profile of Compound XXCAN consists of oxidation and glucuronide conjugation.

[0404] General methods / reviews for obtaining metabolite profiles of compounds and identifying metabolites are described in King, R., "Biotransformations in Drug Metabolism", Ch. 3, Drug Metabolism Handbook Introduction, https: / / doi.org / 10.1002 / 9781119851042.ch3; Wu, Y. et al., "Metabolite Identification in the Preclinical and Clinical Phase of Drug Development", Current Drug Metabolish, 2021, 22, 11, 838 - 857, 10.2174 / 1389200222666211006104502; Godzien, J. et al., "Chapter Fifteen - Metabolite Annotation and Identification", Comprehensive Analytical Chemistry, 2018, 82, 415 - 445, https: / / doi.org / 10.1016 / bs.coac.2018.07.004; Zhang, Z. et al., "Drug metabolism in drug discovery and development", Acta Pharmaceutica Sinica B, 2018, 8(5), 721 - 732, https: / / doi.org / 10.1016 / j.apsb.2018.04.003.

[0405] The metabolite profiles of compounds can also be obtained from publicly available software tools and commercially available software tools. Examples of such tools include BioTransformer 3.0 (biotransformer.ca / new), which uses a database of known metabolic reactions to predict the metabolic biotransformation of small molecules. Lhasa Meteor Nexus (www.lhasalimited.org / products / meteor-nexus.htm) uses various machine learning models that cover the phase I and phase II biotransformations of small molecules to predict metabolic pathways and the structures of metabolites.

[0406] The predictive deuterated analogs 110-122 shown below in this specification can provide certain therapeutic advantages obtained from higher metabolic stability, such as an extended in vivo half-life, a reduced required dose, a reduced CYP450 inhibition (competitive or time-dependent), or an improved therapeutic index or tolerance.

[0407] One of ordinary skill in the art can prepare further deuterated analogs of the compound of Example 14. Such further deuterated analogs can provide therapeutic advantages similar to those achievable by the non-deuterated analogs.

[0408] (Example 110) 2-tert-Butyl-1'-{7-[(1,1-dideuterio)ethyloxy]-1,3-dimethyl-1H-indazole-5-carbonyl}-5H-spiro[[1,3]benzothiazole-6,4'-piperidine]-4(7H)-one

[0409] [Chemical Structure] (Example 111) 2-tert-Butyl-1'-{7-[(pentadeuterio)ethyloxy]-1,3-dimethyl-1H-indazole-5-carbonyl}-5H-spiro[[1,3]benzothiazole-6,4'-piperidine]-4(7H)-one

[0410]

Chem.

[0411]

Chem.

[0412]

Chem.

[0413]

Chem.

[0414]

Chem.

[0415]

Chem.

[0416]

Chem.

[0417]

Chem.

[0418]

Chem.

[0419] [Chemical formula] (Example 121) 1’-{7-[(Pentadeuterio)ethyloxy]-1,3-bis[(trideuterio)methyl]-1H-indazole-5-carbonyl}-2-[2-(trideuterio)methyl(hexadeuterio)propan-2-yl]-5H-spiro[[1,3]benzothiazole-6,4’-piperidin]-4(7H)-one

[0420] [Chemical formula] (Example 122) 2-tert-butyl-1’-(7-ethoxy-1,3-dimethyl-1H-indazole-5-carbonyl)(5,5-dideuterio)-5H-spiro[[1,3]benzothiazole-6,4’-piperidin]-4(7H)-one

[0421] [Chemical formula]

[0422] Biological protocol The utility of the compounds of the present invention in the treatment and / or prevention of acne vulgaris in patients can be demonstrated by their activity in the in vitro assays described below. Such assays also provide a means by which the activity of the compounds of the present invention can be compared to the activity of other known compounds.

