Novel ACC inhibitors

Abstract

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

Description

[Technical Field]

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

[0002] Acne vulgaris consists of a spectrum of skin lesions, including comedones, inflammatory papules, pustules, nodules, and cysts. The disease is classified as mild, moderate, or severe depending on the severity and anatomical distribution of the lesions. Disease onset typically occurs during puberty due to increased sebum production caused by elevated androgen levels. Approximately 90% of adolescents suffer from acne, with 15% seeking medical treatment. Furthermore, the disease remains prevalent in 23–35% of young adults (aged 18–28). Biologically, acne is considered an inflammatory disease of the pilosebaceous duct and has several distinguishing features, including (a) excessive sebum production, (b) duct obstruction due to abnormal keratinocyte proliferation and desquamation, (c) proliferation of Cutibacterium acnes (C. acnes, formerly known as Propionibacterium acnes), and (d) inflammation. These factors are often interdependent. For example, elevated androgen levels result in epithelial desquamation and hair follicle obstruction, as well as excessive sebum production, which causes the blocked follicles to fill with lipids and form comedones. This excess sebum then serves as a substrate for Propionibacterium acnes bacteria, which metabolize the sebum and release free fatty acids, which promote further bacterial replication and inflammation. Although the pathogenesis of this disorder is multifactorial, acne cannot develop without sebum, as sebum serves as a nutrient source for the acne bacteria (Smith and Thiboutot, J Lipid Research, 49, 271-281 (2008)).

[0003] The current standard of care for acne includes topical treatments for mild to moderate disease and systemic treatments for moderate to severe disease. These current treatments are either only marginally effective or lack a suitable safety profile 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). Hormonal therapy, including oral contraceptives and androgen receptor blockers, is used to treat moderate to severe acne in female patients with moderate effectiveness. Oral antibiotics, including doxycycline, minocycline, tetracycline, and erythromycin, are also moderately effective in treating acne, especially when compared with the resistance patterns of Propionibacterium acnes. However, photosensitivity and gastrointestinal disturbances limit their use (Gannon et al., Family Pract. 2011;60:290-92). Although isotretinoin is highly effective, it has several serious side effects. The drug is highly teratogenic, requiring special caution when prescribing and regular pregnancy testing. Additionally, isotretinoin can cause severe mucocutaneous tolerance problems (e.g., dry skin, eyes, nose, and lips), which can be dose-limiting if not properly managed with palliative care. Isotretinoin treatment is associated with adverse changes in plasma lipids (elevated TG and LDL) and hepatotoxicity (elevated ALT / AST, necessitating liver function testing prior to treatment). Additionally, isotretinoin treatment has been associated with myalgia (elevated CK levels in 50% of patients), ligament calcification, and adverse ocular effects (loss of night vision, loss of color vision, and dry eyes). In extreme cases, isotretinoin has been associated with adverse neurological / psychological effects, including depression, psychosis, and the potential for suicide.

[0004] ACC catalyzes the conversion of acetyl-CoA to malonyl-CoA and plays a crucial role in the regulation of lipid metabolism. ACC is an essential, 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 refer to the synthesis of fatty acids from non-lipid sources. There are two closely related isoforms, ACC1 and ACC2. ACC inhibition has been identified as a potential mechanism for treating type 2 diabetes and obesity (WO2009144554).

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

[0006] Of these lipid classes, triglycerides, wax esters, free fatty acids, and cholesterol esters all contain or are composed of fatty acids. Increased sebum production rates are associated with both the onset and severity of acne (Janiczek-Dolphin et al., Br J. Dermatol. 2010;163:683-688). Human sebaceous glands are known to be capable of de novo fatty acid synthesis (Downie and Kealey, J Invest. Dermatol. 1998;111:199-205), but the relative importance of this pathway within sebocytes versus the use of exogenous circulating fatty acids for sebum biosynthesis has been unknown.

[0007] Therefore, there is a need for a new approach to acne treatment, with a favorable efficacy / safety profile.The present invention provides a new therapeutic approach for treating acne, comprising the use of ACC inhibitor.Therefore, there is a need to provide a new compound that is a potent and selective inhibitor of sebum secretion, with favorable pharmacokinetic properties, and particularly the compound that can be administered topically and is effective for treating acne. Summary of the Invention [Problem to be solved by the invention]

[0008] [Means for solving the problem]

[0009] The present invention provides

[0010] [ka] or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, of formula (Ia and Ib) R is H, C1-C6 alkoxy, C1-C6 alkyl and -(CH2) m-W, where W is a C3-C8 cycloalkyl, bicycloalkyl, bridged bicycloalkyl, phenyl, naphthyl, 5- or 6-membered heteroaryl or heterocyclic containing 1, 2, or 3 heteroatoms selected from the group consisting of N, S, and O atoms, each of said alkyl, cycloalkyl, heterocyclic, phenyl, naphthyl, or heteroaryl may be unsubstituted or substituted with phenyl, halo, cyano, deuterium, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, -SO2-R', -CONR'R'', NR'COR'', -NR'CONR'R'', -NR'CO2R'', -(CH2) n optionally substituted by -SO2-R', -NHSO2-R', -NR''SO2-R', -SO2NR'R'', NR'R'' or SR', where R' and R'' are independently H, C1-C6 alkyl or C3-C8 cycloalkyl; R1 is selected from the group consisting of phenyl, naphthyl, 5- or 6-membered heteroaryl or heterocyclic containing 1, 2, 3, or 4 heteroatoms selected from the group consisting of N, S, and O atoms, and 9- or 10-membered bicyclic aryl, heteroaryl or heterocyclic containing 1, 2, or 3 heteroatoms selected from the group consisting of N, S, and O atoms, each of said phenyl, naphthyl, aryl, heterocyclic, or heteroaryl may be unsubstituted or selected from halo, cyano, deuterium, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, phenyl, -SO2-R', -CONR'R'', NR'COR'', -NR'CONR'R'', -NR'CO2R'', -(CH2) n -SO2-R', -NHSO2-R', -NR''SO2-R', -SO2NR'R'', NR'R'', -P(O)R'R'',

[0011] [ka] or SR', where R' and R'' are independently H, C1-C6 alkyl, or C3-C8 cycloalkyl; m and n are independently 0, 1, 2 or 3.

[0012] In other aspects, the present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a compound of Formula I, or a pharmaceutically acceptable salt thereof, and methods for treating conditions or disorders, including: Arthritis, including rheumatoid arthritis, juvenile arthritis, and psoriatic arthritis Hashimoto's thyroiditis, autoimmune hemolytic anemia, autoimmune atrophic gastritis due to pernicious anemia, autoimmune encephalomyelitis, autoimmune orchitis, Goodpasture's disease, autoimmune thrombocytopenia, sympathetic ophthalmia, myasthenia gravis, Graves' disease, primary biliary cirrhosis, autoimmune hepatitis, primary sclerosing cholangitis, chronic invasive hepatitis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, ulcerative colitis and membranous glomerulopathy, systemic lupus erythematosus, rheumatoid arthritis, psoriatic arthritis, Sjögren's syndrome, Reiter's syndrome, polymyositis, dermatomyositis, Aicardi-Goutières syndrome autoimmune or inflammatory diseases or disorders, including type I interferonopathies, including other Mendelian disorders due to overexpression of group and type I interferons, systemic sclerosis, polyarteritis nodosa, multiple sclerosis, relapsing-remitting multiple sclerosis, primary progressive multiple sclerosis, secondary progressive multiple sclerosis, and bullous pemphigoid, as well as further autoimmune diseases that may be O-cell (humoral) based or T-cell based, including Cogan's syndrome, ankylosing spondylitis, Wegener's granulomatosis, autoimmune alopecia, type I or juvenile-onset diabetes, or thyroiditis; Cancer or tumor, including gastrointestinal / gastrointestinal cancer, colon cancer, liver cancer, skin cancer including mast cell carcinoma and squamous cell carcinoma, breast cancer and breast cancer, ovarian cancer, prostate cancer, lymphoma, leukemia including acute myeloid leukemia and chronic myeloid leukemia, kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer, brain tumor, melanoma including oral and metastatic melanoma, Kaposi's sarcoma, myeloma including multiple myeloma, myeloproliferative disorders, proliferative diabetic retinopathy, or angiogenesis-related diseases including solid tumors; diabetes, including type 1 diabetes or complications from diabetes, Ocular diseases, disorders, or conditions, including ocular autoimmune diseases, uveitis including keratoconjunctivitis, vernal conjunctivitis, uveitis including uveitis associated with Behcet's disease and lens-induced uveitis, keratitis, herpetic keratitis, keratoconus, corneal epithelial dystrophy, corneal leukoplakia, ocular pemphigus, Mooren's ulcer, scleritis, Graves' ophthalmopathy, Vogt-Koyanagi-Harada syndrome, keratoconjunctivitis sicca (dry eye), phlyctenule, iridocyclitis, sarcoidosis, endocrine ophthalmopathy, sympathetic ophthalmia, allergic conjunctivitis, or ocular neovascularization, intestinal inflammation, including Crohn's disease, ulcerative colitis, inflammatory bowel disease, celiac disease, proctitis, eosinophilic gastroenteritis, or mastocytosis; 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, stroke, glutamate neurotoxicity, or hypoxia; stroke, myocardial ischemia, renal ischemia, heart attack, cardiac hypertrophy, atherosclerosis and arteriosclerosis, organ hypoxia, or ischemia / reperfusion injury in platelet aggregation, Atopic dermatitis, hand dermatitis, contact dermatitis, allergic contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerosis, 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 sclerosus, alopecia areata, vitiligo, rosacea, rosacea-like Dermatitis, steroid-induced dermatitis, drug eruptions (including papulopustular drug eruptions), epidermolysis bullosa, keratosis pilaris, pityriasis alba, pemphigus, vulvovaginitis, acne (including but not limited to acne vulgaris, acne nodular, acne nodular cystic, acne cystic, acne globe, steroid-induced acne, and autoinflammatory syndromes [including but not limited to PAPA, PAPASH, PASS, PASH, SAPHO, PCO, and SH] , including acne scars), chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, Vogt-Koyanagi-Harada disease, Sutton nevus, post-inflammatory hypopigmentation, senile vitiligo, chemical / drug-induced vitiligo, cutaneous lupus erythematosus, discoid lupus erythematosus, palmoplantar pustulosis, pemphigoid, Sweet's syndrome, hidradenitis suppurativa, psoriasis, plaque psoriasis, pustular psoriasis, nail psoriasis, flexural psoriasis, guttate psoriasis, psoriatic arthritis, erythrodermic psoriasis, inverse psoriasis Skin diseases, conditions or disorders, including refractory wounds, sebaceous gland hyperplasia, Fordyce disease (Fordyce granules, Fordyce spots), Fox-Fordyce disease, osmidrosis (bromhidrosis), hypertrichosis, or skin tumors (sebaceous nevus, sebaceous adenoma, sebaceous adenoma, sebaceous epithelioma, steatocytoma simplex, multiple sebaceous cysts, Muir-Torre syndrome, sebaceous carcinoma).

[0013] The present invention will be further understood from the following description, which is merely illustrative.The present invention is directed to a class of tricyclic spiropiperidine compounds.In particular, the present invention is directed to a specific tricyclic spiropiperidine compound that is useful as an ACC inhibitor, which is useful for treating acne.The present invention is not limited thereto, and various aspects of the present invention can be understood through the following discussion and examples. DETAILED DESCRIPTION OF THE INVENTION

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0028] As used herein, the terms "co-administration," "co-administered," and "combination" refer to combinations of a compound of Formula I and one or more other therapeutic agents, including: simultaneous administration of said components to a patient in need of treatment, when such combination of a compound of Formula I and an additional therapeutic agent are formulated together in a single dosage form such that such components are released to said patient substantially simultaneously; substantially simultaneous administration of said components to a patient in need of treatment when such combination of a compound of Formula I and an additional therapeutic agent are formulated separately from one another in separate dosage forms that are taken by the patient at substantially the same time, and which also result in substantially simultaneous release of such components to the patient; sequential administration of said components to a patient in need of treatment, where such combination of a compound of Formula I and an additional therapeutic agent are formulated separately from one another in separate dosage forms to be taken sequentially by the patient in need of treatment with a significant time interval between each administration, and where such components are released to the patient at substantially different times; and · sequential administration of such combinations of a compound of Formula I and an additional therapeutic agent to a patient in need of treatment when such combinations are formulated together in a single dosage form that releases such components in a controlled manner.

[0029] As used herein, the term "excipient" is used to describe any ingredient other than the compound of Formula I. The choice of excipient will vary widely depending 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.

[0030] The present invention relates to a novel compound that is an ACC regulator and is useful for treating diseases and conditions related to ACC dysregulation.The present invention also provides pharmaceutical compositions containing such ACC enzyme regulators, and methods for treating and / or preventing such diseases and conditions.Therefore, the present invention provides the compound of formula I as described above, or its pharmaceutically acceptable salt.

[0031] Below, several aspects (E) of the first aspect of the present invention (for convenience, E1 is the same as it) are described.

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

[0033] E2. R is H, C1-C6 alkyl and -(CH2) m -W, wherein W is C3-C8 cycloalkyl, each of said alkyl, cycloalkyl, bicycloalkyl, and bridged bicycloalkyl may be unsubstituted or substituted with halo, cyano, deuterium, hydroxy, C1-C6 alkyl, and C1-C6 alkoxy; and m and n are independently 0, 1, 2, or 3.

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

[0035] E4. The compound according to E1, wherein R1 is phenyl, pyridyl, indolyl, indazolyl, pyrrolopyridinyl, quinolinyl, isoquinolinyl or naphthyl, each of which is optionally unsubstituted or substituted by halo, cyano, hydroxy, 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.

[0036] E5. 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; 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 said compound or pharmaceutically acceptable salt thereof, selected from the group consisting of:

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

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

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

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

[0041] E10. The compound according to E1, which 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 said compound or pharmaceutically acceptable salt.

[0042] E11. A pharmaceutical composition comprising a compound according to any one of E1 to E10 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt, and a pharmaceutically acceptable excipient.

