Novel acc inhibitors

Abstract

# imgabs0. The invention relates to a compound having the structure of formula (Ia) or (Ib) or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or the pharmaceutically acceptable salt wherein: R is selected from: H, C1-C6 alkyl, C1-C6 alkoxy and-(CH2) m-W, wherein W is C3-C8 cycloalkyl, bicycloalkyl, bridged bicycloalkyl, phenyl, 5-or 6-membered heteroaryl or heterocyclic radical containing one, two or three heteroatoms selected from N, S and O atoms; wherein each of the alkyl, cycloalkyl, alkoxy, heterocyclyl, phenyl, naphthyl or heteroaryl may be unsubstituted or substituted with phenyl, halogen, cyano, deuterium, hydroxyl, 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 ', wherein R' and R 'are independently H, C1-C6 alkyl or C3-C8 cycloalkyl; r1 is selected from phenyl, naphthyl, and 5-or 6-membered heteroaryl or heterocyclic radical containing one, two, three or four heteroatoms selected from N, S and O atoms; and a 9-or 10-membered bicyclic aryl group, a heteroaryl group or a heterocyclic group containing one, two or three heteroatoms selected from N, S and O atoms; wherein the phenyl, naphthyl, aryl, heterocyclyl or heteroaryl each may be unsubstituted or substituted by halogen, cyano, deuterium, hydroxyl, 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' ', formula (Ic) or NR' R '''or SR', wherein 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 invention also relates to pharmaceutically acceptable salts and pharmaceutically acceptable solvates of these compounds; compositions containing such compounds; and the use of such compounds in the treatment of various diseases, in particular acne.

Description

[Technical field]

[0001] The present invention relates to novel acetyl CoA-carboxylase (ACC) inhibitors, pharmaceutical compositions comprising such compounds and their use as medicaments. More specifically, the present invention provides novel ACC inhibitors useful for treating and preventing acne. [Existing Technology]

[0002] Acne vulgaris consists of numerous skin lesions, including comedones, inflammatory papules, pustules, nodules, and cysts. Depending on the severity of the lesions and the anatomical distribution of the lesions, the disease can be classified as mild, moderate, or severe. Disease onset usually occurs during adolescence, due to increased androgen levels triggering increased sebum production. Approximately 90% of adolescents are affected by acne and 15% of patients are seeking medical treatment; in addition, the disease is still prevalent in 23-35% of young people (18-28 years old). Biologically, acne can be regarded as an inflammatory sebaceous gland duct disease with several unique characteristics, including: (a) excessive sebum production; (b) abnormal keratinocyte proliferation and shedding that cause duct obstruction; (c) proliferation of Propionibacterium acne (C. acne; formerly known as Propionibacterium acne); and (d) inflammation. These factors are often interdependent. For example, elevated androgen levels can cause epithelial shedding and follicular plugging, as well as excessive sebum production, leading to plugged follicles filled with lipid-forming comedones. This excess sebum then serves as a substrate for Propionibacterium acnes, which metabolizes the sebum to release free fatty acids that promote further bacterial replication and inflammation. Although multiple factors contribute to the etiology of the condition, acne cannot occur without sebum because sebum serves as a nutrient source for Propionibacterium acnes (Smith and Thiboutot, J Lipid Research, 49, 271-281 (2008)).

[0003] The current standard of care for acne includes topical therapies for mild to moderate disease and systemic therapies for moderate to severe disease. These current therapies are barely effective or lack suitable safety features for widespread use. Topical acne treatments include retinoids, topical antibiotics, benzoyl peroxide, and combinations thereof. Systemic treatments include hormone therapy, oral antibiotics, and isotretinoin (Dawson et al., BMJ 2013; 346: 12634). Hormone therapy (including oral contraceptives and androgen receptor blockers) can be used to treat moderate to severe acne in female patients with appropriate efficacy. Oral antibiotics (including doxycycline, minocycline, tetracycline, and erythromycin) are moderately effective in treating acne, especially when targeting patterns of resistance of P. acnes; however, photosensitivity and gastrointestinal disturbances limit their use (Gannon et al., Family Pract. 2011; 60: 290-92). Although highly effective, isotretinoin also presents a number of serious adverse effects. The drug is highly teratogenic and requires special prescription precautions and routine pregnancy testing. In addition, isotretinoin causes severe mucocutaneous tolerance issues (dry skin, eyes, nose, lips) that can limit doses if not properly managed with palliative care. Isotretinoin treatment is associated with adverse plasma lipid changes (increased TG, LDL) and hepatotoxicity (elevated ALT / AST), requiring liver function tests prior to treatment. In addition, isotretinoin therapy has also been associated with myalgia (50% of patients have elevated CK levels), ligament calcification, and adverse ocular effects (loss of night vision, loss of color vision, and dry eyes). In isolated cases, isotretinoin has been associated with neurological / psychological adverse effects, including depression, psychosis, and (possibly) suicide.

[0004] ACC (which catalyzes the conversion of acetyl-CoA to malonyl-CoA) plays a key role in regulating lipid metabolism. ACC is an essential and rate-limiting step in the de novo synthesis of fatty acids and regulates the oxidation of long-chain fatty acids. The terms "de novo lipogenesis", "DNL" and "de novo fatty acid synthesis" are used to address the synthesis of fatty acids from non-lipid-based sources. There are two closely related subtypes, ACC1 and ACC2. ACC inhibition has been a focus of attention as a potential mechanism for the treatment of type 2 diabetes and obesity (WO2009144554).

[0005] During the preclinical in vivo studies in rats and dogs, it was found that a variety of ACC inhibitors induce microscopic morphological changes in sebocytes consistent with the reduction of sebaceous gland lipid / sebum content. Based on these observations, it can be assumed that ACC inhibitors can reduce sebum lipid production in rats and dogs by inhibiting the de novo synthesis of fatty acids. Sebum is a complex lipid mixture including triglycerides (30% to 50%), wax esters (26% to 30%), free fatty acids (15% to 30%), squalene (12% to 20%), cholesterol esters (3% to 6%) and free cholesterol (1.5% to 2.5%) (Ottaviani et al., Lipidmediators in acne.Mediators of Inflammation, 2010.doi:10.1155 / 2010 / 858176).

[0006] Among these lipid classes, triglycerides, wax esters, free fatty acids, and cholesterol esters all contain or include fatty acids. Increased sebum production is associated with both the onset and severity of acne (Janiczek-Dolphin et al., Br J. Dermatol. 2010; 163: 683-688). Although it is known that human sebaceous glands are capable of synthesizing fatty acids de novo (Downie and Kealey, J Invest. Dermatol. 1998; 111: 199-205), the relative importance of this pathway within sebocytes compared to the use of exogenous circulating fatty acids for sebum biosynthesis is unknown.

[0007] Therefore, there is a need for novel approaches to treat acne with a beneficial efficacy / safety profile. The present invention provides novel therapeutic approaches for treating acne that include the use of ACC inhibitors. Therefore, there is a need to provide novel compounds that are potent and selective inhibitors of sebum secretion and have suitable pharmacokinetic properties, especially compounds that can be administered by topical administration and are effective in treating acne. [Summary of the invention]

[0009] The present invention relates to compounds of formula (Ia and Ib) having the following structures:

[0010]

[0011] or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or the pharmaceutically acceptable salt, wherein:

[0012] R is selected from: H, C 1 -C 6 Alkoxy, C 1 -C 6 Alkyl and -(CH 2 ) m -W, where W is C3 -C 8 Cycloalkyl, bicycloalkyl, bridged bicycloalkyl, phenyl, 5- or 6-membered heteroaryl or heterocyclyl containing one, two or three heteroatoms selected from N, S and O atoms; wherein each of the alkyl, cycloalkyl, heterocyclyl, phenyl, naphthyl or heteroaryl may be unsubstituted or substituted with phenyl, halogen, cyano, deuterium, hydroxyl, 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', wherein R' and R" are independently H, C 1 -C 6 Alkyl or C 3 -C 8 Cycloalkyl;

[0013] R 1 is selected from: phenyl, naphthyl, 5- or 6-membered heteroaryl or heterocyclic group containing one, two, three or four heteroatoms selected from N, S and O atoms, and 9- or 10-membered bicyclic aryl, 9- or 10-membered heteroaryl or heterocyclic group containing one, two or three heteroatoms selected from N, S and O atoms; wherein each of the phenyl, naphthyl, aryl, heterocyclic group or heteroaryl group may be unsubstituted or substituted with halogen, cyano, deuterium, hydroxyl, 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", or SR', wherein R' and R" are independently H, C 1 -C 6 Alkyl or C 3-C 8 cycloalkyl; and

[0014] m and n are independently 0, 1, 2 or 3.

[0015] In other aspects, the present invention also provides:

[0016] A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula I or a pharmaceutically acceptable salt thereof; and a method for treating a condition or disorder including:

[0017] Arthritis, including rheumatoid arthritis, juvenile arthritis and psoriatic arthritis;

[0018] Autoimmune or inflammatory diseases or conditions, including Hashimoto's thyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritis caused by 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 invasive hepatitis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, ulcerative colitis and membranous glomerulopathy, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, Sjogren's syndrome syndrome, Reiter's syndrome, polymyositis, dermatomyositis, type I interferon diseases (including Aicardi-Goutières syndrome and other Mendelian diseases with overexpression of type I interferons), systemic sclerosis, polyarteritis nodosa, multiple sclerosis, relapsing-remitting multiple sclerosis, primary progressive multiple sclerosis, secondary progressive multiple sclerosis, and bullous pemphigoid, and other autoimmune diseases that may be O-cell (humoral) or T-cell based (including Cogan's syndrome, ankylosing spondylitis, Wegener's granulomatosis, autoimmune alopecia, type I or juvenile diabetes mellitus, or thyroiditis);

[0019] Cancer or tumor, including digestive tract / gastrointestinal cancer, colon cancer, liver cancer, skin cancer (including mast cell tumor and squamous cell carcinoma), breast and mammary 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 cancer, melanoma (including oral and metastatic melanoma), Kaposi's sarcoma, myeloma (including multiple myeloma), myeloproliferative disorder, proliferative diabetic retinopathy, or angiogenesis-related disorder (including solid tumors);

[0020] Diabetes, including type 1 diabetes or diabetic complications;

[0021] ocular diseases, disorders or conditions, including autoimmune diseases of the eye, keratoconjunctivitis, vernal conjunctivitis, uveitis (including uveitis associated with Behcet's disease and lens-induced uveitis), keratitis, herpetic keratitis, keratoconus, corneal epithelial dystrophy, leukoma, ocular pemphigus, Mooren's ulcer, scleritis, Grave's ophthalmopathy, Vogt-Koyanagi-Harada syndrome, keratoconjunctivitis sicca (dry eyes), phlyctenules, iridocyclitis, sarcoidosis, endocrine eye disease, sympathetic ophthalmia, allergic conjunctivitis, or ocular neovascularization;

[0022] Inflammatory bowel disease, including Crohn's disease, ulcerative colitis, inflammatory bowel disease, celiac disease, proctitis, eosinophilic gastroenteritis, or mastocytosis;

[0023] Neurodegenerative diseases, including motor neuron disease, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, or neurodegenerative diseases caused by traumatic injury, collision, glutamate neurotoxicity or hypoxia; stroke, myocardial ischemia, renal ischemia, heart attack, cardiac hypertrophy, atherosclerosis and arteriosclerosis, ischemia / reperfusion injury caused by organ hypoxia or platelet aggregation;

[0024] Skin diseases, conditions or disorders, including atopic dermatitis, hand dermatitis, contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerotic dermatitis, nummular dermatitis, seborrheic dermatitis, seborrhea, oily skin, eyelid dermatitis, diaper dermatitis, dermatomyositis, scleroderma, keloid, hypertrophic scar, morphea, frontal fibrosing alopecia, cicatricial alopecia, lichen planus, lichen sclerosis, alopecia areata, vitiligo, rosacea, rosacea-like dermatitis, steroid-induced dermatitis, drug eruptions (including papulopustular venereal drug eruption), epidermolysis bullosa, keratosis pilaris, pityriasis alba, pemphigus, vulvovaginitis, acne (including but not limited to acne vulgaris, acne nodularis, acne nodulocystic, acne cystic, acne conglobata, steroid acne, and autoinflammatory syndrome [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 nevus nevus / nevi), postinflammatory hypopigmentation, senile vitiligo, chemical / drug-induced vitiligo, cutaneous lupus erythematosus, discoid lupus, palmoplantar pustulosis, pemphigoid, sweet's syndrome, suppurative hidradenitis, psoriasis, plaque psoriasis, pustular psoriasis, nail psoriasis, flexural psoriasis, guttate psoriasis, psoriatic arthritis, erythrodermic psoriasis, inverse psoriasis, intractable wounds, sebaceous hyperplasia, Fordyce's condition (Fordyce's granules; Fordyce's spots), Fox-Fordyce's disease, axillary odor (body odor), hirsutism or skin tumors (sebaceous nevus, sebaceous adenoma, sebaceous adenoma, sebaceous epithelioma, simple steatocystoma, multiple steatocystoma, Muir-Torre syndrome syndrome), sebaceous gland carcinoma);

[0025] The present invention will be further understood from the following description which is given by way of example only. The present invention relates to a class of tricyclic spiropiperidine compounds. Specifically, the present invention relates to certain tricyclic spiropiperidine compounds which are useful as ACC inhibitors for the treatment of acne. Although the present invention is not limited thereto, various aspects of the present invention may be understood through the following discussion and examples alone. [Detailed description of the invention]

[0027] Unless otherwise defined herein, scientific and technical terms used in the present invention have the meanings commonly understood by those skilled in the art.

[0028] The phrase "therapeutically effective" is intended to qualify that amount of a compound or pharmaceutical composition, or (in the case of combination therapy) combined amounts of the active ingredients, that will achieve the goal of treating the relevant condition.

[0029] As used herein to describe the invention and unless otherwise stated, the term "treatment" means the administration of a compound, pharmaceutical composition or combination to achieve preventive, palliative, supportive, restorative or curative treatment. The term treatment encompasses any objective or subjective improvement in an individual with respect to the relevant condition or disease.

[0030] The term "prophylactic treatment" as used herein to describe the present invention refers to the administration of a compound, pharmaceutical composition or combination to a subject to inhibit or prevent the occurrence of the relevant condition in the subject, especially in a subject or population member who is significantly susceptible to the relevant condition.

[0031] As used herein, the term "ACC inhibitor" refers to a compound that inhibits ACC1 and potentially ACC2. The inhibitory activity (IC) of a compound against ACC1 can be determined using the ACC1 assay disclosed herein. 50 ). In the ACC1 analysis, IC 50 Compounds below about 10 μM are considered ACC inhibitors. Preferred IC in the assay 50 Less than about 1 μM, and a particularly preferred IC in the assay 50 Less than about 0.1 μM. In addition, the ACC inhibitors of the present invention selectively inhibit ACC1 and may inhibit ACC2 compared to other enzymes, g-protein coupled receptors or ion channels. The compounds encompassed by the present invention inhibit other enzymes or binding (K) at concentrations greater than those required to inhibit ACC1. i ) to receptors or ion channels. Preferred ACC inhibitory activity is the IC50 or K of other enzymes, receptors or ion channels. i The amount of the catalyst is about 2 to 10 times, more preferably 10-100 times, and particularly preferably greater than 100 times.

[0032] When used to describe a functionally defined receptor ligand or enzyme inhibitor, the term "selectivity" means the selectivity for a given receptor or enzyme subtype compared to other receptors or enzyme subtypes in the same family. For example, a selective ACC inhibitor is a compound that more potently inhibits an ACC enzyme subtype 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.

[0033] The term "alkyl" (alone or in combination) means a linear or branched chain of the formula C n H 2n+1Examples of such groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl and hexyl. Unless otherwise specified, an alkyl group contains 1 to 6 carbon atoms.

[0034] The carbon atom content of alkyl and various other hydrocarbon-containing moieties is indicated by prefixes designating the minimum and maximum number of carbon atoms in the moiety, that is, the prefix C i -C j indicates a moiety having an integer number "i" to an integer number "j" of carbon atoms, inclusive. Thus, for example, C 1 -C 6 Alkyl refers to an alkyl group having from one to six carbon atoms, inclusive.

[0035] The term "hydroxyl" as used herein refers to an OH group.

[0036] The term "heterocycle" refers to a saturated or partially saturated (i.e., non-aromatic) ring system which may be attached via a ring nitrogen atom (when the heterocycle is attached to a carbon atom) or a ring carbon atom (in all cases). Likewise, when substituted, the substituents may be located on a ring nitrogen atom (if the substituent is attached via a carbon atom) or a ring carbon atom (in all cases). Specific examples include oxiranyl, aziridinyl, glycidyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, piperazinyl, azepanyl, oxepanyl, oxazepanyl, and diazepanyl. base.

[0037] The term "heteroaryl" is an aromatic heterocycle which may be attached via a ring carbon atom or a ring nitrogen atom with appropriate valences (when the heterocycle is attached to a carbon atom). Likewise, when substituted, the substituents may be located on a ring carbon atom (in all cases) or a ring nitrogen atom with appropriate valences (if the substituent is attached via a carbon atom). Specific examples include thienyl, furanyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl.

[0038] The term "fused bicyclic" refers to a ring system comprising two rings fused together. Specific examples include naphthyl, imidazo[2,1-b][1,3]thiazolyl, benzofuranyl, benzothiophenyl, 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 1,2-d]pyrimidinyl, pyrido[4,3-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, pyrido[3,4-b]pyrazinyl, pyrimido[5,4-d]pyrimidinyl, pyrazino[2,3-b]pyrazinyl, and pyrimido[4,5-d]pyrimidine.

[0039] The term "cycloalkyl" refers to a cycloalkyl radical 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 contains 3 to 8 carbon atoms.

[0040] The term "alkoxy" means a group comprising an alkyl group bonded to an oxygen atom, such as methoxy. Examples of such groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert-butoxy. The term "halogen" means fluorine, chlorine, bromine or iodine.

[0041] As used herein, the terms "co-administration", "co-administered" and "in combination with" in reference to a combination of a compound of Formula I and one or more other therapeutic agents include the following:

[0042] administering such a combination of a compound of formula I and another therapeutic agent simultaneously to a patient in need of treatment when such components are formulated together into a single dosage form that releases said components substantially simultaneously to said patient,

[0043] administering such a combination of a compound of formula I and another therapeutic agent to a patient in need of treatment substantially simultaneously when these components are formulated separately from one another into single dosage forms to be taken by the patient at substantially the same time (so that the components are released to the patient at substantially the same time),

[0044] sequential administration to a patient of such a combination of a compound of formula I and another therapeutic agent when such components are formulated separately from one another into separate dosage forms to be taken by a patient in need of treatment at consecutive times with significant time intervals between each administration (so that the components are released to the patient at substantially different times); and

[0045] - Such combinations of a compound of formula I and another therapeutic agent are administered sequentially to a patient in need of treatment when such components are formulated together into a single dosage form that releases the components in a controlled manner.

[0046] As used herein, the term "excipient" describes any ingredient other than a compound of formula I. The choice of excipient depends largely on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. The term "excipient" encompasses a diluent, carrier, or adjuvant.

[0047] The present invention relates to novel compounds as ACC regulators useful for treating diseases and conditions associated with ACC disorders. The present invention further provides pharmaceutical compositions comprising such ACC enzyme regulators and 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.

[0048] A number of embodiments (E) of the first aspect of the present invention are described below, wherein E1 is consistent therewith for convenience.

[0049] E1 is a compound of formula I as defined above or a pharmaceutically acceptable salt thereof.

[0050] E2. A compound as described in E1, wherein R is selected from: H, C 1 -C 6 Alkyl and -(CH 2 ) m -W, where W is C 3 -C 8 wherein the alkyl, cycloalkyl, bicycloalkyl and bridged bicycloalkyl groups are each unsubstituted or substituted with halogen, cyano, deuterium, hydroxyl, C 1 -C 6 Alkyl and C 1 -C 6 and m and n are independently 0, 1, 2 or 3.

[0051] E3. The compound as described in E1, wherein R is tert-butyl.

[0052] E4 is a compound as described in E1, wherein R 1 is phenyl, pyridyl, indolyl, indazolyl, pyrrolopyridyl, quinolyl, isoquinolyl or naphthyl; wherein each of the phenyl, pyridyl, indolyl, indazolyl, pyrrolopyridyl, quinolyl, isoquinolyl or naphthyl groups may be unsubstituted or substituted with halogen, cyano, hydroxyl, C 1 -C 6 Alkyl, C 1 -C 6 substituted with -CONR'R", NR'R" or SR', wherein R' and R" are independently H, C 1 -C 6 Alkyl or C 3 -C 8 and m and n are independently 0, 1, 2 or 3.

[0053] E5. A compound as described in E1, which is selected from:

[0054] 2-(tert-butyl)-1′-(7-methoxy-1,3-dimethyl-1H-indazole-5-carbonyl)-5H-spiro[benzo[d]thiazol-6,4′-piperidin]-4(7H)-one;

[0055] 2-(tert-Butyl)-1'-(7-methyl-1H-indole-5-carbonyl)-5H-spiro[benzo[d]thiazol-6,4'-piperidin]-4(7H)-one;

[0056] 2-(tert-butyl)-1'-(8-methyl-3-(methylamino)quinoline-6-carbonyl)-5H-spiro[benzo[d]thiazol-6,4'-piperidin]-4(7H)-one;

[0057] 2-(tert-butyl)-1'-(7-ethoxy-1,3-dimethyl-1H-indazole-5-carbonyl)-5H-spiro[benzo[d]thiazol-6,4'-piperidin]-4(7H)-one;

[0058] 2-(tert-Butyl)-1'-(4-methyl-2-naphthoyl)-5H-spiro[benzo[d]thiazol-6,4'-piperidin]-4(7H)-one;

[0059] or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or the pharmaceutically acceptable salt.

[0060] E6. A compound as described in E1, wherein the compound 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 the compound or the pharmaceutically acceptable salt thereof.

[0061] E7. A compound as described in E1, wherein the compound 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 the compound or the pharmaceutically acceptable salt thereof.

[0062] E8. A compound as described in E1, wherein the compound 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 the compound or the pharmaceutically acceptable salt thereof.

[0063] E9. A compound as described in E1, wherein the compound 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 the compound or the pharmaceutically acceptable salt thereof.

[0064] E10. A compound as described in E1, wherein the compound 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 the compound or the pharmaceutically acceptable salt thereof.

[0065] E11. A pharmaceutical composition comprising the compound as described in any one of E1 to E10 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt, and a pharmaceutically acceptable excipient.

[0066] E12. A method of treating a disease or condition selected from the group consisting of: inflammation, autoimmune disease, neuroinflammation, arthritis, rheumatoid arthritis, spondyloarthropathies, systemic lupus erythematosus, lupus nephritis, osteoarthritis, gouty arthritis, pain, fever, pulmonary sarcoidosis, silicosis, cardiovascular disease, atherosclerosis, myocardial infarction, thrombosis, congestive heart failure and cardiac reperfusion injury, cardiomyopathy, stroke, ischemia, reperfusion injury, cerebral edema, brain trauma, neurodegeneration, liver disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis, nephritis, retinitis, retinopathy, macular degeneration, glaucoma, diabetes (type 1 and type 2), diabetic neuropathy, viral and bacterial infections, myalgia, endotoxic 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, skin flushing, eczema, psoriasis, atopic dermatitis, sunburn, keloid, hypertrophic scars, rheumatic diseases, urticaria, discoid lupus, cutaneous lupus, central nervous system lupus, psoriatic arthritis, asthma, allergic asthma, type I interferon disease (including Icardi-Gutierrez syndrome and other Mendelian diseases with overexpression of type I interferons), primary progressive multiple sclerosis, relapsing-remitting multiple sclerosis, non-alcoholic Fatty liver disease, nonalcoholic fatty liver disease, scleroderma, alopecia areata, scarring alopecia, prurigo, prurigo nodularis, CPUO, lichen disease, lichen planus, Stevens-Johnson syndrome, spondylosis, myositis, vasculitis, pemphigus, lupus, major depression, allergy, dry eye syndrome, transplant rejection, cancer, septic shock, cardiopulmonary dysfunction, acute respiratory disease, ankylosing spondylitis, cachexia, chronic graft-versus-host disease, acute graft-versus-host disease, celiac disease, idiopathic thrombocytopenic thrombotic purpura, thrombotic thrombocytopenic purpura, myasthenia gravis, Sjögren's syndrome, epidermal hyperplasia, cartilage inflammation, bone degeneration, juvenile arthritis, juvenile rheumatoid arthritis, oligoarticular juvenile rheumatoid arthritis Arthritis, polyarticular juvenile rheumatoid arthritis, systemic juvenile rheumatoid arthritis, juvenile ankylosing spondylitis, juvenile enteropathic arthritis, juvenile Rett syndrome, SEA syndrome, juvenile dermatomyositis, juvenile psoriatic arthritis, juvenile scleroderma, juvenile systemic lupus erythematosus, juvenile vasculitis, oligoarticular rheumatoid arthritis, polyarticular rheumatoid arthritis, systemic rheumatoid arthritis, enteropathic arthritis, reactive arthritis, Rett syndrome, myositis, polymyositis, dermatomyositis, polyarteritis nodosa, Wegener's granulomatosis, arteritis, polymyalgia rheumatica, 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, plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, immune disorders associated with or caused by pathogenic lymphocyte activity, non-infectious uveitis, Behcet's disease and Vogt-Koyanagi-Harada syndrome, which comprises administering to an individual in need thereof a therapeutically effective amount of a compound as described in E1 to E10 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt.