[0423] Direct inhibition of ACC1 activity The ACC inhibitory activity of the compounds of the present invention was demonstrated by a method based on standard procedures. The direct inhibition of ACC1 for the compounds of the present invention was determined using a preparation of recombinant human ACC1 (rhACC1) (SEQ ID NO: 1).

[0424] Preparation of rhACC1 2 liters of SF9 cells infected with a recombinant baculovirus containing full-length human ACC1 cDNA were suspended in ice-cold lysis buffer (25 mM Tris, pH 7.5, 150 mM NaCl, 10% glycerol, 5 mM imidazole (EMD Bioscience, Gibbstown, NJ), 2 mM TCEP (BioVectra, Charlottetown, Canada), benzonase nuclease (10000 U / 100 g cell paste, Novagen, Madison, WI), protease inhibitor cocktail without EDTA (1 tablet / 50 ml, Roche Diagnostics, Mannheim, Germany)). The cells were lysed by 3 cycles of freeze-thaw and centrifuged at 40,000×g for 40 minutes (4 °C). The supernatant was directly loaded onto a His Trap FF crude column (GE Healthcare, Piscataway, NJ) and eluted with an imidazole gradient up to 0.5 M over 20 column volumes (CV). The fractions containing ACC1 were pooled, diluted 1:5 with 25 mM Tris, pH 7.5, 2 mM TCEP, 10% glycerol, and directly loaded onto a CaptoQ (GE Healthcare) column and eluted with an NaCl gradient up to 1 M over 20 CV. The phosphate group was removed from the purified ACC1 by incubating with lambda phosphatase (100 U / 10 μM target protein, New England Biolabs, Beverly, MA) at 4 °C for 14 hours. Okadaic acid (final concentration 1 μM, Roche Diagnostics) was added to inhibit the phosphatase. The purified ACC1 was exchanged with 25 mM Tris, pH 7.5, 2 mM TCEP, 10% glycerol, 0.5 M NaCl by dialysis at 4 °C for 6 hours. Aliquots were prepared and frozen at -80 °C.

[0425] Measurement of rhACC1 Inhibition rhACC1 was assayed in a Corning #3820 (Corning, Tewksbury, MA) 384-well plate using the Transcreener ADP Detection FP Assay Kit (Bellbrook Labs, Madison, Wisconsin) under the manufacturer's recommended conditions for the 50 μM ATP reaction. The final conditions of the assay were 50 mM HEPES, pH 7.2, 10 mM MgCl2, 7.5 mM tripotassium citrate, 2 mM DTT, 0.1 mg / mL BSA, 30 μM acetyl-CoA, 50 μM ATP, and 10 mM KHCO3. Typically, a 10 μM reaction was run at room temperature for 60 minutes, 10 μl of Transcreener Stop and Detection Buffer was added, and the combination was incubated at room temperature overnight (18 hours). Data was acquired using an Envision fluorescence reader (PerkinElmer) with a 620 excitation Cy5 FP universal dual mirror, 620 excitation Cy5 FP filter, 688 emission (S) and 688 (P) emission filters.

[0426]

Table 2-1

[0427]

Table 2-2

[0428]

Table 2-3

[0429]

Table 2-4

[0430]

Table 2-5

[0431]

Table 2-6

[0432]

Table 2-7

[0433]

Table 2-8

[0434]

Table 2-9

[0435]

Table 2-10

[0436]

Table 2-11

[0437]

Table 2-12

[0438]

Table 2-13

[0439]