[0043] E12. Inflammation, autoimmune diseases, 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, muscle pain, endotoxins Other conditions that may be associated with inflammatory bowel disease include: genital shock, toxic shock syndrome, osteoporosis, multiple sclerosis, endometriosis, menstrual cramps, 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, keloids, hypertrophic scars, rheumatic diseases, urticaria, discoid lupus erythematosus, cutaneous lupus, central nervous system lupus, psoriatic arthritis, asthma, allergic asthma, Aicardi-Gouttieres syndrome and other conditions associated with overexpression of type I interferon. Type I interferonopathies including hereditary diseases, primary progressive multiple sclerosis, relapsing-remitting multiple sclerosis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, scleroderma, alopecia areata, cicatricial alopecia, prurigo, prurigo nodularis, CPUO, lichenoid diseases, 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 sprue , idiopathic thrombocytopenic thrombotic purpura, thrombotic thrombocytopenic purpura, myasthenia gravis, Sjogren's syndrome, epidermal hyperplasia, cartilage inflammation, bone degradation, juvenile arthritis, juvenile rheumatoid arthritis, oligoarticular juvenile rheumatoid arthritis, polyarticular juvenile rheumatoid arthritis, systemic onset juvenile rheumatoid arthritis, juvenile ankylosing spondylitis, juvenile enteropathic arthritis, juvenile Reiter syndrome, SEA syndrome, juvenile dermatomyositis, juvenile psoriatic arthritis, juvenile scleroderma, juvenile systemic lupus erythematosus, juvenile vasculitis, oligoarticular rheumatoid arthritis, polyarticular rheumatoid arthritis, systemic onset rheumatoid arthritis,Enteropathic arthritis, reactive arthritis, Reiter's syndrome, myositis, polymyolitis, dermatomyolitis, 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, psoriasis vulgaris, guttate psoriasis A method for treating a disease or condition selected from the group consisting of inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, immune disorders associated with or resulting from the activity of pathogenic lymphocytes, non-infectious uveitis, Behcet's disease, and Vogt-Koyanagi-Harada syndrome, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described in E1 to E10 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt.

[0044] E13. The method of E12, wherein the compound is administered topically.

[0045] E14. The method of E12 or E13, wherein the compound is administered as a cream, ointment, lotion, gel, solution, suspension, foam, aerosol, spray, shampoo, patch, or tape.

[0046] E15. A method of treating acne, comprising administering to a subject a therapeutically effective amount of a compound according to E1 to E10 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt.

[0047] E16. The method of E15, wherein the compound is administered topically.

[0048] E17. The method of E15 or E16, wherein the compound is administered as a cream, ointment, lotion, gel, solution, suspension, foam, aerosol, spray, shampoo, patch, or tape.

[0049] E18. Use of a compound according to any of E1 to E10 for the manufacture of a medicament for the treatment of a disorder for which an ACC inhibitor is indicated.

[0050] E19. Use of a compound according to any one of E1 to E10 for the manufacture of a medicament for the treatment of acne.

[0051] E20. A compound according to any one of E1 to E10 for use in the treatment of a disorder in which an ACC inhibitor is indicated.

[0052] Compounds of the present invention that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are called "isomers." Isomers that differ in the arrangement of their atoms in space are called "stereoisomers." These stereoisomers are "R" or "S," depending on the arrangement of substituents around the chiral carbon atom. As used herein, the terms "R" and "S" refer to the configurations defined in Section E of IUPAC 1974, Recommendation on Fundamental Stereochemistry, Pure Appl. Chem., 1976, 45:13-30. (R), (S), or * The enantiomers of the present invention designated by are substantially free of other enantiomers. "Substantially free" means an enantiomeric excess of 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%. The symbol *depicts the chiral carbon atom as either (R) or (S) stereochemistry, depending on the configuration of substituents around the chiral carbon atom. The present invention contemplates various stereoisomers and mixtures thereof, which are specifically included within the scope of the present invention. Stereoisomers include enantiomers and mixtures of enantiomers. Individual stereoisomers of the compounds of the present invention can be prepared synthetically from commercially available starting materials containing asymmetric or chiral centers, or by preparing a racemic mixture followed by resolution procedures well known to those skilled in the art. These resolution methods include, but are not limited to, (1) coupling a chiral auxiliary to the enantiomeric mixture, recrystallizing or chromatographically separating the resulting diastereomeric mixture, and liberating the optically pure product from the auxiliary, or (2) directly separating the optically enantiomeric mixture on a chiral chromatographic column. (R), (S), or * Compounds of the invention not designated by can exist as racemates (i.e., 50% (R) and 50% (S)) or as mixtures of two enantiomers in which one enantiomer is in excess. For example, an enantiomeric mixture can contain 51% (R) enantiomer and 49% (S) enantiomer, or vice versa, or any combination of (R) and (S) enantiomers other than a racemic mixture of 50% (R) and 50% (S).

[0053] The scope of the described compounds includes all isomers (e.g., cis, trans, or diastereomers) of the compounds described herein, individually and in any mixture thereof. All of these forms, including enantiomers, diastereomers, cis, trans, syn, anti, solvates (including hydrates), tautomers, and mixtures thereof, are included in the described compounds. Stereoisomeric mixtures, e.g., diastereomeric mixtures, can be separated into their corresponding isomers in a known manner by using suitable separation methods. For example, diastereomeric mixtures can be separated into their individual diastereomers by fractional crystallization, chromatography, solvent distribution, and similar procedures. This separation can be carried out either at the level of one of the starting compounds or at the compound of Formula I itself. Enantiomers can be separated by the formation of diastereomeric salts, e.g., by salt formation with an enantiomerically pure chiral acid, or by chromatography, e.g., HPLC, using chromatographic substrates bearing chiral ligands. The present invention includes all pharmaceutically acceptable isotopically labeled compounds of Formula I, or pharmaceutically acceptable salts thereof, in which one or more atoms are replaced by an atom having the same atomic number but an atomic mass or mass number that is different from the atomic mass or mass number that predominates in nature.

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

[0055] 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. The radioactive isotope tritium, i.e. 3 H and carbon-14, i.e. 14 C are particularly useful for this purpose given their ease of incorporation and straightforward means of detection.

[0056] Heavier isotopes, such as deuterium, i.e. 2 Substitution with H may confer certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements, and may therefore be preferred in some circumstances. Positron-emitting isotopes, e.g. 11 C. 18 F, 15 O and 13 Substitution at N may be useful in positron emission topography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of formula I can generally be prepared by conventional techniques known to those skilled in the art, or by processes analogous to those described in the accompanying Examples and Preparations, substituting the appropriate isotopically labeled reagent for the previously used non-labeled reagent.

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

[0058] "Deuterium enrichment factor," as used herein, refers to the ratio of the deuterium abundance to the natural abundance of deuterium, respectively, relative to the hydrogen abundance. Atomic positions designated as having deuterium typically have a deuterium enrichment factor of at least 1000 (15% deuterium incorporation), at least 2000 (30% deuterium incorporation), at least 3000 (45% deuterium incorporation), at least 3500 (52.5% deuterium incorporation), at least 3500 (52.5% deuterium incorporation at each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 ( 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).

[0059] It is understood that under physiological conditions, one or more deuterium atoms may be exchanged for hydrogen.

[0060] In some embodiments, the present disclosure provides deuterated compounds of Formula I, or pharmaceutically acceptable salts thereof, in place of previously used non-labeled reagents.

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

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

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

[0064] Isotopically labeled compounds of the present invention can generally be prepared by conventional techniques known to those skilled in the art, or by processes similar to those described in the accompanying examples and preparations, substituting an appropriate isotopically labeled reagent for the previously used non-labeled reagent. It is also well recognized in the art that synthesized compounds may exhibit some variation in natural isotopic abundance, which may depend on the origin of the synthetic materials used to synthesize the compounds.

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

[0066] Pharmaceutically acceptable solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, eg D2O, d6-acetone, d6-DMSO.

[0067] For therapeutic use in treating mammalian disorders, the compounds of the present invention or their pharmaceutical compositions can be administered orally, parenterally, topically, rectally, transmucosally, or intestinally. Parenteral administration includes indirect injection or direct injection into the affected area, which produces a systemic effect. Local administration includes treatment of the skin or organs that are easily accessible by topical application, such as the eyes or ears. It also includes transdermal delivery, which produces a systemic effect. Rectal administration includes the form of suppositories. The preferred administration routes are oral and parenteral.

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

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

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

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

[0072] The pharmaceutical compositions of the present invention may be manufactured by methods well known in the art, for example, by using conventional mixing, dissolving, granulating, dragee-making, comminuted, emulsifying, encapsulating, entrapping, lyophilizing processes or spray drying.

[0073] Pharmaceutical compositions for use according to the present invention can be formulated in a conventional manner using one or more pharmaceutically acceptable carriers, including excipients and adjuvants, which facilitate the processing of active compounds into preparations that can be used as pharmaceuticals. The appropriate formulation depends 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. Such excipients and carriers are described, for example, in Remington's Pharmaceutical Sciences, Mack Pub. Co., New Jersey (1991). The formulations of the present invention can be designed to be short-acting, rapid-release, long-acting, and sustained-release. Therefore, pharmaceutical formulations can also be formulated for controlled release or sustained release.

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

[0075] The amount of the active ingredient, which is the compound of the present invention, in the pharmaceutical composition and its unit dosage form can be widely varied or adjusted depending on the mode of administration, the potency of the particular compound, and the desired concentration. The determination of a therapeutically effective amount is within the capabilities of those skilled in the art. Generally, the amount of the active ingredient ranges from 0.01% to 99% by weight of the composition.

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

[0077] The desired dose can conveniently be presented as a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four or more sub-doses per day, which sub-doses themselves can be further divided, for example, into several loosely spaced individual administrations, such as multiple inhalations from an insufflator, or by application of a plurality of drops to the eye.

[0078] It should also be understood that the initial dosage administered may be increased above the upper limit level above in order to rapidly achieve the desired concentration at the site of action. On the other hand, the initial dosage may be less than optimal, and the daily dosage may be gradually increased over the course of treatment depending on the specific circumstances. If desired, the daily dose may also be divided into multiple doses, for example, for administration two to four times per day.

[0079] The present invention also includes the following embodiments. 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; Inflammation, autoimmune diseases, 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, muscle pain, endotoxic shock , toxic shock syndrome, osteoporosis, multiple sclerosis, endometriosis, menstrual pain, 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, allergic contact dermatitis, irritant contact dermatitis, neurodermatitis, perioral dermatitis, stasis dermatitis, dyshidrotic eczema, xerosis, 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 eruptions (including papulopustular drug eruptions), epidermolysis bullosa, keratosis pilaris, pityriasis alba, pemphigus, vulvovaginitis, acne (including but not limited to acne vulgaris, acne nodularis, acne nodularis, acne cysticis, acne globe, and steroid-induced acne), and autoinflammatory syndromes (including but not limited to PAPA, PAPASH, PASS, PASH, SAPHO, PCO, and SH], and acne scars), Chronic spontaneous urticaria, chronic idiopathic urticaria, chronic physical urticaria, Vogt-Koyanagi-Harada disease, Sutton nevus, post-inflammatory hypopigmentation, senile vitiligo, chemical / drug-induced vitiligo, cutaneous lupus erythematosus, palmoplantar pustulosis, pemphigoid, Sweet's syndrome, hidradenitis suppurativa, nail psoriasis, flexural psoriasis, intractable wounds, sebaceous gland hyperplasia, Fordyce's disease (Fordyce's granules, Fordyce's spots), Fox-Fordyce disease, osmidrosis (bromhidrosis), hypertrichosis, or skin tumors (sebaceous nevus, sebaceous adenoma, sebaceous adenoma, sebaceous epithelioma, simple sebaceous cyst,Multiple sebaceous cysts (Murr-Torre syndrome), sebaceous carcinoma, hypertrophic scars, rheumatic diseases, urticaria, discoid lupus erythematosus, central nervous system lupus, psoriatic arthritis, asthma, allergic asthma, type I interferonopathies including Aicardi-Goutières syndrome and other Mendelian disorders of type I interferon overexpression, primary progressive multiple sclerosis, relapsing-remitting multiple sclerosis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, scleroderma, alopecia areata, spondylosis, myositis, vasculitis, pemphigus, lupus, major depression Disease disorders, allergies, 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 sprue, idiopathic thrombocytopenic purpura, myasthenia gravis, Sjogren's syndrome, epidermal hyperplasia, cartilage inflammation, bone degradation, juvenile arthritis, juvenile rheumatoid arthritis, oligoarticular juvenile rheumatoid arthritis, polyarticular juvenile rheumatoid arthritis, systemic onset juvenile rheumatoid arthritis, juvenile ankylosing spondylitis, juvenile enteropathic arthritis, juvenile Reiter's syndrome, SEA syndrome, juvenile dermatomyositis, juvenile psoriatic arthritis, juvenile scleroderma, juvenile systemic lupus erythematosus, juvenile vasculitis, oligoarticular rheumatoid arthritis, polyarticular rheumatoid arthritis, systemic-onset rheumatoid arthritis, enteropathic arthritis, reactive arthritis, Reiter's 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 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 use in the treatment of selected from psoriatic epidermal hyperplasia, Addison's disease, Raynaud's phenomenon, psoriatic epidermal hyperplasia, plaque psoriasis, guttate psoriasis, inverse psoriasis, pustular psoriasis, erythrodermic psoriasis, immune disorders associated with or resulting from the activity of pathogenic lymphocytes, non-infectious uveitis, Behcet's disease or Vogt-Koyanagi-Harada syndrome, A method of treating a disease for which an ACC inhibitor is indicated in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof, as defined in any of the embodiments described herein, or a pharmaceutically acceptable solvate of said compound or salt; Use of a compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt, as defined in any of the embodiments described herein, for the manufacture of a medicament for the treatment of a disease or condition for which an ACC inhibitor is indicated; and A pharmaceutical composition for treating a disease or condition for which an ACC inhibitor is indicated, comprising a compound of formula I as defined in any of the embodiments described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt.

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

[0081] Suitable agents for use in combination therapy with a compound of Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt, include sulfasalazine, mesalazine, prednisone, azathioprine, infliximab, adalimumab, belimumab, becertolizumab, natalizumab, vedolizumab, hydrocortisone, budesonide, cyclosporine, tacrolimus, fexofena Antihistamines include rifampin, 6-mercaptopurine, methotrexate, ursodeoxycholic acid, obeticholic acid, antihistamines, rifampin, prednisone, methotrexate, azathioprine, cyclophosphamide, hydroxychloroquine, mofetil, mycophenolate sodium, tacrolimus, leflunomide, chloroquine and quinacrine, thalidomide, Rituxan, NSAIDs, solumedrol, depomedrol, and dexamethasone.

