Aryl Alkyne Amide Derivatives

Abstract

The present invention provides a compound that is useful as a STING inhibitor. The present inventors have found an aryl alkinamide derivative that has an inhibitory effect on STING. The aryl alkinamide derivative of the present invention has an inhibitory effect on STING and can be used as a drug for treating autoimmune diseases, neurodegenerative diseases, type I interferonopathy, and / or other STING-mediated diseases.

Description

[Technical field]

[0001] [CROSS REFERENCE TO RELATED APPLICATIONS] This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 314,783, filed February 28, 2022, the entire contents of which are incorporated herein by reference.

[0002] [Technical field] The present invention relates to aryl alkinamide derivatives that are useful as stimulator of interferon genes (STING) inhibitors and are expected to be useful as active ingredients in pharmaceutical compositions, such as pharmaceutical compositions for treating autoimmune diseases, neurodegenerative diseases, type I interferonopathies, and / or other STING-mediated diseases. [Background technology]

[0003] STING is an adaptor protein that is widely expressed in immune cells and is involved in immune responses. When endogenous and exogenous double-stranded DNA (dsDNA) in the cytoplasm is recognized by the DNA sensor cyclic GMP-AMP (cGAMP) synthase (cGAS), STING functions as a mediator of inflammation, leading to the secretion of proinflammatory cytokines such as type I interferons (IFNs) and downstream cytokines of nuclear factor kappa B (NF-kB) through the production of second messenger cGAMP.

[0004] The cGAS-STING pathway plays an important role in host defense against viral infection, but accumulation of endogenous dsDNA in the cytoplasm or gain-of-function mutations in STING can result in exaggerated immune responses known to cause type I interferonopathies, including Aicardi-Goutières syndrome (AGS) and STING-associated vasculopathy of infantile onset (SAVI). In addition, activation of the cGAS-STING pathway or an increase in its ligands has been shown to be an important factor in the pathogenesis of systemic lupus erythematosus (Annals of the Rheumatic Diseases, Vol. 77, No. 10, p. 1507-1515, 2018 (Non-Patent Document 5)), Sjögren's syndrome (Journal of Autoimmunity, Vol. 108, Article No. 102381, 2020 (Non-Patent Document 6)), Crohn's disease (Cell Death and Disease, Vol. 12, Article No. 815, 2021 (Non-Patent Document 7)), amyotrophic lateral sclerosis (Cell, Volume 183, Issue 1, 2021 (Non-Patent Document 8)), and glaucoma (Cell, Volume 183, Issue 1, 2021 (Non-Patent Document 9)). 3, p.636-649, 2020 (Non-Patent Document 8)), and Huntington's disease (PNAS, Vol.117, No.27, p.15989-15999, 2020 (Non-Patent Document 9)).

[0005] Patent Document 1 discloses that compounds represented by the following formula have inhibitory activity on the STING pathway and are useful for treating conditions, diseases, or disorders in which increased STING pathway activation contributes to the progression of pathology and / or symptoms and / or conditions, diseases, or disorders in a subject (for symbols in the formula, please refer to the patent document): [ka]

[0006] Patent Document 2 discloses that a compound represented by the following formula has inhibitory activity against STING and is useful for treating a disease, condition, or disorder associated with STING (for the symbols in the formula, please refer to the patent document). [ka]

[0007] Patent Document 3 discloses that a compound represented by the following formula has inhibitory activity against STING and is useful for treating STING-mediated diseases (for the symbols in the formula, please refer to the patent document). [ka]

[0008] Patent Document 4 discloses that the compound represented by the following formula has inhibitory activity against the production of amyloid beta and is useful for the treatment of neurodegenerative diseases caused by amyloid beta (wherein X1 represents an acetylene group or the like, and Ar1 represents an imidazolyl group or the like which may be substituted. For other symbols in the formula, please refer to the patent document). However, no inhibitory activity against STING is described. [ka]