Table 2-14

[0440] High-content imaging assay for quantifying lipid droplets in human sebocyte cell lines One week before cell administration, SZ95 human sebaceous gland cells were thawed and grown in a T175 tissue culture flask containing 50 mL of medium. The medium was prepared as follows. Sebomed basal medium (Sigma, catalog number F8205) containing stable glutamine and no phenol red, 10% heat-inactivated fetal bovine serum (Invitrogen, catalog number 10082), 5 ng / mL recombinant human epidermal growth factor (Gibco, catalog number PHG0311), 1 mM calcium chloride (Fisher Scientific, catalog number BP9742), and 1× penicillin / streptomycin (Thermo Fisher, catalog number 15140-122). The cells were cultured at 37 °C and the medium was changed every 48 - 72 hours until the start of the assay. The compounds were delivered as 75 nL spots by an Echo 550 (Labcyte) to a 384-well assay plate (PerkinElmer, catalog number 6057308) such that the final compound concentrations were 10, 3.162, 1.000, 0.316, 0.100, 0.032, 0.010, 0.003, 0.001, 0.0003, and 0.0001 μM. The final DMSO concentration was 0.1%. The SZ-95 cells were washed with Dulbecco's phosphate buffered saline (DPBS, Lonza, catalog number 17-512Q) and then detached with 0.25% trypsin-EDTA (Gibco, catalog number 25200056). Growth medium (25 mL) was added to the flask and the cells were further 1.33×10 5It was diluted to cells / mL. SZ-95 cells were seeded at a density of 10,000 cells / well with 75 μL and incubated at 37 °C for 48 hours. Using a Biomek FX (Beckman), 25 μL of the medium was removed, and the cells were fixed by adding 18.7 μL of 16% paraformaldehyde (Electron Microscopy Sciences, catalog number 50980488). After incubation at room temperature for 30 minutes, the plate was washed twice with 75 μL of DPBS. After the second wash, all the remaining DPBS was removed. The staining solution was prepared using 2 μM Bodipy (Invitrogen, catalog number D3922, diluted 1:1000) and Hoechst (Life Technologies, catalog number H3570, diluted 1:2000) in DPBS. Using a Biomek FX, 30 μL of the staining solution was added to each well. The cells were incubated at room temperature for 20 minutes and then washed once with 75 μL of DPBS. Finally, 30 μL of DPBS was added to each well, and the plate was sealed with a light-shielding film. The plate was read using an Opera Phenix (PerkinElmer) for high-content imaging. Nuclei were detected by Hoechst staining, and lipid droplets were detected by Bodipy, which stains neutral lipids. The active compound caused a decrease in the number and area of lipid droplets. The percent effect (%) at each concentration of the compound was calculated using a 4-parameter logistic dose-response equation by the Genedata Screener analysis program and calculated relatively based on the amount of lipid droplets in the positive and negative control wells contained in each assay plate to determine the 50% inhibitory concentration (IC50).

[0441]

Table 3-1

[0442]

Table 3-2

[0443]

Table 3-3

[0444]

Table 3-4

[0445]

Table 3-5

[0446]

Table 3-6

[0447]

Table 3-7

[0448]

Table 3-8

[0449]

Table 3-9

[0450]

Table 3-10

[0451]

Table 3-11

[0452]

Table 3-12

[0453]

Table 3-13

[0454]