[0082] Other suitable agents for use in combination therapy with a compound of Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt, 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 For example, histamine type 1 receptor antagonists or histamine type 2 receptor antagonists, such as loratidine, fexofenadine, desloratidine, levocetirizine, methapyrilene or cetirizine; α1-adrenergic receptor agonists or α2-adrenergic receptor agonists, such as phenylephrine, methoxamine, oxymetazoline or methylnorephrine; muscarinic M3 receptor antagonists, such as tiotropium or ipratropium; muscarinic M3 receptor antagonists, such as tiotropium or ipratropium; antagonist / β2 dual agonists; PDE inhibitors, such as PDE3 inhibitors, PDE4 inhibitors or PDE5 inhibitors, for example theophylline, sildenafil, vardenafil, tadalafil, ibudilast, cilomilast or roflumilast; sodium cromoglycate or nedocromil sodium; cyclooxygenase (COX) inhibitors, for example non-selective inhibitors (e.g. aspirin or ibuprofen) or selective inhibitors (e.g. celecoxib or valdecoxib); glucocorticosteroids, for example anti-inflammatory monoclonal antibodies, such as infliximab, adalimumab, tanezumab, ranibizumab, bevacizumab or mepolizumab; beta2 agonists, such as salmeterol, albuterol, salbutamol, fenoterol or formoterol, especially long-acting beta2 agonists; integrin antagonists, such as natalizumab; adhesion molecule inhibitors, such as VLA-4 antagonists;kinin B1 or B2 receptor antagonists; immunosuppressants, such as inhibitors of the IgE pathway (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, chymase, or cateopsin G; adenosine A2a receptor agonists; adenosine A2b receptor antagonists; urokinase inhibitors; dopamine receptor agonists (e.g., ropinirole), in particular dopamine D2 receptor agonists (e.g., bromocriptine); modulators of the NFκB pathway, such as IKK inhibitors; further modulators of cytokine signaling pathways, such as inhibitors of JAK kinase, syk kinase, p38 kinase, SPHK-1 kinase, Rho kinase, EGF-R or MK-2; mucolytic agents, mucodynamic agents or antihistamines. cough suppressants; antibiotics; antivirals; vaccines; chemokines; epithelial sodium channel (ENaC) blockers or inhibitors; nucleotide receptor agonists, such as P2Y2 agonists; thromboxane inhibitors; 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 receptors, 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;Included are 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 the specifically named compounds and salts. These agents can be administered with another active agent, and the second active agent can be administered orally or topically.

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

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

[0085] Prodrugs according to the present invention can be produced, for example, by replacing appropriate functional groups present in compounds of formula I with certain moieties known to those skilled in the art as "promoieties," for example, as described in "Design of Prodrugs" by H. Bundgaard (Elsevier, 1985).

[0086] Thus, prodrugs according to 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 hydroxyl groups in compounds of formula I; (c) amide, imine, carbamate or amine derivatives of amino groups in the form of 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.

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

[0088] Certain compounds of Formula I may themselves act as prodrugs of other compounds of Formula I. It is also possible for two compounds of Formula I to be linked together in the form of a prodrug. In certain circumstances, a prodrug of a compound of Formula I may be produced by internally linking two functional groups of a compound of Formula I, for example, by forming a lactone.

[0089] Reference to a compound of Formula I is intended to include the compound itself and its prodrugs. The present invention includes such compounds of Formula I, as well as pharmaceutically acceptable salts of such compounds, and pharmaceutically acceptable solvates of said compounds and salts.

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

[0091] The compounds of formula I can be administered per se or in the form of a pharmaceutical composition containing, as the active component, an effective dose of at least one compound of the invention in addition to customary pharmaceutically harmless excipients and / or additives.

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

[0093] The compound of formula I can be administered orally.Oral administration can involve swallowing, so that compound enters the gastrointestinal tract, or buccal or sublingual administration can be used, so that compound enters the bloodstream directly from the mouth.The formulation suitable for oral administration includes solid formulations, such as tablets, granules, capsules containing liquid or powder, lozenges (including liquid-filled), chewable tablets, multiparticulate and nanoparticle formulations, gels, solid solutions, liposomes, films, vaginal suppositories, sprays and liquid formulations.

[0094] Liquid preparations include suspensions, solutions, syrups and elixirs.Such preparations can be used as filling materials for soft capsules or hard capsules, and typically comprise carriers such as water, ethanol, polyethylene glycol, propylene glycol, methylcellulose or suitable oils, and one or more emulsifiers and / or suspending agents.Liquid preparations can also be prepared by reconstituting solids, for example, from sachets.

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

[0096] In tablet dosage forms, depending on the dosage, the drug may comprise 1% to 80% by weight of the dosage form, more typically 5% to 60% by weight. Tablets generally contain a disintegrant in addition to the drug. Examples of disintegrants include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methylcellulose, microcrystalline cellulose, lower alkyl-substituted hydroxypropyl cellulose, starch, pregelatinized starch, and sodium alginate. Generally, the disintegrant comprises 1% to 25% by weight. In one embodiment of the present invention, the disintegrant comprises 5% to 20% by weight of the dosage form. Binders are generally used to impart cohesive properties to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugars, 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 calcium hydrogen phosphate dihydrate. Tablets may also contain surfactants such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc. When present, surfactants may comprise 0.2% to 5% by weight of the tablet, and glidants may comprise 0.2% to 1% by weight of the tablet. Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate and sodium lauryl sulfate. Lubricants generally comprise 0.25% to 10% by weight. In one embodiment of the present invention, the lubricant comprises 0.5% to 3% by weight of the tablet. Other possible ingredients include antioxidants, colorants, flavorants, preservatives, and taste-masking agents.

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

[0098] Tablet blends can be directly or roller compressed to form tablets. Tablet blends or portions of blends can alternatively be wet-, dry-, or melt-granulated, melt-congealed, or extruded before tableting. The final formulation can comprise one or more layers, and can be coated or uncoated, or even encapsulated. Tablet formulations are discussed in Pharmaceutical Dosage Forms: Tablets, Vol. 1, by H. Lieberman and L. Lachman (Marcel Dekker, New York, 1980).

[0099] Consumable oral films for human or veterinary use are typically flexible, water-soluble or water-swellable, thin-film dosage forms that can be fast-dissolving or mucoadhesive and typically contain a compound of Formula I, a film-forming polymer, a binder, a solvent, a humectant, a plasticizer, a stabilizer or emulsifier, a viscosity modifier, and a solvent. Some components of the formulation can serve more than one function. The film-forming polymer can be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and is typically present in an amount ranging from 0.01 to 99% by weight, more typically from 30 to 80% by weight. Other possible ingredients include antioxidants, colorants, flavors and flavor enhancers, preservatives, salivation stimulants, cooling agents, cosolvents (including oils), emollients, bulking agents, antifoaming agents, surfactants, and taste masking agents. Films according to the present invention are typically prepared by evaporative drying of a thin aqueous film coated onto a peelable backing substrate or paper. This can be done in a drying oven or tunnel, typically a combined coater dryer, or by freeze-drying or vacuuming.

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

[0101] The compound of formula I can also be administered directly into bloodstream, muscle or internal organs.Such parenteral administration includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, ​​intrasternal, intracranial, intramuscular, intraarticular and subcutaneous administration.The device suitable for parenteral administration includes needle (including microneedle) injector, needleless injector and infusion technology.

[0102] The compounds of formula I may also be administered topically to the skin or mucosa, that is, transdermally or transdermally.

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

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

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

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

[0107] In addition to the compounds of the present invention, the ointment, paste, cream, lotion, gel, suppository, powder, solution, spray, drop, inhalant and patch for topical administration can contain one or more pharmaceutically acceptable excipients, such as animal or vegetable fat, oil, wax, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc, zinc oxide, preservatives, antioxidants, flavorings, emulsifiers, dyes, inert fillers, anti-irritants, tackifiers, fragrances, opacifiers, antioxidants, gelling agents, stabilizers, surfactants, emollients, coloring agents, preservatives, buffers, penetration enhancers, etc. Such excipients should not interfere with the effectiveness of the biological activity of the active agent and should not be harmful to epithelial cells or their function.

[0108] Transdermal administration can be accomplished by use of a transdermal patch, which may be of the "reservoir and porous membrane" type or may utilize a "matrix system."

[0109] The solubility of compounds of the invention used in preparing pharmaceutical compositions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.

[0110] The compound of formula I can be typically administered in the form of dry powder from a dry powder inhaler (alone, as a mixture, for example, as a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids such as phosphatidylcholine), as an aerosol spray from a pressurized container, pump, spray, atomizer (preferably, an atomizer that uses electrohydrodynamics to generate a fine mist) or nebulizer, with or without the use of suitable propellants such as 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane, or as nasal drops, or by inhalation.For intranasal use, the powder can contain a bioadhesive agent, for example, chitosan or cyclodextrin.Delivery by inhalation is the preferred administration route of the compound of the present invention.

[0111] The pressurized container, pump, spray, atomizer, or nebulizer contains a solution or suspension of a compound of Formula I, for example, with ethanol, aqueous ethanol, or an alternative agent suitable for dispersing, solubilizing, or prolonging the release of the compound, a propellant as a solvent, and an optional surfactant, for example, sorbitan trioleate, oleic acid, or oligolactic acid.

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

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

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

[0115] The formulation of the present invention intended for intranasal administration can be added with suitable fragrance, such as fruit or floral fragrance.The formulation for intranasal administration can be formulated to be immediate release and / or modified release, for example, using PGLA.Modified release includes delayed release, sustained release, pulsed release, controlled release, targeted release and programmed release.

[0116] The compounds of formula I may also be administered directly to the eye or ear, typically in the form of drops of a micronised suspension or solution in pH-adjusted, isotonic, sterile saline.

[0117] When using any of the aforementioned administration methods, the compound of Formula I can be combined with a soluble macromolecular entity, such as cyclodextrin and its suitable derivatives or polyethylene glycol-containing polymers, to improve solubility, dissolution rate, taste, bioavailability, and / or stability. For example, drug-cyclodextrin complexes have been found to be generally useful for most dosage forms and administration routes. Both inclusion 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., carriers, diluents, or solubilizers. The most commonly used for these purposes are alpha-, beta-, and gamma-cyclodextrins, examples of which can be found in International Patent Publications WO91 / 11172, WO94 / 02518, and WO98 / 55148.

[0118] For example, when it is desired to administer a combination of active compounds for the purpose of treating a specific disease or condition, it is within the scope of the present invention that two or more pharmaceutical compositions, at least one of which contains a compound of Formula I, can be conveniently combined in the form of a kit suitable for the combined administration of the compositions.Thus, the kit of the present invention comprises two or more individual pharmaceutical compositions, at least one of which contains a compound of Formula I, and a means for separately holding the compositions, such as a container, a divided bottle, or a divided foil packet.An example of such a kit is the familiar blister pack used for packaging tablets, capsules, etc.Such a kit is particularly suitable for administering different dosage forms, such as oral and parenteral dosage forms, administering individual compositions at different dosage intervals, or titrating individual compositions together.To support compliance, the kit typically includes instructions for administration, and a so-called memory aid may be provided.

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

[0120] Those skilled in the art will understand that the experimental conditions set forth in the following schemes are illustrative of conditions suitable for carrying out the transformations shown, and that it may be necessary or desirable to vary the exact conditions used in preparing the compounds of formula I. Furthermore, it will be understood that it may be necessary or desirable to carry out the transformations in a different order than that set forth in the schemes, or to adjust one or more transformations, in order to obtain the desired compounds of the invention.

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

[0122] Compounds of formula I (generally designated as compound G) can be prepared from compounds A-G as shown by Scheme 1 or Scheme 2. Compounds of formula A-G are commercially available or can be synthesized by one of ordinary skill in the art following literature or preparations described herein.

[0123] [ka]

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

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

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

[0127] Compounds of formula G can be prepared from compounds of formula F by process step (f), i.e., acylation with a heteroaryl carboxylic acid under suitable basic conditions. Preferred conditions include N-ethyl-N-(propan-2-yl)propan-2-amine (DIPEA) in the presence of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU). Alternatively, the reagent can include propanephosphonic anhydride in a dipolar solvent, such as DMF, in the presence of triethylamine at 25°C. Other effective conditions include 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.

[0128] [ka]

[0129] Compounds prepared according to Scheme 2 Compounds of formula I can be prepared from compounds of formula H by Miniski coupling with a carboxylic acid using 9-mesityl-10-methylacridinium perchlorate and irradiation.

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

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

[0132] In the following non-limiting examples and preparations illustrating the invention, and in the foregoing schemes, the following abbreviations, definitions and analytical procedures may be referenced. AcOH: acetic acid atm: atmospheric pressure aq: water-based BOC2O: BOC anhydride, di-tert-butyl dicarbonate br: Broad ℃: Celsius CBZ: carboxybenzyl, benzyloxycarbonyl conc. or c.: concentrated δ: chemical shift d: double line dd: Double line of double lines ddd: double line double line double line dt: Triple line double line DCM: dichloromethane DHP: dihydropyran DMAC: N,N-dimethylacetamide DMAP: 4-dimethylaminopyridine DMF: dimethylformamide DMSO: dimethyl sulfoxide EDCI: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride ESI-MS: Electrospray ionization mass spectrometry EtOAc: ethyl acetate Et3N: Triethylamine equiv.: equivalent g: grams h: time HATU: (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HOPO: 2-hydroxypyridine 1-oxide HPLC: High-pressure liquid chromatography iPr2NEt: N,N-diisopropylethylamine, Hunig's base iPrOH: isopropanol, 2-propanol Kg: kilogram KOtBu: potassium tert-butoxide L: Liter LAH: Lithium aluminum hydride, LiAlH4 LCMS: Liquid Chromatography Mass Spectrometry LDA: lithium diisopropylamide LiHMDS: lithium bis(trimethylsilyl)amide M: Multiplet M: mole MeCN: acetonitrile MHz: Megahertz min:minutes mL: milliliter mm: millimeters mmol: millimolar μmol: micromol mol: mole MS m / z: mass spectrum peak MTBE: Methyl tert-butyl ether N:Normal n-BuLi: n-butyllithium NBS: N-bromosuccinimide NCS: N-chlorosuccinimide NH4OH: Ammonia water solution NMP: N-methylpyrrolidine NMR: nuclear magnetic resonance Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium(0) Pd / C: Palladium supported on carbon PE: Petroleum ether Prep: preparative pTSA·H2O: p-Toluenesulfonic acid monohydrate q:Quarter quint:quintet RT: room temperature s: single line sat.: saturation SFC: Supercritical Fluid Chromatography t: Mie line t-BuOH: tert-butanol TFA: Trifluoroacetic acid THF: tetrahydrofuran TMSOTf: Trimethylsilyl trifluoromethanesulfonate TTBP·HBF4: Tri-tert-butylphosphonium tetrafluoroborate T3P: Propylphosphonic anhydride X-Phos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl μm: micrometer μL: microliter

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

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

[0135] Mass spectra were recorded using either ESI-MS. Where relevant, unless otherwise stated, m / z data provided are isotopic 19 F, 35 Cl, 79 Br and / or 81 It is about Br.