[0067] E13. The method of E12, wherein the compound is administered topically.

[0068] E14. The method of E12 or E13, wherein the compound is administered in the form of a cream, ointment, lotion, gel, solution, suspension, foam, aerosol, spray, shampoo, patch or tape.

[0069] E15. A method for treating acne, comprising administering to an individual a therapeutically effective amount of a compound as described in E1 to E10 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt.

[0070] E16. The method of E15, wherein the compound is administered topically.

[0071] E17. The method of E15 or E16, wherein the compound is administered in the form of a cream, ointment, lotion, gel, solution, suspension, foam, aerosol, spray, shampoo, patch or tape.

[0072] E18. Use of a compound as described in any one of E1 to E10 for the preparation of a medicament for treating a condition requiring treatment with an ACC inhibitor.

[0073] E19. Use of a compound as described in any one of E1 to E10 for preparing a medicament for treating acne.

[0074] E20. The compound of any one of E1 to E10, for use in treating a condition requiring treatment with an ACC inhibitor.

[0075] Compounds of the invention having the same molecular formula but differing in the nature or order of bonding of their atoms or in the spatial arrangement of their atoms are referred to as "isomers". Isomers whose atoms are differently arranged in space are referred to as "stereoisomers". These stereoisomers are "R" or "S", depending on the configuration of the substituents around the chiral carbon atom. The terms "R" and "S" as used herein are configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., 1976, 45: 13-30. Enantiomers of the invention indicated by (R), (S) or * are substantially free of other enantiomers. "Substantially free" means that the enantiomeric excess is greater than about 90%, preferably greater than about 95% and more preferably greater than about 99%. In the context of enantiomeric excess, the term "about" means ± 1.0%. Depending on the configuration of the substituents around the chiral carbon atom, the symbol * designates the chiral carbon atom as (R) or (S) stereochemistry. The present invention encompasses various stereoisomers and mixtures thereof that are specifically included within the scope of the invention. Stereoisomers include enantiomers and mixtures of enantiomers. Individual stereoisomers of the compounds of the invention can be prepared synthetically from commercially available starting materials containing asymmetric or chiral centers or by preparing racemic mixtures and then performing resolutions well known to those skilled in the art. These resolution methods include (but are not limited to) (1) attaching a chiral auxiliary to the enantiomeric mixture, separating the resulting mixture of diastereomers by recrystallization or chromatography and releasing the optically pure product from the auxiliary; or (2) directly separating the mixture of optical enantiomers on a chiral chromatographic column. Compounds of the invention that are not designated (R), (S) or * may exist as racemates (i.e., 50% (R) and 50% (S)) or as a mixture of two enantiomers (one enantiomer in excess). For example, an enantiomeric mixture may comprise 51% of the (R) enantiomer and 49% of the (S) enantiomer or vice versa, or any combination of (R) and (S) except a racemic mixture of 50% (R) and 50% (S).

[0076] All individual isomers (e.g., cis-, trans-, or diastereomers) and any mixtures of the compounds described herein are included within the scope of the compounds. All of these forms (including enantiomers, diastereomers, cis, trans, syn, anti, solvates (including hydrates), tautomers, and mixtures thereof) are included in the compounds. Stereoisomers (e.g., diastereoisomer mixtures) can be separated into their corresponding isomers by suitable separation methods in a known manner. Diastereoisomer mixtures can be separated into their respective diastereomers, for example, by fractional crystallization, chromatography, solvent distribution, and similar operations. This separation can be performed at the level of one of the starting compounds or in the compound of formula I itself. Enantiomers can be separated by forming diastereomeric salts (e.g., by using enantiomer-pure chiral acids to form salts) or by chromatography (e.g., by HPLC) using a chromatographic matrix with a chiral ligand. 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 an atomic mass or mass number different from the atomic mass or mass number predominant in nature.

[0077] Examples of suitable isotopes for incorporation into the compounds of the invention include isotopes of: hydrogen (e.g. 2 H and 3 H), carbon (e.g. 11 C. 13 C and 14 C), chlorine (e.g. 36 Cl), fluorine (e.g. 18 F), iodine (e.g. 123 I and 125 I), nitrogen (e.g. 13 N and 15 N), oxygen (e.g. 15 O. 17 O and 18 O), phosphorus (e.g. 32 P) and sulfur (e.g. 35 S).

[0078] Certain isotopically-labeled compounds of Formula I or pharmaceutically acceptable salts thereof, for example those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. 3 H) and carbon-14 (i.e. 14 C) is particularly useful for this purpose due to its ease of incorporation and ease of detection.

[0079] The use of heavier isotopes (such as deuterium, 2H) substitution may offer certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and thus may be preferred in some circumstances. 11 C. 18 F. 15 O and 13 N) can be used for detecting substrate receptor occupancy in positron emission tomography (PET) studies. Isotopically labeled compounds of formula I can generally be prepared by conventional techniques known to those skilled in the art or by methods analogous to those described in the accompanying examples and preparations using an appropriate isotopically labeled reagent in place of the unlabeled reagent previously employed.

[0080] In some embodiments, the present invention provides deuterium-labeled (or deuterated) compounds and salts, wherein the molecular formulas and variables of these compounds and salts are each and independently as described herein. "Deuterated" means that at least one atom in the compound is deuterium in an abundance greater than the natural deuterium abundance (usually about 0.015%). Those skilled in the art recognize that in a chemical compound with hydrogen atoms, the hydrogen atoms actually represent a mixture of H and D, of which about 0.015% is D. The concentration of deuterium incorporated into the deuterium-labeled compounds and salts of the present invention can be defined by the deuterium enrichment factor.

[0081] As used herein, "deuterium enrichment factor" means the ratio between the deuterium abundance and the natural deuterium abundance (each relative to the hydrogen abundance). In specific embodiments, the deuterium enrichment factor for atomic positions designated as having deuterium is typically 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).

[0082] It is understood that one or more deuteriums may be exchanged for hydrogen under physiological conditions.

[0083] In some embodiments, the present invention provides deuterated compounds of Formula I or pharmaceutically acceptable salts thereof that replace previously employed unlabeled reagents.

[0084] In some embodiments, R1 is selected from CH 3 , CH 2 D. CHD 2and CD 3 .

[0085] In some embodiments, the deuterium compound of Formula I is selected from any one of the compounds described in the Examples section.

[0086] In some embodiments, metabolically labile sites in the compounds of the invention are deuterated.

[0087] Isotopically labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art, or can be prepared by methods analogous to those described in the accompanying Examples and Preparations using appropriate isotopically labeled reagents in place of the unlabeled reagents previously employed. It is also well recognized in the art that certain variations in natural isotopic abundance may occur in synthesized compounds, which may depend on the source of the synthetic materials used to synthesize the compound.

[0088] Deuterium enrichment of compounds provided herein can be determined using conventional analytical methods known to those of skill in the art, including mass spectrometry, nuclear magnetic resonance spectroscopy, and crystallographic analysis.

[0089] Pharmaceutically acceptable solvates of the invention include those wherein the solvent of crystallization may be isotopically substituted, for example D 2 O、d 6 -acetone, d 6 -DMSO.

[0090] In therapeutic uses for treating a disorder in a mammal, the compounds of the invention or pharmaceutical compositions thereof may be administered orally, parenterally, topically, rectally, mucosally 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, such as the eyes or ears, which are easily accessible by topical application. It also includes transdermal delivery to produce a systemic effect. Rectal administration includes suppository forms. Preferred routes of administration are oral and parenteral.

[0091] The pharmaceutically acceptable salts of the compounds of formula I or their pharmaceutically acceptable salts include acid addition salts and basic salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, borate, camphorsulfonate, citrate, cyclaminate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, glucarate, stearate, succinate, tannate, tartrate, toluenesulfonate, trifluoroacetate, and xinofoate.

[0092] Suitable base salts are formed from bases which form non-toxic salts. Examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, and zinc salts.

[0093] Hemi-salts of acids and bases, such as hemisulphate and hemicalcium salts, can also be formed. For a review of suitable salts, see Handbook of Pharmaceutical Salts: Properties, Selection, and Use, Stahl and Wermuth (Wiley-VCH, 2002).

[0094] The pharmaceutically acceptable salt of the compound of formula I or its pharmaceutically acceptable salt can be prepared by one or more of the following three methods: (i) by reacting the compound of formula I with the desired acid or base; (ii) by removing the acid- or base-labile protecting group from a suitable precursor of the compound of formula I or by opening the ring of a suitable cyclic precursor (e.g., lactone or lactam) using the desired acid or base; or (iii) by reacting with an appropriate acid or base or by passing through a suitable ion exchange column to convert one salt of the compound of formula I into another salt. All three reactions are usually carried out in solution. The resulting salt can be precipitated and collected by filtration, or can be recovered by evaporating the solvent. The degree of ionization of the resulting salt can be from completely ionized to almost unionized.

[0095] The pharmaceutical composition of the present invention can be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, encapsulating, embedding, lyophilizing process or spray-drying.

[0096] The pharmaceutical composition used according to the present invention can be prepared in a conventional manner using one or more pharmaceutically acceptable carriers, which include excipients and adjuvants that help to process the active compound into a pharmaceutically usable preparation. Suitable preparations depend on the selected route of administration. Pharmaceutically acceptable excipients and carriers are generally known to those skilled in the art and are therefore included in the present invention. These excipients and carriers are described in (for example) Remington's Pharmaceutical Sciences, Mack Pub. Co., New Jersey (1991). The preparations of the present invention can be designed to be short-acting, rapid-release, long-acting and sustained-release. Therefore, the pharmaceutical preparations can also be formulated for controlled release or slow release.

[0097] Pharmaceutical compositions suitable for use in the present invention include compositions wherein the amount of active ingredients contained therein is sufficient to achieve the intended purpose (i.e., control or treat a condition or disease). More specifically, a therapeutically effective amount means an amount that can effectively prevent, alleviate or improve the symptoms / signs of a disease or prolong the survival of the treated individual.

[0098] The amount of the active ingredient (which is a compound of the invention) in a pharmaceutical composition and its unit dosage form may vary or be widely adjusted depending on the mode of administration, the efficacy of the particular compound, and the desired concentration. Those skilled in the art are familiar with the determination of a therapeutically effective amount. Typically, the amount of the active ingredient is between 0.01% and 99% by weight of the composition.

[0099] Typically, the therapeutically effective amount of the active ingredient dosage is in the range of about 0.01 mg / kg body weight / day to about 100 mg / kg body weight / day, preferably about 0.1 mg / kg body weight / day to about 10 mg / kg body weight / day, more preferably about 0.3 mg / kg body weight / day to 3 mg / kg body weight / day, and even more preferably about 0.3 mg / kg body weight / day to 1.5 mg / kg body weight / day. It should be understood that the dosage may vary depending on the needs of each individual and the severity of the disorder or disease being treated.

[0100] The desired dose may conveniently be provided in a single dose or in 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 a number of loosely spaced discrete administrations, such as multiple inhalations from an insufflator or by application of a plurality of drops to the eye.

[0101] Likewise, it should be understood that the initial dose administered can be increased to exceed the above-mentioned upper limit to quickly achieve the desired concentration at the site of action. On the other hand, the initial dose can be less than the most preferred value and can be gradually increased daily doses depending on specific circumstances during the course of treatment. If desired, the daily dose can also be divided into multiple dosages, for example two to four times a day.

[0102] The present invention also includes the following embodiments:

[0103] A compound of 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 use as a medicament;

[0104] A compound of I as defined in any embodiment described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt, for use in treating a disease selected from the group consisting of inflammation, autoimmune disease, neuroinflammation, arthritis, rheumatoid arthritis, spondyloarthropathies, systemic lupus erythematosus, lupus nephritis, osteoarthritis, gouty arthritis, pain, fever, pulmonary sarcoidosis, silicosis, cardiovascular disease, atherosclerosis, myocardial infarction, thrombosis, congestive heart failure and cardiac reperfusion injury, cardiomyopathy, stroke, ischemia, reperfusion injury, cerebral edema, brain trauma, neurodegeneration, liver disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis, nephritis, retinitis, retinopathy, macular degeneration, glaucoma, diabetes (type 1 and type 2), diabetic neuropathy, viral and bacterial infections, myalgia, endotoxic 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, skin flushing, eczema, psoriasis, atopic dermatitis, sunburn, keloids, hand dermatitis, contact dermatitis, allergies Contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerotic dermatitis, nummular dermatitis, seborrheic dermatitis, seborrhea, oily skin, eyelid dermatitis, diaper dermatitis, dermatomyositis, scleroderma, hypertrophic scars, morphea, frontal fibrosing alopecia, cicatricial alopecia, lichen planus, lichen sclerosis, alopecia areata, vitiligo, rosacea, rosacea-like dermatitis, steroid-induced dermatitis, drug eruption (including papulopustular drug eruption), epidermolysis bullosa, keratosis pilaris, pityriasis alba, pemphigus, vulvovaginitis, acne (including but not limited to acne vulgaris, acne nodularis, acne nodulocysticis, Cystic acne, conglobate acne, steroid acne) and autoinflammatory syndrome (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, post-inflammatory hypopigmentation, senile vitiligo, chemical / drug-induced vitiligo, cutaneous lupus erythematosus, palmoplantar pustulosis, pemphigoid, Schwetter's syndrome, suppurative hidradenitis, nail psoriasis, flexural psoriasis, intractable wounds, sebaceous hyperplasia, Fordyce's disease (Fordyce's granules;Fordyce spots), Fox-Fordyce disease, axillary odor (body odor), hirsutism or skin tumors (sebaceous nevus, sebaceous adenoma, sebaceous adenoma, sebaceous epithelioma, simple steatocystoma, multiple steatocystoma, Merle-Tower syndrome, sebaceous gland carcinoma, hypertrophic scars, rheumatic diseases, urticaria, discoid lupus, central nervous system lupus, psoriatic arthritis, asthma, allergic asthma, type I interferon disease (including Icardi-Gutierrez syndrome and other Mendelian diseases with overexpression of type I interferons), primary progressive multiple sclerosis, relapsing-remitting multiple sclerosis, Nonalcoholic fatty liver disease, nonalcoholic fatty liver disease, scleroderma, alopecia areata, spondylosis, myositis, vasculitis, pemphigus, lupus, major depression, allergy, dry eye syndrome, transplant rejection, cancer, septic shock, cardiopulmonary dysfunction, acute respiratory disease, ankylosing spondylitis, cachexia, chronic graft-versus-host disease, acute graft-versus-host disease, celiac disease, idiopathic thrombocytopenic thrombotic purpura, myasthenia gravis, Sjögren's syndrome, epidermal hyperplasia, cartilage inflammation, bone degeneration, juvenile arthritis, juvenile rheumatoid arthritis, Articular juvenile rheumatoid arthritis, polyarticular juvenile rheumatoid arthritis, systemic juvenile rheumatoid arthritis, juvenile ankylosing spondylitis, juvenile enteropathic arthritis, juvenile Rett syndrome, SEA syndrome, juvenile dermatomyositis, juvenile psoriatic arthritis, juvenile scleroderma, juvenile systemic lupus erythematosus, juvenile vasculitis, oligoarticular rheumatoid arthritis, polyarticular rheumatoid arthritis, systemic rheumatoid arthritis, enteropathic arthritis, reactive arthritis, Rett syndrome, myolitis, polymyositis, Dermatomyositis, polyarteritis nodosa, Wegener's granulomatosis, arteritis, polymyalgia rheumatica, 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, plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, immune disorders associated with or caused by pathogenic lymphocyte activity, noninfectious uveitis, Behcet's disease, or Vogt-Koyanagi-Harada syndrome;

[0105] A method for treating a disease requiring treatment with an ACC inhibitor in an individual in need of treatment, comprising administering to the individual 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 the compound or salt;

[0106] 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 preparation of a medicament for treating a disease or condition requiring treatment with an ACC inhibitor; and,

[0107] A pharmaceutical composition for treating a disease or condition requiring treatment with an ACC inhibitor, 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 the compound or salt.

[0108] The present invention also provides any of the uses, methods or compositions as 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 drugs can be administered as part of the same dosage form or separate dosage forms via the same or different routes of administration and based on the same or different dosing schedules according to standard pharmaceutical practices known to those skilled in the art.

[0109] Suitable drugs for use in combination therapy with a compound of formula I or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate of the compound or salt include sulfasalazine, mesalazine, prednisone, azathioprine, infliximab, adalimumab, belimumab, becertolizumab, natalizumab, vedolizumab, hydrocortisone, budesonide, cyclosporin, tacrolimus, fexofenadine, 6-mercaptopurine, methotrexate, ursodeoxycholic acid, obeticholic acid, acid, antihistamines, rifampin, prednisone, methotrexate, azathioprine, cyclophosphamide, hydroxychloroquine, mofetil, sodium mycophenolate, tacrolimus, leflunomide, chloroquine and quinacrine, thalidomide, rituxan, NSAIDs, solumedrol, depomedrol, and dexamethasone.

[0110] Other suitable drugs for use in combination therapy with a compound of formula I or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable solvate of the compound or salt include: retinoids, antibiotics, benzoyl peroxide, ITK or TRK inhibitors, 5-lipoxygenase activating protein (FLAP) antagonists; leukotriene antagonists (LTRAs), such as antagonists of LTB4, LTC4, LTD4, LTE4, CysLT1 or CysLT2, such as montelukast or zafirlukast; histamine receptor antagonists, such as type 1 histamine receptor antagonists or type 2 histamine receptor antagonists, such as loratidine, fexofenadine, desloratidine, levocetirizine, methapyrilene or cetirizine; α1-adrenergic a muscarinic M3 receptor antagonist, such as tiotropium or ipratropium; a dual muscarinic M3 receptor antagonist / β2 agonist; a PDE inhibitor, such as a PDE3 inhibitor, a PDE4 inhibitor, or a PDE5 inhibitor, such as theophylline, sildenafil, vardenafil, tadalafil, ibudilast, cilomilast, or roflumilast; sodium cromoglycate cromoglycate or sodium nedocromil; 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; beta 2 agonists, such as salmeterol, albuterol, salbutamol, fenoterol or formoterol, especially long-acting beta 2 agonists; integrin antagonists, for example, natalizumab; adhesion molecule inhibitors, such as VLA-4 antagonists; kinin B1 or B2 receptor antagonists; immunosuppressants, such as IgE pathway inhibitors (e.g., omalizumab) or cyclosporine; matrix metalloproteinase (MMP) inhibitors, such as inhibitors of MMP-9 or MMP-12; tachykinin NK1, NK2, or NK3 receptor antagonists; protease inhibitors, such as inhibitors of elastase, chymosin, or cathepsin G; adenosine A2a receptor agonists; adenosine A2b receptor antagonists; urokinase inhibitors; dopamine receptor agonists (e.g., ropinirole), in particular a dopamine D2 receptor agonist (e.g. bromocriptine); a NFκB pathway modulator, such as an IKK inhibitor; another modulator of the cytokine signaling pathway, such as an inhibitor of JAK kinase, syk kinase, p38 kinase, SPHK-1 kinase, Rho kinase, EGF-R or MK-2; a mucolytic, mucodynamic or antitussive agent; an antibiotic; an antiviral agent; a vaccine; a chemokine; an epithelial sodium channel (ENaC) blocker or epithelial sodium channel (ENaC) inhibitor; a nucleotide receptor agonist, such as a P2Y2 agonist; a thromboxane inhibitor; niacin (niacin); 5-lipoxygenase (5-LO) inhibitors, such as Zileuton; adhesion factors, such as VLAM, ICAM or ELAM; CRTH2 receptor (DP2) antagonists; prostaglandin D2 receptor (DP1) antagonists; hematopoietic prostaglandin D2 synthase (HPGDS) inhibitors; interferon-β; soluble human TNF receptor, such as Etanercept; HDAC inhibitors; phosphoinositide 3-kinase gamma (PI3Kγ) inhibitors; phosphoinositide 3-kinase delta (PI3Kδ) inhibitors; CXCR-1 or CXCR-2 receptor antagonists; IRAK-4 inhibitors;Diacylglycerol acyltransferase-1 (DGAT1) or diacylglycerol acyltransferase-2 (DGAT2) inhibitors and TLR-4 or TLR-9 inhibitors, including pharmaceutically acceptable salts of the specifically named compounds and pharmaceutically acceptable solvates of these specifically named compounds and salts. These drugs can be administered together with another active agent, wherein the second active agent can be administered orally or topically. ;

[0111] Thus, the present invention provides methods of treating or preventing a disease, condition or disorder associated with ACC in a subject (eg, a human or non-human mammal) comprising administering to the subject in need thereof an effective amount of one or more compounds described herein.

[0112] One way to implement the present invention is to administer the compound of formula I in the form of a prodrug. Therefore, certain derivatives of the compound of formula I may have little or no pharmacological activity themselves, but when administered to or on the body, they can be converted into compounds of formula I having the desired activity by, for example, hydrolytic dissociation, especially hydrolytic dissociation promoted by esterases or peptidases. These derivatives are called "prodrugs". For additional information on the use of prodrugs, see "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 (EB Roche, ed., American Pharmaceutical Association). Also see Nature Reviews / Drug Discovery, 2008, 7, 355 and Current Opinion in Drug Discovery and Development, 2007, 10, 550.

[0113] Prodrugs of the invention can be prepared, for example, by replacing appropriate functional groups present in the compounds of formula I with certain moieties known to those skilled in the art as "pro-moieties", as described, for example, in "Design of Prodrugs", H. Bundgaard (Elsevier, 1985).

[0114] Thus, the prodrugs of the present invention are (a) ester or amide derivatives of carboxylic acids in compounds of formula I; (b) ester, carbonate, carbamate, phosphate or ether derivatives of hydroxy groups in compounds of formula I; (c) amide, imine, carbamate or amine derivatives of amino groups in compounds of formula I; (d) thioester, thiocarbonate, thiocarbamate or sulfide derivatives of thiol groups in compounds of formula I; or (e) oxime, enol ester or imine derivatives of carbonyl groups in compounds of formula I.

[0115] Some specific examples of prodrugs of the present invention include:

[0116] (i) Where the compound of formula I contains a carboxylic acid functional group (-COOH), an ester thereof, for example wherein the hydrogen of the carboxylic acid functional group of the compound of formula I is replaced by C 1 -C 8 Alkyl (e.g. ethyl) or (C 1 -C 8 alkyl)C(=O)OCH 2 -(e.g. t-BuC(=O)OCH 2 -) substituted compounds;

[0117] (ii) In the case where the compound of formula I contains an alcohol function (-OH), an ester thereof, for example, wherein the hydrogen of the alcohol function of the compound of formula I is replaced by -CO(C 1 -C 8 Compounds in which the alcohol is esterified with an amino acid;

[0118] (iii) In the case where the compound of formula I contains an alcohol function (-OH), an ether thereof, for example wherein the hydrogen of the alcohol function of the compound of formula I is replaced by (C 1 -C 8 alkyl)C(=O)OCH 2 -or-CH 2 OP(=O)(OH) 2 Replaced compounds;

[0119] (iv) In the case where the compound of formula I contains an alcohol function (-OH), its phosphate, for example, wherein the hydrogen of the alcohol function of the compound of formula I is replaced by -P(=O)(OH) 2 or -P(=O)(ONa) 2 or -P(=O)(O-) 2 Ca 2+ Replaced compounds;

[0120] (v) In the compound of formula I containing a primary or secondary amino functional group (-NH 2 or -NHR, wherein R≠H), the amides thereof, for example wherein one or both hydrogen atoms of the amino group of the compound of Form I are replaced by (C1-C10)alkanoyl, -COCH2 NH 2 Compounds whose amino groups are replaced or derived from amino acids;

[0121] (vi) In the compound of formula I, a primary or secondary amino group (-NH 2 or -NHR, wherein R≠H), the amine, for example wherein one or both hydrogen atoms of the amino group of the compound of Form I are replaced by -CH 2 OP(=O)(OH) 2 Replaced compounds.

[0122] (vii) in case the keto function of the compound of formula I is replaced by an oxime, imines or enol esters.

[0123] Certain compounds of Formula I can themselves serve as prodrugs of other compounds of Formula I. Two compounds of Formula I can also be joined together in a prodrug form. In some cases, a prodrug of a compound of Formula I can be produced by internally linking two functional groups in a compound of Formula I (e.g., by forming a lactone).

[0124] References to compounds of formula I are intended to include the compounds themselves and prodrugs thereof. The present invention includes these compounds of formula I as well as pharmaceutically acceptable salts of these compounds and pharmaceutically acceptable solvates of these compounds and salts.