Table 3-14

[0455] Radiometric measurement of de novo lipogenesis in cultured human sebaceous gland cells SZ95 sebaceous gland cells were grown in human sebaceous gland growth medium (HSGM) containing Sebomed® basal medium (Sigma-Aldrich, F8205) supplemented with 10% heat-inactivated fetal bovine serum (Gibco, 10100-147), 1% penicillin / streptomycin (Gibco, 15070-063), 1 mM calcium chloride (Fisher, BP9742-10×5), and 5 ng / mL recombinant human epidermal growth factor (Gibco, PHG0311). At 90% confluence, the cells were washed with PBS and then detached with 0.05% trypsin-EDTA (Gibco, 25300054). Prior to starting the assay, the cells were centrifuged and resuspended in HSGM containing 5% charcoal-treated serum (Life Technologies, 12676-029) instead of 10% heat-inactivated fetal bovine serum. The cells were added to 24-well plates at a density of 0.25×10 6 cells / well and incubated overnight at 37°C to allow the cells to adhere to the culture plates. Next, the cells were treated with dose-response compounds (30, 1, 0.03, 0.006, 0.0009, 0.0002, and 0.00003 μM), and each concentration was tested in duplicate. Briefly, the compounds were dissolved in DMSO stock and diluted 1:1000 in HSGM containing charcoal-treated medium. Vehicle control wells were treated with 0.1% DMSO. After pre-incubating the compounds or vehicle at 37°C for 1 hour, 0.25 μCi 14 sodium acetate (American Radiolabeled Chemicals: ARC, 0173A) was added to each well. The plates were incubated for an additional 2 hours at 37°C. At the end of the incubation period, the cells were removed from the incubator, placed on ice, and then washed twice with ice-cold PBS to remove free 14The C-sodium acetate was removed. The plates were sealed and stored at -20 °C until analysis. To induce lysis, 125 μL of mammalian protein extraction reagent (MPER, Fisher, 78501) was added to each well. The plates were shaken at room temperature for 1 hour and the lysates were transferred to individual 2 mL polypropylene tubes. Next, the wells were washed with 175 μL of PBS and this was added to the lysates. Chloroform:methanol solution (1:1 v / v, 450 μL) was added to each tube. All tubes were vortexed for 10 seconds and centrifuged at 14,000 × g for 5 minutes at room temperature to separate the aqueous and organic phases. A 25 μL aliquot was removed from the lower organic layer of each sample and added to 6 mL of Optiphase Supermix scintillation fluid (PerkinElmer, 1200-439). 14 The counts of C were evaluated by scintillation counting. The DNL (counts of C incorporated into lipids) was expressed as the percentage of compound-treated cells compared to the vehicle control. The IC 14 values were determined using non-linear regression (four parameters with variable slope) in GraphPad Prism. 50

[0456]

Table 4-1

[0457]

Table 4-2

Claims

1. Structure 【Chemical 1】 A compound of formula (I) having the same, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt [wherein, R is H, C １ ~C ６ alkoxy, C １ ~C ６ alkyl and -(CH ２ ) ｍ -W, and is selected from the group consisting of, W is C ３ ~C ８ cycloalkyl, bicycloalkyl, bridged bicycloalkyl, phenyl, naphthyl, 5- or 6-membered heteroaryl or heterocyclic containing 1, 2 or 3 heteroatoms selected from the group consisting of N, S and O atoms, and each of said alkyl, cycloalkyl, heterocyclic, phenyl, naphthyl or heteroaryl may be unsubstituted or phenyl, halo, cyano, deuterium, hydroxy, C １ ~C ６ alkyl, C １ ~C ６ alkoxy, -SO ２ -R', -CONR'R'', NR'COR'', -NR'CONR'R'', -NR'CO ２ R'', -(CH ２ ) ｎ -SO ２ -R', -NHSO ２ -R', -NR''SO ２ -R', -SO ２ NR'R'', NR'R'' or SR', and R' and R'' are independently H, C １ ~C ６ alkyl or C ３ ~C ８ cycloalkyl, R １ is selected from the group consisting of 5- or 6-membered heteroaryl or heterocyclic containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of phenyl, naphthyl, N, S and O atoms, and 9- or 10-membered bicyclic aryl, heteroaryl or heterocyclic containing 1, 2 or 3 heteroatoms selected from the group consisting of N, S and O atoms, each of said phenyl, naphthyl, aryl, heterocyclic, or heteroaryl may be unsubstituted or halo, cyano, deuterium, hydroxy, C １ -C ６ -alkyl, C １ -C ６ -alkoxy, phenyl, -SO ２ -R', -CONR'R'', NR'COR'', -NR'CONR'R'', -NR'CO ２ R'', -(CH ２ ) ｎ -SO ２ -R', -NHSO ２ -R', -NR''SO ２ -R', -SO ２ NR'R'', NR'R'', -P(O)R'R'', [Chemical 2] or may be replaced by SR', and R' and R'' are independently H, C １ -C ６ alkyl or C ３ -C ８ cycloalkyl, m and n are each independently 0, 1, 2 or 3].