[0136] If silica gel chromatography, preparative HPLC, or SFC chromatography is used, one skilled in the art will appreciate that any suitable solvent or combination of solvents can be used to purify the desired compound.

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

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

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

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

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

[0142] Preparation 1: 2-(tert-butyl)-5H-spiro[benzo[d]thiazol-6,4'-piperidin]-4(7H)-one hydrochloride (P1)

[0143] [ka] Step 1: Synthesis of tert-butyl 2-(tert-butyl)-7H-spiro[benzo[d]thiazole-6,4'-piperidine]-1'-carboxylate (C1)

[0144] [ka] 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 EtN (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 minutes, then warmed to about 0° C. and stirred at about 0° C. for about 2 hours. 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 hours, then warmed to about 0° C. BocO (52.6 g, 241 mmol) was added, and the mixture was stirred at about 0 °C for about 2 hours. Saturated NaHCO (aq) (1.6 L) was added, and the organic phase was separated and concentrated under reduced pressure. To the residue, 2,2-dimethylpropanethioamide (84.8 g, 723 mmol), pyridine (436 mL, 542 mmol), and EtOH (2.1 L) were added. The solution was heated at about 80 °C for about 16 hours and then cooled to about 23 °C. The mixture was washed with saturated NaHCO (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 give the title compound (149 g, 68%). 1H NMR (400 MHz, CDCl3) 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.

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

[0146] [ka] Compound C1 (188 g, 519 mmol) was added with MeOH (1.88 L). 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 hours 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 (1 M in THF, 2.1 L) was added, and the solution was stirred at about 15° C. for 16 hours. Water (4.9 L) was added, and the mixture was extracted with isopropyl acetate (3×2.8 L). The combined organic phase was concentrated under reduced pressure to give crude tert-butyl 2-(tert-butyl)-4-methoxy-7H-spiro[benzo[d]thiazole-6,4′-piperidine]-1′-carboxylate (Intermediate C1b). To the resulting residue was added additional Intermediate C1b (21.6 g, 55 mmol) from a previous batch and dioxane (970 mL), followed by the dropwise addition of HCl (4 M in dioxane, 2.26 L). The solution was stirred at about 25° C. for about 16 hours and then concentrated under reduced pressure. MeOH (3.5 L) was added, and the solution was heated at 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 hours. EtOAc (2.0 L) was added, and the resulting mixture was stirred at about 25° C. for about 16 hours. The resulting slurry was filtered, and the cake was dried under reduced pressure at about 40° C. to provide the title compound (157 g, 87%). 1 H NMR (400 MHz, 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.

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

[0148] [ka] Step 1: 7-Bromo-N,5-dimethylquinolin-2-amine (C2)

[0149] [ka] 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), WO2013185103) in methylamine (175 mL of a 2 M solution in THF, 349 mmol) was added cesium fluoride (10.6 g, 69.9 mmol) at about 25 °C. The mixture was heated at about 100 °C for about 48 h. The mixture was diluted with saturated NH4Cl (30 mL) and extracted with EtOAc. The combined organic phase was washed with brine (30 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by SFC (column: Chiral Tech OX-H, 30 x 250 mm, 5 μm; mobile phase A: carbon dioxide; mobile phase B: MeOH / 1% NH3; gradient from 95% to 70% B in 3.5 min; flow rate 80 mL / min) to give the title compound (2.81 g, 32%). LC / MS m / z (M+H) + = 252.1.

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

[0151] [ka] To a solution of compound C2 (1.15 g, 4.59 mmol) in MeOH (50 mL) was added triethylamine (2.0 mL, 14 mmol) and Pd(dppf)Cl.CH.Cl. (613 mg, 0.751 mmol). The solution was added to a Parr reactor and flushed with nitrogen three times. The reactor was flushed with CO three times and then sealed with CO at about 75 PSI. The reactor was heated at about 80°C for about 24 hours. The solution was cooled to about 25°C and diluted with EtOAc. The solution was washed with water and brine. The organic phase was dried over Na.sub.2SO.sub.4 and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (853 mg, 81%). LC / MS m / z (M+H) + = 231.3.

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

[0153] [ka] 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 hours. HCl (1 M) was added dropwise until a precipitate formed (pH about 5). The precipitate was filtered to give the title compound (789 mg, 88%). 1 H NMR (400 MHz, DMSO-d6) δ 8.01 (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.

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

[0155] [ka] Step 1: Synthesis of 4-(1,3-dimethyl-1H-pyrazol-4-yl)-3-(ethoxycarbonyl)but-3-enoic acid (C4)

[0156] [ka] To a solution of solid KOtBu (36.2 g, 322 mmol) in ethanol (200 mL) at approximately 25 °C was added 1,3-dimethyl-1H-pyrazole-4-carbaldehyde (CAS: 25016-21-0, 20 g, 160 mmol) and diethyl succinate (42.1 g, 40 mL, 242 mmol). The reaction was heated at approximately 80 °C for approximately 18 h, then cooled to RT and quenched using AcOH (23 mL, 403 mmol). The reaction mixture was concentrated to approximately 40 mL, heptane (2 × 100 mL) was added, and the reaction mixture was concentrated. The reaction was cooled to approximately 0–10 °C, charged with water (200 mL), and the pH of the aqueous layer was adjusted to 4–5 with aqueous HCl. The resulting suspension was filtered and rinsed with water (60 mL). The solid was dried to give the title compound (33.4 g, 82.1%). 1 H NMR (400 MHz, methanol-d4) δ 7.81 (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.

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

[0158] [ka] 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 was heated at about 95-105 °C for about 18 hours, 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 using water and dried to give 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.

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

[0160] [ka] To a solution of compound C5 (1.11 g, 4.0 mmol) in ethanol (16 mL) was added potassium carbonate (2.76 g, 5.0 mmol). The reaction was heated to reflux for approximately 1.5 hours 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), dried over MgSO4, filtered, and concentrated. The residue was diluted with hexane (25 mL), and the resulting mixture was concentrated under reduced pressure and dried at approximately 50 °C using high vacuum to afford the title compound (0.89 g, 95% yield) as a pale pink solid. 1 H NMR (400 MHz, DMSO-d6) δ 10.47 (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.

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

[0162] [ka] 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 methyl iodide (0.64 g, 0.28 mL, 4.5 mmol). The reaction was heated to reflux for approximately 24 hours and then concentrated. The residue was diluted with water (25 mL) and extracted with EtOAc (2 × 25 mL). The combined EtOAc extracts were washed with brine (25 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by chromatography (silica, 0–25% EtOAc in hexanes) to afford the title compound (0.71 g, 95.3% yield) as a white solid. 1 H NMR (400 MHz, chloroform-d) δ 8.04 (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.

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

[0164] [ka] To compound C7 (0.3 g, 1.21 mmol) in EtOH (4.8 mL) and THF (4.3 mL) was added 1 N NaOH (4.83 mL, 4.83 mmol). The mixture was heated at about 45°C for about 2 hours, 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 give 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]

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

[0166] [ka] A solution of 2-(1-methylcyclopropyl)-5H-spiro[benzo[d]thiazol-6,4'-piperidin]-4(7H)-one (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), prepared similarly to Compound P1, was microwaved at about 110°C for about 30 minutes. 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; gradient of 30–50% B over 11 min, hold at 100% B for 2 min; flow rate 35 mL / min to give the title compound (15 mg, 16%). 1 H NMR (400 MHz, methanol-d4) δ 7.64 (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.

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

[0168] [ka] A solution of 2-(1-methylcyclobutyl)-5H-spiro[benzo[d]thiazol-6,4'-piperidin]-4(7H)-one (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), prepared similarly to Compound P1, was microwaved at approximately 110°C for approximately 30 minutes. The resulting mixture was filtered, and the residue was purified by preparative HPLC using water / acetonitrile (Sunfire C18 column, 19 x 100 mm, 5 μm) to give the title compound (6.9 mg, 19%). LC / MS m / z (M+H) + = 463.3.

[0169] Example 3 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

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

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

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

[0173] [ka] 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 hours. The reaction mixture was concentrated to give a yellow oil, acetonitrile (2×5 mL) was added, and the reaction was concentrated under reduced pressure and dried in vacuo to give the title compound (25 mg, 99%). LC / MS m / z (M+H) + = 307.1.

[0174] 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

[0175] [ka] 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 minutes. The resulting mixture was concentrated, and the residue was purified by preparative HPLC (column: Phenomenex Gemini-NX C18, 40 × 80 mm, 3 μm); mobile phase A: water (0.05 v / v% concentrated NH4OH); mobile phase B: MeCN; gradient of 31–71% B over 9 min, hold at 100% B for 2 min; flow rate 25 mL / min to give the title compound (5.56 mg, 16%). 1 H NMR (400 MHz, methanol-d4) δ 7.67 (dd, 1H), 7.23 (t, 1H), 3.82 (m, 2H), 3.58 (m, 2H), 3.27 (s, 2H), 2.76 (s, 2H), 2.55 (s, 3H), 2.54 (s, 3H), 2.12 (h, 1H), 1.53 (m, 4H), 1.37 (s, 6H), 0.88 (s, 3H), 0.87 (s, 3H); LC / MS m / z (M+H) + = 479.4.

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

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

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

[0179] [ka] Prepared in the same manner as Example 3, using 2,2-dimethylbutanoic acid instead of 2,2,3-trimethylbutanoic acid in step 1, to give the title compound (8.3 mg). LC / MS m / z (M+H) + = 465.3.

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

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

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

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

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

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

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

[0187] [ka] According to amidation method A, 2-(1-methylcyclopropyl)-5H-spiro[benzo[d]thiazol-6,4'-piperidin]-4(7H)-one (0.036 g, 0.116 mmol), prepared as in Example P1, was coupled with 5-methyl-2-(methylamino)quinoline-7-carboxylic acid (0.03 g, 0.14 mmol). The residue was purified by preparative HPLC (column: Boston Prime C18, 150 × 30 mm, 5 μm); mobile phase A: water (0.05% v / v concentrated NH4OH); mobile phase B: MeCN; gradient of 26–56% B over 9 min, hold at 100% B for 2 min; flow rate: 25 mL / min) to give the title compound (24.7 mg, 38%). 1 H NMR (400 MHz, methanol-d4) δ 8.06 (dd, 1H), 7.57–7.50 (m, 1H), 7.05 (dd, 1H), 6.83 (d, 1H), 3.91 - 3.78 (m, 2H), 3.57 - 3.51 (m, 2H), 3.25 (s, 2H), 3.03 (s, 3H), 2.73 (d, 2H), 2.61 (s, 3H), 1.80 - 1.74 (m, 2H), 1.68 - 1.62 (m, 2H), 1.58 (s, 3H), 1.36 - 1.27 (m, 2H), 1.06 - 0.93 (m, 2H); LC / MS m / z (M+H) + = 475.4.

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

[0189] [ka] According to amidation method A, 2-isopropyl-5H-spiro[benzo[d]thiazol-6,4'-piperidin]-4(7H)-one (0.047 g, 0.159 mmol), prepared as in Example P1, was coupled with 7-methoxy-1,3-dimethyl-1H-indazole-5-carboxylic acid (0.035 g, 0.16 mmol). The residue was purified by preparative HPLC (column: Boston Prime C18, 150 × 30 mm, 5 μm); mobile phase A: water (0.05% v / v formic acid); mobile phase B: MeCN; gradient from 14 to 54% B over 9 min, with a hold of 100% B for 2 min; flow rate: 25 mL / min) to give the title compound (17.7 mg, 24%). 1 H NMR (400 MHz, methanol-d4) δ 7.35 (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.

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

[0191] [ka] According to amidation method A, 2-(1-methylcyclopropyl)-5H-spiro[benzo[d]thiazol-6,4'-piperidin]-4(7H)-one (0.05 g, 0.16 mmol), prepared as in Example P1, was coupled with 7-methoxy-1,3-dimethyl-1H-indazole-5-carboxylic acid (0.035 g, 0.16 mmol). The residue was purified by preparative HPLC (column: YMC Triart C18, 150 × 25 mm, 5 μm); mobile phase A: water (0.05% v / v concentrated NH4OH); mobile phase B: MeCN; gradient of 26–56% B over 9 min, 100% B held for 2 min; flow rate: 25 mL / min) to give the title compound (19 mg, 25%). 1 H NMR (400 MHz, methanol-d4) δ 7.35 (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), 2.73 (s, 2H), 2.51 (s, 3H), 1.72 - 1.66 (m, 4H), 1.58 (s, 3H), 1.36 - 1.27 (m, 2H), 1.07 - 0.97 (m, 2H); LC / MS m / z (M+H) + = 479.4.

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

[0193] [ka] 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 (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), prepared as in Preparation P1, in DMF (15 mL) was added EtN (0.51 mL, 3.66 mmol) at about 25 °C. The mixture was stirred at about 25 °C for about 16 hours and then diluted with EtOAc (50 mL). The mixture was washed with saturated aqueous Na2CO3 (2 x 25 mL) and brine (2 x 25 mL). The organic phase was dried over MgSO4, filtered, and concentrated. The residue was purified by chromatography (silica, EtOAc:heptane, 0-100%) to afford the title compound (0.15 g, 67.5%) as a white solid. 1 H NMR (400 MHz, methanol-d4) δ 7.35 (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.

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

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

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

[0197] [ka] Step 1: Synthesis of ethyl 7-ethoxy-1,3-dimethyl-1H-indazole-5-carboxylate (C10)

[0198] [ka] 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 ethyl iodide (0.30 g, 0.16 mL, 1.96 mmol). The reaction was heated to reflux for approximately 24 hours and then concentrated. The residue was diluted with water (25 mL) and extracted with EtOAc (2 × 25 mL). The combined EtOAc extracts were washed with brine (25 mL), dried over MgSO4, filtered, and concentrated. The residue was purified by chromatography (silica, EtOAc / hexanes, 0–25%) to afford the title compound (0.27 g, 74% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 7.99 (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.

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

[0200] [ka] To compound C10 (268 mg, 1.02 mmol) in EtOH (5.1 mL) and THF (5.1 mL) was added 1 M aqueous NaOH solution (5.1 mL, 5.1 mmol). The mixture was stirred at about 25° C. for about 17 hours and then concentrated under reduced pressure. To the mixture was added 1.5 M aqueous citric acid solution (2.5 mL) and water (2 mL). After stirring for about 3 minutes, the precipitate was isolated by filtration to give the title compound (230 mg, 96.3%). 1H NMR (400 MHz, DMSO-d6) δ 12.78 (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).