[0125] Also included within the scope of the present invention are active metabolites of compounds of formula (I), in other words compounds formed in vivo upon administration of the drug, usually by oxidation, reduction or dealkylation. Some examples of metabolites of the present invention include

[0126] (i) In the case where the compound of formula I contains a methyl group, its hydroxymethyl derivative (—CH 3 ->-CH 2 OH or -CH 3 ->-COOH);

[0127] (ii) in case the compound of formula I contains an alkoxy group, its hydroxy derivative (-OR->-OH);

[0128] (iii) in case the compound of formula I contains a tertiary amino group, its secondary amino group derivative (-NRR'->-NHR or -NHR');

[0129] (iv) In case the compound of formula I contains a secondary amino group, its primary amine derivative (-NHR->-NH 2 );

[0130] (v) in case the compound of formula I contains a phenyl moiety, its phenolic derivatives (-Ph->-PhOH); and

[0131] (vi) In the case where the compound of formula I contains an amide group, its carboxylic acid derivative (-CONH 2 ->COOH).

[0132] (vii) In case the compound of formula I contains a carbonyl group, it is (-C=O(R))->-CHOH(R)).

[0133] The compound of formula I can be administered alone or in the form of a pharmaceutical composition containing an effective dose of at least one compound of the present invention (as an active ingredient) and pharmaceutically harmless conventional excipients and / or additives.

[0134] Pharmaceutical compositions suitable for delivering the compounds of the invention and methods for their preparation will be clear to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in Remington's Pharmaceutical Sciences, 19th edition (Mack Publishing Company, 1995).

[0135] The compounds of formula I can be administered orally. Oral administration may involve swallowing so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be used, whereby the compound enters the bloodstream directly from the mouth. Formulations suitable for oral administration include solid preparations (e.g., tablets), capsules containing microparticles, liquids or powders, lozenges (including liquid-filled lozenges), chewables, multi-microparticles and nano-microparticles, gels, solid solutions, liposomes, films, vaginal suppositories, sprays, and liquid preparations.

[0136] Liquid preparations include suspensions, solutions, syrups and elixirs. These preparations can be used as fillers in soft or hard capsules and generally contain a carrier (e.g., water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or a suitable oil) and one or more emulsifiers and / or suspending agents. Liquid preparations can also be prepared, for example, by reconstituting a solid in a medicine bag.

[0137] The compounds of formula I may also be used in fast dissolving, fast disintegrating dosage forms, such as those described in Expert Opinion in Therapeutic Patents, 11(6), 981-986, Liang and Chen (2001).

[0138] For tablet dosage forms, depending on the dosage, the drug can account for 1% to 80% by weight of the dosage form, more usually 5% to 60% by weight of the dosage form. In addition to the drug, tablets usually contain disintegrants. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, cross-linked sodium carboxymethylcellulose, cross-linked polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, low-carbon alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch and sodium alginate. Usually, disintegrants account for 1% to 25% by weight. In one embodiment of the present invention, disintegrants account for 5% to 20% by weight of the dosage form. Adhesives are usually used to give tablet formulations adhesion quality. Suitable adhesives include microcrystalline cellulose, gelatin, sugar, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose. Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous, etc.), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dihydrated calcium phosphate. Tablets may also optionally include surfactants (such as sodium lauryl sulfate and polysorbate 80) and glidants (such as silicon dioxide and talc). When present, surfactants may account for 0.2% to 5% by weight of the tablet, and glidants may account for 0.2% to 1% by weight of the tablet. Tablets also typically contain lubricants, such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and a mixture of magnesium stearate and sodium lauryl sulfate. Lubricants typically account for 0.25% to 10% by weight. In one embodiment of the present invention, lubricants account for 0.5% to 3% by weight of the tablet. Other possible ingredients include antioxidants, colorants, flavoring agents, preservatives, and taste masking agents.

[0139] Exemplary tablets contain up to about 80% by weight of drug, about 10% to about 90% by weight of binder, about 0% to about 85% by weight of diluent, about 2% to about 10% by weight of disintegrant, and about 0.25% to about 10% by weight of lubricant.

[0140] Tablet blends can be compressed directly or by roller compaction to form tablets. Alternatively, tablet blends or blend portions can be wet-, dry-, or melt-granulated, melt-congealed, or extruded prior to tableting. The final formulation can comprise one or more layers and can be coated or uncoated; it can even be encapsulated. Tablet formulations are discussed in Pharmaceutical Dosage Forms: Tablets, Vol. 1, H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).

[0141] Edible oral films for human or veterinary applications are usually pliable water-soluble or water-swellable film dosage forms that can dissolve quickly or have mucoadhesive properties, and usually include a compound of formula I, a film-forming polymer, an adhesive, a solvent, a humectant, a plasticizer, a stabilizer or an emulsifier, a viscosity modifier, and a solvent. Some components of the preparation can perform more than one function. The film-forming polymer can be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and is usually present in the range of 0.01% to 99% by weight, more usually in the range of 30% to 80% by weight. Other possible ingredients include antioxidants, colorants, flavoring agents and flavor enhancers, preservatives, saliva stimulants, coolants, cosolvents (including oils), softeners, extenders, defoamers, surfactants, and masking agents. The film of the present invention is usually prepared by evaporative drying of a thin aqueous film applied to a peelable backing carrier or paper. This can be carried out in a drying oven or channel (usually a combined coating dryer) or by freeze drying or vacuum treatment.

[0142] Solid preparations for oral administration can be formulated for immediate release and / or sustained release. Sustained release includes delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release. Suitable sustained release formulations for the purposes of the present invention are described in U.S. Patent No. 6,106,864. Details of other suitable release technologies (e.g., high energy dispersions and permeable and coated particles) are described in Pharmaceutical Technology On-line, 25 (2), 1-14, Verma et al. (2001). Controlled release using chewing gum is described in WO-A-00 / 35298.

[0143] The compounds of formula I can also be administered directly into the bloodstream, muscle or internal organs. Such parenteral administration includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, intraarticular and subcutaneous administration. Applicable devices for parenteral administration include needle (including microneedle) syringes, needle-free syringes and infusion techniques.

[0144] The compounds of formula I may also be administered topically to the skin or mucosa, ie, dermally or transdermally.

[0145] Parenteral formulations of the compounds of the invention are typically aqueous solutions that may contain excipients such as salts, carbohydrates, and buffers (preferably buffered to pH 3-9). Formulations for parenteral administration may also be sterile non-aqueous solutions or dry (e.g., lyophilized) forms intended for administration after reconstitution with a suitable vehicle (e.g., sterile, pyrogen-free water).

[0146] Pharmaceutical compositions for topical or transdermal administration of the compounds of the invention include ointments, pastes, creams, lotions, gels, suppositories, powders, solutions, sprays, drops, inhalants and patches. If necessary, the compounds of the invention may be mixed with a pharmaceutically acceptable topical carrier and any preservative or buffer under aseptic conditions. Volatile compounds may need to be mixed with formulations or packaging materials to ensure appropriate dose delivery. The compounds of the invention with poor skin permeability may require one or more penetration enhancers, while compounds that are rapidly absorbed through the skin may need to be formulated using an absorption delay agent or barrier.

[0147] The term "pharmaceutically acceptable topical carrier" refers to a carrier medium suitable for topical application and appropriately delivering 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 appreciate that this term also encompasses carrier materials approved for topical cosmetics.

[0148] The term "penetration enhancer" refers to increasing the permeability of the skin, nail, hair, claw or hoof to the compounds of the invention to increase the rate and extent of penetration of the compound. Enhanced penetration can be observed, for example, by measuring the rate at which a drug diffuses through the skin, nail, hair, claw or hoof of an animal or human using a diffusion cell apparatus. Diffusion cells are described by Merritt et al. in Diffusion Apparatus for Skin Penetration, J of Controlled Release, 1 (1984) pp. 161-162.

[0149] In addition to the compounds of the present invention, ointments, pastes, creams, lotions, gels, suppositories, powders, solutions, sprays, drops, inhalants and patches for topical administration may also contain one or more pharmaceutically acceptable excipients, such as animal or vegetable fats, oils, waxes, paraffins, starches, tragacanth gum, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc, zinc oxide, preservatives, antioxidants, fragrances, emulsifiers, dyes, inert fillers, anti-irritants, viscosity enhancers, fragrances, sunscreens, antioxidants, gelling agents, stabilizers, surfactants, emollients, colorants, preservatives, buffers, penetration enhancers. These excipients should not interfere with the biological activity effectiveness of the active agent and should not be harmful to epithelial cells or their functions.

[0150] Transdermal drug delivery can be achieved via a transdermal patch. Transdermal patches can be either of the "reservoir and porous membrane" type or employ a "matrix system."

[0151] The solubility of the compounds of the invention used in the preparation of pharmaceutical compositions may be enhanced by the use of appropriate formulation techniques, such as the incorporation of solubilizing agents.

[0152] The compounds of formula I may also be administered intranasally or by inhalation, usually in the form of dry powders from a dry powder inhaler (alone, as a mixture (e.g., a dry blend with lactose), or as mixed component particles (e.g., mixed with a phospholipid, such as phosphatidylcholine)) or as an aerosol spray from a pressurized container, pump, injector, nebulizer (preferably a nebulizer using electrohydrodynamics to generate a fine mist) or sprayer (with or without a suitable propellant, such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane) or as nasal drops. For intranasal use, the powder may contain a bioadhesive, such as chitosan or cyclodextrin. Inhaled delivery is a preferred route of administration for the compounds of the invention.

[0153] The pressurized container, pump, spray, atomizer or nebulizer contains a solution or suspension of a compound of Formula I comprising, for example, ethanol, aqueous ethanol, or a suitable alternative for dispersion, solubilization or prolonged release of the compound, a propellant as a solvent, and optionally a surfactant (e.g., sorbitan trioleate, oleic acid or oligolactic acid).

[0154] Prior to use in a dry powder or suspension formulation, the drug product is micronized to a size suitable for delivery by inhalation (usually less than 5 microns). This can be achieved by any suitable comminution method (e.g., spiral jet milling, fluidized bed jet milling, supercritical fluid processing) to form nanoparticles, high pressure homogenization, or spray drying.

[0155] Capsules (e.g. made of gelatin or hydroxypropylmethylcellulose), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of a compound of the invention, a suitable powder base such as lactose or starch and a performance enhancer such as l-leucine, mannitol or magnesium stearate. Lactose may be in anhydrous form or in the form of a monohydrate, preferably a monohydrate. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.

[0156] Solution formulations suitable for use in atomizers that use electrohydrodynamics to produce a fine mist may contain 1 μg to 20 mg of the compound of the invention per actuation, and the actuation volume may vary from 1 μL to 100 μL. A typical formulation may include a compound of formula I, propylene glycol, sterile water, ethanol, and sodium chloride. Alternative solvents that can be used to replace propylene glycol include glycerol and polyethylene glycol.

[0157] Suitable scents (e.g., fruit or flower flavors) may be added to those formulations of the invention intended for intranasal administration. Formulations for intranasal administration may be formulated for immediate and / or sustained release using, for example, PGLA. Sustained release includes delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release.

[0158] The compounds of formula I may also be administered directly to the eye or ear, typically in the form of drops of a micronized suspension or solution in isotonic, pH adjusted sterile saline.

[0159] The compounds of formula I can be used in combination with soluble macromolecules (e.g., cyclodextrins and suitable derivatives thereof or polymers containing polyethylene glycol) to improve their solubility, dissolution rate, taste, bioavailability and / or stability when used in any of the above-mentioned administration methods. It is found that drug-cyclodextrin complexes (for example) are generally useful for most dosage forms and routes of administration. Inclusion and non-inclusion complexes can be used. As an alternative to direct complexation with the drug, cyclodextrins can be used as auxiliary additives, i.e., as carriers, diluents or solubilizers. The most commonly used for these purposes are α, β and γ cyclodextrins, examples of which can be found in International Patent Publications WO91 / 11172, WO94 / 02518 and WO98 / 55148.

[0160] In view of the fact that it may be desirable to administer a combination of active compounds for the purpose of, for example, treating a particular disease or condition, two or more pharmaceutical compositions, at least one of which contains a compound of formula I, can be conveniently combined into a kit form suitable for co-administered compositions within the scope of the present invention. Therefore, the kit of the present invention comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of formula I, and a device (e.g., a container, a separate bottle, or a separate foil package) for storing these compositions separately. Examples of such kits are common blister packages for packaging tablets, capsules, etc. Such kits are particularly suitable for administering different dosage forms (e.g., oral and parenteral), for administering separate compositions at different dosage intervals, or for titrating separate compositions against each other. To aid compliance, the kit typically includes instructions for administration, and so-called memory aids may be provided.

[0161] The compounds of the present invention can be prepared by any method known in the art for preparing compounds of similar structures. Specifically, the compounds of the present invention can be prepared by the operation described with reference to the reaction scheme below, or by the specific method described in the examples or by an analogous method of any one.

[0162] It will be appreciated by those skilled in the art that the experimental conditions described in the following reaction schemes are exemplary of suitable conditions for carrying out the transformations shown, and that it may be necessary or desirable to vary the precise conditions employed to prepare compounds of Formula I. It will be further appreciated that it may be necessary or desirable to carry out the transformations in an order different from that described in the reaction schemes or to modify one or more of the transformations to provide the desired compounds of the invention.

[0163] In addition, it will be appreciated by those skilled in the art that it may be necessary or desirable to protect one or more sensitive groups at any stage of the synthesis of the compounds of the invention to prevent undesirable side reactions. Specifically, it may be necessary or desirable to protect amino or carboxylic acid groups. The protecting groups used in the preparation of the compounds of the invention can be used in a conventional manner. See, for example, those described in Protective Groups in Organic Synthesis, Theodora W Greene and Peter G M Wuts, 3rd edition (John Wiley and Sons, 1999), specifically the substituents in Chapter 7 ("Protection for the Amino Group") and Chapter 5 ("Protection for the Carboxyl Group"), which also describe methods for removing these groups.

[0164] Compounds of formula I (generally shown as compound G) can be prepared from compound AG as illustrated by Scheme 1 or Scheme 2. Compounds of formula AG are commercially available or can be synthesized by one skilled in the art according to the preparations described in the literature or herein.

[0165] Reaction Scheme 1

[0166]

[0167] Compounds prepared via reaction scheme 1

[0168] Compounds of formula B may be prepared from compounds of formula A according to process step (a), which is bromination under suitable conditions, including treatment with TMS triflate in the presence of an organic base (e.g. triethylamine), followed by reaction with a brominating agent (e.g. N-bromosuccinimide). Alternative conditions for step (b) include the use of trimethylphenylammonium tribromide in THF at 25°C.

[0169] Compounds of formula C can be prepared from compounds of formula B according to process step (b) by cyclization using 2,2-dimethylthiopropionamide under suitable alkaline conditions. Preferred conditions include the use of pyridine in ethanol at about 80°C. Compounds of formula D can be prepared from compounds of formula C according to process step (c) by bromo-alkoxylation, which can be achieved using a brominating agent (e.g., N-bromosuccinimide) in the presence of an alcohol. The reaction is typically carried out under ambient conditions.

[0170] Compounds of formula E can be prepared from compounds of formula D according to process step (d) by elimination using a non-nucleophilic base (e.g. potassium tert-butoxide) in an inert solvent (e.g. tetrahydrofuran) under ambient conditions. Compounds of formula F can be prepared from compounds of formula E according to process step (e) by deprotection / hydrolysis using a suitable acid (e.g. hydrochloric acid) in a mixed aqueous / organic solvent (e.g. dioxane).

[0171] Compounds of formula G may be prepared from compounds of formula F according to process step (f) by acylation with a heteroaryl carboxylic acid under suitable basic conditions. Preferred conditions include the use of N-ethyl-N-(propan-2-yl)propan-2-amine (DIPEA) in the presence of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium hexafluorophosphate 3-oxide (HATU). In alternative conditions, the reagent may include propanephosphonic anhydride in a bipolar solvent such as DMF at 25°C in the presence of triethylamine. Other effective conditions include the use of a water-soluble carbodiimide such as 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) in the presence of hydroxybenzotriazole (HOBt) and triethylamine in DMF at 25°C.

[0172] Reaction Scheme 2

[0173]

[0174] Compounds prepared via reaction route 2

[0175] Compounds of formula I can be prepared from compounds of formula H via Minisch coupling with carboxylic acids using 9-trimethylphenyl-10-methylacridinium perchlorate and irradiation.

[0176] Steps (e) and (f) follow the same process as described in Scheme 1.

[0177] Thus, the derivatives of formula I can be prepared by the operations described in the general methods presented below or by conventional modifications thereof. The present invention also encompasses any one or more of these methods for preparing the derivatives of formula I and any novel intermediates used therein. It will be appreciated by those skilled in the art that the following reactions can be heated thermally or under microwave irradiation.

[0178] In the non-limiting Examples and Preparations described hereinafter, which illustrate the present invention, and in the above-mentioned reaction schemes, reference may be made to the following abbreviations, definitions and analytical procedures:

[0179] AcOH: acetic acid

[0180] atm: atmospheric pressure

[0181] aq: aqueous solution

[0182] BOC 2 O: BOC anhydride, di-tert-butyl dicarbonate

[0183] br: broad peak

[0184] ℃: Celsius

[0185] CBZ: carboxybenzyl; benzyloxycarbonyl

[0186] conc. or c.: concentrated

[0187] δ: Chemical shift

[0188] d: Doublet

[0189] dd: double doublet

[0190] ddd: doublet of doublets

[0191] dt: double triplet

[0192] DCM: dichloromethane

[0193] DHP: Dihydropyran

[0194] DMAC: N,N-dimethylacetamide

[0195] DMAP: 4-dimethylaminopyridine

[0196] DMF: dimethylformamide

[0197] DMSO: dimethyl sulfoxide

[0198] EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide

[0199] ESI-MS: Electrospray ionization-mass spectrometry

[0200] EtOAc: ethyl acetate

[0201] Et 3 N: Triethylamine

[0202] equiv.: equivalent

[0203] g: grams

[0204] h: hours

[0205] HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0206] HOPO: 2-Hydroxypyridine 1-oxide

[0207] HPLC: High Pressure Liquid Chromatography

[0208] i 2 NEt: N,N-diisopropylethylamine, Hunig's base

[0209] iPrOH: isopropanol, 2-propanol

[0210] Kg: kilogram

[0211] KOtBu: Potassium tert-butoxide

[0212] L: Lift

[0213] LAH: Lithium Aluminum Hydride, LiAlH 4

[0214] LCMS: Liquid chromatography-mass spectrometry

[0215] LDA: lithium diisopropylamide

[0216] LiHMDS: Lithium bis(trimethylsilyl)amide

[0217] M: multiple peaks

[0218] M: molar concentration

[0219] MeCN: Acetonitrile

[0220] MHz: Megahertz

[0221] min: minutes

[0222] mL: milliliters

[0223] mm: millimeters

[0224] mmol: millimole

[0225] μmol: micromole

[0226] mol: mole

[0227] MS m / z: mass spectrum peak

[0228] MTBE: Methyl tert-butyl ether

[0229] N: Positive

[0230] n-BuLi: n-butyllithium.

[0231] NBS: N-bromosuccinimide

[0232] NCS: N-chlorosuccinimide

[0233] NH 4 OH: 33% ammonia solution

[0234] NMP: N-methylpyrrolidine

[0235] NMR: Nuclear Magnetic Resonance

[0236] Pd 2 (dba) 3 :Tris(dibenzylideneacetone)dipalladium(0)

[0237] Pd / C: Palladium on carbon

[0238] PE: Petroleum ether

[0239] Prep: Preparation

[0240] pTSA·H 2 O: p-Toluenesulfonic acid monohydrate

[0241] q: quartet

[0242] quint: quintet

[0243] RT: Room temperature

[0244] s: Single peak

[0245] sat.: saturated

[0246] SFC: Supercritical Fluid Chromatography

[0247] t: triplet

[0248] t-BuOH: tert-butyl alcohol

[0249] TFA: trifluoroacetic acid

[0250] THF: Tetrahydrofuran

[0251] TMSOTf: trimethylsilyl trifluoromethanesulfonate

[0252] TTBP·HBF 4 : Tri-tert-butylphosphonium tetrafluoroborate

[0253] T3P: Propylphosphonic anhydride

[0254] X-Phos: 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0255] μm: micrometer

[0256] μL: microliter

[0257] General experimental part:

[0258] Unless otherwise stated, all reactions are run under a nitrogen atmosphere. The abbreviation RT refers to "room temperature" and generally means about 22°C (±5°C). Unless otherwise stated, the term "concentration" refers to the process of removing volatile compounds (e.g., solvents) under reduced pressure by using a rotary evaporator. The term "chromatography" refers to silica gel chromatography using a mobile phase consisting of a mixture or gradient of EtOAc / heptane or methanol / DCM or some combination thereof.

[0259] 1 H NMR spectra were consistent with the proposed structures in all cases. Major peak assignments were reported using conventional abbreviations relative to the residual solvent signal (for CDCl 3 , δH = 7.27 ppm; for DMSO-d 6 , δH = 2.50ppm, for CD 3 OD, δH = 3.30ppm) 1 Characteristic δ of H NMR. Those skilled in the art will appreciate that tautomers may be recorded in NMR data and some exchangeable protons may not be visible. Likewise, those skilled in the art will appreciate that mixtures of rotational isomers may be recorded in NMR data.

[0260] Mass spectra were recorded using either ESI-MS. Where relevant and unless otherwise stated, m / z data are provided for isotopes 19 F. 35 Cl, 79 Br and / or 81 Br.

[0261] In the case of using silica gel chromatography, preparative HPLC or SFC chromatography, those skilled in the art will appreciate that any suitable solvent or combination of solvents may be employed to purify the desired compound.

[0262] The compound names in the following preparations and examples were generated using ChemDraw Professional 19.0 (PerkinElmer) according to IUPAC (International Union of Pure and Applied Chemistry).

[0263] Amidation method

[0264] A) DIPEA (4.0 eq.) (c=0.14 M) in DMF was added to the carboxylic acid mixture (1.0 eq.), followed by HATU (1.5 eq.). The resulting mixture was stirred at about 15°C for about 10 min, and then the amine (1.0 eq.) was added to the mixture. The reaction was stirred at about 15°C for about 16 h. The reaction was filtered and the filtrate was purified by preparative HPLC.

[0265] B) To the carboxylic acid (1.0 eq.) was added TPTU stock solution (1.5 eq., 0.30 M in DMF), followed by the amine (1.0 eq., 0.20 M stock solution in DMF) and 2 eq. of DIPEA (2.20 mmol, 383 μl). The mixture was stirred at about 65 °C for about 14 h. The mixture was heated to 40 °C under N 2 The solvent was evaporated under a stream of gas. The resulting residue was dissolved in DMSO, filtered and purified by preparative HPLC.

[0266] C) A mixture of amine (1.0 eq.), acid (1.0 eq.) and EDCI (1.5 eq.) in pyridine (final concentration = 65 mM) was heated to about 110° C. for about 30 min using a microwave reactor. The solvent was evaporated and it was further purified by preparative HPLC.

[0267] D) In ​​N 2 To the carboxylic acid mixture (1.0 equiv) was added a solution of amine (1.0 equiv) in DMF (c = 0.25 M) and triethylamine (6.0 equiv). The resulting mixture was stirred at about 23 °C for about 5 min and then cooled in an ice / water bath for another 5 min. T3P (50% in DMF) was slowly added dropwise (2.0 equiv) to the reaction mixture over 10 min. The reaction solution was slowly warmed to about 15 °C over about 1.5 h and then H 2 O (3 x reaction mixture volume). The mixture was worked up by filtration and the precipitate was collected, dried and purified by preparative HPLC.

[0268] Preparation Example 1: 2-(tert-Butyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidinyl]-4(7H)-one hydrochloride (P1)

[0269]

[0270] Step 1: Synthesis of tert-butyl 2-(tert-butyl)-7H-spiro[benzo[d]thiazole-6,4'-piperidine]-1'-carboxylate (C1)

[0271]

[0272] To a solution of tert-butyl 9-oxo-3-azaspiro[5.5]undec-7-ene-3-carboxylate (CAS: 873924-07-3; 160 g, 603 mmol) in DCM (2.4 L) was added Et 3 N (251 mL, 1.81 mol). The solution was cooled to about -78 ° C and a solution of TMSOTf (164 mL, 904 mmol) in DCM (800 mL) was added dropwise. The solution was stirred at about -78 ° C for about 30 min, then warmed to about 0 ° C and stirred at about 0 ° C for about 2 h. The solution was cooled to about -78 ° C and a suspension of NBS (118 g, 663 mmol) in DCM (800 mL) was added. The mixture was stirred at about -78 ° C for about 2 h, then warmed to about 0 ° C. Boc 2 O (52.6 g, 241 mmol), and the mixture was stirred at about 0 °C for about 2 h. Saturated NaHCO 3 (aq) (1.6 L), and the organic phase was separated and concentrated under reduced pressure. To the residue were added 2,2-dimethylthiopropionamide (84.8 g, 723 mmol), pyridine (436 mL, 542 mmol) and EtOH (2.1 L). The solution was heated to about 80 ° C and maintained for about 16 h, and then cooled to about 23 ° C. Using saturated NaHCO 3 The mixture was washed with (aq) (2.0 L) and the organic phase was concentrated under reduced pressure. The residue was purified by column chromatography (silica, petroleum ether:EtOAc=1:0 to 3:1) to provide the title compound (149 g, 68%). 1 H NMR (400 MHz, CDCl 3 )δ=6.65(d,1H),5.87(d,1H),3.57-3.51(m,2H),3.40-3.33(m,2H),2.82(s ,2H),1.71-1.67(m,2H),1.53-1.48(m,2H),1.46(s,9H),1.43(s,9H); LC / MS m / z(M+H) + =363.1.