[0009] Patent Document 5 discloses that the compound represented by the following formula has an antagonistic effect on retinoic acid receptors (RAR) and is useful for treating a wide variety of disease states, such as skin diseases, rheumatic diseases, respiratory diseases, cardiovascular diseases, bone diseases, and ophthalmological diseases (wherein XY represents an alkinamide group. For other symbols in the formula, please refer to the patent document). However, no inhibitory activity against STING is described. [ka]

[0010] Non-Patent Document 1 discloses that the compound represented by the following formula has inhibitory activity against arylalkylamine N-acetyltransferase (AANAT) (wherein R represents an amine). However, no inhibitory activity against STING is described. [ka]

[0011] Non-Patent Document 2 discloses a compound represented by the following formula as a result of an aminocarbonylation reaction. However, no inhibitory activity against STING is described. [ka]

[0012] Non-Patent Document 3 discloses a compound represented by the following formula as a starting material for the iodocyclization reaction. However, no inhibitory activity against STING is described. [ka]

[0013] Non-Patent Document 4 discloses a compound represented by the following formula as a starting material for spiro tricyclization reaction. However, no inhibitory activity against STING is described. [ka] [Prior art documents] [Patent documents]

[0014] [Patent Document 1] International Publication No. 2020 / 106741 [Patent Document 2] International Publication No. 2019 / 122202 [Patent Document 3] International Publication No. 2019 / 182886 [Patent Document 4] International Publication No. 2005 / 115990 [Patent Document 5] U.S. Patent No. 6,150,413 [Non-patent literature]

[0015] [Non-Patent Document 1] Journal of Chemical Information and Modeling,50,pp 446-460(2010) [Non-Patent Document 2] European Journal of Organic Chemistry,pp 2235-2243(2015) [Non-Patent Document 3] Journal of Organic Chemistry,86,pp 15498-15508(2021) [Non-Patent Document 4] Synthesis,54,pp 3105-3113(2022) [Non-Patent Document 5] Annals of the Rheumatic Diseases,Vol.77,No.10,p.1507-1515,2018 [Non-Patent Document 6] Journal of Autoimmunity,Vol.108,Article No.102381,2020 [Non-Patent Document 7] Cell Death and Disease,Vol.12,Article No.815,2021 [Non-Patent Document 8] Cell,Volume 183,Issue 3,p.636-649,2020 [Non-Patent Document 9] PNAS,Vol.117,No.27,p.15989-15999,2020 Summary of the Invention

[0016] [Disclosure of the Invention] [Problem to be solved by the invention] Compounds are provided that are useful as STING inhibitors and are expected to be useful as active ingredients in pharmaceutical compositions, e.g., pharmaceutical compositions for treating autoimmune diseases, neurodegenerative diseases, type I interferonopathies, or other STING-mediated diseases.

[0017] [Means for solving the problem] The present inventors have extensively studied compounds having an inhibitory effect on STING, and as a result, have found that aryl alkinamide derivatives have an inhibitory effect on STING and are expected to be useful as active ingredients of pharmaceutical compositions for treating autoimmune diseases, neurodegenerative diseases, type I interferonopathy, and / or other STING-mediated diseases, particularly Sjogren's syndrome and systemic lupus erythematosus. Thus, the present invention has been achieved.