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

[0202] [ka] 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 i PrNEt (2.18 mL, 2.5 mmol) was added. The mixture was heated at about 50° C. for about 2 hours and then cooled to room temperature. Preparation P1 (2.23 g, 5.5 mmol), iPrNEt (3.48 mL, 4.00 mmol) and water (5.0 mL) were added, and the mixture was again heated at about 50° C. for about 2 hours, followed by stirring at room temperature for about 16 hours. The reaction mixture was diluted with EtOAc (150 mL) and washed with water (2×100 mL). The aqueous layer was back-extracted with EtOAc (50 mL). The combined EtOAc extracts were then washed with 0.25 N HCl (2×50 mL), and the aqueous layer was back-extracted with EtOAc (50 mL). The combined EtOAc extracts were then washed with saturated aqueous NaHCO (2×50 mL), and the aqueous layer was back-extracted with EtOAc (50 mL). The combined EtOAc extracts were washed with brine (50 mL), dried over MgSO, filtered through Celite, and concentrated to give a light yellow solid (2.47 g, 99%). The solid was dissolved in EtOAc (20 mL) and heated at about 50° C. for about 10 minutes, followed by the addition of heptane (200 mL) and further heating at about 70° C. for about 2 hours. After cooling to room temperature, the mixture was stirred for about 72 hours. The solid was filtered, washed with premixed and chilled 25% EtOAc-heptane (100 mL), and dried under high vacuum to provide the title compound (2.1 g, 84.9%). 1 H NMR (400 MHz, CD3OD) δ 7.31 (s, 1H), 6.82 (s, 1H), 4.23 (q, 2H), 4.21 (s, 3H), 3.80-3.60 (m, 4H), 3.25 (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

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

[0204] [ka] Step 1: Synthesis of ethyl 8-methylquinoline-6-carboxylate (C12)

[0205] [ka] To a solution of 6-bromo-8-methylquinoline (900 mg, 4.05 mmol) in EtOH (25 mL) was added Pd(OAc) (91 mg, 0.405 mmol), DBU (0.91 mL, 6.08 mmol), Mo(CO) (588 mg, 2.23 mmol), and TTBP·HBF (118 mg, 0.405 mmol). The mixture was sparged with N for approximately 1 minute, sealed in a microwave tube, and irradiated in a microwave (Biotage Smith Synthesizer) at approximately 120 °C for approximately 70 minutes. The mixture was concentrated under reduced pressure to give the crude residue. Purification by chromatography (0–25% EtOAc in petroleum ether) afforded the title compound (800 mg, 92%). LC / MS m / z (M+H) + = 215.9.

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

[0207] [ka] The following reaction was carried out in two batches in parallel. To a solution of compound C12 (350 mg, 1.63 mmol) in CCl4 (15 mL) was added pyridine (0.26 mL, 3.25 mmol) and Br2 (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 H2O (20 mL). The mixture was extracted with EtOAc (2 × 15 mL), washed with saturated aqueous NaHCO3, dried over Na2SO4, filtered, and concentrated under reduced pressure. The two batches were combined, and the residue was purified by chromatography (0% to 20% EtOAc in petroleum ether) to give the title compound (500 mg, 26% per reaction). 1H NMR (400 MHz, 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.

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

[0209] [ka] To compound C13 (500 mg, 1.70 mmol) was added tert-butyl methylcarbamate (334 mg, 2.55 mmol), Pd(dba) (78 mg, 0.085 mmol), X-Phos (81 mg, 0.17 mmol), CsCO (1.66 g, 5.1 mmol), and toluene (17 mL). The mixture was sparged with N. The mixture was stirred at about 120 °C for about 16 hours. The mixture was cooled to about 25 °C and filtered. The filtrate was concentrated under reduced pressure and diluted with EtOAc (20 mL). The mixture was washed with H0 (3 × 5 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by chromatography (0% to 30% EtOAc in petroleum ether) to give the title compound (450 mg, 77%). LC / MS m / z (M+H) + = 345.2.

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

[0211] [ka] To compound C14 (450 mg, 1.31 mmol) in MeOH (12 mL) and HO (4.0 mL) was added LiOH·HO (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 diluted with HO (10 mL). 1N HCl was added until the pH was 3-4, and the mixture was extracted with EtOAc (2 × 20 mL). The combined organic phases were dried over NaSO, filtered, and concentrated under reduced pressure to give the title compound (400 mg, 97%). 1 H NMR (400 MHz, 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.

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

[0213] [ka] 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 hours and then concentrated under reduced pressure to provide the title compound (399 mg, 100%). LC / MS m / z (M+H) + = 217.0.

[0214] Step 6: Synthesis of 2-(tert-butyl)-1′-(8-methyl-3-(methylamino)quinoline-6-carbonyl)-5H-spiro[benzo[d]thiazol-6,4′-piperidin]-4(7H)-one (Example 15)

[0215] [ka] To a solution of compound C16 (200 mg, 0.79 mmol) in DMF (4.0 mL) was added HATU (301 mg, 0.79 mmol) and iPrNEt (0.40 mL, 2.31 mmol). The mixture was stirred at about 25 °C for about 10 minutes. Preparation P1 (208 mg, 0.66 mmol) was then added. The mixture was stirred at about 25 °C for about 1 hour. The residue was concentrated and purified by preparative HPLC (column: Boston Prime C18, 30 × 150 mm, 5 μm; mobile phase A: water (0.05% v / v concentrated NHOH); mobile phase B: MeCN; gradient of 28–58% B over 9 minutes, 100% B held for 2 minutes; flow rate: 25 mL / min) to give the title compound (229 mg, 61%). 1 H NMR (400 MHz, CD3OD) δ = 8.45 (d, 1H), 7.58 (d, 1H), 7.21 (dd, 1H), 7.10 (d, 1H), 3.83 (m, 2H), 3.52 (s, 2H), 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.

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

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

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

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

[0220] [ka] To a solution of methyl 4-hydroxy-2-naphthoate C17 (19.4 g, 96 mmol) in CHCl (480 mL) at about 0 °C was added iPrNEt (83.6 mL, 480 mmol), followed by the slow addition of N-phenyl-bis(trifluoromethanesulfonamide) (45.3 g, 127 mmol) in portions over about 10 minutes. The mixture was stirred at about 25 °C for about 16 hours. The reaction was quenched using 1 N HCl (350 mL), and the organic phase was then separated. The aqueous phase was extracted with additional CHCl. ​​The combined organic phases were washed sequentially with saturated aqueous NaCO (200 mL) and brine (100 mL), dried over MgSO, filtered, and concentrated. The residue was purified by chromatography (silica, EtOAc / hexanes, 0–10%) to afford the title compound (30 g, 93% yield) as a white solid. 1H NMR (400 MHz, chloroform-d) δ 8.65 (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.

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

[0222] [ka] To a solution of methyl 4-(((trifluoromethyl)sulfonyl)oxy)-2-naphthoate C18 (22.4 g, 67 mmol) in dioxane (134 mL) was added potassium carbonate (30.6 g, 221 mmol), trimethylboroxine (25.2 g, 28.1 mL, 210 mmol), and water (3.36 mL, 2.78 mmol). The mixture was degassed and purged with N2 / vacuum cycles (3 times), then Pd(dppf)Cl2 (1.37 g, 1.68 mmol) was added. The reaction was heated at about 60 °C for about 2 hours. The mixture was cooled to about 25 °C and diluted with EtOAc (250 mL). The EtOAc layer was washed with water (100 mL), brine (100 ml), dried over MgSO4, filtered, and concentrated. The residue was purified by chromatography (silica, EtOAc / hexanes, 0-5%) to afford the title compound (10.2 g, 75% yield) as a white solid. 1 H NMR (400 MHz, chloroform-d) δ 8.38 (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.

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

[0224] [ka] 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 approximately 96 h, the mixture was concentrated and the residue was diluted with 1 N NaOH (50 mL). The aqueous residue 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 give the title compound (9.6 g, 74.8%). 1 H NMR (400 MHz, methanol-d4) δ 8.48 (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.

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

[0226] [ka] To a solution of Preparation 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 100 mL of EDCI·HCl (14.4 g, 75 mmol) at approximately 25 °C. iPrNEt (61 mL, 350 mmol) was added. The mixture was stirred at about 25 °C for about 16 h and then diluted with EtOAc (300 mL). The mixture was washed sequentially with 1 N HCl (300 mL), saturated aqueous NaHCO (200 mL), and brine (200 mL). The organic phase was dried over MgSO, 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 dried over MgSO to give a solid. The residue was purified by chromatography (silica, EtOAc / hexanes, 10–86%) to give the title compound (16.9 g, 76% yield) as a white solid. 1 H NMR (400 MHz, methanol-d4) δ 8.08 (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.

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

[0228] [ka] A solution of Preparation P1 (6.3 g, 20 mmol), 7-methyl-1H-indole-5-carboxylic acid (4.2 g, 24 mmol, supplied by PharmaBlock), EDCI·HCl (4.79 g, 25 mmol), and HOBt (3.97 g, 25 mmol) in DMF (100 mL) was heated at approximately 25 °C. iPrNEt (20.9 mL, 120 mmol) was added. The mixture was stirred at about 25 °C for about 16 h and then diluted with EtOAc (200 mL). The resulting mixture was washed sequentially with 5% aqueous LiCl (100 mL), saturated aqueous NaHCO (50 mL), and brine (50 mL). The organic phase was dried over MgSO, filtered, and concentrated. The residue was purified by chromatography (silica, EtOAc / hexanes, 5–100%, then MeOH-EtOAc, 0–10%) to afford the title compound (8.0 g, 84% yield) as a white solid. 1 H NMR (400 MHz, methanol-d4) δ 7.52 (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.

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

[0230] [ka] Prepared in the same manner as Example 15 using tert-butyl ethyl carbamate instead of tert-butyl methyl carbamate in step 3 to give the title compound (353 mg). 1 H NMR (400 MHz, CD3OD) δ 8.46 (s, 1H), 7.56 (s, 1H), 7.20 (s, 1H), 7.11 (s, 1H), 3.86-3.79 (m, 4H), 3.52 (m, 2H), 3.25-3.20 (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.

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

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

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

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

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

[0236] [ka] Prepared in the same manner as example 15 using 2-methyl-2-thiopseudourea hemisulfate instead of tert-butyl methylcarbamate and PdCl2dppf in step 3 to give the title compound (28 mg). 1 H NMR (400 MHz, CD3OD) δ 8.78 (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.

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

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

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

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

[0241] [ka] To a solution of Preparation P1 (50 mg, 0.16 mmol), Compound C21 (68 mg, 0.24 mmol), and EDCI (61 mg, 0.32 mmol) in a microwave vial, pyridine (3.0 mL) was added. The mixture was irradiated in a microwave at approximately 110 °C for approximately 30 minutes. The mixture was concentrated under reduced pressure and purified by preparative HPLC (column: C18-1, 30 × 150 mm, 5 μm); mobile phase A: water (0.05% v / v concentrated NH4OH); mobile phase B: MeCN; gradient of 30–70% B for 9 minutes, hold at 100% B for 2 minutes; flow rate 30 mL / min) to give the title compound (21 mg, 24%). 1 H NMR (400 MHz, CD3OD) δ 8.16 (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.

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

[0243] [ka] Prepared in the same manner as Example 22 using 2-chloro-6-methoxyisonicotinic acid instead of methyl 2-chloro-6-(dimethylamino)isonicotinate in step 1 to give the title compound (18 mg). 1 H NMR (400 MHz, CD3OD) δ 8.23 ​​(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.

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

[0245] [ka] Step 1: 3-Bromo-N-(2,2-dimethoxyethyl)-5-methylbenzamide (C22)

[0246] [ka] To a solution of 2,2-dimethoxyethan-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 hours. Water (10 mL) was added, and the mixture was extracted with DCM (2×20 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography to provide the title compound (3.0 g, 85%).

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

[0248] [ka] To compound C22 (3.50 g, 12.3 mmol) was added concentrated H2SO4 (30 mL) at about 0 °C. The mixture was stirred at about 25 °C for about 16 hours and then heated at about 50 °C for about 5 hours. The mixture was slowly poured into ice water (200 mL) and then extracted with EtOAc (3 x 300 mL). The combined organic phases were dried over Na2SO4, 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 minutes. The solid was collected by filtration to give a mixture of the title compound and the regioisomer, 5-bromo-7-methylisoquinolin-1(2H)-one (1.8 g, 76%). LC / MS m / z (M+H) + = 238.0.

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

[0250] [ka] To compound C23 (mix of regioisomers, 1.00 g, 4.2 mmol) in MeOH (50 mL) was added Pd(dppf)Cl (461 mg, 0.63 mmol) and triethylamine (1.28 g, 12.6 mmol). The mixture was heated at about 80 °C under a CO atmosphere (50 psi) for about 48 hours. 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 give the title compound and the regioisomer, methyl 7-methyl-1-oxo-1,2-dihydroisoquinoline-5-carboxylate (600 mg, 66%). The isomers were separated by preparative SFC (column: Daicel Chiralpak AD, 30 x 250 mm, 10 μm; mobile phase A: water (0.1% v / v NHOH); mobile phase B: EtOH; 35% B, flow rate 80 mL / min) to give the title compound (100 mg, 11%). LC / MS m / z (M+H) + = 218.0.

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

[0252] [ka] To compound C24 (100 mg, 0.46 mmol) was added POCl3 (1.41 g, 9.2 mmol). The mixture was heated at about 100 °C for about 2 hours. The reaction was concentrated under reduced pressure and the pH was adjusted to about 8 with NaHCO3 (aq). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography (0% to 50% EtOAc in petroleum ether) to give the title compound (105 mg, 97%). LC / MS m / z (M+H) + = 236.0.

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

[0254] [ka] To compound C25 (105 mg, 0.45 mmol) in NMP (5 mL) was added i-PrNEt (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 hours. The solution was cooled to about 30 °C and diluted with water (10 mL). The mixture was extracted with EtOAc (2 × 10 mL), and the combined organic phases were dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by chromatography (0% to 50% EtOAc in petroleum ether) to give the title compound (50 mg, 49%). LC / MS m / z (M+H) + = 231.0.

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

[0256] [ka] 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 hours. 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 formed, which was collected by filtration to provide the title compound (28 mg, 60%). LC / MS m / z (M+H) + = 217.0.

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

[0258] [ka] Compound C27 (28 mg, 0.13 mmol) was coupled to Preparation P1 according to amidation method A. The residue was purified by preparative HPLC (column: Boston Prime C18, 30 × 150 mm, 5 μm); mobile phase A: water (0.05% v / v concentrated NH4OH); mobile phase B: MeCN; gradient of 29–69% B over 9 min, hold at 100% B for 2 min; flow rate 25 mL / min) to give the title compound (40 mg, 64%). 1 H NMR (400 MHz, CD3OD) δ 8.02 (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.