[0273] Step 2: Synthesis of 2-(tert-butyl)-5H-spiro[benzo[d]thiazol-6,4'-piperidin]-4(7H)-one hydrochloride (P1)

[0274]

[0275] MeOH (1.88 L) was added to compound C1 (188 g, 519 mmol). The solution was cooled to about 15 ° C and NBS (96.9 g, 545 mmol) was added in batches. The resulting mixture was stirred at about 15 ° C for about 2 h and concentrated under reduced pressure. THF (2.5 L) was added to the residue and the resulting solution was cooled to about 15 ° C. KOtBu (1M in THF, 2.1 L) was added and the solution was stirred at about 15 ° C for 16 h. Water (4.9 L) was added and the mixture was extracted with isopropyl acetate (3× 2.8 L). The combined organic phases were concentrated under reduced pressure to provide crude 2-(tert-butyl)-4-methoxy-7H-spiro[benzo[d]thiazole-6,4′-piperidine]-1′-carboxylic acid tert-butyl ester (Intermediate C1b). To the resulting residue was added additional intermediate C1b (21.6 g, 55 mmol) and dioxane (970 mL) from the previous batch, followed by dropwise addition of HCl (4 M in dioxane, 2.26 L). The solution was stirred at about 25 °C for about 16 h and then concentrated under reduced pressure. MeOH (3.5 L) was added and the solution was heated to about 60 °C and cooled to about 25 °C. The solution was concentrated under reduced pressure to remove 2.8 L of MeOH. The resulting mixture was stirred at about 25 °C for about 16 h. EtOAc (2.0 L) was added and the resulting mixture was stirred at about 25 °C for about 16 h. The resulting slurry was filtered and the filter cake was dried under reduced pressure and about 40 °C to provide the title compound (157 g, 87%). 1 H NMR (400MHz, DMSO-d6)δ=9.01(br s,1H),8.93(br s,1H),3.22(s,2H),3.06(br s,4H),2.62(s,2H),1.76-1.65(m,4H),1.37(s,9H); LC / MS m / z(M+H) + =279.2.

[0276] Preparation Example 2: 5-Methyl-2-(methylamino)quinoline-7-carboxylic acid (P2)

[0277]

[0278] Step 1: 7-Bromo-N,5-dimethylquinolin-2-amine (C2)

[0279]

[0280] To a solution of 7-bromo-2-chloro-5-methylquinoline (8.96 g, 34.9 mmol, prepared by the method of Aciro, C. et al., PCT Int. Appl. (2013), WO 2013185103) in methylamine (175 mL of a 2M solution in THF, 349 mmol) was added cesium fluoride (10.6 g, 69.9 mmol) at about 25°C. The mixture was heated to about 100°C and maintained for about 48 h. Using saturated NH 4 The mixture was diluted with Cl (30 mL) and extracted with EtOAc. The combined organic phases were washed with brine (30 mL) and purified by MgSO 4 The product was dried, filtered, and concentrated under reduced pressure. SFC (column: Chiral Tech OX-H, 30x250 mm, 5 μm; mobile phase A: carbon dioxide; mobile phase B: MeOH / 1% NH 3 ; 95%-70% B gradient, 3.5 min; flow rate: 80 mL / min) to provide the title compound (2.81 g, 32%). LC / MS m / z (M+H) + =252.1.

[0281] Step 2: 5-Methyl-2-(methylamino)quinoline-7-carboxylic acid methyl ester (C3)

[0282]

[0283] To a solution of compound C2 (1.15 g, 4.59 mmol) in MeOH (50 mL) were added triethylamine (2.0 mL, 14 mmol) and Pd(dppf)Cl 2. CH 2 Cl 2 (613 mg, 0.751 mmol). The solution was added to a Parr reactor and flushed three times with nitrogen. The reactor was flushed three times with CO and then sealed under about 75 PSI CO. The reactor was heated to about 80 ° C and maintained for about 24 h. The solution was cooled to about 25 ° C and diluted with EtOAc. The solution was washed with water and brine. The reaction mixture was stirred for 24 hours ... 2 SO 4 The organic phase was dried and concentrated under reduced pressure. The residue was purified by column chromatography to provide the title compound (853 mg, 81%). LC / MS m / z (M+H) + =231.3.

[0284] Step 3: 5-Methyl-2-(methylamino)quinoline-7-carboxylic acid (P2)

[0285]

[0286] To a solution of compound C3 (840 mg, 3.65 mmol) in THF (18 mL) was added 1 M sodium hydroxide (22 mL, 22 mmol). The solution was stirred at about 25 °C for about 16 h. HCl (1 M) was added dropwise until a precipitate formed (pH ~5). The precipitate was filtered to provide the title compound (789 mg, 88%). 1 H NMR (400MHz, DMSO-d6) δ8.01(d,1H),7.94(s,1H),7.49(s,1H),7.11(d,1H),6.86(d,1H),2.91(d,3H),2.55(s,3H); LC / MS m / z(M+H) + =217.2.

[0287] Preparation Example 3: 2-(tert-Butyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidinyl]-4(7H)-one hydrochloride (P3)

[0288]

[0289] Step 1: Synthesis of 4-(1,3-dimethyl-1H-pyrazol-4-yl)-3-(ethoxycarbonyl)but-3-enoic acid (C4)

[0290]

[0291] To a solution of solid KOtBu (36.2 g, 322 mmol) in ethanol (200 mL) at about 25 °C, 1,3-dimethyl-1H-pyrazole-4-carboxaldehyde (CAS: 25016-21-0; 20 g, 160 mmol) and diethyl succinate (42.1 g, 40 mL, 242 mmol) were added. The reaction solution was heated at about 80 °C for about 18 h, then cooled to room temperature and quenched with AcOH (23 mL, 403 mmol). The reaction mixture was concentrated to about (40 mL) and heptane (2 x 100 mL) was added, and the reaction mixture was concentrated. The reaction solution was cooled to about 0-10 °C, water (200 mL) was added, and the pH of the aqueous layer was adjusted to 4-5 using aqueous HCl solution. The resulting suspension was filtered and rinsed with water (60 mL). The solid was dried to provide the title compound (33.4 g, 82.1%). 1 H NMR (400 MHz, methanol-d4) δ7.81 (s, 1H), 7.63 (s, 1H), 4.25 (q, 2H), 3.85 (s, 3H), 3.53 (s, 2H), 2.28 (s, 3H), 1.32 (t, 2H); LC / MS m / z (M+H) + =253.1.

[0292] Step 2: Synthesis of ethyl 7-acetoxy-1,3-dimethyl-1H-indazole-5-carboxylate (C5)

[0293]

[0294] To a solution of compound C4 (32.0 g, 126.9 mmol) in DMAC (128 mL) was added sodium acetate (26.0 g, 317 mmol) and acetic anhydride (32 mL, 2.67 mmol). The reaction solution was heated at about 95-105 ° C for about 18 h, then cooled to about 0-10 ° C, and water (512 mL) was added dropwise. The resulting suspension was filtered and rinsed with water (100 mL). The precipitate was recrystallized with water and dried to provide the title compound (28.8 g, 82.9%). 1 H NMR (400 MHz, methanol-d4) δ 8.33 (s, 1H), 7.76 (s, 1H), 4.42 (q, 2H), 4.11 (s, 3H), 2.59 (s, 3H), 2.47 (s, 3H), 1.44 (t, 3H); %); LC / MS m / z (M+H) + =277.1.

[0295] Step 3: Synthesis of ethyl 7-hydroxy-1,3-dimethyl-1H-indazole-5-carboxylate (C6)

[0296]

[0297] Potassium carbonate (2.76 g, 5.0 mmol) was added to a solution of compound C5 (1.11 g, 4.0 mmol) in ethanol (16 mL). The reaction solution was heated under reflux for about 1.5 h and then concentrated. The residue was diluted with EtOAc (25 mL) and water (25 mL) and the pH of the aqueous layer was adjusted to 4-5 with aqueous citric acid. The organic layer was separated, washed with brine (25 mL), filtered through MgSO 4 Dry, filter, and concentrate, dilute the residue with hexanes (25 mL) and concentrate the resulting mixture under reduced pressure, dry using high vacuum at about 50 °C to afford the title compound as a light pink solid (0.89 g, 95% yield). 1 H NMR (400MHz, DMSO-d6) δ10.47(s,1H),7.81(d,1H),7.26(s,1H),4.29(q,2H),4.15(s,3H),2.45(s,3H),1.33(t,3H); LC / MS m / z(M+H) + =235.1.

[0298] Step 4: Synthesis of ethyl 7-methoxy-1,3-dimethyl-1H-indazole-5-carboxylate (C7)

[0299]

[0300] To a solution of compound C6 (0.7 g, 3.0 mmol) in acetone (20 mL) was added potassium carbonate (0.83 g, 6.0 mmol) and iodomethane (0.64 g, 0.28 mL, 4.5 mmol). The reaction was heated at reflux for about 24 h and then concentrated. The residue was diluted with water (25 mL) and extracted with EtOAc (2 x 25 mL). The combined EtOAc extracts were washed with brine (25 mL) and purified by MgSO 4 Dried, filtered, and concentrated.The residue was purified by chromatography (silica, 0-25% EtOAc in hexanes) to provide the title compound (0.71 g, 95.3% yield) as a white solid. 1 H NMR (400 MHz, chloroform-d) δ8.04 (s, 1H), 7.37 (s, 1H), 4.44 (q, 2H), 4.27 (s, 3H), 4.03 (s, 3H), 2.59 (s, 3H), 1.46 (t, 3H); LC / MS m / z (M+H) + =249.1.

[0301] Step 5: Synthesis of 7-methoxy-1,3-dimethyl-1H-indazole-5-carboxylic acid (P3)

[0302]

[0303] To compound C7 (0.3 g, 1.21 mmol) in EtOH (4.8 mL), THF (4.3 mL) was added 1N NaOH (4.83 mL, 4.83 mmol). The mixture was heated to about 45 ° C and maintained for about 2 h, then cooled to about 25 ° C and concentrated. The residue was diluted with water (2 mL) and the pH of the aqueous layer was adjusted to 4-5 using 1.5 M citric acid. The resulting suspension was filtered and rinsed with water (5 mL). The precipitate was dried at 50 ° C to provide the title compound (0.23 g, 86.4%). 1 H NMR (400 MHz, methanol-d4) δ 7.99 (d, J = 1.2 Hz, 1H, 4), 7.38 (d, J = 1.2 Hz, 1H, 2), 4.19 (s, 3H, 16), 4.00 (s, 3H, 10), 2.51 (s, 3H, 11); LC / MS m / z (M+H) + =221.1. [Example]

[0304] Example 1: 1'-(3,7-dimethyl-2H-indazole-5-carbonyl)-2-(1-methylcyclopropyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidin]-4(7H)-one

[0305]

[0306] A solution of 2-(1-methylcyclopropyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidin]-4(7H)-one (prepared as for compound P1, 0.06 g, 0.22 mmol), 3,7-dimethyl-1H-indazole-5-carboxylic acid (0.05 g, 0.26 mmol), EDCI·HCl (0.08 g, 0.43 mmol) and pyridine (2 mL) was microwaved at about 110° C. for about 30 min. The resulting mixture was filtered and the residue was purified by preparative HPLC (column: YMC Actus Triart C18, 150×30 mm, 5 μm; mobile phase A: water (0.225% v / v formic acid); mobile phase B: MeCN; 30-50% B gradient, 11 min, hold at 100% B for 2 min; flow rate: 35 mL / min) to provide the title compound (15 mg, 16%). 1 H NMR (400MHz, methanol-d4) δ7.64(d,1H),7.20(t,1H),3.79(m,2H),3.55(m,2H),3.21(s,2H),2.70(s, 2H),2.56(s,3H),2.55(s,3H),1.64(s,4H),1.55(s,3H),1.29(q,2H),1.04-0.95(m,2H); LC / MS m / z(M+H) + =449.4.

[0307] Example 2: 1'-(3,7-dimethyl-1H-indazole-5-carbonyl)-2-(1-methylcyclobutyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidinyl]-4(7H)-one

[0308]

[0309] A solution of 2-(1-methylcyclobutyl)-5H-spiro[benzo[d]thiazol-6,4'-piperidin]-4(7H)-one (prepared as compound P1, 0.022 g, 0.077 mmol), 3,7-dimethyl-1H-indazole-5-carboxylic acid (0.017 g, 0.092 mmol), EDCI·HCl (0.029 g, 0.154 mmol) and pyridine (1 mL) was microwaved at about 110° C. for about 30 min. The resulting mixture was filtered, and the residue was purified by preparative HPLC using water / acetonitrile (column: Sunfire C18, 19×100 mm, 5 μm) to provide the title compound (6.9 mg, 19%). LC / MS m / z (M+H) + =463.3.

[0310] Example 3: 1'-(3,7-dimethyl-1H-indazole-5-carbonyl)-2-(2,3-dimethylbutan-2-yl)-5H-spiro[benzo[d]thiazole-6,4'-piperidin]-4(7H)-one

[0311]

[0312] Step 1: Synthesis of tert-butyl 2-(2,3-dimethylbutan-2-yl)-4-oxo-4,7-dihydro-5H-spiro[benzo[d]thiazole-6,4'-piperidinyl]-1'-carboxylate (C8)

[0313]

[0314] To a solution of tert-butyl 4-oxo-4,7-dihydro-5H-spiro[benzo[d]thiazole-6,4'-piperidine]-1'-carboxylate (prepared as for compound P1, 0.1 g, 0.31 mmol) in acetonitrile (1.5 mL) and water (1.5 mL) were added 2,2,3-trimethylbutanoic acid (0.121 g, 0.93 mmol), Na 2 HPO 4 (0.132 g, 0.93 mmol) and 9-trimethylphenyl-10-methylacridinium perchlorate (3.83 g, 0.0093 mmol). The reaction mixture was irradiated using a 72W blue LED light bar for about 60 h. The resulting mixture was filtered and purified by preparative HPLC (column: Phenomenex Gemini-NX C18, 50x250 mm, 10 μm; mobile phase A: water (0.05% v / v conc. NH 4 OH); mobile phase B: MeCN; 63-83% B gradient, 9 min, hold at 100% B for 2 min; flow rate: 25 mL / min) to provide the title compound (30 mg, 23.8%).1 H NMR (400MHz, methanol-d4) δ3.52-3.44(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.

[0315] Step 2: Synthesis of 2-(2,3-dimethylbutan-2-yl)-5H-spiro[benzo[d]thiazol-6,4'-piperidin]-4(7H)-one (C9)

[0316]

[0317] To a solution of compound C8 (0.03 g, 0.074 mmol) in MeOH (2 mL) was added 4N HCl in dioxane (1 mL) and stirred at about 20°C for about 2 h. The reaction mixture was concentrated to give a yellow oil, acetonitrile (2 x 5 mL) was added, and the reaction was concentrated under reduced pressure and dried in vacuo to provide the title compound (25 mg, 99%). LC / MS m / z (M+H) + =307.1.

[0318] Step 3: Synthesis of 1'-(3,7-dimethyl-1H-indazole-5-carbonyl)-2-(2,3-dimethylbutan-2-yl)-5H-spiro[benzo[d]thiazol-6,4'-piperidin]-4(7H)-one

[0319]

[0320] A solution of 2-(2,3-dimethylbutan-2-yl)-5H-spiro[benzo[d]thiazol-6,4'-piperidin]-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 microwaved at about 110° C. for about 30 min. The resulting mixture was concentrated and purified by preparative HPLC (column: Phenomenex Gemini-NX C18, 40×80 mm, 3 μm; mobile phase A: water (0.05% v / v conc. NH 4 OH); mobile phase B: MeCN; 31-71% B gradient, 9 min, hold at 100% B for 2 min; flow rate: 25 mL / min) to provide the title compound (5.56 mg, 16%). 1H NMR (400 MHz, methanol-d 4 )δ7.67(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.

[0321] Example 4: 1'-(3,7-dimethyl-1H-indazole-5-carbonyl)-2-(1-methylcyclopentyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidin]-4(7H)-one

[0322]

[0323] A solution of 2-(1-methylcyclopentyl)-5H-spiro[benzo[d]thiazol-6,4'-piperidin]-4(7H)-one (prepared as compound C9, 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) was microwaved at about 110° C. for about 30 min. The resulting mixture was filtered and purified by preparative HPLC (column: Phenomenex Gemini-NX C18, 40×80 mm, 3 μm; mobile phase A: water (0.05% v / v conc. NH 4 OH); mobile phase B: MeCN; 29-69% B gradient, 9 min, hold at 100% B for 2 min; flow rate: 25 mL / min) to provide the title compound (7.2 mg, 21%). 1 H NMR (400 MHz, methanol-d4) δ7.66 (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.

[0324] Example 5: 1'-(3,7-dimethyl-1H-indazole-5-carbonyl)-2-(tert-pentyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidin]-4(7H)-one

[0325]

[0326] Prepared in the same manner as Example 3 by using 2,2-dimethylbutyric acid instead of 2,2,3-trimethylbutyric acid in step 1 to provide the title compound (8.3 mg). LC / MS m / z (M+H) + =465.3.

[0327] Example 6: 1'-(3,7-dimethyl-1H-indazole-5-carbonyl)-2-ethyl-5H-spiro[benzo[d]thiazole-6,4'-piperidin]-4(7H)-one

[0328]

[0329] 2-Ethyl-5H-spiro[benzo[d]thiazole-6,4'-piperidin]-4(7H)-one (prepared as compound P1, 0.08 g, 0.28 mmol) was coupled with 3,7-dimethyl-1H-indazole-5-carboxylic acid (0.056 g, 0.28 mmol) according to the amidation method A. The reaction mixture was purified by preparative HPLC (column: Phenomenex Gemini-NX C18, 40x80 mm, 3 μm; mobile phase A: water (0.05% v / v conc. NH 4 OH); mobile phase B: MeCN; 9-60% B gradient, 9 min, hold at 100% B for 2 min; flow rate: 25 mL / min) to provide the title compound (45 mg, 38%). 1 H NMR (400 MHz, methanol-d 4 )δ7.67(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.

[0330] 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'-piperidin]-4(7H)-one

[0331]

[0332] 2-(Bicyclo[1.1.1]pentan-1-yl)-5H-spiro[benzo[d]thiazol-6,4'-piperidin]-4(7H)-one (prepared as compound P1, 0.08 g, 0.28 mmol) was coupled with 3,7-dimethyl-1H-indazole-5-carboxylic acid (0.056 g, 0.28 mmol) according to the amidation method A. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18, 40x80 mm, 3 μm); mobile phase A: water (0.225% v / v formic acid; mobile phase B: MeCN; 19-59% B gradient, 9 min, hold at 100% B for 2 min; flow rate: 25 mL / min) to provide the title compound (28.5 mg, 40%). 1 H NMR (400 MHz, methanol-d 4 )δ7.66(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.

[0333] Example 8: 2-Isopropyl-1'-(5-methyl-2-(methylamino)quinoline-7-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidin]-4(7H)-one

[0334]

[0335] 2-Isopropyl-5H-spiro[benzo[d]thiazole-6,4'-piperidin]-4(7H)-one (prepared as compound P1, 0.034 g, 0.116 mmol) was coupled with 5-methyl-2-(methylamino)quinoline-7-carboxylic acid (0.03 g, 0.14 mmol) according to the amidation method A. The residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18, 40x80 mm, 3 μm); mobile phase A: water (0.225% v / v formic acid; mobile phase B: MeCN; 20-50% B gradient, 9 min, hold at 100% B for 2 min; flow rate: 25 mL / min) to provide the title compound (23.2 mg, 36%). 1 H NMR (400 MHz, methanol-d 4)δ8.06(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.

[0336] Example 9: 1'-(5-methyl-2-(methylamino)quinoline-7-carbonyl)-2-(1-methylcyclopropyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidin]-4(7H)-one

[0337]

[0338] According to the amidation method A, 2-(1-methylcyclopropyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidin]-4(7H)-one (prepared as in Example P1, 0.036 g, 0.116 mmol) was coupled with 5-methyl-2-(methylamino)quinoline-7-carboxylic acid (0.03 g, 0.14 mmol). The reaction mixture was purified by preparative HPLC (column: Boston Prime C18, 150x30 mm, 5 μm; mobile phase A: water (0.05% v / v conc. NH 4 OH); mobile phase B: MeCN; 26-56% B gradient, 9 min, hold at 100% B for 2 min; flow rate: 25 mL / min) to provide the title compound (24.7 mg, 38%). 1 H NMR (400 MHz, methanol-d 4 )δ8.06(dd,1H),7.57-7.50(m,1H),7.05(dd,1H),6.83(d,1H),3.91-3.78(m,2H),3.57-3.51(m,2H),3.25(s,2H),3.03(s,3 LC / MS m / z(M+H) + =475.4.

[0339] Example 10: 2-Isopropyl-1'-(7-methoxy-1,3-dimethyl-1H-indazole-5-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidin]-4(7H)-one

[0340]

[0341] 2-Isopropyl-5H-spiro[benzo[d]thiazole-6,4'-piperidin]-4(7H)-one (prepared as in Example P1, 0.047 g, 0.159 mmol) was coupled with 7-methoxy-1,3-dimethyl-1H-indazole-5-carboxylic acid (0.035 g, 0.16 mmol) according to the amidation method A. The residue was purified by preparative HPLC (column: Boston Prime C18, 150x30 mm, 5 μm; mobile phase A: water (0.05% v / v formic acid); mobile phase B: MeCN; 14-54% B gradient, 9 min, hold at 100% B for 2 min; flow rate: 25 mL / min) to provide the title compound (17.7 mg, 24%). 1 H NMR (400 MHz, methanol-d 4 )δ7.35(d,1H),6.87(d,1H),4.21(s,3H),4.02(s,3H),3.80(m,2H),3.61(m,2H),3 .29(h,1H),3.27(s,2H),2.75(s,2H),2.51(s,3H),1.71(m,4H),1.40(d,6H); LC / MS m / z(M+H) + =467.3.

[0342] Example 11: 1'-(7-methoxy-1,3-dimethyl-1H-indazole-5-carbonyl)-2-(1-methylcyclopropyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidin]-4(7H)-one

[0343]

[0344] According to the amidation method A, 2-(1-methylcyclopropyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidin]-4(7H)-one (prepared as in Example P1, 0.05 g, 0.16 mmol) was coupled with 7-methoxy-1,3-dimethyl-1H-indazole-5-carboxylic acid (0.035 g, 0.16 mmol). The reaction mixture was purified by preparative HPLC (column: YMC Triart C18, 150x25 mm, 5 μm; mobile phase A: water (0.05% v / v conc. NH 4OH); mobile phase B: MeCN; 26-56% B gradient, 9 min, hold at 100% B for 2 min; flow rate: 25 mL / min) to provide the title compound (19 mg, 25%). 1 H NMR (400 MHz, methanol-d 4 )δ7.35(d,1H),6.86(d,1H),4.21(s,3H),4.02(s,3H),3.83-3.76(m,2H),3.63-3.57(m,2H),3.24(s,2H LC / MS m / z(M+H) + =479.4.

[0345] 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'-piperidin]-4(7H)-one

[0346]

[0347] To a solution of 2-(2-(methyl-d3)propan-2-yl-1,1,1,3,3,3-d6)-5H-spiro[benzo[d]thiazol-6,4′-piperidin]-4(7H)-one (prepared as compound P1, 0.105 g, 0.366 mmol), 7-methoxy-1,3-dimethyl-1H-indazole-5-carboxylic acid (0.1 g, 0.454 mmol), EDCI·HCl (0.126 g, 1.8 mmol) and HOBt (0.79 g, 0.586 mmol) in DMF (15 mL) was added Et 3 N (0.51 mL, 3.66 mmol). The mixture was stirred at about 25 °C for about 16 h and then diluted with EtOAc (50 mL). Saturated Na 2 CO 3 The mixture was washed with aqueous solution (2 x 25 mL) and brine (2 x 25 mL). 4 The organic phase was dried, filtered, and concentrated.The residue was purified by chromatography (silica, EtOAc:heptane, 0-100%) to provide the title compound (0.15 g, 67.5%) as a white solid. 1H NMR (400 MHz, methanol-d4) δ7.35 (s, 1H), 6.87 (s, 1H), 4.22 (s, 3H), 4.03 (s, 3H), 3.64 (m, 4H, 11), 3.28 (s, 2H), 2.76 (s, 2H), 2.52 (s, 3H), 1.72 (m, 4H); LC / MS m / z (M+H) + =490.2.