[0018] The present invention relates to compounds of formula (I) or salts thereof, and to pharmaceutical compositions comprising compounds of formula (I) or salts thereof and one or more pharma- ceutically acceptable excipients. [ka] (In the formula, Ring A is phenyl optionally fused to a 5-membered heterocyclyl, a 6-membered heteroaryl containing 1 or 2 nitrogen atoms, pyrazolyl, or a 6-membered saturated or partially unsaturated heterocyclyl; Ring B is phenyl optionally fused to phenyl or to a 6-membered heteroaryl containing 1 or 2 nitrogen atoms, a 6-membered heteroaryl containing 1 or 2 nitrogen atoms, pyrazolyl, or imidazolyl; R a1 and R a2 However, independently, H, C 1-6 Alkyl, -OC 1-6 Alkyl, -OC 1-6 Alkylene-C 2-6 Alkenyl, -OC 1-6 Alkylene-C 2-6 Alkynyl, halogen, halogeno-C 1-6 Alkyl, -O-halogeno-C1-6 alkyl or -OH; R b1 and R b2 However, independently, H, C 1-6 Alkyl, -OC 1-6 Alkyl, halogeno-C 1-6 Alkyl, -O-halogeno-C 1-6 Alkyl, halogen, -C 1-6 Alkylene -OH, -C 1-6 Alkylene-NR c R d , -C(=O)-NR c R d , -NR c R d , -CN, or -OH; R c and R d However, independently, H, C 1-6 Alkyl, C 3-8 Cycloalkyl, -C(=O)-C 1-6 Alkyl, or -S(=O)2-C 1-6 Is it an alkyl group? Or R c and R d are connected to each other, R c and R d may form a 4- to 7-membered saturated heterocyclyl together with the nitrogen atom to which it is bonded, and the heterocyclyl may be one or two R e may be substituted with R e But, C 1-6 Alkyl, -OC 1-6 alkyl or halogen; R 1 is H, optionally substituted C 1-6 Alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted 4- to 7-membered saturated heterocyclyl, optionally substituted phenyl, or optionally substituted heteroaryl; R 2 But one or two R 3 C replaced with 1-6 Alkyl, one or two R 4 C replaced with3-8 Cycloalkyl, one or two R 5 or one or two R 6 or Or R 1 and R 2 are connected to each other, R 1 and R 2 together with the nitrogen atom to which it is attached form a 4-7 membered saturated heterocyclyl, the heterocyclyl may be fused to a phenyl, and the heterocyclyl and / or the fused phenyl may be fused to one or more of R 7 may be substituted with Each R 3 Independently, -OH, -OC 1-6 Alkyl, -C(=O)-NH2, -C(=O)-NH-C 1-6 Alkyl, -C(=O)-N(C 1-6 alkyl)2, -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH-C(=O)-C 1-6 Alkyl, -NH-S(=O)2-C 1-6 Alkyl, -NH-S(=O)2-C 1-6 Alkylene-OH, -NH-S(=O)2-C 1-6 Alkylene-C(=O)-OH, -S(=O)2-NH2, -S(=O)2-C 1-6 Alkyl, or -S(=O)(=NH)-C 1-6 is alkyl, Each R 4 Independently, -OH, -OC 1-6 Alkyl, -C(=O)-NH2, -C(=O)-NH-C 1-6 Alkyl, -C(=O)-N(C 1-6 alkyl)2, -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH-C(=O)-C 1-6 Alkyl, -NH-S(=O)2-C 1-6 Alkyl, -S(=O)2-NH2, -S(=O)2-C 1-6 Alkyl, or -S(=O)(=NH)-C 1-6is alkyl, Each R 5 is independently -OH, oxo, or imino; Each R 6 are independently -C(=O)-OH, -S(=O)2-NH2, -S(=O)2-C 1-6 Alkyl, -S(=O)(=NH)-C 1-6 Alkyl, or -NH-S(=O)2-C 1-6 is alkyl, Each R 7 But independently, C 1-6 Alkyl, -C 1-6 Alkylene -OH, -C 1-6 Alkylene-C(=O)-OH, C 3-8 Cycloalkyl, -OH, -OC 1-6 Alkyl, -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH-C(=O)-C 1-6 Alkyl, -NH-S(=O)2-C 1-6 Alkyl, -S(=O)2-C 1-6 Alkyl, -S(=O)(=NH)-C 1-6 Alkyl, -C(=O)-OH, -C(=O)-NH2, -C(=O)-NH-C 1-6 Alkyl, -C(=O)-N(C 1-6 alkyl)2, oxo, imino, or 4- to 7-membered saturated heterocyclyl optionally substituted by 1 or 2 oxo; provided that the compound of formula (I) is not a compound of formula (II), (III), (IV), or (IVa). [ka]

[0019] Furthermore, unless otherwise stated, when a symbol in one formula in this specification is used in other formulas, the same symbol has the same meaning.