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

[0260] [ka] Prepared in the same manner as example 24 using cyclopropylboronic acid instead of methylamine hydrochloride in step 5 to give the title compound (32 mg). 1 H NMR (400 MHz, CD3OD) δ 8.37 (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), 2.76 (m, 1H), 2.66 (s, 2H), 2.63 (s, 3H), 1.71 (m, 2H), 1.57 (m, 2H), 1.35 (s, 9H), 1.08 (d, 4H); LC / MS m / z (M+H) + = 488.4.

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

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

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

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

[0265] [ka] 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 hours. The mixture was concentrated under reduced pressure to provide the title compound (10 mg, 96%). LC / MS m / z (M+H) + = 231.0.

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

[0267] [ka] 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 hour. EtOH was removed under reduced pressure, and the mixture was acidified to pH 7 with 2N HCl. The precipitate was filtered and dried in vacuo to give the title compound (9.4 mg, 100%). LC / MS m / z (M+H) + = 217.0.

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

[0269] [ka] Compound C30 (9 mg, 0.044 mmol) was coupled to Preparation P1 according to amidation method C. The residue was purified by preparative HPLC (column: Boston Prime C18, 30 × 150 mm, 5 μm); mobile phase A: water (0.05% v / v concentrated NH4OH); mobile phase B: MeCN; gradient of 32–62% B over 9 min, hold at 100% B for 2 min; flow rate 25 mL / min) to give the title compound (2.9 mg, 14%). 1H NMR (400 MHz, CD3OD) δ 8.17 (s, 1H), 7.89 (d, 1H), 7.72-7.70 (m, 2H), 3.87-3.81 (m, 2H), 3.50 (m, 2H), 3.25 (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.

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

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

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

[0273] [ka] Step 1: Methyl 5-methoxyisoquinoline-7-carboxylate (C31)

[0274] [ka] To methyl 5-bromoisoquinoline-7-carboxylate (1.00 g, 3.76 mmol, prepared as described in International Patent Application WO2021 / 028806), RockPhos-Pd-G3 (95 mg, 0.113 mmol), and Cs2CO3 (1.22 g, 3.76 mmol) was added MeOH (1.2 g, 37.6 mmol) and dioxane (20 mL). The mixture was heated at about 70 °C for about 16 hours. 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 give the title compound (450 mg, 55%). LC / MS m / z (M+H) + = 217.9.

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

[0276] [ka] 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 hours. Saturated NaSO (aq) was added, followed by saturated NaCO (aq) until the pH was greater than 8. The mixture was stirred for about 30 minutes and then extracted with DCM (2×10 mL) and HO (2×10 mL). The DCM extract was dried over NaSO, filtered, and concentrated under reduced pressure to provide the title compound (450 mg, 93%). LC / MS m / z (M+H) + = 234.0.

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

[0278] [ka] To a solution of compound C32 (450 mg, 1.93 mmol) in DCM (10 mL) was added POCl (0.90 mL, 9.65 mmol). The mixture was stirred at about 50° C. for about 2 hours and then cooled to about 25° C. The mixture was concentrated under reduced pressure, and NaHCO (aq) was added until the pH was about 8. The organic phase was separated, dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by chromatography (0% to 40% EtOAc in petroleum ether) to give the title compound (200 mg, 41%). LC / MS m / z (M+H) + = 252.0.

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

[0280] [ka] To a solution of compound C33 (60 mg, 0.24 mmol) and trimethylboroxine (60 mg, 0.24 mmol) in THF (2 mL) was added Pd(dtbpf)Cl (7.8 mg, 0.012 mmol) and CsCO (155 mg, 0.477 mmol). The mixture was heated at about 70 °C for about 2 hours and then concentrated under reduced pressure. The residue was purified by chromatography (0% to 30% EtOAc in petroleum ether) to give the title compound (40 mg, 73%). LC / MS m / z (M+H) + = 232.0.

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

[0282] [ka] To a solution of compound C34 (40 mg, 0.17 mmol) in MeOH (2 mL) and water (1 mL) was added LiOH·HO (15 mg, 0.35 mmol). The mixture was stirred at about 25° C. for about 2 hours and then heated at about 50° C. for about 2 hours. The solution was concentrated under reduced pressure and the pH was adjusted to about 5 with 1 M HCl. The resulting precipitate was filtered to give the title compound (38 mg, 100%). LC / MS m / z (M+H) + = 217.9.

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

[0284] [ka] Compound C35 (38 mg, 0.17 mmol) was coupled to Preparation P1 according to amidation method A. The residue was purified by preparative HPLC (column: Boston Prime C18, 30 × 150 mm, 5 μm); mobile phase A: water (0.05% v / v concentrated NH4OH); mobile phase B: MeCN; gradient of 29–59% B over 9 min, hold at 100% B for 2 min; flow rate 30 mL / min) to give the title compound (24 mg, 28%). 1 H NMR (400 MHz, CD3OD) δ 8.33 (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.

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

[0286] [ka] Prepared in the same manner as Example 28 using triethylborane instead of trimethylboroxine in Step 1 to give the title compound (5.0 mg). 1 H NMR (400 MHz, CD3OD) δ 8.37 (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, 2H), 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.

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

[0288] [ka] Step 1: Methyl 2-(isopropylamino)quinoline-7-carboxylate (C36)

[0289] [ka] To a solution of 7-(methoxycarbonyl)quinoline 1-oxide (200 mg, 0.98 mmol) in DCM (15 mL) was added dropwise trifluoromethanesulfonic anhydride (304 mg, 1.08 mmol) at about −70° C. The mixture was stirred at about −70° C. for about 5 minutes, and then a 2 M solution of isopropylamine in THF (2.94 mL, 5.88 mmol) was added dropwise. The mixture was stirred at about −70° C. for about 5 minutes, and then water (15 mL) was added. The layers were separated, and the aqueous phase was extracted with DCM (20 mL). The combined DCM extracts were washed with brine (2×10 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by chromatography (0% to 40% EtOAc in petroleum ether) to give the title compound (150 mg, 63%). LC / MS m / z (M+H) + = 245.1.

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

[0291] [ka] 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 at about 50° C. for about 16 hours. The mixture was concentrated under reduced pressure and treated with 2 M HCl until the pH was about 5. The resulting precipitate was filtered to give the title compound (135 mg, 96%). LC / MS m / z (M+H) + = 231.1.

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

[0293] [ka] Compound C37 (50 mg, 0.22 mmol) was coupled to Preparation P1 according to amidation method A. The residue was purified by preparative HPLC (column: Boston Prime C18, 30 × 150 mm, 5 μm); mobile phase A: water (0.05% v / v concentrated NH4OH); mobile phase B: MeCN; gradient of 32–62% B over 9 min, hold at 100% B for 2 min; flow rate 25 mL / min) to give the title compound (36 mg, 34%). 1 H NMR (400 MHz, CD3OD) δ 7.83 (d, 1H), 7.68-7.63 (m, 2H), 7.19 (dd, 1H), 6.78 (d, 1H), 4.30 (Septet, 1H), 3.88-3.83 (m, 2H), 3.55 (m, 2H), 3.27 (s, LC / MS m / z (M+H) + = 491.4.

[0294] Example 31 2-(tert-butyl)-1'-(2-(cyclobutylamino)quinoline-7-carbonyl)-5H-spiro[benzo[d]thiazol-6,4'-piperidin]-4(7H)-one

[0295] [ka] Prepared in the same manner as Example 30 using cyclobutylamine instead of isopropylamine in step 1 to give the title compound (46 mg). 1 H NMR (400 MHz, CD3OD) δ 7.83 (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.

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

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

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

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

[0300] [ka] 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 hours. The reaction mixture was concentrated under reduced pressure. The resulting residue was purified by chromatography (17% EtOAc in petroleum ether, then 20% MeOH in EtOAc) to give the title compound (600 mg, 79%). 1 H NMR (400 MHz, CDCl3) δ = 6.88 (s, 1H), 3.77 (s, 3H), 2.18 (s, 3H), 2.15 (s, 3H); LC / MS m / z (M+H) + = 231.9.

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

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

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

[0304] [ka] To compound C39 in EtOH (5.0 mL) was added Mo(CO) (93 mg, 0.353 mmol), TTBP·HBF (21 mg, 0.0705 mmol), DBU (0.16 mL, 1.06 mmol), and Pd(OAc) (15.8 mg, 0.0705 mmol). The mixture was irradiated in a microwave reactor at about 100 °C for about 1 hour and then cooled to about 25 °C. The mixture was concentrated under reduced pressure and purified by chromatography (17% EtOAc in petroleum ether) to give the title compound (70 mg, 42%). 1 H NMR (400 MHz, CDCl3) 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.

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

[0306] [ka] To compound C40 (70 mg, 0.30 mmol) in MeOH (1.0 mL) and THF (2.0 mL) was added a solution of LiOH·HO (38 mg, 0.90 mmol) in HO (1.0 mL). The mixture was stirred at about 25 °C for about 16 hours, and then HO (10 mL) was added. The mixture was washed with EtOAc (10 mL), and the aqueous phase was then acidified to pH about 6 with 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.

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

[0308] [ka] To a solution of compound C41 (62 mg, 0.30 mmol) in DMF (2.0 mL) was added EtN (0.17 mL, 1.2 mmol) and T3P (0.36 mL of a 50 w / w% solution in EtOAc, 0.60 mmol) at about 0 °C. Preparation 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) and washed with water (15 mL) and brine (15 mL). The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Boston Green ODS, 30 × 150 mm, 5 μm; mobile phase A: water (0.2 v / v% concentrated HCl); mobile phase B: MeCN; gradient of 23–63% B over 9 min, hold at 100% B for 2 min; flow rate 30 mL / min) to give the title compound (27 mg, 19%). 1 H NMR (400 MHz, CD3OD) 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.

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

[0310] [ka] Prepared in the same manner as example 33 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 (400 MHz, CD3OD) δ 8.11 (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.

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

[0312] [ka] Prepared in the same manner as example 33 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 (400 MHz, CD3OD) δ 8.13 (s, 1H), 7.26 (s, 1H), 3.70-3.59 (m, 4H), 3.23 (s 2H), 2.73 (s, 2H), 2.55 (s, 3H), 2.39 (s, 3H), 1.76-1.67 (m, 4H), 1.43 (s, 9H); LC / MS m / z (M+H) + = 451.4.

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

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

[0315] [ka] To 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-ol (2.5 g, 10.76 mmol) and K2CO3 (2.98 g, 21.5 mmol) was added DMF (30 mL). The mixture was cooled to about 0-5 °C and stirred for about 10 minutes. Iodomethane (1.01 mL, 16.1 mmol) was added dropwise, and the mixture was stirred at about 25 °C for about 20 hours. Water (30 mL) was added, and the mixture was extracted with EtOAc (3 × 30 mL). The combined EtOAc extracts were washed with saturated brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (0-20% EtOAc in petroleum ether) to give the title compound (2.40 g, 91%). LC / MS m / z (M+H) + = 247.0.

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

[0317] [ka] 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 hours. Water (30 mL) was added, and the mixture was extracted with EtOAc (3×20 mL). The combined EtOAc extracts were washed with saturated brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (0-20% EtOAc in petroleum ether) to give the title compound (1.90 g, 81%). LC / MS m / z (M+H) + = 242.8.

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

[0319] [ka] To a solution of compound C43 (1.20 g, 3.0 mmol) in EtOH (20 mL) was added Pd(OAc) (54 mg, 0.239 mmol), tBuP·BF (87 mg, 0.30 mmol), DBU (682 mg, 4.48 mmol), and Mo(CO) (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 give the title compound (450 mg, 64%). LC / MS m / z (M+H) + = 235.0.

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

[0321] [ka] 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 hours. The mixture was concentrated under reduced pressure, and the residue was acidified to pH 5 with 2N HCl. The precipitate was filtered to give the title compound (580 mg, 94%). LC / MS m / z (M+H) + = 206.9.

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

[0323] [ka] Compound C45 (300 mg, 1.45 mmol) was coupled to Preparation P1 according to amidation method A. The residue was purified by preparative HPLC (column: Boston Prime C18, 30 × 150 mm, 5 μm); mobile phase A: water (0.05% v / v concentrated NH4OH); mobile phase B: MeCN; gradient of 30–60% B over 9 min, hold at 100% B for 2 min; flow rate 30 mL / min) to give the title compound (345 mg, 51%). 1 H NMR (400 MHz, CD3OD) δ 8.32 (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.

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

[0325] [ka] Step 1: Synthesis of 1-bromo-4-chloro-5-methoxy-2-nitrobenzene (C46)

[0326] [ka] To 4-bromo-1-chloro-2-methoxybenzene (1.00 g, 4.52 mmol) was added H2SO4 (3 mL), and the mixture was cooled to approximately 0 °C and stirred for approximately 10 min. HNO3 (0.43 mL, 11.3 mmol) was added portionwise. The mixture was slowly warmed to approximately 20 °C over approximately 16 h. The mixture was poured onto ice water and adjusted to pH 7–9 with Na2CO3. The mixture was extracted with EtOAc (3 × 200 mL), and the combined EtOAc extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (0–2% EtOAc in DCM) to afford the title compound and the dinitrated by-product, 2-bromo-5-chloro-4-methoxy-1,3-dinitrobenzene (1.10 g, <91% yield). 1 H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 7.22 (s, 1H), 4.01 (s, 3H).

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

[0328] [ka] To compound C46 (1.10 g, approximately 20% purity, 0.83 mmol) in THF (10 mL) was added vinylmagnesium bromide (1 M, 15 mL, 15 mmol) at approximately −50° C. The mixture was warmed to approximately −20° C. and stirred for approximately 16 hours. The mixture was warmed to 0° C., and NH4Cl (30 mL) and EtOAc (50 mL) were added. The phases were separated, and the aqueous phase was extracted with EtOAc (3×20 mL). The combined EtOAc extracts were washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (5% EtOAc in petroleum ether) to give the title compound (30 mg, 14% yield). LC / MS m / z (M+H) + = 261.8.

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

[0330] [ka] To a solution of compound C47 (50 mg, 0.19 mmol) in EtOH (10 mL) was added Pd(OAc) (3.5 mg, 0.0154 mmol), tBuP·BF (5.6 mg, 0.0192 mmol), DBU (44 mg, 0.288 mmol), and Mo(CO) (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 give the title compound (20 mg, 41%). LC / MS m / z (M+H) + = 254.0.