[0348] Example 13: 2-(tert-butyl)-1'-(7-methoxy-1,3-dimethyl-1H-indazole-5-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidinyl]-4(7H)-one

[0349]

[0350] To a solution of compound P1 (0.97 g, 3.1 mmol), compound P3 (0.68 g, 3.1 mmol), EDCI·HCl (0.89 g, 4.65 mmol), and HOBt (0.73 g, 4.65 mmol) in DMF (25.8 mL) was added at about 25°C. i Pr 2 NEt (2.97 mL, 17.0 mmol). The mixture was stirred at about 25 °C for about 16 h and then diluted with EtOAc (50 mL). 5% aqueous LiCl solution (25 mL), 0.5N HCl (25 mL), saturated NaHCO 3 The mixture was washed sequentially with aqueous solution (20 mL) and 1:1 brine-water (30 mL). 4 The organic phase was dried, filtered, concentrated, heptane (2 x 25 mL) was added and the resulting mixture was concentrated under reduced pressure. The residual product was purified by chromatography (silica, 0-100% EtOAc / hexanes then 0-10% MeOH:EtOAc) to afford the title compound (1.05 g, 70.4% yield) as a white solid. 1 H NMR (400 MHz, CDCl 3 )δ7.23(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.

[0351] Example 14: 2-(tert-butyl)-1'-(7-ethoxy-1,3-dimethyl-1H-indazole-5-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidinyl]-4(7H)-one

[0352]

[0353] Step 1: Synthesis of ethyl 7-ethoxy-1,3-dimethyl-1H-indazole-5-carboxylate (C10)

[0354]

[0355] To a solution of compound C6 (0.328 g, 1.4 mmol) in acetone (9.3 mL) was added potassium carbonate (0.33 g, 1.7 mmol) and iodoethane (0.30 g, 0.16 mL, 1.96 mmol). The reaction was heated at reflux for about 24 h and then concentrated. The residue was diluted with water (25 mL) and extracted with EtOAc (2 x 25 mL). The combined EtOAc extracts were washed with brine (25 mL) and purified by MgSO 4 Dry, filter, and concentrate.The residue was purified by chromatography (silica, EtOAc / hexanes, 0-25%) to provide the title compound (0.27 g, 74% yield) as a white solid. 1 H NMR (400 MHz, CDCl 3 )δ7.99(s,1H),7.32(s,1H),4.40(q,2H),4.23(s,3H),4.22(q,2H),2.56(s,3H),1.52(t,3H),1.42(t,3H); LC / MS m / z(M+H) + =263.1.

[0356] Step 2: Synthesis of 7-ethoxy-1,3-dimethyl-1H-indazole-5-carboxylic acid (C11)

[0357]

[0358] To compound C10 (268 mg, 1.02 mmol) in EtOH (5.1 mL) and THF (5.1 mL) was added 1 M NaOH aqueous solution (5.1 mL, 5.1 mmol). The mixture was stirred at about 25 °C for about 17 h and then concentrated under reduced pressure. To the mixture was added 1.5 M citric acid aqueous solution (2.5 mL) and water (2 mL). After stirring for about 3 minutes, the precipitate was separated by filtration to provide the title compound (230 mg, 96.3%). 1H NMR (400MHz, DMSO-d6) δ12.78(s,1H),7.91(d,1H),7.27(s,1H),4.22(q,2H),4.16(s,3H),2.46(s,3H),1.45(t,3H).

[0359] Step 3: 2-(tert-butyl)-1'-(7-ethoxy-1,3-dimethyl-1H-indazole-5-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidin]-4(7H)-one (Example 14)

[0360]

[0361] To a flask containing compound C11 (1.23 g, 5.0 mmol), EDCI.HCl (1.2 g, 6.25 mmol) and HOPO (0.694 mg, 6.25 mmol) was added acetonitrile (25.0 mL), followed by addition of i Pr 2 NEt (2.18 mL, 2.5 mmol). The mixture was heated to about 50° C. for about 2 h, and then cooled to room temperature. Compound P1 (2.23 g, 5.5 mmol), i Pr 2 NEt (3.48 mL, 4.00 mmol) and water (5.0 mL), and the mixture was heated again to about 50 ° C and maintained for about 2 h, then stirred at room temperature for about 16 h. The reaction mixture was diluted with EtOAc (150 mL) and washed with water (2 x 100 mL). The aqueous layer was back-extracted with EtOAc (50 mL). The combined EtOAc extracts were then washed with 0.25N HCl (2 x 50 mL) and the aqueous layer was back-extracted with EtOAc (50 mL). The saturated NaHCO 3 The combined EtOAc extracts were washed with aqueous solution (2 x 50 mL) and the aqueous layer was back extracted with EtOAc (50 mL). The combined EtOAc extracts were washed with brine (50 mL) and purified by MgSO 4 The mixture was stirred for about 72 hours. The solid was filtered, filtered through diatomite and concentrated to give a light yellow solid (2.47 g, 99%). The solid was dissolved in EtOAc (20 ml) and heated to about 50 ° C and kept for about 10 min, then heptane (200 mL) was added and further heated to about 70 ° C and kept for about 2 h. After cooling to room temperature, the mixture was stirred for about 72 hours. The solid was filtered, washed with frozen pre-mixed 25% EtOAc-heptane (100 mL), and dried in a high vacuum to provide the title compound (2.1 g, 84.9%). 1 H NMR (400MHz, CD 3OD)δ7.31(s,1H),6.82(s,1H),4.23(q,2H),4.21(s,3H),3.80-3.60(m,4H),3.2 5(s,2H),2.73(s,2H),2.49(s,3H),1.68(m,4H),1.52(t,3H),1.43(s,9H); LC / MS m / z(M+H) + =495.1

[0362] Example 15: 2-(tert-butyl)-1'-(8-methyl-3-(methylamino)quinoline-6-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidin]-4(7H)-one

[0363]

[0364] Step 1: Synthesis of ethyl 8-methylquinoline-6-carboxylate (C12)

[0365]

[0366] To a solution of 6-bromo-8-methylquinoline (900 mg, 4.05 mmol) in EtOH (25 mL) was added Pd(OAc) 2 (91mg,0.405mmol), DBU (0.91mL, 6.08mmol), Mo(CO) 6 (588 mg, 2.23 mmol) and TTBP·HBF 4 (118 mg, 0.405 mmol). 2 The mixture was purged for about 1 min, sealed in a microwave tube, and irradiated in a microwave (BiotageSmith synthesizer) at about 120 ° C for about 70 min. The mixture was concentrated under reduced pressure to provide a crude residue. Purification by chromatography (0% to 25% EtOAc in petroleum ether) provided the title compound (800 mg, 92%). LC / MS m / z (M+H) + =215.9.

[0367] Step 2: Synthesis of ethyl 3-bromo-8-methylquinoline-6-carboxylate (C13)

[0368]

[0369] The following reaction was carried out in parallel in 2 batches. Compound C12 (350 mg, 1.63 mmol) was dissolved in CCl 4 Pyridine (0.26 mL, 3.25 mmol) and Br were added to the solution in 1 mL (15 mL). 2(0.10 mL, 1.95 mmol). The resulting solution was stirred at about 70 °C for about 4 h. The mixture was cooled to about 25 °C and poured into H 2 O (20 mL). The mixture was extracted with EtOAc (2× 15 mL) and washed with saturated NaHCO 3 Wash with aqueous solution, pass through Na 2 SO 4 Dried, filtered, and concentrated under reduced pressure.The 2 batches were combined, and the residue was purified by chromatography (0% to 20% EtOAc in petroleum ether) to provide the title compound (500 mg, 26% / reaction). 1 H NMR (400MHz, DMSO-d6)δ=9.08(d,1H),8.91(d,1H),8.49(s,1H),8.10(s,1H),4.39(q,2H),2.74(s,3H),1.38(t,3H); LC / MS m / z(M+H) + =295.8.

[0370] Step 3: Ethyl 3-((tert-butoxycarbonyl)(methyl)amino)-8-methylquinoline-6-carboxylate (C14)

[0371]

[0372] To compound C13 (500 mg, 1.70 mmol) were added tert-butyl methylcarbamate (334 mg, 2.55 mmol), Pd 2 (dba) 3 (78mg,0.085mmol), X-Phos (81mg, 0.17mmol), Cs 2 CO 3 (1.66 g, 5.1 mmol) and toluene (17 mL). 2 The mixture was purged. The mixture was stirred at about 120°C for about 16 h. The mixture was cooled to about 25°C and filtered. The filtrate was concentrated under reduced pressure and diluted with EtOAc (20 mL). 2 O (3 x 5 mL), washed with Na 2 SO 4 Dry, filter, and concentrate under reduced pressure. The residue was purified by chromatography (0% to 30% EtOAc in petroleum ether) to provide the title compound (450 mg, 77%). LC / MS m / z (M+H) + =345.2.

[0373] Step 4: 3-((tert-Butoxycarbonyl)(methyl)amino)-8-methylquinoline-6-carboxylic acid (C15)

[0374]

[0375] To MeOH (12 mL) and H 2 To compound C14 (450 mg, 1.31 mmol) in 2% CO (4.0 mL) was added LiOH . H 2 O (164 mg, 3.92 mmol). The mixture was stirred at about 25 ° C for about 4 h. The reaction mixture was concentrated under reduced pressure and then used for 5 min. 2 0 (10 mL). 1N HCl was added until the pH was 3-4 and the mixture was extracted with EtOAc (2X 20 mL). 2 SO 4 The combined organic phases were dried, filtered, and concentrated under reduced pressure to provide the title compound (400 mg, 97%). 1 H NMR (400MHz, DMSO-d6)δ=9.01(d,1H),8.46(s,1H),8.39(d,1H),8.03(s,1H),3.33(s,3H),2.74(s,3H),1.43(s,9H); LC / MS m / z(M+H) + =317.3.

[0376] Step 5: 8-Methyl-3-(methylamino)quinoline-6-carboxylic acid hydrochloride (C16)

[0377]

[0378] To compound C15 (500 mg, 1.58 mmol) in dioxane (6.0 mL) was added 4N HCl in dioxane (6.0 mL). The solution was stirred at about 25 °C for about 1.5 h and then concentrated under reduced pressure to provide the title compound (399 mg, 100%). LC / MS m / z (M+H) + =217.0.

[0379] Step 6: Synthesis of 2-(tert-butyl)-1'-(8-methyl-3-(methylamino)quinoline-6-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidin]-4(7H)-one (Example 15)

[0380]

[0381] To a solution of compound C16 (200 mg, 0.79 mmol) in DMF (4.0 mL) were added HATU (301 mg, 0.79 mmol) and iPr 2NEt (0.40 mL, 2.31 mmol). The mixture was stirred at about 25 ° C for about 10 min. Compound P1 (208 mg, 0.66 mmol) was then added. The mixture was stirred at about 25 ° C for about 1 h. The residue was concentrated and purified by preparative HPLC (column: Boston Prime C18, 30x150 mm, 5μm; mobile phase A: water (0.05% v / v conc. NH 4 OH); mobile phase B: MeCN; 28-58% B gradient, 9 min, hold at 100% B for 2 min; flow rate: 25 mL / min) to provide the title compound (229 mg, 61%). 1 H NMR (400MHz, CD 3 OD)δ=8.45(d,1H),7.58(d,1H),7.21(dd,1H),7.10(d,1H),3.83(m,2H),3.52(s,2 H),3.25(s,2H),2.89(s,3H),2.73(d,2H),2.69(s,3H),1.70(m,4H),1.43(s,9H). LC / MS m / z(M+H) + =477.3.

[0382] Example 16: 2-(tert-butyl)-1'-(4-methyl-2-naphthoyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidinyl]-4(7H)-one

[0383]

[0384] Step 1: Synthesis of methyl 4-hydroxy-2-naphthoate (C17)

[0385]

[0386] To a solution of 4-hydroxy-2-naphthoic acid (18.8 g, 100 mmol) in MeOH (500 mL) was slowly added concentrated H 2 SO 4 (8.33 mL, 150 mmol), and then the reaction solution was refluxed for about 48 h. The solvent was concentrated under reduced pressure and the residue was diluted with EtOAc (250 mL), washed with water (150 mL) and brine (150 mL) in sequence, and filtered through MgSO 4 Dry, filter, and concentrate to provide a dark brown solid (19.6 g, 96.9%), which was used directly in the next step without further purification; 1H NMR (400 MHz, chloroform-d) δ8.28 (d, 1H), 8.23 ​​(s, 1H), 7.94 (d, 1H), 7.67-7.54 (m, 4H), 4.02 (s, 3H); LC / MS m / z (MH) + =201.1.

[0387] Step 2: Synthesis of methyl 4-(((trifluoromethyl)sulfonyl)oxy)-2-naphthoate (C18)

[0388]

[0389] At about 0°C, methyl 4-hydroxy-2-naphthoate C17 (19.4 g, 96 mmol) was added to CH 2 Cl 2 iPr was added to the solution (480 mL) 2 NEt (83.6 mL, 480 mmol) was added, followed by the slow addition of N-phenyl-bis(trifluoromethanesulfonamide) (45.3 g, 127 mmol) in portions over about 10 min. The mixture was stirred at about 25 °C for about 16 h. The reaction was quenched with 1N HCl (350 mL), and the organic phase was separated. Additional CH 2 Cl 2 The aqueous phase was extracted using saturated Na 2 CO 3 The combined organic phases were washed sequentially with aqueous solution (200 mL) and brine (100 mL), and the mixture was purified by MgSO 4 Dry, filter, and concentrate. The residue was purified by chromatography (silica, EtOAc / hexanes, 0-10%) to provide the title compound as a white solid (30 g, 93% yield); 1 H NMR (400 MHz, chloroform-d) δ8.65 (s, 1H), 8.12 (d, 1H), 8.08-8.01 (m, 2H), 7.78 (t, 1H), 7.69 (t, 1H), 7.56 (dt, 1H), 7.41 (d, 1H), 4.01 (s, 3H); LC / MS m / z (M+H) + =335.1.

[0390] Step 3: Synthesis of methyl 4-methyl-2-naphthoate (C19)

[0391]

[0392] To a solution of methyl 4-(((trifluoromethyl)sulfonyl)oxy)-2-naphthoate C18 (22.4 g, 67 mmol) in dioxane (134 mL) were added potassium carbonate (30.6 g, 221 mmol), trimethylboroxane (25.2 g, 28.1 mL, 210 mmol) and water (3.36 mL, 2.78 mmol). The mixture was degassed and heated using N 2 / Vacuum cycle (3 times) purge, then add Pd(dppf)Cl 2 (1.37 g, 1.68 mmol). The reaction solution was heated to about 60 °C and maintained for about 2 h. The mixture was cooled to about 25 °C and diluted with EtOAc (250 mL). The EtOAc layer was washed with water (100 mL) and brine (100 mL), and then filtered through MgSO 4 Dry, filter, and concentrate. The residue was purified by chromatography (silica, EtOAc / hexanes, 0-5%) to provide the title compound as a white solid (10.2 g, 75% yield); 1 H NMR (400 MHz, chloroform-d) δ8.38 (s, 1H), 7.93 (d, 1H), 7.87 (d, 1H), 7.83 (d, 1H), 7.59-7.39 (m, 2H), 3.92-3.87 (m, 3H), 2.64 (s, 3H); LC / MS m / z (M+H) + =201.1.

[0393] Step 4: Synthesis of 4-methyl-2-naphthoic acid (C20)

[0394]

[0395] To a solution of methyl 4-methyl-2-naphthoate C19 (13.8 g, 68.9 mmol) in THF (230 mL) and methanol (230 mL) was added a premixed solution of LiOH (6.6 g, 276 mmol) in water (138 mL). After about 96 h, the mixture was concentrated and the residue was diluted with 1N NaOH (50 mL). The aqueous phase was extracted with EtOAc (2×50 mL) and the organic layer was discarded. The pH of the aqueous layer was adjusted to 4-5 with concentrated HCl. The resulting suspension was filtered. The solid was dried to provide the title compound (9.6 g, 74.8%). 1 H NMR (400MHz, methanol-d4) δ8.48(s,1H),8.10(d,1H),8.01(d,1H),7.91(s,1H),7.72-7.64(m,1H),7.59(t,1H),2.75(s,3H); LC / MS m / z(MH) + =185.2.

[0396] Step 5: Synthesis of 2-(tert-butyl)-1'-(4-methyl-2-naphthoyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidinyl]-4(7H)-one (Example 16)

[0397]

[0398] To a solution of compound P1 (15.7 g, 50 mmol), 4-methyl-2-naphthoic acid C20 (9.31 g, 50 mmol), EDCI·HCl (14.4 g, 75 mmol) and HOBt (11.9 g, 75 mmol) in DMF (333 mL) was added at about 25°C. i Pr 2 NEt (61 mL, 350 mmol). The mixture was stirred at about 25 °C for about 16 h, then diluted with EtOAc (300 mL). 1N HCl (300 mL), saturated NaHCO 3 The mixture was washed with aqueous solution (200 mL) and brine (200 mL) in that order. 4 The organic phase was dried, filtered, and concentrated. The residue was redissolved in DCM (300 mL) and washed with 5% aqueous LiCl (100 mL). The DCM layer was separated and purified by MgSO 4 Drying afforded a solid. The residue was purified by chromatography (silica, EtOAc / hexanes, 10-86%) to afford the title compound as a white solid (16.9 g, 76% yield); 1 H NMR (400MHz, methanol-d4) δ8.08(d,1H),7.95(d,1H),7.80(s,1H),7.60(m,2H),7.37(s,1H),3.87(m,2H) ,3.55(m,2H),3.27(s,2H),2.75(s,2H),2.74(s,3H),1.79(m,2H),1.65(m,2H),1.45(s,9H); LC / MS m / z(M+H) + =447.2.

[0399] Example 17: 2-(tert-butyl)-1'-(7-methyl-1H-indole-5-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidinyl]-4(7H)-one

[0400]

[0401] To a solution of compound P1 (6.3 g, 20 mmol), 7-methyl-1H-indole-5-carboxylic acid (4.2 g, 24 mmol, commercial supplier PharmaBlock), EDCI·HCl (4.79 g, 25 mmol) and HOBt (3.97 g, 25 mmol) in DMF (100 mL) was added at about 25°C. i Pr 2 NEt (20.9 mL, 120 mmol). The mixture was stirred at about 25 °C for about 16 h, then diluted with EtOAc (200 mL). 5% aqueous LiCl solution (100 mL), saturated NaHCO 3 The resulting mixture was washed with aqueous solution (50 mL) and brine (50 mL) in that order. 4 The organic phase was dried, filtered, and concentrated. The residue was purified by chromatography (silica, 5-100% EtOAc / hexanes, then 0-10% MeOH-EtOAc) to provide the title compound as a white solid (8.0 g, 84% yield); 1 H NMR (400MHz, methanol-d4) δ7.52(s,1H),7.32(d,1H),7.00(s,1H),6.53(d,1H),3.65 (m,4H),3.23(s,2H),2.72(s,2H),2.54(s,3H),1.67(m,4H),1.45(s,9H); LC / MS m / z(M+H) + =436.1.

[0402] Example 18: 2-(tert-butyl)-1'-(3-(ethylamino)-8-methylquinoline-6-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidin]-4(7H)-one

[0403]

[0404] Prepared in the same manner as Example 15 by using tert-butyl ethylcarbamate instead of tert-butyl methylcarbamate in step 3 to give the title compound (353 mg). 1 H NMR (400MHz, CD 3 OD)δ8.46(s,1H),7.56(s,1H),7.20(s,1H),7.11(s,1H),3.86-3.79(m,4H),3.52(m,2H),3.2 5-3.20(m,2H),2.72(s,2H),2.69(s,3H),1.76-1.63(m,4H),1.43(s,9H),1.32(t,3H); LC / MS m / z(M+H)+ =491.2.

[0405] Example 19: 2-(tert-butyl)-1'-(3-methoxy-8-methylquinoline-6-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidin]-4(7H)-one

[0406]

[0407] The preparation was carried out in the same manner as Example 15 by using methanol instead of tert-butyl methylcarbamate in step 3 to give the title compound (56 mg). 1 H NMR (400MHz, CD 3 OD)δ8.63(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.

[0408] Example 20: 2-(tert-butyl)-1'-(3-ethoxy-8-methylquinoline-6-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidin]-4(7H)-one

[0409]

[0410] Prepared in the same manner as Example 15 by using ethanol instead of tert-butyl methylcarbamate in step 3 to give the title compound (2.5 mg). 1 H NMR (400MHz, CD 3 OD)δ8.64(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.

[0411] Example 21: 2-(tert-butyl)-1'-(8-methyl-3-(methylthio)quinoline-6-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidinyl]-4(7H)-one

[0412]

[0413] The reaction mixture was prepared in the same manner as in Example 15 by using 2-methyl-2-thiopseudocurea hemisulfate instead of tert-butyl methylcarbamate and PdCl in step 3. 2 dppf was prepared to provide the title compound (28 mg). 1 H NMR (400MHz, CD 3 OD)δ8.78(d,1H),8.13(d,1H),7.77(s,1H),7.54(s,1H),3.90-3.84(m,2H),3.53(m,2H), 3.28(s,2H),2.78(s,3H),2.76(s,2H),2.66(s,3H),1.79-1.60(m,4H),1.45(s,9H); LC / MS m / z(M+H) + =494.3.

[0414] 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

[0415]

[0416] Step 1: Synthesis of 2-(4-carbamoylphenyl)-6-(dimethylamino)isonicotinic acid (C21)

[0417]

[0418] 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) was added Na 2 CO 3 (64 mg, 0.61 mmol), Pd(PPh 3 ) 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 purged with nitrogen, placed in a microwave, and irradiated at about 100 ° C for about 45 min. The mixture was cooled to about 25 ° C and concentrated under reduced pressure. The aqueous residue was acidified to about pH 5 using 2N HCl and the resulting precipitate was filtered to provide the title compound (78 mg, 68% yield). 1 H NMR (400MHz, CD 3OD)δ8.20(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.

[0419] 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)

[0420]

[0421] In a microwave vial, pyridine (3.0 mL) was added to a solution of compound P1 (50 mg, 0.16 mmol), compound C21 (68 mg, 0.24 mmol) and EDCI (61 mg, 0.32 mmol). The mixture was irradiated in a microwave at about 110 °C for about 30 min. The mixture was concentrated under reduced pressure and purified by preparative HPLC (column: C18-1, 30x150 mm, 5 μm); mobile phase A: water (0.05% v / v conc. NH 4 OH); mobile phase B: MeCN; 30-70% B gradient, 9 min, hold at 100% B for 2 min; flow rate: 30 mL / min) to afford the title compound (21 mg, 24%). 1 H NMR (400MHz, CD 3 OD)δ8.16(d,2H),7.96(d,2H),7.13(s,1H),6.58(s,1H),3.90-3.75(m,2H),3.54(m ,2H),3.26(s,2H),3.21(s,6H),2.76(s,2H),1.80-1.62(m,4H),1.43(s,9H); LC / MS m / z(M+H) + =546.4.

[0422] 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

[0423]

[0424] Prepared in the same manner as Example 22 by using 2-chloro-6-methoxyisonicotinic acid instead of methyl 2-chloro-6-(dimethylamino)isonicotinate in step 1 to provide the title compound (18 mg). 1H NMR (400MHz, CD 3 OD)δ8.23(d,2H),8.01(d,2H),7.54(s,1H),6.77(s,1H),4.06(s,3H),3.49( m,2H),3.30-3.25(m,4H),2.73(s,2H),1.80-1.63(m,4H),1.43(s,9H); LC / MS m / z(M+H) + =533.4.

[0425] Example 24: 2-(tert-butyl)-1'-(5-methyl-1-(methylamino)isoquinoline-7-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidin]-4(7H)-one

[0426]

[0427] Step 1: 3-Bromo-N-(2,2-dimethoxyethyl)-5-methylbenzamide (C22)

[0428]

[0429] To a solution of 2,2-dimethoxyethane-1-amine (1.34 g, 12.8 mmol) in DCM (50 mL) was added triethylamine (1.76 g, 17.4 mmol). The reaction was cooled to about 0 °C and then 3-bromo-5-methylbenzoyl chloride (2.71 g, 11.6 mmol) in DCM (10 mL) was added dropwise. The reaction was warmed to about 30 °C over about 16 h. Water (10 mL) was added and the mixture was extracted with DCM (2×20 mL). The reaction mixture was purified by Na 2 SO 4 The combined organic phases were dried, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to provide the title compound (3.0 g, 85%).

[0430] Step 2: 7-Bromo-5-methylisoquinolin-1(2H)-one (C23)

[0431]

[0432] To compound C22 (3.50 g, 12.3 mmol) was added concentrated H 2 SO 4 (30 mL). The mixture was stirred at about 25 ° C for about 16 h, then heated to about 50 ° C and maintained for about 5 h. The mixture was slowly poured into ice water (200 mL) and then extracted with EtOAc (3X 300 mL). 2 SO 4The combined organic phases were dried, filtered, and concentrated under reduced pressure. The residue was suspended in petroleum ether / EtOAc (50 mL / 20 mL) and stirred at about 25 °C for about 10 min. The solid was collected by filtration to provide a mixture of the title compound and regioisomer 5-bromo-7-methylisoquinolin-1(2H)-one (1.8 g, 76%). LC / MS m / z (M+H) + =238.0.