[0020] Furthermore, the present invention relates to a pharmaceutical composition for the treatment of autoimmune diseases, neurodegenerative diseases, type I interferonopathies, and / or other STING-mediated diseases comprising a compound of formula (I) or a salt thereof. [ka] (In the formula, Ring A is phenyl optionally fused to a 5-membered heterocyclyl, a 6-membered heteroaryl containing 1 or 2 nitrogen atoms, pyrazolyl, or a 6-membered saturated or partially unsaturated heterocyclyl; Ring B is phenyl optionally fused to phenyl or to a 6-membered heteroaryl containing 1 or 2 nitrogen atoms, a 6-membered heteroaryl containing 1 or 2 nitrogen atoms, pyrazolyl, or imidazolyl; R a1 and R a2 However, independently, H, C 1-6 Alkyl, -OC 1-6 Alkyl, -OC 1-6 Alkylene-C 2-6 Alkenyl, -OC 1-6 Alkylene-C 2-6 Alkynyl, halogen, halogeno-C 1-6 Alkyl, -O-halogeno-C 1-6 alkyl or -OH; R b1 and R b2 However, independently, H, C 1-6 Alkyl, -OC 1-6 Alkyl, halogeno-C 1-6 Alkyl, -O-halogeno-C 1-6 Alkyl, halogen, -C 1-6 Alkylene -OH, -C 1-6 Alkylene-NR c R d , -C(=O)-NR c R d , -NR c R d , -CN, or -OH; R c and R d However, independently, H, C 1-6 Alkyl, C3-8 Cycloalkyl, -C(=O)-C 1-6 Alkyl, or -S(=O)2-C 1-6 Is it an alkyl group? Or R c and R d are connected to each other, R c and R d may form a 4- to 7-membered saturated heterocyclyl together with the nitrogen atom to which it is bonded, and the heterocyclyl may be one or two R e may be substituted with R e But, C 1-6 Alkyl, -OC 1-6 alkyl or halogen; R 1 is H, optionally substituted C 1-6 Alkyl, optionally substituted C 3-8 cycloalkyl, optionally substituted 4- to 7-membered saturated heterocyclyl, optionally substituted phenyl, or optionally substituted heteroaryl; R 2 But one or two R 3 C replaced with 1-6 Alkyl, one or two R 4 C replaced with 3-8 Cycloalkyl, one or two R 5 or one or two R 6 or Or R 1 and R 2 are connected to each other, R 1 and R 2 together with the nitrogen atom to which it is attached form a 4-7 membered saturated heterocyclyl, the heterocyclyl may be fused to a phenyl, and the heterocyclyl and / or the fused phenyl may be fused to one or more of R 7 may be substituted with Each R 3 Independently, -OH, -OC 1-6 Alkyl, -C(=O)-NH2, -C(=O)-NH-C 1-6Alkyl, -C(=O)-N(C 1-6 alkyl)2, -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH-C(=O)-C 1-6 Alkyl, -NH-S(=O)2-C 1-6 Alkyl, -NH-S(=O)2-C 1-6 Alkylene-OH, -NH-S(=O)2-C 1-6 Alkylene-C(=O)-OH, -S(=O)2-NH2, -S(=O)2-C 1-6 Alkyl, or -S(=O)(=NH)-C 1-6 is alkyl, Each R 4 Independently, -OH, -OC 1-6 Alkyl, -C(=O)-NH2, -C(=O)-NH-C 1-6 Alkyl, -C(=O)-N(C 1-6 alkyl)2, -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH-C(=O)-C 1-6 Alkyl, -NH-S(=O)2-C 1-6 Alkyl, -S(=O)2-NH2, -S(=O)2-C 1-6 Alkyl, or -S(=O)(=NH)-C 1-6 is alkyl, Each R 5 is independently -OH, oxo, or imino; Each R 6 are independently -C(=O)-OH, -S(=O)2-NH2, -S(=O)2-C 1-6 Alkyl, -S(=O)(=NH)-C 1-6 Alkyl, or -NH-S(=O)2-C 1-6 is alkyl, Each R 7 But independently, C 1-6 Alkyl, -C 1-6 Alkylene -OH, -C 1-6 Alkylene-C(=O)-OH, C 3-8 Cycloalkyl, -OH, -OC 1-6 Alkyl, -NH2, -NH-C 1-6Alkyl, -N(C 1-6 Alkyl)2, -NH-C(=O)-C 1-6 Alkyl, -NH-S(=O)2-C 1-6 Alkyl, -S(=O)2-C 1-6 Alkyl, -S(=O)(=NH)-C 1-6 Alkyl, -C(=O)-OH, -C(=O)-NH2, -C(=O)-NH-C 1-6 Alkyl, -C(=O)-N(C 1-6 alkyl) 2, oxo, imino, or 4- to 7-membered saturated heterocyclyl optionally substituted with 1 or 2 oxo.