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

[0332] [ka] To a solution of compound C48 (20 mg, 0.079 mmol) in water (1 mL) and THF (2 mL) was added LiOH·HO (6.6 mg, 0.16 mmol) at about 15° C. The mixture was stirred at about 50° C. for about 16 hours. The mixture was concentrated under reduced pressure, and the residue was acidified to pH 5 with 2N HCl. The solution was concentrated to give the title compound (15 mg, 84%). LC / MS m / z (M+H) + = 225.9.

[0333] 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

[0334] [ka] Compound C49 (15 mg, 1.45 mmol) was coupled to Preparation P1 according to amidation method A. The residue was purified by preparative HPLC (column: Boston Prime C18, 30 × 150 mm, 5 μm); mobile phase A: water (0.05% v / v concentrated NH4OH); mobile phase B: MeCN; gradient of 40–70% B over 9 min, hold at 100% B for 2 min; flow rate 30 mL / min) to give the title compound (4.5 mg, 14%). 1 H NMR (400 MHz, CD3OD) δ 7.35 (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.

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

[0336] [ka] To a solution of Preparation P1 (1.26 g, 4.01 mmol), Preparation 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 1.26 g of EDCI (1.26 g, 4.01 mmol), 5.26 mg of EDCI (581 mg, 2.69 mmol), 5.26 mg of EDCI (773 mg, 4.04 mmol), and 5.26 mg of HOBt (582 mg, 4.31 mmol) at approximately 25° C. iPrNEt (5 mL, 26.9 mmol) was added. The mixture was stirred at about 25 °C for about 16 h and then diluted with EtOAc. The mixture was washed sequentially with 5% aqueous LiCl, saturated aqueous NaHCO, and 1:1 brine:water (30 mL). The organic phase was dried over MgSO, filtered, and concentrated. The residue was purified by column chromatography (0-20% MeOH in DCM) to give the title compound (1.28 g, 86%). 1 H NMR (400 MHz, DMSO-d6) δ 7.99 (d, 1H), 7.31 (s, 1H), 7.07 (s, 1H), 6.96 (s, 1H), 6.81 (d, 1H), 3.75-3.35 (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.

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

[0338] [ka] Step 1: Synthesis of 7-bromo-N-ethyl-5-methylquinolin-2-amine (C50)

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

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

[0341] [ka] To compound C50 (80 mg, 0.30 mmol) were 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 at about 80° C. for about 18 hours. The mixture was diluted with ether and filtered through Celite. The mixture was concentrated under reduced pressure, redissolved in DCM, and filtered through silica. The mixture was concentrated under reduced pressure. To the residue were added THF (0.2 mL), triethylamine (21 μL, 0.15 mmol), Preparation P1 (25 mg, 0.087 mmol), and DMAP (0.5 mg, 0.004 mmol). The mixture was stirred at about 50° C. for about 16 hours. Water was added, and the mixture was extracted with EtOAc (twice). The combined EtOAc extracts were dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: XBridge C18, 19 x 100 mm, 5 μm) to give the title compound (27 mg, 18%). LC / MS m / z (M+H) + = 491.5.

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

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

[0344] [ka] The following reaction was carried out in two parallel 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 aqueous NaSO was added. Saturated aqueous NaCO was added until the pH was greater than 8, and the mixture was then stirred for about 30 min. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was diluted with DCM (50 mL) and washed with water (3 × 20 mL). The DCM extract was dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (0% to 15% MeOH in EtOAc) to give the title compound (1.90 g, average yield 95%). LC / MS m / z (M+H) + = 233.9.

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

[0346] [ka] To compound C51 (1.20 g, 5.15 mmol) in DCM (30 mL) was added TfO (1.60 g, 5.66 mmol) dropwise at about −70° C. The mixture was stirred at −70° C. for about 15 minutes, and then MeNH (2 M in THF, 20.6 mL, 41.2 mmol) was added dropwise. The mixture was stirred at about −70° C. for about 15 minutes, and then water (30 mL) was added. The aqueous phase was extracted with DCM (30 mL). The combined DCM extracts were washed with brine (2×10 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (0% to 60% EtOAc in petroleum ether) to give the title compound (800 mg, 63% yield). LC / MS m / z (M+H) + = 247.0.

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

[0348] [ka] 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 hours. The ethanol was removed under reduced pressure and the residue was acidified to pH 5 with 2N HCl. The precipitate was filtered to give the title compound (730 mg, 97% yield). LC / MS m / z (M+H) + = 232.9.

[0349] 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

[0350] [ka] Compound C53 (300 mg, 1.29 mmol) was coupled according to general amide coupling procedure A. The residue was purified by preparative HPLC (column: Boston Prime C18, 30 × 150 mm, 5 μm); mobile phase A: water (0.05 v / v % concentrated NH4OH); mobile phase B: MeCN; gradient of 28–58% B over 9 min, hold at 100% B for 2 min; flow rate 30 mL / min) to give the title compound (259 mg, 41%). 1 H NMR (400 MHz, CD3OD) δ 8.14 (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.

[0351] Example 41 2-(tert-butyl)-1'-(4-methoxy-8-methylquinoline-6-carbonyl)-5H-spiro[benzo[d]thiazol-6,4'-piperidin]-4(7H)-one

[0352] [ka] Step 1: Synthesis of 6-bromo-4-methoxy-8-methylquinoline (C54)

[0353] [ka] 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 hours. The mixture was cooled to about 25° C. and diluted with EtOAc. The mixture was washed with water (twice) and brine. The combined EtOAc extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure to give 6-bromo-4-chloro-8-methylquinoline, a 1:1 mixture of the title compounds (2.50 g). LC / MS m / z (M+H) + = 254.2.

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

[0355] [ka] To a solution of compound C54 (3.06 g, 12.2 mmol) in MeOH (100 mL) was added triethylamine (5.5 mL, 39 mmol) and Pd(dppf)Cl2 (720 mg, 0.882 mmol). The mixture was added to a Parr reactor and flushed with nitrogen (3 times) and CO2 (3 times). The mixture was stirred at about 80 °C and 75 PSI of CO2 for about 16 hours. 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 give the title compound (1.96 g, 70%). LC / MS m / z (M+H) + = 232.5.

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

[0357] [ka] To a solution of compound C55 (1.96 g, 8.48 mmol) in THF (65 mL) was added 2 M NaOH (25 mL, 50 mmol). The mixture was stirred at about 25° C. for about 18 hours. The mixture was acidified to pH 6 with concentrated HCl. The mixture was extracted with EtOAc (2×), and the combined EtOAc extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to provide the title compound (1.46 g, 79%). LC / MS m / z (M+H) + = 218.0.

[0358] 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

[0359] [ka] To a solution of Preparation 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 10 mL of ethanol at approximately 25° C. i PrNEt (1.0 mL, 5.6 mmol) was added. The mixture was stirred at about 25 °C for about 16 hours. To the mixture, additional EDCI (225 mg, 1.17 mmol), HOBt (198 mg, 1.40 mmol), and EtN (0.72 mL, 5.2 mmol) were added. The mixture was stirred at about 25 °C for about 2 hours and then diluted with EtOAc. The mixture was washed sequentially with 5% aqueous LiCl, saturated aqueous NaHCO, and 1:1 brine:water. The organic phase was dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (0-8% MeOH in DCM) to give the title compound (435 mg, 88%). 1 H NMR (400 MHz, DMSO-d6) δ 8.82 (d, 1H), 7.98 (s, 1H), 7.60 (s, 1H), 7.11 (d, 1H), 4.06 (s, 3H), 3.66-3.41 (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.

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

[0361] [ka] Step 1: Synthesis of ethyl 3-chloro-7-methyl-1H-indole-5-carboxylate (C61)

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

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

[0364] [ka] To compound ethyl 3-chloro-7-methyl-1H-indole-5-carboxylate C61 (0.38 g, 1.6 mmol) in MeOH (9 mL) and HO (3 mL) was added LiOH·HO (0.2 g, 4.80 mmol). The mixture was heated at about 25 °C for about 4 hours and then concentrated. The mixture was diluted with water (6 mL) and extracted with EtOAc (2 × 20 mL), and the EtOAc extract was discarded. The pH of the aqueous layer was adjusted to 3-4 with 1 N HCl and extracted with EtOAc (2 × 20 mL). The combined EtOAc extract was dried over MgSO, filtered, and concentrated under reduced pressure to give the title compound (210 mg, 63%) as a yellow solid. 1H 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).

[0365] 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

[0366] [ka] Preparation 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 amidation method C (EDCI, pyridine, MW). The residue was purified by preparative HPLC (column: Boston Prime C18, 150 × 30 mm, 3 μm); mobile phase A: water (0.05% v / v concentrated NH4OH); mobile phase B: MeCN; gradient from 9 to 60% B over 9 min, hold at 100% B for 2 min; flow rate 25 mL / min) to give the title compound (170 mg, 34.5%). 1 H NMR (400 MHz, DMSO-d6) δ 11.56 (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 / MS m / z (M+H) + = 470.3.

[0367] Example 43 2-(tert-butyl)-1'-(4,8-dimethoxyisoquinoline-6-carbonyl)-5H-spiro[benzo[d]thiazol-6,4'-piperidin]-4(7H)-one

[0368] [ka] Step 1: Synthesis of ethyl 8-bromoisoquinoline-6-carboxylate (C63)

[0369] [ka] To a solution of ethyl isoquinoline-6-carboxylate (commercially available, 22.6 g, 112.3 mmol) in concentrated H2SO4 (200 mL) was added NBS (22 g, 124 mmol) in small portions. 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 an additional 16 h. The reaction was quenched by pouring onto ice (500 mL), cooled to 0 °C, and the pH was adjusted to about 8 using 3 N NaOH (500 mL). The reaction mixture was extracted using DCM (2 x 800 mL), washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography using silica gel [(petroleum ether / DCM=1:1): EtOAc=100:0 to 90:10] to give the title compound (22.2 g, 70.6%) as a white solid. 1 H NMR (400 MHz, chloroform-d) δ 9.69 (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.

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

[0371] [ka] 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, then the temperature was increased to about 60 °C for an additional 16 h. The reaction was concentrated and then diluted with EtOAc (50 mL) and saturated aqueous NaHCO (20 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (3 × 50 mL). The combined EtOAc layers were washed with brine (2 × 30 mL), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by chromatography (0% to 20% EtOAc in petroleum ether) to give the title compound (0.2 g, 71.2%). 1 H NMR (400 MHz, chloroform-d) δ 9.51 (d, 1H), 8.82 (t, 1H), 8.67 (s, 1H), 8.42 (d, 1H), 4.43 (q, 2H), 1.41 (t, 3H); LC / MS m / z (M+H) + = 315.9.

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

[0373] [ka] To a solution of ethyl 8-bromo-4-chloroisoquinoline-6-carboxylate (0.2 g, 0.636 mmol) in dioxane (5 mL) was added Rockphos-Pd-G (0.053 g, 0.0636 mmol), CsCO (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 hours, cooled to room temperature, filtered, and concentrated. The residue was purified by chromatography (0% to 40% EtOAc in petroleum ether) to afford the title compound (0.09 g, 57%) as a yellow solid. 1 H NMR (400 MHz, chloroform-d) δ 9.22 (d, 1H), 8.42 (dt, 1H), 8.11 (s, 1H), 7.43 (d, 1H), 4.10 - 3.99 (m, 6H), 3.93 (s, 3H); LC / MS m / z (M+H) + = 248.1.

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

[0375] [ka] To compound methyl 4,8-dimethoxyisoquinoline-6-carboxylate C65 (0.09 g, 0.36 mmol) in MeOH (3 mL) and HO (1 mL) was added LiOH·HO (0.076 g, 1.82 mmol). The reaction mixture was stirred at about 20 °C for about 16 hours. The solvent was concentrated, and the pH of the residue was adjusted to 3-4 using 1 N HCl. The resulting solid was filtered and dried under vacuum to give the title compound (40 mg, 47%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 13.45 (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.

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

[0377] [ka] Preparation P1 (0.06 g, 0.17 mmol) was coupled with 4,8-dimethoxyisoquinoline-6-carboxylic acid (0.04 g, 0.17 mmol) according to amidation method A. The residue was purified by preparative HPLC (column: Boston Prime C18, 150 × 30 mm, 5 μm); mobile phase A: water (0.05% v / v concentrated NH4OH); mobile phase B: MeCN; gradient of 25–55% B over 9 min, hold at 100% B for 2 min; flow rate 25 mL / min to give the title compound (57.4 mg, 68%). 1 H NMR (400 MHz, methanol-d4) δ 9.03 (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.

[0378] The following compounds of the invention were similarly prepared using the amidation method described above. For those examples characterized by HPLC retention time, the following HPLC conditions were used:

[0379] Method 1 Column: ACQUITY UPLC BEH C18 50 x 2.1 mm, 1.7 μm Mobile phase A: 10 mM ammonium acetate in water / acetonitrile-95 / 5 v / v Mobile phase B: 10 mM ammonium acetate in acetonitrile / water-95 / 5 v / v Gradient: increase from 5% D to 100% D within 1 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.

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

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

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

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

[0384] [Table 1-1]

[0385] [Table 1-2]

[0386] [Table 1-3]

[0387] [Table 1-4]

[0388] [Table 1-5]

[0389] [Table 1-6]

[0390] [Table 1-7]

[0391] [Table 1-8]

[0392] [Table 1-9]

[0393] [Table 1-10]

[0394] [Table 1-11]

[0395] [Table 1-12]

[0396] [Table 1-13]

[0397] [Table 1-14]

[0398] [Table 1-15]

[0399] [Table 1-16]

[0400] [Table 1-17]

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

[0402] [ka] To a solution of Example 14 (100 mg, 0.2 mmol) in MeOH (3.5 mL) was added NaBH (23 mg, 0.6 mmol) and stirred at about 25 °C for about 17 hours. The reaction 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 × 20 mL). The combined EtOAc extracts were dried over MgSO, filtered, and concentrated under reduced pressure. The residue was purified by HPLC (column: Xbridge C18, 19 × 100 mm, 5 μm), mobile phase A: 0.05% TFA in water (v / v); mobile phase B: 0.05% TFA in acetonitrile (v / v), 10 min gradient time, to give the title compound (67 mg, 68%). 1 H NMR (600 MHz, DMSO-d6) δ 7.27 (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, overlaps with d-DMSO), 2.75 (d, 1H), 2.68 (d, 1H), 2.43 (s, 3H), 1.99 (dd, 1H), 1.72 (dd, 1H), 1.69 - 1.59 (m, 2H), 1.53 (dd, 2H), 1.44 (t, 3H), 1.35 (s, 9H); LC / MS m / z (M+H) + = 497.3.