[0433] Step 3: 5-Methyl-1-oxo-1,2-dihydroisoquinoline-7-carboxylic acid methyl ester (C24)

[0434]

[0435] To compound C23 (regioisomer mixture, 1.00 g, 4.2 mmol) in MeOH (50 mL) was added Pd(dppf)Cl 2 (461 mg, 0.63 mmol) and triethylamine (1.28 g, 12.6 mmol). The mixture was heated to about 80 °C under a CO atmosphere (50 psi) for about 48 h. The mixture was cooled to about 25 °C, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (0% to 30% EtOAc in petroleum ether) to provide the title compound and regioisomer 7-methyl-1-oxo-1,2-dihydroisoquinoline-5-carboxylic acid methyl ester (600 mg, 66%). The reaction mixture was purified by preparative SFC (column: Daicel Chiralpak AD, 30x250 mm, 10 μm; mobile phase A: water (0.1% v / v NH 4 OH); mobile phase B: EtOH; 35% B, flow rate: 80 mL / min) to separate the isomers to provide the title compound (100 mg, 11%). LC / MS m / z (M+H) + =218.0.

[0436] Step 4: 1-Chloro-5-methylisoquinoline-7-carboxylic acid methyl ester (C25)

[0437]

[0438] To compound C24 (100 mg, 0.46 mmol) was added POCl 3 (1.41 g, 9.2 mmol). The mixture was heated to about 100 °C and maintained for about 2 h. The reaction solution was concentrated under reduced pressure and NaHCO 3 (aq) The pH was adjusted to about 8. 2 SO 4The organic phase was dried, filtered, and concentrated under reduced pressure. The residue was purified by chromatography (0% to 50% EtOAc in petroleum ether) to provide the title compound (105 mg, 97%). LC / MS m / z (M+H) + =236.0.

[0439] Step 5: 5-Methyl-1-(methylamino)isoquinoline-7-carboxylic acid methyl ester (C26)

[0440]

[0441] To compound C25 (105 mg, 0.45 mmol) in NMP (5 mL) was added i-Pr 2 NEt (0.39 mL, 2.23 mmol) and methylamine hydrochloride (90 mg, 1.3 mmol). The mixture was stirred at about 110 °C for about 16 h. The solution was cooled to about 30 °C and diluted with water (10 mL). The mixture was extracted with EtOAc (2X 10 mL), and the combined organic phases were washed with Na 2 SO 4 Dry, filter, and concentrate under reduced pressure. The residue was purified by chromatography (0% to 50% EtOAc in petroleum ether) to provide the title compound (50 mg, 49%). LC / MS m / z (M+H) + =231.0.

[0442] Step 6: 5-Methyl-1-(methylamino)isoquinoline-7-carboxylic acid (C27)

[0443]

[0444] To compound C26 (50 mg, 0.22 mmol) in MeOH (5 mL) and water (2 mL) was added LiOH monohydrate (36 mg, 0.87 mmol). The mixture was stirred at about 30 °C for about 16 h. The mixture was concentrated under reduced pressure and cooled to about 0 °C. 1 M HCl (aq) was added to adjust the solution to pH 5. A precipitate was formed and collected by filtration to provide the title compound (28 mg, 60%). LC / MS m / z (M+H) + =217.0.

[0445] Step 7: 2-(tert-butyl)-1'-(5-methyl-1-(methylamino)isoquinoline-7-carbonyl)-5H-spiro[benzo[d]thiazol-6,4'-piperidin]-4(7H)-one

[0446]

[0447] Compound C27 (28 mg, 0.13 mmol) was coupled with compound P1 according to the amidation method A. The product was purified by preparative HPLC (column: Boston Prime C18, 30x150 mm, 5 μm); mobile phase A: water (0.05% v / v conc. NH 4 OH); mobile phase B: MeCN; 29-69% B gradient, 9 min, hold at 100% B for 2 min; flow rate: 25 mL / min) to provide the title compound (40 mg, 64%). 1 H NMR (400MHz, CD 3 OD)δ8.02(s,1H),7.93(d,1H),7.51(s,1H),7.04(d,1H),3.88-3.83(m,2H),3.53(m,1H ),3.27(s,2H),3.06(s,3H),2.75(s,2H),2.62(s,3H),1.78-1.66(m,4H),1.45(s,9H). LC / MS m / z(M+H) + =477.3.

[0448] Example 25: 2-(tert-butyl)-1'-(1-cyclopropyl-5-methylisoquinoline-7-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidin]-4(7H)-one

[0449]

[0450] Prepared in the same manner as Example 24 by using cyclopropylboronic acid instead of methylamine hydrochloride in step 5 to give the title compound (32 mg). 1 H NMR (400MHz, CD 3 OD)δ8.37(s,1H),8.27(d,1H),7.65(d,1H),7.53(s,1H),3.81-3.77(m,2H),3.46(m,2H),3.18(s,2H LC / MS m / z(M+H) + =488.4.

[0451] Example 26: 2-(tert-butyl)-1'-(4-methyl-1-(methylamino)isoquinoline-7-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidin]-4(7H)-one

[0452]

[0453] Step 1: Methyl 1-((tert-Butyloxycarbonyl)(methyl)amino)-4-methylisoquinoline-7-carboxylate (C28)

[0454]

[0455] 1-Chloro-4-methylisoquinoline-7-carboxylate (140 mg, 0.594 mmol), tert-butyl N-methylcarbamate (100 mg, 0.594 mmol), Pd 2 (dba) 3 (27 mg, 0.030 mmol), Cs 2 CO 3 (581 mg, 1.78 mmol) and X-Phos (28 mg, 0.059 mmol) were added toluene (5 mL). The mixture was purged with nitrogen. The mixture was heated to about 110 °C for about 16 h. The solution was concentrated under reduced pressure and the residue was purified by chromatography (0% to 30% EtOAc in petroleum ether) to provide the title compound (15 mg, 8%). LC / MS m / z (M+H-Boc) + =231.1.

[0456] Step 2: 4-Methyl-1-(methylamino)isoquinoline-7-carboxylic acid methyl ester (C29)

[0457]

[0458] 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 was stirred at about 50 °C for about 2 h. The mixture was concentrated under reduced pressure to provide the title compound (10 mg, 96%). LC / MS m / z (M+H) + =231.0.

[0459] Step 3: 4-Methyl-1-(methylamino)isoquinoline-7-carboxylic acid (C30)

[0460]

[0461] To compound C29 (10 mg, 0.043 mmol) in EtOH (4.0 mL) was added NaOH (8.7 mg, 0.217 mmol) and water (4.0 mL). The reaction was stirred at about 50 °C for about 1 h. EtOH was removed under reduced pressure and the mixture was acidified to pH 7 using 2N HCl. The precipitate was filtered and dried in vacuo to provide the title compound (9.4 mg, 100%). LC / MS m / z (M+H) + =217.0.

[0462] Step 3: 2-(tert-butyl)-1'-(4-methyl-1-(methylamino)isoquinoline-7-carbonyl)-5H-spiro[benzo[d]thiazol-6,4'-piperidin]-4(7H)-one

[0463]

[0464] Compound C30 (9 mg, 0.044 mmol) was coupled with compound P1 according to the amidation method C. The product was purified by preparative HPLC (column: Boston Prime C18, 30x150 mm, 5 μm); mobile phase A: water (0.05% v / v conc. NH 4 OH); mobile phase B: MeCN; 32-62% B gradient, 9 min, hold at 100% B for 2 min; flow rate: 25 mL / min) to provide the title compound (2.9 mg, 14%). 1 H NMR (400MHz, CD 3 OD)δ8.17(s,1H),7.89(d,1H),7.72-7.70(m,2H),3.87-3.81(m,2H),3.50(m,2H),3.2 5(s,2H),3.03(s,3H),2.73(s,2H),2.40(s,3H),1.77-1.58(m,4H),1.42(s,9H); LC / MS m / z(M+H) + =477.3.

[0465] Example 27: 2-(tert-butyl)-1'-(1,4-dimethylisoquinoline-7-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidin]-4(7H)-one

[0466]

[0467] Prepared in the same manner as Example 26 by using trimethylboroxane instead of tert-butyl N-methylcarbamate in step 1 to provide the title compound (42 mg). 1H NMR (400MHz, CD 3 OD)δ8.31(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.

[0468] Example 28: 2-(tert-butyl)-1'-(5-methoxy-1-methylisoquinoline-7-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidinyl]-4(7H)-one

[0469]

[0470] Step 1: 5-methoxyisoquinoline-7-carboxylic acid methyl ester (C31)

[0471]

[0472] To methyl 5-bromoisoquinoline-7-carboxylate (1.00 g, 3.76 mmol; prepared as described in International Patent Application WO 2021 / 028806), RockPhos-Pd-G3 (95 mg, 0.113 mmol) and Cs 2 CO 3 (1.22 g, 3.76 mmol) was added MeOH (1.2 g, 37.6 mmol) and dioxane (20 mL). The mixture was heated to about 70 °C and maintained for about 16 h. The mixture was cooled to about 25 °C, filtered, and concentrated under reduced pressure. The residue was purified by chromatography (0% to 40% EtOAc in petroleum ether) to provide the title compound (450 mg, 55%). LC / MS m / z (M+H) + =217.9.

[0473] Step 2: 5-Methoxy-7-(methoxycarbonyl)isoquinoline 2-oxide (C32)

[0474]

[0475] To a solution of compound C31 (450 mg, 2.07 mmol) in DCM (10 mL) was added m-CPBA (429 mg, 2.49 mmol) at about 0° C. The mixture was stirred at about 45° C. for about 16 h. Saturated Na 2 S 2 O3 (aq), followed by addition of saturated Na 2 CO 3 (aq) until pH> 8. The mixture was stirred for about 30 min, then treated with DCM (2×10 mL) and H 2 O (2X 10mL). 2 SO 4 The DCM extracts were dried, filtered, and concentrated under reduced pressure to provide the title compound (450 mg, 93%). LC / MS m / z (M+H) + =234.0.

[0476] Step 3: 1-Chloro-5-methoxyisoquinoline-7-carboxylic acid methyl ester (C33)

[0477]

[0478] To a solution of compound C32 (450 mg, 1.93 mmol) in DCM (10 mL) was added POCl 3 (0.90 mL, 9.65 mmol). The mixture was stirred at about 50 °C for about 2 h and then cooled to about 25 °C. The mixture was concentrated under reduced pressure and NaHCO 3 (aq) until the pH is about 8. The organic phase is separated and 2 SO 4 Dry, filter, and concentrate under reduced pressure. The residue was purified by chromatography (0% to 40% EtOAc in petroleum ether) to provide the title compound (200 mg, 41%). LC / MS m / z (M+H) + =252.0.

[0479] Step 4: 5-methoxy-1-methylisoquinoline-7-carboxylic acid methyl ester (C34)

[0480]

[0481] To a solution of compound C33 (60 mg, 0.24 mmol) and trimethylboroxane (60 mg, 0.24 mmol) in THF (2 mL) was added Pd(dtbpf)Cl 2 (7.8 mg, 0.012 mmol) and Cs 2 CO 3 (155 mg, 0.477 mmol). The mixture was heated to about 70 °C for about 2 h and then concentrated under reduced pressure. The residue was purified by chromatography (0% to 30% EtOAc in petroleum ether) to provide the title compound (40 mg, 73%). LC / MS m / z (M+H) +=232.0.

[0482] Step 5: 5-Methoxy-1-methylisoquinoline-7-carboxylic acid (C35)

[0483]

[0484] To a solution of compound C34 (40 mg, 0.17 mmol) in MeOH (2 mL) and water (1 mL) was added LiOH·H 2 O (15 mg, 0.35 mmol). The mixture was stirred at about 25 °C for about 2 h, then heated to about 50 °C and maintained for about 2 h. The solution was concentrated under reduced pressure and the pH was adjusted to about 5 using 1 M HCl. The resulting precipitate was filtered to provide the title compound (38 mg, 100%). LC / MS m / z (M+H) + =217.9.

[0485] Step 6: 2-(tert-butyl)-1'-(5-methoxy-1-methylisoquinoline-7-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidin]-4(7H)-one (Example 28)

[0486]

[0487] Compound C35 (38 mg, 0.17 mmol) was coupled with compound P1 according to the amidation method A. The product was purified by preparative HPLC (column: Boston Prime C18, 30x150 mm, 5 μm); mobile phase A: water (0.05% v / v conc. NH 4 OH); mobile phase B: MeCN; 29-59% B gradient, 9 min, hold at 100% B for 2 min; flow rate: 30 mL / min) to provide the title compound (24 mg, 28%). 1 H NMR (400MHz, CD 3 OD)δ8.33(d,1H),7.97(d,1H),7.81(s,1H),7.18(s,1H),4.07(s,3H),3.89-3.84(m,2H), 3.54(m,2H),3.26(s,2H),2.93(s,3H),2.75(s,2H),1.79-1.65(m,4H),1.43(s,9H); LC / MS m / z(M+H) + =478.4.

[0488] Example 29: 2-(tert-butyl)-1'-(1-ethyl-5-methoxyisoquinoline-7-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidin]-4(7H)-one

[0489]

[0490] Prepared in the same manner as Example 28 by using triethylborane instead of trimethylboroxane in step 1 to give the title compound (5.0 mg). 1 H NMR (400MHz, CD 3 OD)δ8.37(d,1H),7.98(d,1H),7.85(s,1H),7.18(s,1H),4.07(s,3H),3.91-3.83(m,2H),3.55(m,2 H),3.35-3.31(m,2H),3.27(s,2H),2.75(s,2H),1.80-1.65(m,4H),1.43(s,9H),1.37(t,3H);LC / MS m / z(M+H) + =492.3.

[0491] Example 30: 2-(tert-butyl)-1'-(2-(isopropylamino)quinoline-7-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidin]-4(7H)-one

[0492]

[0493] Step 1: Methyl 2-(isopropylamino)quinoline-7-carboxylate (C36)

[0494]

[0495] At about -70 ° C, 7- (methoxycarbonyl) quinoline 1-oxide (200mg, 0.98mmol) in DCM (15mL) was added dropwise trifluoromethanesulfonic anhydride (304mg, 1.08mmol). The mixture was stirred at about -70 ° C for about 5min, and then a 2M solution of isopropylamine in THF (2.94mL, 5.88mmol) was added dropwise. The mixture was stirred at about -70 ° C for about 5min, and then water (15mL) was added. The layers were separated and the aqueous phase was extracted with DCM (20mL). The combined DCM extracts were washed with brine (2X 10mL) and washed with Na 2 SO 4 Dry, filter, and concentrate under reduced pressure. The residue was purified by chromatography (0% to 40% EtOAc in petroleum ether) to provide the title compound (150 mg, 63%). LC / MS m / z (M+H)+ =245.1.

[0496] Step 2: 2-(Isopropylamino)quinoline-7-carboxylic acid (C37)

[0497]

[0498] To a solution of compound C36 (150 mg, 0.614 mmol) in EtOH (4 mL) and water (4 mL) was added NaOH (123 mg, 3.07 mmol). The mixture was heated to about 50 °C for about 16 h. The mixture was concentrated under reduced pressure and treated with 2M HCl until the pH was about 5. The resulting precipitate was filtered to provide the title compound (135 mg, 96%). LC / MSm / z (M+H) + =231.1.

[0499] Step 3: 2-(tert-butyl)-1'-(2-(isopropylamino)quinoline-7-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidin]-4(7H)-one (Example 30)

[0500]

[0501] Compound C37 (50 mg, 0.22 mmol) was coupled with compound P1 according to the amidation method A. The product was purified by preparative HPLC (column: Boston Prime C18, 30x150 mm, 5 μm); mobile phase A: water (0.05% v / v conc. NH 4 OH); mobile phase B: MeCN; 32-62% B gradient, 9 min, hold at 100% B for 2 min; flow rate: 25 mL / min) to provide the title compound (36 mg, 34%). 1 H NMR (400MHz, CD 3 OD)δ7.83(d,1H),7.68-7.63(m,2H),7.19(dd,1H),6.78(d,1H),4.30(sept,1H),3.88-3.83(m, 2H),3.55(m,2H),3.27(s,2H),2.75(d,2H),1.78-1.66(m,4H),1.45(s,9H),1.28(d,6H); LC / MS m / z(M+H) + =491.4.

[0502] Example 31: 2-(tert-butyl)-1'-(2-(cyclobutylamino)quinoline-7-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidin]-4(7H)-one

[0503]

[0504] Prepared in the same manner as Example 30 by using cyclobutylamine instead of isopropylamine in step 1 to give the title compound (46 mg). 1 H NMR (400MHz, CD 3 OD)δ7.83(d,1H),7.65(d,1H),7.60(s,1H),7.17(d,1H),6.76(d,1H),4.54(m,1H),3.87-3.79(m,2H), 3.52(m,1H),3.26(s,2H),2.73(s,2H),2.46(m,2H),2.04(m,2H),1.82-1.64(m,6H),1.43(s,9H); LC / MS m / z(M+H) + =503.4.

[0505] Example 32: 2-(tert-butyl)-1'-(2-(ethylamino)quinoline-7-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidinyl]-4(7H)-one

[0506]

[0507] The preparation was carried out in the same manner as Example 30 by using ethylamine instead of isopropylamine in step 1 to give the title compound (27 mg). 1 H NMR (400MHz, CD 3 OD)δ7.82(d,1H),7.66(d,1H),7.63(s,1H),7.17(d,1H),6.78(d,1H),3.87-3.81(m,2H),3.5 2-3.46(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.

[0508] Example 33: 2-(tert-butyl)-1'-(5-methoxy-4-methyl-1H-indazole-7-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidinyl]-4(7H)-one

[0509]

[0510] Step 1: Synthesis of 6-bromo-4-methoxy-2,3-dimethylaniline (C38)

[0511]

[0512] To 4-methoxy-2,3-dimethylaniline (500 mg, 3.31 mmol) in MeCN (10 mL) was added NBS (706 mg, 3.97 mmol). The mixture was stirred at about 25 °C for about 2 h. 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 provide the title compound (600 mg, 79%). 1 H NMR (400 MHz, CDCl 3 )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.

[0513] Step 2: Synthesis of 7-bromo-5-methoxy-4-methyl-1H-indazole (C39)

[0514]

[0515] Towards H 2 Concentrated HCl (4 mL) was added to compound C38 (600 mg, 2.61 mmol) in 2% CO (4 mL). The mixture was heated to about 60 °C for about 30 min and then cooled to about 0 °C. NaNO was added dropwise 2 (198 mg, 2.87 mmol) in H 2 O (1mL) and the mixture was stirred at about 0 ° C for about 1 h. Saturated aqueous NaOAc was added to the mixture until the pH was 4-5. A solution of 2-methylpropane-2-thiol (259 mg, 2.87 mmol) in EtOH (7mL) was added. The mixture was slowly warmed to about 25 ° C and stirred for about 16 h. The mixture was diluted with EtOAc (20mL), washed with water (20mL), and washed with brine (20mL). 2 SO 4 The organic phase was dried, 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 h. The mixture was diluted with EtOAc (50 mL), washed with water (50 mL), and washed with brine (50 mL). 2 SO 4The organic phase was dried, filtered, and concentrated under reduced pressure.The residue was purified by chromatography (17% EtOAc in petroleum ether) to provide the title compound (170 mg, 27%). 1 H NMR (400 MHz, CDCl 3 )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.

[0516] Step 3: Synthesis of ethyl 5-methoxy-4-methyl-1H-indazole-7-carboxylate (C40)

[0517]

[0518] To compound C39 in EtOH (5.0 mL) was added Mo(CO) 6 (93 mg, 0.353 mmol), TTBP·HBF 4 (21 mg, 0.0705 mmol), DBU (0.16 mL, 1.06 mmol) and Pd(OAc) 2 (15.8 mg, 0.0705 mmol). The mixture was irradiated in a microwave reactor at about 100° C. for about 1 h, then cooled to about 25° C. The mixture was concentrated under reduced pressure and purified by chromatography (17% EtOAc in petroleum ether) to provide the title compound (70 mg, 42%). 1 H NMR (400 MHz, CDCl 3 )δ=8.11(s,1H),7.78(s,1H),4.51(q,2H),3.96(s,3H),2.57(s,3H),1.51(t,3H); LC / MS m / z(M+H) + =235.0.

[0519] Step 4: Synthesis of 5-methoxy-4-methyl-1H-indazole-7-carboxylic acid (C41)

[0520]

[0521] To compound C40 (70 mg, 0.30 mmol) in MeOH (1.0 mL) and THF (2.0 mL) was added LiOH·H 2 O (38 mg, 0.90 mmol) in H 2 The mixture was stirred at about 25 °C for about 16 h, and then H 2O (10 mL). The mixture was washed with EtOAc (10 mL), and the aqueous phase was then acidified to pH ˜6 using saturated aqueous citric acid. The resulting suspension was filtered and the filter cake was collected to provide the title compound (62 mg, 100%). LC / MS m / z (M+H) + =207.0.

[0522] Step 5: Synthesis of 2-(tert-butyl)-1'-(5-methoxy-4-methyl-1H-indazole-7-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidin]-4(7H)-one (Example 33)

[0523]

[0524] To a solution of compound C41 (62 mg, 0.30 mmol) in DMF (2.0 mL) was added Et 3 N (0.17 mL, 1.2 mmol) and T3P (0.36 mL of a 50% w / w solution in EtOAc, 0.60 mmol). Compound P1 (95 mg, 0.30 mmol) was added. The resulting solution was stirred at about 25 °C for about 16 hours. The mixture was diluted with EtOAc (15 mL), washed with water (15 mL) and brine (15 mL). 2 SO 4 The organic phase was dried, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Boston Green ODS, 30x150mm, 5μm; mobile phase A: water (0.2% v / v conc. HCl); mobile phase B: MeCN; 23-63% B gradient, 9min, hold at 100% B 2min; flow rate: 30mL / min) to provide the title compound (27mg, 19%). 1 H NMR (400MHz, CD 3 OD)δ=8.19(d,1H),7.29(t,1H),3.90(s,3H),3.65(m,4H),3.24(s,2H),2.73(s,2H),2.48(s,3H),1.69(m,4H),1.43(s,9H). LC / MS m / z(M+Na) + =489.1.

[0525] Example 34: 2-(tert-butyl)-1'-(4-chloro-5-methyl-1H-indazole-7-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidinyl]-4(7H)-one

[0526]

[0527] Prepared in the same manner as Example 33 by using 3-chloro-2,4-dimethylaniline instead of 4-methoxy-2,3-dimethylaniline in step 1 to give the title compound (15 mg). 1 H NMR (400MHz, CD 3 OD)δ8.11(s,1H),7.37(s,1H),3.87-3.48(m,4H),3.24(s,2H),2.73(s,2H),2.49(s,3H),1.77-1.58(m,4H),1.43(s,9H); LC / MS m / z(M+H) + =471.3.

[0528] Example 35: 2-(tert-butyl)-1'-(4,5-dimethyl-1H-indazole-7-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidin]-4(7H)-one

[0529]

[0530] Prepared in the same manner as Example 33 by using 2,3,4-trimethylaniline instead of 4-methoxy-2,3-dimethylaniline in step 1 to give the title compound (26 mg). 1 H NMR (400MHz, CD 3 OD)δ8.13(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.

[0531] Example 36: 2-(tert-butyl)-1'-(4-methoxy-5-methyl-1H-indazole-7-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidinyl]-4(7H)-one

[0532]

[0533] Step 1: Synthesis of 4-methoxy-5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (C42)

[0534]

[0535] 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-ol (2.5 g, 10.76 mmol) and K2 CO 3 (2.98 g, 21.5 mmol) was added with DMF (30 mL). The mixture was cooled to about 0-5 ° C and stirred for about 10 min. Iodomethane (1.01 mL, 16.1 mmol) was added dropwise, and the mixture was stirred at about 25 ° C for about 20 h. Water (30 mL) was added and the mixture was extracted with EtOAc (3X 30 mL). The combined EtOAc extracts were washed with saturated brine and filtered through MgSO 4 Dry, filter, and concentrate under reduced pressure. The residue was purified by column chromatography (0-20% EtOAc in petroleum ether) to provide the title compound (2.40 g, 91%). LC / MS m / z (M+H) + =247.0.

[0536] Step 2: Synthesis of 7-bromo-4-methoxy-5-methyl-1H-indazole (C43)

[0537]

[0538] To a solution of compound C42 (2.40 g, 9.74 mmol) in DCM (50 mL) was added pyridinium tribromide (3.43 g, 10.7 mmol). The mixture was stirred at about 25 °C for about 2 h. Water (30 mL) was added and the mixture was extracted with EtOAc (3 x 20 mL). The combined EtOAc extracts were washed with saturated brine and filtered through MgSO 4 Dry, filter, and concentrate under reduced pressure. The residue was purified by column chromatography (0-20% EtOAc in petroleum ether) to provide the title compound (1.90 g, 81%). LC / MS m / z (M+H) + =242.8.