[0021] Here, the pharmaceutical composition comprises a drug for the treatment of autoimmune diseases, neurodegenerative diseases, type I interferonopathies, and / or other STING-mediated diseases, comprising a compound of formula (I) or a salt thereof.

[0022] The present invention further relates to a compound of formula (I) or a salt thereof which is a STING inhibitor, a compound of formula (I) or a salt thereof for use as a STING inhibitor, a STING inhibitor comprising a compound of formula (I) or a salt thereof, use of a compound of formula (I) or a salt thereof for the manufacture of a pharmaceutical composition for the treatment of an autoimmune disease, a neurodegenerative disease, type I interferonopathy, and / or other STING mediated disease, use of a compound of formula (I) or a salt thereof for the treatment of an autoimmune disease, a neurodegenerative disease, type I interferonopathy, and / or other STING mediated disease, a compound of formula (I) or a salt thereof for use in the treatment of an autoimmune disease, a neurodegenerative disease, type I interferonopathy, and / or other STING mediated disease, and a method for the treatment of an autoimmune disease, a neurodegenerative disease, type I interferonopathy, and / or other STING mediated disease, comprising administering to a subject an effective amount of a compound of formula (I) or a salt thereof.

[0023] As used herein, a "subject" is a human or non-human animal in need of treatment, and in one embodiment, a human in need of treatment.

[0024] [Effects of the invention] The compound of formula (I) or a salt thereof has a STING inhibitory effect and can be used as a drug for the treatment of autoimmune diseases, neurodegenerative diseases, type I interferonopathy, and / or other STING-mediated diseases. [Brief description of the drawings]