[0403] Deuterated analog of the compound of Example 14 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 consists of oxidation and glucuronidation.

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

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

[0406] The predictive deuterated analogs 110-122 presented herein below may offer 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.

[0407] One skilled in the art can make additional deuterated analogs of the compound of Example 14. Such additional deuterated analogs may provide therapeutic benefits similar to those that can be achieved by the non-deuterated analogs.

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

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

[0410] [ka] Example 112 1'-{7-[(pentadeuterioethyloxy)-1,3-bis[(trideuterio)methyl](dideuterio)-1H-indazole-5-carbonyl}-2-[2-(trideuterio)methyl(hexadeuterio)propan-2-yl](dodecaterio)-5H-spiro[[1,3]benzothiazole-6,4'-piperidin]-4(7H)-one

[0411] [ka] Example 113 2-tert-Butyl-1'-{7-[(pentadeuterio)ethyloxy]-1,3-bis[(trideuterio)methyl](dideuterio)-1H-indazole-5-carbonyl}-5H-spiro[[1,3]benzothiazole-6,4'-piperidin]-4(7H)-one

[0412] [ka] Example 114 2-tert-Butyl-1'-{7-[(1,1-dideuterio)ethyloxy]-1,3-bis[(trideuterio)methyl]-1H-indazole-5-carbonyl}-5H-spiro[[1,3]benzothiazole-6,4'-piperidin]-4(7H)-one

[0413] [ka] Example 115 2-tert-Butyl-1'-{7-ethoxy-1,3-bis[(trideuterio)methyl]-1H-indazole-5-carbonyl}-5H-spiro[[1,3]benzothiazole-6,4'-piperidin]-4(7H)-one

[0414] [ka] Example 116 2-tert-Butyl-1'-[7-ethoxy-1-methyl-3-(trideuterio)methyl-1H-indazole-5-carbonyl]-5H-spiro[[1,3]benzothiazole-6,4'-piperidin]-4(7H)-one

[0415] [ka] Example 117 2-tert-Butyl-1'-[7-ethoxy-3-methyl-1-(trideuterio)methyl-1H-indazole-5-carbonyl]-5H-spiro[[1,3]benzothiazole-6,4'-piperidin]-4(7H)-one

[0416] [ka] Example 118 2-tert-Butyl-1'-{7-[(pentadeuterio)ethyloxy]-1,3-bis[(trideuterio)methyl]-1H-indazole-5-carbonyl}-5H-spiro[[1,3]benzothiazole-6,4'-piperidin]-4(7H)-one

[0417] [ka] Example 119 1'-{7-[(pentadeuterio)ethyloxy]-1,3-bis[(trideuterio)methyl]-1H-indazole-5-carbonyl}-2-[2-(trideuterio)methyl(hexadeuterio)propan-2-yl]-5H-spiro[[1,3]benzothiazole-6,4'-piperidin]-4(7H)-one

[0418] [ka] Example 120 1'-{7-[(pentadeuterio)ethyloxy]-1,3-bis[(trideuterio)methyl]-1H-indazole-5-carbonyl}-2-[2-(trideuterio)methyl(hexadeuterio)propan-2-yl](5,5-dideuterio)-5H-spiro[[1,3]benzothiazole-6,4'-piperidin]-4(7H)-one

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

[0420] [ka] Example 122 2-tert-Butyl-1'-(7-ethoxy-1,3-dimethyl-1H-indazole-5-carbonyl)(5,5-dideuterio)-5H-spiro[[1,3]benzothiazol-6,4'-piperidin]-4(7H)-one

[0421] [ka]

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

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

[0424] Preparation of rhACC1 Two liters of SF9 cells infected with recombinant baculovirus containing the full-length human ACC1 cDNA were suspended in ice-cold lysis buffer (25 mM Tris, pH 7.5, 150 mM NaCl, 10% glycerol, 5 mM imidazole (EMD Bioscience, Gibbstown, NJ), 2 mM TCEP (BioVectra, Charlottetown, Canada), benzonase nuclease (10,000 U / 100 g cell paste, Novagen, Madison, WI), and EDTA-free protease inhibitor cocktail (1 tablet / 50 ml, Roche Diagnostics, Mannheim, Germany). Cells were lysed by three cycles of freeze-thawing and centrifuged at 40,000 × g for 40 minutes (4°C). The supernatant was then loaded onto a HisTrap FF crude column (GE The purified ACC1 was loaded directly onto a GE Healthcare (Piscataway, NJ) column and eluted with an imidazole gradient to 0.5M over 20 column volumes (CV). Fractions containing ACC1 were pooled, diluted 1:5 with 25 mM Tris, pH 7.5, 2 mM TCEP, 10% glycerol, loaded directly onto a CaptoQ (GE Healthcare) column, and eluted with a NaCl gradient to 1M over 20 CV. Phosphate groups were removed from the purified ACC1 by incubation with lambda phosphatase (100 U / 10 μM target protein, New England Biolabs, Beverly, MA) for 14 h at 4°C. Okadaic acid (final concentration 1 μM, Roche Diagnostics) was added to inhibit the phosphatase. The purified ACC1 was dialyzed for 6 h at 4°C against 25 mM Tris, pH 7.5, 2 mM TCEP, 10% glycerol, 0.5M The solution was exchanged for NaCl, and aliquots were prepared and frozen at -80°C.

[0425] Measurement of rhACC1 inhibition rhACC1 was assayed in Corning #3820 (Corning, Tewksbury, MA) 384-well plates using the Transcreener ADP Detection FP Assay Kit (Bellbrook Labs, Madison, Wisconsin) 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, 7.5 mM tripotassium citrate, 2 mM DTT, 0.1 mg / mL BSA, 30 μM acetyl-CoA, 50 μM ATP, and 10 mM KHCO. Typically, a 10 μM reaction was run at room temperature for 60 minutes, 10 μl of Transcreener Stop and Detection Buffer was added, and the combination was incubated overnight (18 hours) at room temperature. Data were acquired on an Envision fluorescence reader (PerkinElmer) using a 620 excitation Cy5 FP generic dual mirror, a 620 excitation Cy5 FP filter, and 688 emission (S) and 688 (P) emission filters.

[0426] [Table 2-1]

[0427] [Table 2-2]

[0428] [Table 2-3]

[0429] [Table 2-4]

[0430] [Table 2-5]

[0431] [Table 2-6]

[0432] [Table 2-7]

[0433] [Table 2-8]

[0434] [Table 2-9]

[0435] [Table 2-10]

[0436] [Table 2-11]

[0437] [Table 2-12]

[0438] [Table 2-13]

[0439] [Table 2-14]

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

[0441] [Table 3-1]

[0442] [Table 3-2]

[0443] [Table 3-3]

[0444]

Table 3-4

[0445]

Table 3-5

[0446]

Table 3-6

[0447]

Table 3-7

[0448]

Table 3-8

[0449]

Table 3-9

[0450]

Table 3-10

[0451]

Table 3-11

[0452]

Table 3-12

[0453]

Table 3-13

[0454] [Table 3-14]

[0455] Radiometric determination of de novo lipogenesis in cultured human sebocytes SZ95 sebocytes were grown in human sebocyte growth medium (HSGM) containing Sebomed® basal medium (Sigma-Aldrich, F8205) supplemented with 10% heat-inactivated fetal bovine serum (Gibco, 10100-147), 1% penicillin / streptomycin (Gibco, 15070-063), 1 mM calcium chloride (Fisher, BP9742-10x5), and 5 ng / mL recombinant human epidermal growth factor (Gibco, PHG0311). At 90% confluence, cells were washed with PBS and then detached with 0.05% trypsin-EDTA (Gibco, 25300054). Prior to starting the assay, cells were centrifuged and resuspended in HSGM containing 5% charcoal-stripped serum (Life Technologies, 12676-029) instead of 10% heat-inactivated fetal bovine serum. 0.25 x 10 cells 6 Cells were added to 24-well plates at a density of 1000 cells / well and incubated overnight at 37°C to allow cells to adhere to the culture plate. Cells were then treated with a dose response of compounds (30, 1, 0.03, 0.006, 0.0009, 0.0002, and 0.00003 μM), with each concentration tested in duplicate. Briefly, compounds were dissolved in DMSO stocks and diluted 1:1000 in HSGM containing charcoal-stripped media. Vehicle control wells were treated with 0.1% DMSO. Compounds or vehicle were preincubated at 37°C for 1 hour, followed by 0.25 μCi 14 Sodium acetate (American Radiolabeled Chemicals: ARC, 0173A) was added to each well. The plates were incubated for an additional 2 hours at 37°C. At the end of the incubation period, the cells were removed from the incubator, placed on ice, and then washed twice with ice-cold PBS to remove the released 14The C-sodium acetate was removed. The plates were sealed and stored at -20°C until analysis. To induce lysis, 125 μL of mammalian protein extraction reagent (MPER, Fisher, 78501) was added to each well. The plates were shaken at room temperature for 1 hour, and the lysate was transferred to individual 2 mL polypropylene tubes. Next, the wells were washed with 175 μL of PBS, which was added to the lysate. A chloroform:methanol solution (1:1 v / v, 450 μL) was added to each tube. All tubes were vortexed for 10 seconds and centrifuged at 14,000 × g for 5 minutes at room temperature to separate the aqueous and organic phases. A 25 μL aliquot was removed from the lower organic layer of each sample and added to 6 mL of Optiphase Supermix scintillation fluid (PerkinElmer, 1200-439). 14 C counts were assessed by scintillation counting. DNL (lipid-incorporated 14 IC counts) were expressed as a percentage of compound-treated cells compared to vehicle controls. 50 Values ​​were determined using nonlinear regression (four parameters with variable slope) in GraphPad Prism.

[0456] [Table 4-1]

[0457] [Table 4-2]

Claims

1. structure 【Chemical Formula 1】 or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt thereof, wherein: R is C １ ~C ６ Alkyl and -(CH ２ ) ｍ -W, W is selected from the group consisting of C ３ ~C ８ cycloalkyl, bicycloalkyl, or bridged bicycloalkyl, each of which may be unsubstituted or may contain deuterium or C １ ~C ６ optionally substituted by alkyl, R １ is selected from the group consisting of phenyl, naphthyl, 5- or 6-membered heteroaryl or heterocyclic containing 1, 2, 3, or 4 N atoms, and 9- or 10-membered bicyclic aryl, heteroaryl or heterocyclic containing 1, 2, or 3 N atoms, each of said phenyl, naphthyl, aryl, heterocyclic, or heteroaryl may be unsubstituted or may be substituted with halo, cyano, deuterium, hydroxy, C １ ~C ６ Alkyl, C １ ~C ６ Alkoxy, phenyl, —SO ２ -R', -CONR'R'', NR'COR'', -NR'CONR'R'', -NR'CO ２ R'', -(CH ２ ) ｎ -SO ２ -R', -NHSO ２ -R', -NR''SO ２ -R', -SO ２ NR'R'', NR'R'', -P(O)R'R'', 【Chemistry 2】 or SR′, where R′ and R″ are independently H, C １ ~C ６ Alkyl or C ３ ~C ８ is cycloalkyl, m and n are independently 0, 1, 2 or 3.

2. R is C １ ~C ６ Alkyl and -(CH ２ ) ｍ -W, W is C ３ ~C ８ and cycloalkyl, each of which may be unsubstituted or may be substituted with deuterium or C. １ ~C ６ optionally substituted by alkyl, 2. The compound of claim 1, wherein m and n are independently 0, 1, 2, or 3, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt.

3. 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt, wherein R is t-butyl.

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

5. 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; 2. The compound of claim 1 selected from the group consisting of: or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or pharmaceutically acceptable salt.

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

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

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

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

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

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

12. Inflammation, autoimmune diseases, neuroinflammation, arthritis, rheumatoid arthritis, 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, muscle pain, endotoxic shock, Toxic shock syndrome, osteoporosis, multiple sclerosis, endometriosis, menstrual cramps, vaginitis, candidiasis, cancer, fibrosis, obesity, muscular dystrophy, polymyositis, dermatomyositis, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, vitiligo, Alzheimer's disease, flushing of the skin, eczema, psoriasis, atopic dermatitis, sunburn, keloids, hypertrophic scars, rheumatic diseases, urticaria, discoid lupus erythematosus, cutaneous lupus, central nervous system lupus, psoriatic arthritis, asthma, allergic asthma, Aicardi-Goutieres syndrome and other Mendelian disorders due to overexpression of type I interferon Type I interferonopathies including primary progressive multiple sclerosis, relapsing-remitting multiple sclerosis, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, scleroderma, alopecia areata, cicatricial alopecia, prurigo, prurigo nodularis, CPUO, lichenoid diseases, 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 sprue, idiopathic hematopoietic syndrome thrombotic thrombocytopenic purpura, thrombotic thrombocytopenic purpura, myasthenia gravis, Sjogren's syndrome, epidermal hyperplasia, cartilage inflammation, bone degradation, juvenile arthritis, juvenile rheumatoid arthritis, oligoarticular juvenile rheumatoid arthritis, polyarticular juvenile rheumatoid arthritis, systemic onset juvenile rheumatoid arthritis, juvenile ankylosing spondylitis, juvenile enteropathic arthritis, juvenile Reiter's syndrome, SEA syndrome, juvenile dermatomyositis, juvenile psoriatic arthritis, juvenile scleroderma, juvenile systemic lupus erythematosus, juvenile vasculitis, oligoarticular rheumatoid arthritis, polyarticular rheumatoid arthritis, systemic onset rheumatoid arthritis, enteropathic arthritis, reactive arthritis,11. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt, for treating a disease or condition selected from Reiter's 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 resulting from the activity of pathogenic lymphocytes, non-infectious uveitis, Behcet's disease, and Vogt-Koyanagi-Harada syndrome.

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

14. 13. The pharmaceutical composition of claim 12, wherein the compound is administered as a cream, ointment, lotion, gel, solution, suspension, foam, aerosol, spray, shampoo, patch, or tape.

15. 11. A pharmaceutical composition comprising a compound according to claims 1 to 10, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt, for treating acne.

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

17. 16. The pharmaceutical composition of claim 15, wherein the compound is administered as a cream, ointment, lotion, gel, solution, suspension, foam, aerosol, spray, shampoo, patch, or tape.

18. 11. A pharmaceutical composition comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of said compound or salt, for treating inflammatory skin diseases, seborrheic dermatitis, rosacea, steroid acne, papulopustular drug eruption, and hidradenitis suppurativa.

19. 20. The pharmaceutical composition of claim 18, wherein the compound is administered topically.

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

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

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

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