[0539] Step 3: Synthesis of ethyl 4-methoxy-5-methyl-1H-indazole-7-carboxylate (C44)

[0540]

[0541] To a solution of compound C43 (1.20 g, 3.0 mmol) in EtOH (20 mL) was added Pd(OAc) 2 (54 mg, 0.239 mmol), tBu 3 P.BF 4 (87 mg, 0.30 mmol), DBU (682 mg, 4.48 mmol) and Mo(CO) 6(237 mg, 0.90 mmol). The mixture was irradiated in a microwave at 100 °C for 30 min. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (0-30% EtOAc in petroleum ether) to provide the title compound (450 mg, 64%). LC / MS m / z (M+H) + =235.0.

[0542] Step 4: Synthesis of 4-methoxy-5-methyl-1H-indazole-7-carboxylic acid (C45)

[0543]

[0544] To a solution of compound C44 (700 mg, 2.99 mmol) in EtOH (5 mL) was added NaOH (598 mg, 14.9 mmol) and water (5 mL). The mixture was stirred at about 50 °C for about 16 h. The mixture was concentrated under reduced pressure and the residue was acidified to pH 5 using 2N HCl. The precipitate was filtered to provide the title compound (580 mg, 94%). LC / MS m / z (M+H) + =206.9.

[0545] Step 5: Synthesis of 2-(tert-butyl)-1'-(4-methoxy-5-methyl-1H-indazole-7-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidinyl]-4(7H)-one

[0546]

[0547] Compound C45 (300 mg, 1.45 mmol) was coupled with compound P1 according to the amidation method A. The product was purified by preparative HPLC (column: Boston Prime C18, 30x150 mm, 5 μm); mobile phase A: water (0.05% v / v conc. NH 4 OH); mobile phase B: MeCN; 30-60% B gradient, 9 min, hold at 100% B for 2 min; flow rate: 30 mL / min) to provide the title compound (345 mg, 51%). 1 H NMR (400MHz, CD 3 OD)δ8.32(s,1H),7.28(s,1H),4.25(s,3H),3.69(m,4H),3.24(s,2H),2.73(s,2H),2.29(s,3H),1.68(m,4H),1.43(s,9H); LC / MS m / z(M+H) + =467.4.

[0548] Example 37: 2-(tert-butyl)-1'-(4-chloro-5-methoxy-1H-indole-7-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidinyl]-4(7H)-one

[0549]

[0550] Step 1: Synthesis of 1-bromo-4-chloro-5-methoxy-2-nitrobenzene (C46)

[0551]

[0552] To 4-bromo-1-chloro-2-methoxybenzene (1.00 g, 4.52 mmol) was added H 2 SO 4 (3 mL), and the mixture was cooled to about 0 °C and stirred for about 10 min. HNO 3 (0.43 mL, 11.3 mmol). The mixture was slowly warmed to about 20° C. over about 16 h. The mixture was poured onto ice water and Na 2 CO 3 Adjust to pH 7-9. The mixture was extracted with EtOAc (3×200 mL), and the combined EtOAc extracts were subjected to Na 2 SO 4 Dried, filtered, and concentrated under reduced pressure.The residue was purified by column chromatography (0-2% EtOAc in DCM) to provide the title compound and dinitration byproduct 2-bromo-5-chloro-4-methoxy-1,3-dinitrobenzene (1.10 g, <91% yield). 1 H NMR (400 MHz, CDCl 3 )δ8.10(s,1H),7.22(s,1H),4.01(s,3H).

[0553] Step 2: Synthesis of 7-bromo-4-chloro-5-methoxy-1H-indole (C47)

[0554]

[0555] To compound C46 (1.10 g, about 20% purity, 0.83 mmol) in THF (10 mL) at about -50 °C was added vinylmagnesium bromide (1 M, 15 mL, 15 mmol). The mixture was warmed to about -20 °C and stirred for about 16 h. The mixture was warmed to 0 °C and NH 4 Cl (30 mL) and EtOAc (50 mL). The phases were separated and the aqueous phase was extracted with EtOAc (3 x 20 mL). The combined EtOAc extracts were washed with brine (20 mL) and washed with Na 2 SO4 Dry, filter, and concentrate under reduced pressure. The residue was purified by column chromatography (5% EtOAc in petroleum ether) to provide the title compound (30 mg, 14% yield). LC / MS m / z (M+H) + =261.8.

[0556] Step 3: Synthesis of ethyl 4-chloro-5-methoxy-1H-indole-7-carboxylate (C48)

[0557]

[0558] To a solution of compound C47 (50 mg, 0.19 mmol) in EtOH (10 mL) was added Pd(OAc) 2 (3.5 mg, 0.0154 mmol), tBu 3 P.BF 4 (5.6 mg, 0.0192 mmol), DBU (44 mg, 0.288 mmol) and Mo(CO) 6 (51 mg, 0.192 mmol). The mixture was irradiated in a microwave at about 100 °C for about 1 h. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (0-2% EtOAc in petroleum ether) to provide the title compound (20 mg, 41%). LC / MS m / z (M+H) + =254.0.

[0559] Step 4: Synthesis of 4-chloro-5-methoxy-1H-indole-7-carboxylic acid (C49)

[0560]

[0561] To a solution of compound C48 (20 mg, 0.079 mmol) in water (1 mL) and THF (2 mL) was added LiOH·H 2 O (6.6 mg, 0.16 mmol). The mixture was stirred at about 50 °C for about 16 h. The mixture was concentrated under reduced pressure and the residue was acidified to pH 5 using 2N HCl. The solution was concentrated to provide the title compound (15 mg, 84%). LC / MS m / z (M+H) + =225.9.

[0562] Step 5: Synthesis of 2-(tert-butyl)-1'-(4-chloro-5-methoxy-1H-indole-7-carbonyl)-5H-spiro[benzo[d]thiazol-6,4'-piperidin]-4(7H)-one

[0563]

[0564] Compound C49 (15 mg, 1.45 mmol) was coupled with compound P1 according to the amidation method A. The product was purified by preparative HPLC (column: Boston Prime C18, 30x150 mm, 5 μm); mobile phase A: water (0.05% v / v conc. NH 4 OH); mobile phase B: MeCN; 40-70% B gradient, 9 min, hold at 100% B for 2 min; flow rate: 30 mL / min) to provide the title compound (4.5 mg, 14%). 1 H NMR (400MHz, CD 3 OD)δ7.35(d,1H),7.00(s,1H),6.52(d,1H),3.90(s,3H),3.89-3.48(m,4H),3.23(s,2H),2.73(s,2H),1.79-1.64(m,4H),1.43(s,9H); LC / MS m / z(M+H) + =486.3.

[0565] Example 38: 2-(tert-butyl)-1'-(5-methyl-2-(methylamino)quinoline-7-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidin]-4(7H)-one

[0566]

[0567] To a solution of compound P1 (1.26 g, 4.01 mmol), compound P2 (581 mg, 2.69 mmol), EDCI (773 mg, 4.04 mmol) and HOBt (582 mg, 4.31 mmol) in DMF (35 mL) was added at about 25°C. i Pr 2 NEt (5 mL, 26.9 mmol). The mixture was stirred at about 25 °C for about 16 h, then diluted with EtOAc. 5% aqueous LiCl solution, saturated NaHCO 3 The mixture was washed with aqueous solution and 1:1 brine:water (30 mL) sequentially. 4 The organic phase was dried, filtered, and concentrated. The residue was purified by column chromatography (0% to 20% MeOH in DCM) to provide the title compound (1.28 g, 86%). 1H NMR(400MHz,DMSO-d6)δ7.99(d,1H),7.31(s,1H),7.07(s,1H),6.96(s,1H),6.81(d,1H),3.75-3.3 5(m,4H),3.23(s,2H),2.91(d,3H),2.66(s,2H),2.54(s,3H),1.60-1.53(m,4H),1.38(s,9H); LC / MS m / z(M+H) + =477.5.

[0568] Example 39: 2-(tert-butyl)-1'-(2-(ethylamino)-5-methylquinoline-7-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidin]-4(7H)-one

[0569]

[0570] Step 1: Synthesis of 7-bromo-N-ethyl-5-methylquinolin-2-amine (C50)

[0571]

[0572] To 7-bromo-2-chloro-5-methylquinoline (prepared as described in patent application WO 2013185103 A1, 50 mg, 0.19 mmol) was added iPr 2 NEt (67 μL, 0.39 mmol), ethylamine (70% aqueous solution, 0.234 mmol) and NMP (0.2 mL). The mixture was heated to about 110 ° C and maintained for about 18 h, then heated to about 140 ° C and maintained for about 24 h. The mixture was cooled to about 25 ° C and diluted with water. The mixture was extracted with diethyl ether (3X). The mixture was filtered through MgSO 4 The combined ether extracts were dried, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (0% to 60% EtOAc in heptane) to provide the title compound (14 mg, 27%). LC / MS m / z (M+H) + =265.2.

[0573] Step 2: Synthesis of 2-(tert-butyl)-1'-(2-(ethylamino)-5-methylquinoline-7-carbonyl)-5H-spiro[benzo[d]thiazol-6,4'-piperidin]-4(7H)-one

[0574]

[0575] To compound C50 (80 mg, 0.30 mmol) was added 2,4,6-trichlorophenyl formate (136 mg, 0.60 mmol) and Xantphos (11 mg, 0.018 mmol). A degassed solution of triethylamine (85 μL, 0.60 mmol) and toluene (0.30 mL) was added. The mixture was heated to about 80 °C and maintained for about 18 h. The mixture was diluted with ether and filtered through diatomaceous earth. The mixture was concentrated under reduced pressure, redissolved in DCM, and filtered through silica. The mixture was concentrated under reduced pressure. THF (0.2 mL), triethylamine (21 μL, 0.15 mmol), compound P1 (25 mg, 0.087 mmol) and DMAP (0.5 mg, 0.004 mmol) were added to the residue. The mixture was stirred at about 50 °C for about 16 h. Water was added and the mixture was extracted with EtOAc (2x). The residue was purified by MgSO 4 The combined EtOAc extracts were dried, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XBridge C18, 19x100 mm, 5 μm) to provide the title compound (27 mg, 18%). LC / MS m / z (M+H) + =491.5.

[0576] Example 40: 2-(tert-butyl)-1'-(5-methoxy-2-(methylamino)quinoline-7-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidin]-4(7H)-one

[0577]

[0578] Step 1: Synthesis of 5-methoxy-7-(methoxycarbonyl)quinoline 1-oxide (C51)

[0579]

[0580] The following reaction was performed in parallel in 2 batches. To methyl 5-methoxyquinoline-7-carboxylate (1.20 g, 4.70 mmol) in DCM (25 mL) was added m-CPBA (972 mg, 5.63 mmol). The mixture was stirred at about 20 °C for about 16 h. The two batches were combined and saturated Na 2 S 2 O 3 Aqueous solution. Add saturated Na 2 CO 3 The aqueous solution was stirred until pH>8, and 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 purified by Na 2 SO4 Dry, filter, and concentrate under reduced pressure. The residue was purified by column chromatography (0% to 15% MeOH in EtOAc) to provide the title compound (1.90 g, 95% average yield). LC / MS m / z (M+H) + =233.9.

[0581] Step 2: Synthesis of methyl 5-methoxy-2-(methylamino)quinoline-7-carboxylate (C52)

[0582]

[0583] To compound C51 (1.20 g, 5.15 mmol) in DCM (30 mL) was added Tf dropwise at about -70 °C. 2 O (1.60 g, 5.66 mmol). The mixture was stirred at -70 °C for about 15 min, and then MeNH 2 (2M in THF, 20.6 mL, 41.2 mmol). The mixture was stirred at about -70 °C for about 15 min, then water (30 mL) was added. The aqueous phase was extracted with DCM (30 mL). The combined DCM extracts were washed with brine (2X 10 mL) and washed with Na 2 SO 4 Dry, filter, and concentrate under reduced pressure. The residue was purified by column chromatography (0% to 60% EtOAc in petroleum ether) to provide the title compound (800 mg, 63% yield). LC / MS m / z (M+H) + =247.0.

[0584] Step 3: Synthesis of 5-methoxy-2-(methylamino)quinoline-7-carboxylic acid (C53)

[0585]

[0586] To compound C52 (800 mg, 3.25 mmol) in EtOH (6 mL) was added NaOH (650 mg, 16.2 mmol) and water (6 mL). The reaction was stirred at about 50 °C for about 2 h. Ethanol was removed under reduced pressure and the residue was acidified to pH 5 using 2N HCl. The precipitate was filtered to provide the title compound (730 mg, 97% yield). LC / MS m / z (M+H) + =232.9.

[0587] Step 4: Synthesis of 2-(tert-butyl)-1'-(5-methoxy-2-(methylamino)quinoline-7-carbonyl)-5H-spiro[benzo[d]thiazol-6,4'-piperidin]-4(7H)-one

[0588]

[0589] Compound C53 (300 mg, 1.29 mmol) was coupled according to the general amide coupling procedure A. The product was purified by preparative HPLC (column: Boston Prime C18, 30x150 mm, 5 μm); mobile phase A: water (0.05% v / v conc. NH 4 OH); mobile phase B: MeCN; 28-58% B gradient, 9 min, hold at 100% B for 2 min; flow rate: 30 mL / min) to provide the title compound (259 mg, 41%). 1 H NMR (400MHz, CD 3 OD)δ8.14(d,1H),7.25(s,1H),6.72(d,1H),6.66(s,1H),3.97(s,3H),3.88-3.79(m,2H), 3.55(m,2H),3.26(s,2H),2.99(s,3H),2.74(s,2H),1.77-1.65(m,4H),1.43(s,9H); LC / MS m / z(M+H) + =493.4.

[0590] Example 41: 2-(tert-butyl)-1'-(4-methoxy-8-methylquinoline-6-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidinyl]-4(7H)-one

[0591]

[0592] Step 1: Synthesis of 6-bromo-4-methoxy-8-methylquinoline (C54)

[0593]

[0594] To 6-bromo-4-chloro-8-methylquinoline (2.67 g, 9.9 mmol) in MeOH (30 mL) was added sodium methoxide (2.61 g, 48.3 mmol). The mixture was stirred at about 80 °C for about 48 h. The mixture was cooled to about 25 °C and diluted with EtOAc. The mixture was washed with water (2x) and brine. The mixture was purified by Na 2 SO 4 The combined EtOAc extracts were dried, filtered, and concentrated under reduced pressure to provide a 1:1 mixture of 6-bromo-4-chloro-8-methylquinoline and the title compound (2.50 g). LC / MS m / z (M+H) + =254.2.

[0595] Step 2: Synthesis of methyl 4-methoxy-8-methylquinoline-6-carboxylate (C55)

[0596]

[0597] To a solution of compound C54 (3.06 g, 12.2 mmol) in MeOH (100 mL) were added triethylamine (5.5 mL, 39 mmol) and Pd(dppf)Cl 2 (720 mg, 0.882 mmol). The mixture was added to a Parr reactor, flushed with nitrogen (3X), and flushed with CO (3X). The mixture was stirred at about 80°C and 75 PSI CO for about 16 h. The mixture was cooled to about 25°C and filtered through celite. The filtrate was concentrated under reduced pressure and then purified by column chromatography (0% to 100% EtOAc in heptane) to provide the title compound (1.96 g, 70%). LC / MS m / z (M+H) + =232.5.

[0598] Step 3: Synthesis of 4-methoxy-8-methylquinoline-6-carboxylic acid (C56)

[0599]

[0600] To a solution of compound C55 (1.96 g, 8.48 mmol) in THF (65 mL) was added 2M NaOH (25 mL, 50 mmol). The mixture was stirred at about 25 °C for about 18 h. The mixture was acidified to pH 6 using concentrated HCl. The mixture was extracted with EtOAc (2X) and the combined EtOAc extracts were washed with brine and washed with Na 2 SO 4 Dry, filter, and concentrate under reduced pressure to provide the title compound (1.46 g, 79%). LC / MS m / z (M+H) + =218.0.

[0601] Step 4: Synthesis of 2-(tert-butyl)-1'-(4-methoxy-8-methylquinoline-6-carbonyl)-5H-spiro[benzo[d]thiazol-6,4'-piperidin]-4(7H)-one

[0602]

[0603] To a solution of compound P1 (325 mg, 1.03 mmol), compound C56 (264 mg, 1.22 mmol), EDCI (243 mg, 1.27 mmol) and HOBt (263 mg, 1.80 mmol) in DMF (5 mL) was added at about 25°C. iPr 2 NEt (1.0 mL, 5.6 mmol). The mixture was stirred at about 25 °C for about 16 h. Additional EDCI (225 mg, 1.17 mmol), HOBt (198 mg, 1.40 mmol) and Et 3 N (0.72 mL, 5.2 mmol). The mixture was stirred at about 25 °C for about 2 h and then diluted with EtOAc. 5% aqueous LiCl solution, saturated NaHCO 3 The mixture was washed with aqueous solution and 1:1 brine:water. 4 The organic phase was dried, filtered, and concentrated under reduced pressure.The residue was purified by column chromatography (0% to 8% MeOH in DCM) to provide the title compound (435 mg, 88%). 1 H NMR(400MHz,DMSO-d6)δ8.82(d,1H),7.98(s,1H),7.60(s,1H),7.11(d,1H),4.06(s,3H),3.6 6-3.41(m,4H),3.23(s,2H),2.72(s,3H),2.66(s,2H),1.62-1.51(m,4H),1.38(s,9H); LC / MS m / z(M+H) + =478.5.

[0604] Example 42: 2-(tert-butyl)-1'-(3-chloro-7-methyl-1H-indole-5-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidinyl]-4(7H)-one

[0605]

[0606] Step 1: Synthesis of ethyl 3-chloro-7-methyl-1H-indole-5-carboxylate (C61)

[0607]

[0608] To a solution of ethyl 7-methyl-1H-indole-5-carboxylate (commercial; 0.45 g, 2.21 mmol) in THF (22 mL) was added NCS (0.5 g, 3.76 mmol). The reaction was stirred at about 25 °C for about 3 h and diluted with EtOAc (20 mL) and water (20 mL). The organic layer was separated and the aqueous layer was extracted with EtOAc (2 x 20 mL). The residue was purified by MgSO 4 The combined EtOAc extracts were dried, filtered, and concentrated under reduced pressure to provide the title compound (380 mg, 72%) as a yellow solid. 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).

[0609] Step 2: Synthesis of 3-chloro-7-methyl-1H-indole-5-carboxylic acid (C62)

[0610]

[0611] To MeOH (9 mL) and H 2 To the compound 3-chloro-7-methyl-1H-indole-5-carboxylic acid ethyl ester C61 (0.38 g, 1.6 mmol) in O (3 mL) was added LiOH·H 2 O (0.2 g, 4.80 mmol). The mixture was heated to about 25 ° C and maintained for about 4 h, and then concentrated. The mixture was diluted with water (6 mL) and extracted with EtOAc (2 x 20 mL); the EtOAc extract was discarded. The pH of the aqueous layer was adjusted to 3-4 with 1N HCl and extracted with EtOAc (2 x 20 mL). The MgSO 4 The combined EtOAc extracts were dried, filtered, and concentrated under reduced pressure to provide the title compound (210 mg, 63%) as a yellow solid. 1 H 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, overlap with d-DMSO).

[0612] Step 3: Synthesis of 2-(tert-butyl)-1'-(3-chloro-7-methyl-1H-indole-5-carbonyl)-5H-spiro[benzo[d]thiazol-6,4'-piperidin]-4(7H)-one

[0613]

[0614] Compound P1 (0.3 g, 0.95 mmol) was coupled with 3-chloro-7-methyl-1H-indole-5-carboxylic acid (0.2 g, 0.95 mmol) according to the amidation method C (EDCI, pyridine, MW). The reaction mixture was purified by preparative HPLC (column: Boston Prime C18, 150x30 mm, 3 μm; mobile phase A: water (0.05% v / v conc. NH 4OH); mobile phase B: MeCN; 9-60% B gradient, 9 min, hold at 100% B for 2 min; flow rate: 25 mL / min) to provide the title compound (170 mg, 34.5%). 1 H NMR(400MHz,DMSO-d6)δ11.56(d,1H),7.60(d,1H),7.36-7.30(m,1H),7.03(d,1H),3.52 (m,4H),3.22(s,2H),2.64(s,2H),2.48(s,3H),1.54(m,4H),1.37(s,9H); LC / MSm / z(M+H) + =470.3.

[0615] Example 43: 2-(tert-butyl)-1'-(4,8-dimethoxyisoquinoline-6-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidinyl]-4(7H)-one

[0616]

[0617] Step 1: Synthesis of ethyl 8-bromoisoquinoline-6-carboxylate (C63)

[0618]

[0619] Isoquinoline-6-carboxylic acid ethyl ester (commercial; 22.6 g, 112.3 mmol) was dissolved in H 2 SO 4 To a solution in 4% paraformaldehyde (200 mL) was added NBS (22 g, 124 mmol) portionwise. The reaction was stirred at about 10 °C for about 16 h. Additional NBS (3 g, 16.9 mmol) was added and the reaction was stirred at about 10 °C for another 16 h. The reaction was quenched by pouring into ice (500 mL), cooled to 0 °C and the pH was adjusted to about 8 using 3N NaOH (500 mL). The reaction mixture was extracted with DCM (2×800 mL), washed with brine (100 mL), and filtered through Na 2 SO 4 Dry, filter, and concentrate under reduced pressure.The residue was purified by chromatography using silica gel [(petroleum ether / DCM=1:1):EtOAc=100:0 to 90:10] to provide the title compound (22.2 g, 70.6%) as a white solid. 1 H NMR (400 MHz, chloroform-d) δ9.69 (s, 1H), 8.72 (d, 1H), 8.54 (t, 1H), 8.45 (d, 1H), 7.79-7.73 (m, 1H), 4.49 (q, 2H), 1.48 (t, 3H); LC / MS m / z (M+H)+ =279.9.

[0620] Step 2: Synthesis of 8-bromo-4-chloroisoquinoline-6-carboxylic acid ethyl ester (C64)

[0621]

[0622] 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 increased to about 60 °C and maintained for another 16 h. The reaction was concentrated and then quenched with EtOAc (50 mL) and saturated NaHCO 3 The mixture was diluted with aqueous solution (20 mL). The layers were separated and the aqueous layer was extracted with EtOAc (3 x 50 mL). The combined EtOAc layers were washed with brine (2 x 30 mL) and washed with Na 2 SO 4 Dry, filter, and concentrate under reduced pressure.The residue was purified by chromatography (0% to 20% EtOAc in petroleum ether) to provide the title compound (0.2 g, 71.2%). 1 H NMR (400 MHz, chloroform-d) δ9.51 (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.

[0623] Step 3: Synthesis of methyl 4,8-dimethoxyisoquinoline-6-carboxylate (C65)

[0624]

[0625] 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), Cs 2 CO 3 (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% to 40% EtOAc in petroleum ether) to provide the title compound (0.09 g, 57%) as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ9.22 (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.

[0626] Step 4: Synthesis of 4,8-dimethoxyisoquinoline-6-carboxylic acid (C66)

[0627]

[0628] To MeOH (3 mL) and H 2 To the compound 4,8-dimethoxyisoquinoline-6-carboxylic acid methyl ester C65 (0.09 g, 0.36 mmol) in O (1 mL) was added LiOH·H 2 O (0.076 g, 1.82 mmol). The reaction mixture was stirred at about 20° C. for about 16 h. The solvent was concentrated and the pH of the residue was adjusted to 3-4 using 1N HCl. The resulting solid was filtered and dried under vacuum to provide the title compound (40 mg, 47%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6) δ13.45(s,1H),9.16(s,1H),8.32(s,2H),7.51(s,1H),4.08(d,6H); LC / MS m / z(M+H) + =233.9.

[0629] Step 5: Synthesis of 2-(tert-butyl)-1'-(4,8-dimethoxyisoquinoline-6-carbonyl)-5H-spiro[benzo[d]thiazole-6,4'-piperidin]-4(7H)-one (Example 43)

[0630]

[0631] Compound P1 (0.06 g, 0.17 mmol) was coupled with 4,8-dimethoxyisoquinoline-6-carboxylic acid (0.04 g, 0.17 mmol) according to the amidation method A. The reaction mixture was purified by preparative HPLC (column: Boston Prime C18, 150x30 mm, 5 μm; mobile phase A: water (0.05% v / v conc. NH 4 OH); mobile phase B: MeCN; 25-55% B gradient, 9 min, hold at 100% B for 2 min; flow rate: 25 mL / min) to provide the title compound (57.4 mg, 68%). 1H NMR (400MHz, methanol-d4) δ9.03(s,1H),8.03(s,1H),7.65(t,1H),7.00(d,1H),3.99(s,6H),3.76 (d,2H),3.39(s,2H),3.16(s,2H),2.63(d,2H),1.68(s,2H),1.52(s,2H),1.32(s,9H); LC / MS m / z(M+H) + =494.4.