[0025] [Figure 1] Figure 1 shows the results of saliva production to evaluate the ameliorative effect of the compound of Example 33 on salivary dysfunction in a mouse drug-induced Sjogren's syndrome-like model. Data are expressed as mean ± SEM. Statistical significance between vehicle-treated control group and DMXAA-treated negative control group was determined using Student's t-test. ## represents P<0.01. Statistical significance between groups treated with DMXAA was determined using Dunnett's multiple comparison test. ** represents P<0.01. Quaque die (QD) represents once daily administration. [Diagram 2] Figure 1 shows the results of saliva production to evaluate the ameliorative effect of the compound of Example 34 on salivary dysfunction in a mouse drug-induced Sjogren's syndrome-like model. Data are expressed as mean ± SEM. Statistical significance between vehicle-treated control group and DMXAA-treated negative control group was determined using Student's t-test. ## represents P<0.01. Statistical significance between groups treated with DMXAA was determined using Dunnett's multiple comparison test. ** represents P<0.01. Quaque die (QD) represents once daily administration. [Diagram 3] Shows the results of saliva production to evaluate the ameliorative effect of the compound of Example 99 on salivary dysfunction in mouse drug-induced Sjogren's syndrome-like model. Data are expressed as mean ± SEM. Statistical significance between vehicle-treated control group and DMXAA-treated negative control group was determined using Student's t-test. ## represents P<0.01. Statistical significance between DMXAA-treated groups was determined using Dunnett's multiple comparison test. *, ** represent P<0.05 and 0.01, respectively. Quaque die (QD) represents once-daily administration. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0026] The present invention will be described in detail below. In this specification, the following terms have the following meanings unless otherwise specified. The following definitions are intended to clarify the defined terms, but are not intended to be limiting. If a particular term used in this specification is not specifically defined, the term is used within the meaning accepted by those skilled in the art.

[0027] In this specification, "C 1-6 "Alkyl" refers to a linear or branched alkyl group having 1 to 6 carbon atoms (hereinafter, C 1-6 For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc. 1-6 "Alkyl" in one embodiment means a straight or branched C 1-4 In another embodiment, it is alkyl, and in another embodiment, it is methyl, ethyl, n-propyl, isopropyl, or t-butyl, and in another embodiment, it is methyl, ethyl, n-propyl, isopropyl, and in another embodiment, it is ethyl or n-propyl, and in another embodiment, it is methyl or isopropyl, and in another embodiment, it is methyl, or in yet another embodiment, it is t-butyl.

[0028] "C 1-6 "Alkylene" refers to a straight or branched C 1-6 Alkylene, for example, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene, propylene, 2-methyltrimethylene, ethylethylene, 1,2-dimethylethylene, or 1,1,2,2-tetramethylethylene. 1-6 In one embodiment, alkylene is 1-4 It is alkylene, in another embodiment methylene, ethylene, or trimethylene, or in yet another embodiment methylene.

[0029] "C2-6 "Alkenyl" refers to straight or branched C 2-6 Alkenyl, for example, ethenyl, propenyl, butenyl, pentenyl, hexenyl, etc. 2-6 Alkenyl, in one embodiment, is C 2-4 In another embodiment it is alkenyl, in another embodiment it is ethenyl, propenyl, or butenyl, in another embodiment it is ethenyl, or in yet another embodiment it is propenyl.

[0030] "C 2-6 "Alkynyl" refers to straight or branched C 2-6 Alkynyl, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. 2-6 Alkynyl, in one embodiment, is C 2-4 In another embodiment it is alkynyl, in another embodiment it is ethynyl, propynyl, or butynyl, in another embodiment it is ethynyl, or in yet another embodiment it is propynyl.

[0031] "C 3-8 Cycloalkyl" is C 3-8 It is a saturated hydrocarbon ring group, which may form a bridged bicyclic ring or a spiro ring. 3-8 Cycloalkyl" is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.0]hexyl, bicyclo[3.1.1]heptyl, or spiro[2.5]octyl. 3-8 "Cycloalkyl" in one embodiment is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, or cyclooctyl, in another embodiment cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, in another embodiment cyclopropyl or cyclopentyl, in yet another embodiment cyclopropyl, or in yet another embodiment cyclopentyl.

[0032] "Halogen" means F, Cl, Br, or I. "Halogen" is in one embodiment F or Cl, in another embodiment F, and in yet another embodiment Cl, with Br being another embodiment, or I being yet another embodiment.

[0033] "Halogeno C 1-6 "Alkyl" refers to a straight or branched C alkyl group substituted with one or more halogens. 1-6 It is an alkyl group. 1-6 "Alkyl" in one embodiment is trifluoromethyl, trifluoroethyl, difluoromethyl, difluoroethyl, fluoromethyl, fluoroethyl, chloromethyl, bromomethyl, or iodomethyl, in another embodiment trifluoromethyl or difluoromethyl, in another embodiment trifluoromethyl, or in yet another embodiment difluoromethyl.