2. R is H, C １ ~C ６ alkyl and -(CH ２ ) ｍ -W, where W is C ３ ~C ８ cycloalkyl, and each of said alkyl, cycloalkyl, bicycloalkyl, and bridged bicycloalkyl may be unsubstituted or substituted by halo, cyano, deuterium, hydroxy, C １ ~C ６ alkyl and C １ ~C ６ alkoxy, The compound according to claim 1, wherein m and n are each independently 0, 1, 2 or 3.

3. The compound according to claim 1, wherein R is tert-butyl.

4. R １ is phenyl, pyridyl, indolyl, indazolyl, pyrrolopyridinyl, quinolinyl, isoquinolinyl or naphthyl, each of which may be unsubstituted or may be substituted with halo, cyano, hydroxy, C １ ~C ６ Alkyl, C １ ~C ６ alkoxy, phenyl, -CONR'R'', NR'R'', or SR', where R' and R'' are independently H, C １ ~C ６ Alkyl or C ３ ~C ８ cycloalkyl, and m and n are independently 0, 1, 2, or 3.

5. 2-(tert-Butyl)-1'-(7-methoxy-1,3-dimethyl-1H-indazole-5-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one; 2-(tert-Butyl)-1'-(7-methyl-1H-indole-5-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one; 2-(tert-Butyl)-1'-(8-methyl-3-(methylamino)quinoline-6-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one; 2-(tert-Butyl)-1'-(7-ethoxy-1,3-dimethyl-1H-indazole-5-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one; and, 2-(tert-Butyl)-1'-(4-methyl-2-naphthoyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one; The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, selected from the group consisting of.

6. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, which is 2-(tert-butyl)-1'-(7-methoxy-1,3-dimethyl-1H-indazole-5-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one.

7. The compound according to claim 1 which is 2-(tert-butyl)-1'-(7-methyl-1H-indole-5-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt.

8. The compound according to claim 1 which is 2-(tert-butyl)-1'-(8-methyl-3-(methylamino)quinoline-6-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt.

9. The compound according to claim 1 which is 2-(tert-butyl)-1'-(7-ethoxy-1,3-dimethyl-1H-indazole-5-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt.

10. The compound according to claim 1 which is 2-(tert-butyl)-1'-(4-methyl-2-naphthoyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-4(7H)-one, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt.

11. A pharmaceutical composition comprising the compound according to claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt, and a pharmaceutically acceptable excipient.