[0632] The above amidation method was used in a similar manner to prepare the following compounds of the invention. For those examples characterized by HPLC retention time, the following HPLC conditions were used:

[0633] Method 1

[0634] Column: ACQUITY UPLC BEH C18 50x2.1mm, 1.7μm.

[0635] Mobile phase A: 10 mM ammonium acetate in water / acetonitrile - 95 / 5 v / v.

[0636] Mobile phase B: 10 mM ammonium acetate in acetonitrile / water - 95 / 5 v / v.

[0637] Gradient: 5% D to 100% D in 1 min; hold at 100% D for 0.2 min; then return to 0% D at 1.21 min and hold for 0.29 min. Flow rate: 1.0 mL / min.

[0638] Method 2

[0639] Column: Atlantis dC18 4.6x50mm 5μm.

[0640] Mobile phase A: 0.05% TFA in water (v / v).

[0641] Mobile phase B: 0.05% TFA (v / v) in acetonitrile.

[0642] Gradient: linear change from 95% water / 5% acetonitrile to 5% water / 95% acetonitrile in 4.0 min, hold at 5% water / 95% acetonitrile for 5 min.

[0643] Flow rate: 2mL / min.

[0644] Method 3

[0645] Column: Xbridge C18 2.1×50mm 5μm

[0646] Mobile phase A: 0.0375% TFA in water

[0647] Mobile phase B: 0.01875% TFA in acetonitrile

[0648] Gradient: hold 10% B for 0.5 min, then linearly change to 100% B in 4 min, drop to 10% B at 4.30 min until 4.70 min.

[0649] Flow rate: 0.8mL / min.

[0650] Method 4

[0651] Column: Xbridge C18 2.1×50mm 5μm

[0652] Mobile phase A: 0.0375% TFA in water.

[0653] Mobile phase B: 0.01875% TFA in acetonitrile.

[0654] Gradient: hold 1% B for 0.6 min, then linearly change to 100% B in 4 min, drop to 1% B at 4.30 min until 4.70 min.

[0655] Flow rate: 0.8mL / min.

[0656] Method 5

[0657] Column: Waters Acquity HSS T3, 2.1mmx50mm, 1.7μm.

[0658] Mobile phase A: 0.1% formic acid in water (v / v).

[0659] Mobile phase B: 0.1% formic acid in acetonitrile (v / v).

[0660] Gradient: initial condition is A-95%:B-5%; maintain at initial condition from 0.0-0.1 min; linearly change to A-5%:B-95% within 0.1-1.0 min; maintain at A-5%:B-95% from 1.0-1.1 min; return to initial condition from 1.1-1.5 min.

[0661] Flow rate: 1.25mL / min.

[0662]

[0663]

[0664]

[0665]

[0666]

[0667]

[0668]

[0669]

[0670]

[0671]

[0672]

[0673]

[0674]

[0675] Example 109: rac-(R)-(2-(tert-butyl)-4-hydroxy-4,7-dihydro-5H-spiro[benzo[d]thiazol-6,4'-piperidin]-1'-yl)(7-ethoxy-1,3-dimethyl-1H-indazol-5-yl)methanone

[0676]

[0677] To a solution of Example 14 (100 mg, 0.2 mmol) in MeOH (3.5 mL) was added NaBH 4 (23 mg, 0.6 mmol) and stirred at about 25 °C for about 17 h. The reaction solution was diluted with 10% MeOH-EtOAc (20 mL) and water (20 mL) and the organic layer was separated. The aqueous layer was extracted with EtOAc (2 x 20 mL). MgSO 4 The combined EtOAc extracts were dried, filtered, and concentrated under reduced pressure. The residue was purified by HPLC (column: Xbridge C18, 19x100 mm, 5 μm, mobile phase A: 0.05% TFA (v / v) in water; mobile phase B: 0.05% TFA (v / v) in acetonitrile, gradient time: 10 min) to provide the title compound (67 mg, 68%); 1H NMR (600MHz, DMSO-d6) δ7.27(s,1H),6.77(s,1H),5.35-5.02(m,1H),4.62(t,1H),4.19(q,2H),4.14(s,3H),3.45-3.39(m,4H, heavy with d-DMSO LC / MS m / z(M+H) + =497.3.

[0678] Deuterated analogs of the compound of Example 14

[0679] The metabolite profile of the compound of Example 14 was evaluated in liver microsomes and hepatocytes (mouse, rat, rabbit, dog, monkey and human), recombinant human cytochrome P450 enzymes, recombinant human UGT enzymes and animal plasma (mouse, rat and dog). The metabolite profile of compound XXCAN included oxidation and glucuronidation.

[0680] General methods / reviews for obtaining metabolite profiles of compounds and identifying metabolites of compounds are described in the following references: 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., "Drugmetabolismin drug discovery and development," Acta Pharmaceutica Sinica B, 2018, 8(5), 721-732, https: / / doi.org / 10.1016 / j.apsb.2018.04.003.

[0681] Metabolite profiles of compounds can also be obtained from publicly available and commercially available software tools. Examples of these tools include BioTransformer 3.0 (biotransformer.ca / new), which uses a database of known metabolic reactions to predict metabolic biotransformations of small molecules; Lhasa Meteor Nexus (www.lhasalimited.org / products / meteor-nexus.htm), which uses a variety of machine learning models to predict metabolic pathways and metabolite structures, covering phase I and phase II biotransformations of small molecules.

[0682] The prophetic deuterated analogs 110-122 described below may provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life, reduced dosage requirements, reduced CYP450 inhibition (competitive or time-dependent), or improved therapeutic index or tolerability.

[0683] One skilled in the art may prepare other deuterated analogs of the compound of Example 14. These other deuterated analogs may provide therapeutic advantages similar to those achieved by the non-deuterated analogs.

[0684] Embodiment 110

[0685] 2-tert-Butyl-1'-{7-[(1,1-dideutero)ethyloxy]-1,3-dimethyl-1H-indazole-5-carbonyl}-5H-spiro[[1,3]benzothiazole-6,4'-piperidinyl]-4(7H)-one

[0686]

[0687] Embodiment 111

[0688] 2-tert-Butyl-1'-{7-[(pentadeuterated)ethyloxy]-1,3-dimethyl-1H-indazole-5-carbonyl}-5H-spiro[[1,3]benzothiazole-6,4'-piperidinyl]-4(7H)-one

[0689]

[0690] Embodiment 112

[0691] 1'-{7-[(pentadeuterated ethyloxy]-1,3-bis[(trideuterated)methyl](dideuterated)-1H-indazole-5-carbonyl}-2-[2-(trideuterated)methyl(hexadeuterated)propan-2-yl](dodeuterated)-5H-spiro[[1,3]benzothiazole-6,4'-piperidinyl]-4(7H)-one

[0692]

[0693] Embodiment 113

[0694] 2-tert-Butyl-1'-{7-[(pentadeuterated)ethyloxy]-1,3-bis[(trideuterated)methyl](dideuterated)-1H-indazole-5-carbonyl}-5H-spiro[[1,3]benzothiazole-6,4'-piperidinyl]-4(7H)-one

[0695]

[0696] Embodiment 114

[0697] 2-tert-Butyl-1'-{7-[(1,1-dideutero)ethyloxy]-1,3-bis[(trideutero)methyl]-1H-indazole-5-carbonyl}-5H-spiro[[1,3]benzothiazole-6,4'-piperidinyl]-4(7H)-one

[0698]

[0699] Embodiment 115

[0700] 2-tert-Butyl-1'-{7-ethoxy-1,3-bis[(trideuterated)methyl]-1H-indazole-5-carbonyl}-5H-spiro[[1,3]benzothiazole-6,4'-piperidinyl]-4(7H)-one

[0701]

[0702] Embodiment 116

[0703] 2-tert-Butyl-1'-[7-ethoxy-1-methyl-3-(trideuterated)methyl-1H-indazole-5-carbonyl]-5H-spiro[[1,3]benzothiazole-6,4'-piperidinyl]-4(7H)-one

[0704]

[0705] Embodiment 117

[0706] 2-tert-Butyl-1'-[7-ethoxy-3-methyl-1-(trideuterated)methyl-1H-indazole-5-carbonyl]-5H-spiro[[1,3]benzothiazole-6,4'-piperidinyl]-4(7H)-one

[0707]

[0708] Embodiment 118

[0709] 2-tert-Butyl-1'-{7-[(pentadeuterated)ethyloxy]-1,3-bis[(trideuterated)methyl]-1H-indazole-5-carbonyl}-5H-spiro[[1,3]benzothiazole-6,4'-piperidinyl]-4(7H)-one

[0710]

[0711] Embodiment 119

[0712] 1'-{7-[(pentadeuterated)ethyloxy]-1,3-bis[(trideuterated)methyl]-1H-indazole-5-carbonyl}-2-[2-(trideuterated)methyl(hexadeuterated)propan-2-yl]-5H-spiro[[1,3]benzothiazole-6,4'-piperidin]-4(7H)-one

[0713]

[0714] Embodiment 120

[0715] 1'-{7-[(pentadeuterated)ethyloxy]-1,3-bis[(trideuterated)methyl]-1H-indazole-5-carbonyl}-2-[2-(trideuterated)methyl(hexadeuterated)propan-2-yl](5,5-dideuterated)-5H-spiro[[1,3]benzothiazole-6,4'-piperidinyl]-4(7H)-one

[0716]

[0717] Embodiment 121

[0718] 1'-{7-[(pentadeuterated)ethyloxy]-1,3-bis[(trideuterated)methyl]-1H-indazole-5-carbonyl}-2-[2-(trideuterated)methyl(hexadeuterated)propan-2-yl]-5H-spiro[[1,3]benzothiazole-6,4'-piperidin]-4(7H)-one

[0719]

[0720] Embodiment 122

[0721] 2-tert-Butyl-1'-(7-ethoxy-1,3-dimethyl-1H-indazole-5-carbonyl)(5,5-dideutero)-5H-spiro[[1,3]benzothiazole-6,4'-piperidinyl]-4(7H)-one

[0722]

[0723] Biological solutions

[0724] The use of compounds of the invention in treating and / or preventing acne vulgaris in patients can be demonstrated by activity in the following in vitro assays. These assays also provide a means by which the activity of compounds of the invention can be compared with the activity of other known compounds.

[0725] Direct inhibition of ACC1 activity

[0726] The ACC inhibitory activity of the compounds of the invention was confirmed by a method based on standard procedures. A preparation of recombinant human ACC1 (rhACC1) (SEQ ID NO. 1) was used to determine the direct inhibition of ACC1 by the compounds of the invention.

[0727] Preparation of rhACC1

[0728] Two liters of SF9 cells infected with recombinant baculovirus containing full-length human ACC1 cDNA were suspended in ice-cold lysis buffer (25 mM Tris, pH 7.5; 150 mM NaCI; 10% glycerol; 5 mM imidazole (EMD Bioscience; Gibbstown, NJ); 2 mM TCEP (BioVectra; Charlottetown, Canada); Benzonase nuclease (10000 U / 100 g cell slurry; Novagen; Madison, Wl); EDTA-free protease inhibitor cocktail (1 tab / 50 ml; Roche Diagnostics; Mannheim, Germany)). Cells were lysed by 3 freeze-thaw cycles and centrifuged at 40,000X g for 40 minutes (4°C). The supernatant was directly loaded onto a HisTrap FF crude column (GE Healthcare; Piscataway, NJ) and eluted using an imidazole gradient up to 0.5 M in 20 column volumes (CV). The ACC1 fractions were pooled and diluted 1:5 using 25mM Tris (pH 7.5), 2mM TCEP, 10% glycerol, and directly loaded on a CaptoQ (GE Healthcare) column and eluted in 20CV using a NaCl gradient up to 1M. The phosphate group was removed from the purified ACC1 by incubation with λ phosphatase (100U / 10μM target protein; New England Biolabs; Beverly, MA) for 14 hours at 4°C; okadaic acid (1μM final concentration; Roche Diagnostics) was added to inhibit phosphatase. Purified ACC1 was exchanged to 25mM Tris (pH 7.5), 2mM TCEP, 10% glycerol, 0.5M NaCl at 4°C by 6-hour dialysis. Aliquots were prepared and frozen at -80°C.

[0729] Measurement of rhACC1 inhibition

[0730] rhACC1 was analyzed using the Transcreener ADP Detection FP Assay Kit (Bellbrook Labs, Madison, Wisconsin) in Corning #3820 (Corning, Tewksbury, MA) 384-well plates using the manufacturer's recommended conditions for a 50 μM ATP reaction. Final assay conditions were 50 mM HEPES (pH 7.2), 10 mM MgCl 2, 7.5 mM tripotassium citrate, 2 mM DTT, 0.1 mg / mL BSA, 30 μM acetyl-CoA, 50 μM ATP, and 10 mM KHCO 3 Typically, 10 μM reactions were run for 60 min at room temperature, and 10 μl of Transcreener stop and detection buffer was added and the combination was incubated overnight (18 hours) at room temperature. Data were acquired on an Envision fluorescence reader (PerkinEImer) using a 620 excitation Cy5 FP universal dual mirror, a 620 excitation Cy5 FP filter, a 688 emission (S) and a 688 (P) emission filter.

[0731] Table 1

[0732]

[0733]

[0734]

[0735]

[0736]

[0737]

[0738]

[0739]

[0740]

[0741]

[0742]

[0743]

[0744]

[0745] Gives the geometric mean IC 50 , number of repetitions n ≥ 2, unless marked with the symbol "*" (n = 1); NA = not available

[0746] High-content imaging analysis to quantify lipid droplets in a human sebocyte cell line

[0747] One week before cell dosing, SZ95 human sebocytes were thawed and grown in T175 tissue culture flasks containing 50 mL of culture medium. The following culture medium was prepared: Sebomed basal medium containing stabilized glutamine and without phenol red (Sigma; catalog number: F8205), 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 1X penicillin / streptomycin (Thermo Fisher; catalog number: 15140-122). Cells were cultured at 37°C and the culture medium was changed every 48-72 hours until the start of the analysis. Compounds were delivered to 384-well assay plates (PerkinElmer; Catalog No. 6057308) in 75 nL spots by Echo550 (Labcyte) and 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%. SZ-95 cells were washed with Dulbecco's phosphate buffered saline (DPBS, Lonza; Catalog No. 17-512Q) and then stripped using 0.25% trypsin-EDTA (Gibco; Catalog No. 25200056). Growth medium (25 mL) was added to the flask and the cells were further diluted to 1.33 x 10^5 cells / mL. SZ-95 cells were plated at a density of 10,000 cells / well in 75 μL and incubated at 37°C for 48 hours. Using Biomek FX (Beckman), 25 μL of medium was removed and the cells were fixed by adding 18.7 μL of 16% paraformaldehyde (Electron Microscopy Sciences; Catalog No.: 50980488). After incubation at room temperature for 30 minutes, the plate was washed twice with 75 μl DPBS. After the second wash, all remaining DPBS was removed. A staining solution was prepared in DPBS using 2 μM Bodipy (Invitrogen; Catalog No.: D3922, diluted 1:1000) and Hoechst (Life Technologies; Catalog No.: H3570, diluted 1:2000). Using Biomek FX, 30 μL of staining solution was added to each well. The cells were incubated at room temperature for 20 minutes and then washed once with 75 μL DPBS.Finally, 30 μL of DPBS was added to each well and the plate was sealed using a light shielding film. Plates were read on Opera Phenix (PerkinElmer) for high content imaging. Cell nuclei were detected by Hoechst staining and lipid droplets were detected by Bodipy (which stains neutral lipids). Active compounds can reduce the number and area of ​​lipid droplets. The percentage (%) effect at each compound concentration was calculated using a 4-parameter logistic dose-response equation by Genedata Screener analysis operation, and the 50% inhibitory concentration (IC50) was determined based on and relative to the amount of lipid droplets in the positive and negative control wells contained in each assay plate.

[0748] Table 2

[0749]

[0750]

[0751]

[0752]

[0753]

[0754]

[0755]

[0756]

[0757]

[0758]

[0759]

[0760]

[0761]

[0762] Gives the geometric mean IC 50 , the number of repetitions n ≥ 2, unless marked with the symbol "*", then n = 1; NA = cannot be obtained

[0763] Radiometric Measurement of De Novo Lipid Production in Cultured Human Sebocytes

[0764] The cells were cultured in a 4% flask containing 10% heat-inactivated fetal bovine serum (Gibco, 10100-147), 1% penicillin / streptomycin (Gibco, 15070-063), 1 mM calcium chloride (Fisher, BP9742-10X5), and 5 ng / mL recombinant human epidermal growth factor (Gibco, PHG0311). SZ95 sebocytes were grown in human sebocyte growth medium (HSGM) with basal medium (Sigma-Aldrich, F8205). At 90% confluence, cells were washed with PBS and then stripped using 0.05% trypsin-EDTA (Gibco, 25300054). Prior to starting the analysis, cells were centrifuged and resuspended in HSGM containing 5% charcoal stripped serum (Life Technologies, 12676-029) instead of 10% heat-inactivated fetal bovine serum. Cells were plated at 0.25×10 6 Cells were added to 24-well plates at a density of 10 cells / well and incubated overnight at 37°C to allow cells to adhere to the culture plates. Cells were then treated with a dose response of the compound (30, 1, 0.03, 0.006, 0.0009, 0.0002, and 0.00003 μM) and each concentration was tested twice. Briefly, the compound was dissolved in a DMSO stock solution and diluted 1:1000 into HSGM containing charcoal stripping medium. Vehicle control wells were treated with 0.1% DMSO. After pre-incubation with compound or vehicle at 37°C for 1 hour, 0.25 μCi 14 C sodium acetate (American Radiolabeled Chemicals: ARC, 0173A) was added to each well. The plate was incubated for another two 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 14 C-sodium acetate. Seal the plates and store at -20°C until analysis. To induce lysis, add 125 μL of mammalian protein extraction reagent (MPER; Fisher, 78501) to each well. Shake the plates at room temperature for 1 hour and transfer the lysate to each 2 mL polypropylene tube. Each well is then washed with 175 μL of PBS added to the lysate. Add a chloroform:methanol solution (1:1 v / v, 450 μL) to each tube. Vortex all tubes for 10 seconds and centrifuge at 14,000xg for 5 minutes at room temperature to separate the aqueous and organic phases. Take a 25 μL aliquot from the bottom organic layer of each sample and add it to 6 mL of Optiphase Supermix scintillation fluid (PerkinElmer, 1200-439). Evaluation by scintillation counting 14 C count. DNL (incorporated into lipids 14IC counts) are expressed as the percentage of compound-treated cells relative to vehicle control. IC was determined using nonlinear regression (four parameters with variable slope) in GraphPad Prism. 50 value.

[0765] Table 3.

[0766]

[0767]

[0768]

[0769] Gives the geometric mean IC 50 , the repetition number n≥2, unless marked with the symbol "*", then n=1.

Claims

1. A compound of formula (I) having the following structure: or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or the pharmaceutically acceptable salt, wherein: R is selected from: H, C1-C6 alkoxy, C1-C6 alkyl and -(CH2) m -W, wherein W is a C3-C8 cycloalkyl, a bicycloalkyl, a bridged bicycloalkyl, a phenyl, a 5- or 6-membered heteroaryl or heterocyclyl containing one, two or three heteroatoms selected from N, S and O atoms; wherein each of the alkyl, cycloalkyl, heterocyclyl, phenyl, naphthyl or heteroaryl groups may be unsubstituted or substituted with phenyl, halogen, cyano, deuterium, hydroxyl, 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', wherein R' and R" are independently H, C1-C6 alkyl or C3-C8 cycloalkyl; R1 is selected from: phenyl, naphthyl, 5- or 6-membered heteroaryl or heterocyclic group containing one, two, three or four heteroatoms selected from N, S and O atoms, and 9- or 10-membered bicyclic aromatic group, 9- or 10-membered heteroaryl or heterocyclic group containing one, two or three heteroatoms selected from N, S and O atoms; wherein each of the phenyl, naphthyl, aromatic group, heterocyclic group or heteroaryl group may be unsubstituted or substituted with halogen, cyano, deuterium, hydroxyl, 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", NR'R", -P(O)R'R", or SR', wherein R' and R" are independently H, C1-C6 alkyl or C3-C8 cycloalkyl; and m and n are independently 0, 1, 2 or 3.

2. The compound of claim 1, wherein R is selected from the group consisting of: H, C1-C6 alkyl and -(CH2) m -W, wherein W is a C3-C8 cycloalkyl group, wherein the alkyl group, cycloalkyl group, bicycloalkyl group and bridged bicycloalkyl group are each unsubstituted or substituted with halogen, cyano, deuterium, hydroxyl, C1-C6 alkyl group and C1-C6 alkoxy group; and, m and n are independently 0, 1, 2 or 3.

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

4. The compound of claim 1, wherein R1 is phenyl, pyridyl, indolyl, indazolyl, pyrrolopyridinyl, quinolyl, isoquinolyl or naphthyl; wherein each of the phenyl, pyridyl, indolyl, indazolyl, pyrrolopyridinyl, quinolyl, isoquinolyl or naphthyl is unsubstituted or substituted with halogen, cyano, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, phenyl, -CONR'R", NR'R", or SR', wherein R' and R" are independently H, C1-C6 alkyl or C3-C8 cycloalkyl; and m and n are independently 0, 1, 2 or 3.

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

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

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

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

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

10. The compound of claim 1, wherein the compound is 2-(tert-butyl)-1'-(4-methyl-2-naphthoyl)-5H-spiro[benzo[d]thiazol-6,4'-piperidin]-4(7H)-one; or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or the pharmaceutically acceptable salt thereof.

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

12. A method for treating a disease or condition selected from the following, comprising administering to a subject in need thereof a therapeutically effective amount of a compound as described in claims 1 to 10 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of the compound or salt: inflammation, autoimmune disease, neuroinflammation, arthritis, rheumatoid arthritis, spondyloarthropathies, systemic lupus erythematosus, lupus nephritis, osteoarthritis, gouty arthritis, pain, fever, pulmonary sarcoidosis, silicosis, cardiovascular disease, atherosclerosis, myocardial infarction, thrombosis, congestive heart failure and cardiac reperfusion injury, cardiomyopathy, stroke, ischemia, reperfusion injury, cerebral edema, brain trauma, neurodegeneration, liver disease, inflammatory bowel disease, Crohn's disease, ulcerative colitis, Nephritis, retinitis, retinopathy, macular degeneration, glaucoma, diabetes (type 1 and type 2), diabetic neuropathy, viral and bacterial infections, myalgia, endotoxic 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, skin flushing, eczema, psoriasis, atopic dermatitis, sunburn, keloid, hypertrophic scars, rheumatic diseases, urticaria, discoid lupus, cutaneous lupus, central nervous system lupus, psoriatic arthritis, asthma, allergic asthma, type I Interferonopathy (including Ecardi-Gutierrez syndrome and other Mendelian diseases with overexpression of type I interferons), primary progressive multiple sclerosis, relapsing-remitting multiple sclerosis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, scleroderma, alopecia areata, cicatricial alopecia, prurigo, prurigo nodularis, CPUO, lichen disease, lichen planus, Stevens-Johnson syndrome, spondylosis, myositis, vasculitis, pemphigus, lupus, major depressive disorder, allergy, dry eye syndrome, transplant rejection, cancer, septic shock, cardiopulmonary dysfunction, acute respiratory disease, ankylosing spondylitis, cachexia, chronic graft-versus-host disease, acute graft-versus-host disease, celiac disease, idiopathic thrombocytopenic thrombotic purpura, thrombotic platelet Reductive purpura, myasthenia gravis, Sjögren's syndrome, epidermal hyperplasia, cartilage inflammation, bone degeneration, juvenile arthritis, juvenile rheumatoid arthritis, oligoarticular juvenile rheumatoid arthritis, polyarticular juvenile rheumatoid arthritis, systemic juvenile rheumatoid arthritis, juvenile ankylosing spondylitis, juvenile enteropathic arthritis, juvenile Rett syndrome, SEA syndrome, juvenile dermatomyositis, juvenile psoriatic arthritis, juvenile scleroderma, juvenile systemic lupus erythematosus, juvenile vasculitis, oligoarticular rheumatoid arthritis, polyarticular rheumatoid arthritis, systemic rheumatoid arthritis, enteropathic arthritis, reactive arthritis, Rett syndrome, myositis, polymyositis, dermatomyositis, polyarteritis nodosa,Wegener's granulomatosis, arteritis, polymyalgia rheumatica, 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, plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, immune disorders associated with or caused by pathogenic lymphocyte activity, noninfectious uveitis, Behcet's disease, and Vogt-Koyanagi-Harada syndrome.

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

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

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

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

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

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

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

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

21. Use of a compound as claimed in any one of claims 1 to 10 for the preparation of a medicament for the treatment of a condition requiring treatment with an ACC inhibitor.

22. Use of a compound as claimed in any one of claims 1 to 10 for the preparation of a medicament for the treatment of acne.

23. A compound as claimed in any one of claims 1 to 10 for use in the treatment of a condition requiring treatment with an ACC inhibitor.

Images