[0034] "Heteroaryl" is a 5-6 membered aromatic ring having one or more heteroatoms, particularly oxygen, nitrogen or sulfur atoms, as ring-constituting atoms. Examples of "heteroaryl" include, but are not limited to, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl or triazinyl. In one embodiment, "heteroaryl" is pyrazolyl or pyridyl, and in another embodiment, pyridyl.

[0035] "Oxo" is a group represented by (=O) and "imino" is a group represented by (=NH).

[0036] "6-membered heteroaryl containing one or two nitrogen atoms" means pyridyl, pyrazinyl, pyrimidinyl, or pyridazinyl. "6-membered heteroaryl containing one or two nitrogen atoms" is in one embodiment pyridyl, in another embodiment pyrazinyl, in yet another embodiment pyrimidinyl, or in yet another embodiment pyridazinyl.

[0037] A "six-membered saturated or partially unsaturated heterocyclyl" is a six-membered hydrocarbon ring that is saturated or has one double bond in the ring and has one or more heteroatoms, particularly oxygen, nitrogen, or sulfur atoms, instead of carbon atoms as ring constituent atoms, and may form a bridged bicyclic ring or a spiro ring. Examples of "six-membered saturated or partially unsaturated heterocyclyl" include, but are not limited to, tetrahydropyran, piperidine, tetrahydrothiopyran, morpholine, piperazine, thiomorpholine, dioxane, dihydropyran, tetrahydropyridine, or dihydrothiopyran. In one embodiment, a "six-membered saturated or partially unsaturated heterocyclyl" is tetrahydropyran, dihydropyran, piperidine, tetrahydropyridine, or morpholine, or in another embodiment, tetrahydropyran or dihydropyran.

[0038] The "4- to 7-membered saturated heterocyclyl" is a 4- to 7-membered saturated hydrocarbon ring that has one or more heteroatoms, particularly oxygen, nitrogen, or sulfur atoms, instead of carbon atoms as ring constituent atoms and can form a bridged bicyclic ring or a spiro ring. Examples of the "4- to 7-membered saturated heterocyclyl" include oxetanyl, azetidinyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydropyranyl, piperidinyl, tetrahydrothiopyranyl, oxepanyl, azepanyl, thiepanyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, dithiolazolanyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, and cyclohexyl. Examples of such aryl groups include, but are not limited to, aryl, dioxanyl, piperazinyl, dithianyl, morpholinyl, thiomorpholinyl, oxathianyl, dioxepanyl, diazepanyl, dithiepanyl, oxazepanyl, thiazepanyl, oxathiepyl, 2,6-diazaspiro[3.3]heptyl, 2-oxa-6-azaspiro[3.3]heptyl, 2-azabicyclo[2.2.1]heptyl, or 6-azaspiro[2.5]octyl. In one embodiment, the "4- to 7-membered saturated heterocyclyl" is oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydropyranyl, piperidinyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, thiomorpholinyl, or 2,6-diazaspiro[3.3]heptyl, and in another embodiment, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, or 2,6-diazaspiro[3.3]heptyl. In another embodiment, it is tetrahydrofuranyl or pyrrolidinyl, in another embodiment, it is tetrahydrophenyl, in another embodiment, it is azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, or 2,6-diazaspiro[3.3]heptyl, in another embodiment, it is tetrahydrofuranyl or pyrrolidinyl, in another embodiment, it is tetrahydrophenyl, in another embodiment, it is azetidinyl, pyrrolidinyl, piperidinyl, or thiomorpholinyl.