12. Inflammation, autoimmune diseases, neuroinflammation, arthritis, rheumatoid arthritis, spondyloarthritis, systemic lupus erythematosus, lupus nephritis, osteoarthritis, gouty arthritis, pain, fever, pulmonary sarcoidosis, silicosis, cardiovascular diseases, atherosclerosis, myocardial infarction, thrombosis, congestive heart failure and cardiac reperfusion injury, cardiomyopathy, stroke, ischemia, reperfusion injury, cerebral edema, traumatic brain injury, neurodegeneration, liver diseases, inflammatory bowel diseases, Crohn's disease, ulcerative colitis, nephritis, retinitis, retinopathy, macular degeneration, glaucoma, diabetes (type 1 and type 2), diabetic neuropathy, viral and bacterial infections, myalgia, endotoxin shock, toxic shock syndrome, osteoporosis, multiple sclerosis, endometriosis, dysmenorrhea, vaginitis, candidiasis, cancer, fibrosis, obesity, muscular dystrophy, polymyositis, dermatomyositis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, vitiligo, Alzheimer's disease, flushing of the skin, eczema, psoriasis, atopic dermatitis, sunburn, keloid, hypertrophic scar, rheumatic diseases, urticaria, discoid lupus erythematosus, cutaneous lupus, central nervous system lupus, psoriatic arthritis, asthma, allergic asthma, Aicardi-Goutières syndrome and other Mendelian genetic diseases due to overexpression of type I interferon including type I interferonopathy, primary progressive multiple sclerosis, relapsing-remitting multiple sclerosis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, scleroderma, alopecia areata, cicatricial alopecia, prurigo, nodular prurigo, CPUO, lichen diseases, lichen planus, Stevens-Johnson syndrome, spondylosis, myositis, vasculitis, pemphigus, lupus, major depressive disorder, allergy, dry eye syndrome, graft rejection, cancer, septic shock, cardiopulmonary dysfunction, acute respiratory diseases, ankylosing spondylitis, cachexia, chronic graft-versus-host disease, acute graft-versus-host disease, celiac sprue, idiopathic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, myasthenia gravis, Sjögren's syndrome, epidermal hyperplasia, cartilage inflammation, bone resorption, juvenile arthritis, juvenile rheumatoid arthritis, oligoarticular juvenile rheumatoid arthritis, polyarticular juvenile rheumatoid arthritis, systemic-onset juvenile rheumatoid arthritis, juvenile ankylosing spondylitis, juvenile enteropathic arthritis, juvenile Reiter's syndrome, SEA syndrome, juvenile dermatomyositis, juvenile psoriatic arthritis, juvenile scleroderma, juvenile systemic lupus erythematosus, juvenile vasculitis, oligoarticular rheumatoid arthritis, polyarticular rheumatoid arthritis, systemic-onset rheumatoid arthritis, enteropathic arthritis, reactive arthritis,A method of treating a disease or condition selected from writer's syndrome, myositis, polymyositis, dermatomyositis, polyarteritis nodosa, Wegener's granulomatosis, arteritis, rheumatoid polymyalgia, sarcoidosis, sclerosis, primary biliary sclerosis, sclerosing cholangitis, dermatitis, Still's disease, chronic obstructive pulmonary disease, Guillain - Barré disease, Graves' disease, Addison's disease, Raynaud's phenomenon, psoriatic epidermal hyperplasia, psoriasis vulgaris, guttate psoriasis, inverse psoriasis, pustular psoriasis, psoriatic erythroderma, an immune disorder associated with or resulting from the activity of pathogenic lymphocytes, non - infectious uveitis, Behçet's disease, and Vogt - Koyanagi - Harada syndrome, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof according to claims 1 to 10, or a pharmaceutically acceptable solvate of said compound or salt.

13. The method according to claim 12, wherein the compound is administered topically.

14. The method according to claim 12, wherein the compound is administered as a cream, ointment, lotion, gel, solution, suspension, foam, aerosol, spray, shampoo, patch or tape.

15. A method for treating acne, comprising administering to a subject a therapeutically effective amount of the compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt.

16. The method according to claim 15, wherein the compound is administered topically.

17. The method according to claim 15, wherein the compound is administered as a cream, ointment, lotion, gel, solution, suspension, foam, aerosol, spray, shampoo, patch or tape.

18. A method for treating an inflammatory skin disease, seborrheic dermatitis, rosacea, steroid acne, papulopustular drug eruption, and hidradenitis suppurativa, the method comprising administering to a subject a therapeutically effective amount of the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt.

19. The method according to claim 18, wherein the compound is administered topically.

20. The method according to claim 18, wherein the compound is administered as a cream, ointment, lotion, gel, solution, suspension, foam, aerosol, spray, shampoo, patch or tape.

21. Use of a compound according to any one of claims 1 to 10 for the manufacture of a medicament for the treatment of a disorder for which an ACC inhibitor is indicated.

22. Use of a compound according to any one of claims 1 to 10 for the manufacture of a medicament for the treatment of acne.

23. A compound according to any one of claims 1 to 10 for use in the treatment of a disorder for which an ACC inhibitor is indicated.

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