[0039] "R cand R d are connected to each other, R c and R d may form a 4- to 7-membered saturated heterocyclyl together with the nitrogen atom to which it is bonded," the "4- to 7-membered saturated heterocyclyl" is a 4- to 7-membered saturated hydrocarbon ring having at least one nitrogen atom instead of a carbon atom among the above "4- to 7-membered saturated heterocyclyls," such as azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, or thiomorpholinyl. c and R d are connected to each other, R c and R d may form a 4- to 7-membered saturated heterocyclyl together with the nitrogen atom to which it is bonded”, the “4- to 7-membered saturated heterocyclyl” in one embodiment is piperidinyl or morpholinyl.

[0040] "R 1 and R 2 are connected to each other, R 1 and R 2 is bonded to the nitrogen atom to form a 4- to 7-membered saturated heterocyclyl, and the heterocyclyl may be fused with phenyl." The "4- to 7-membered saturated heterocyclyl" in the above "4- to 7-membered saturated heterocyclyl" is a 4- to 7-membered saturated hydrocarbon ring having at least one nitrogen atom instead of a carbon atom, such as azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl, or 2,6-diazaspiro[3.3]heptyl. "The heterocyclyl may be fused with phenyl" means that the heterocyclyl is not fused with a phenyl ring, or that the heterocyclyl is fused with a phenyl ring to form a bicyclic ring, such as indolinyl, isoindolinyl, tetrahydroquinolinyl, or tetrahydroisoquinolinyl. "R 1 and R 2 are connected to each other, R 1 and R 2is bonded to the nitrogen atom to form a 4- to 7-membered saturated heterocyclyl, the heterocyclyl being optionally fused to phenyl, is, in one embodiment, azetidinyl, pyrrolidinyl, piperidinyl, or thiomorpholinyl, in another embodiment, azetidinyl, pyrrolidinyl, or piperidinyl, in yet another embodiment, pyrrolidinyl, in another embodiment, thiomorpholinyl, or indolinyl.

[0041] The "5-membered heterocyclyl" in the "phenyl optionally fused with a 5-membered heterocyclyl" is a 5-membered unsaturated hydrocarbon ring having one or more heteroatoms, particularly oxygen, nitrogen, or sulfur atoms, instead of carbon atoms as ring constituent atoms. Examples of "5-membered heterocyclyl" include, but are not limited to, dihydrofuranyl, furanyl, dihydropyrrolyl, pyrrolyl, dihydrothiophenyl, thiophenyl, dihydrooxazolyl, oxazolyl, dihydroimidazolyl, imidazolyl, dihydrothiazolyl, thiazolyl, dioxolyl, or 2-oxodihydropyrrolyl. The "phenyl optionally fused with a 5-membered heterocyclyl" is a phenyl, or a phenyl fused with a "5-membered heterocyclyl" by sharing its double bond to form a bicyclic ring. Examples of "phenyl optionally fused with a 5-membered heterocyclyl" include, but are not limited to, phenyl, indolyl, benzofuranyl, benzothiophenyl, indazolyl, benzimdazolyl, benzoisoxazolyl, benzoxazolyl, benzoisothiazolyl, benzothiazolyl, 1,3-benzodioxolyl, or 1-oxoisoindolinyl. In one embodiment, "phenyl optionally fused with a 5-membered heterocyclyl" is phenyl.

[0042] "Phenyl optionally fused to phenyl or 6-membered heteroaryl containing 1 or 2 nitrogen atoms" is phenyl, or phenyl fused to another phenyl or 6-membered heteroaryl having 1 or 2 nitrogen atoms. Examples of "phenyl optionally fused to phenyl or 6-membered heteroaryl containing 1 or 2 nitrogen atoms" include, but are not limited to, naphthyl, quinolyl, quinazolyl, or quinoxalyl. "Phenyl optionally fused to phenyl or 6-membered heteroaryl containing 1 or 2 nitrogen atoms" is, in one embodiment, phenyl or quinolyl, in another embodiment, phenyl, or in yet another embodiment, quinolyl.

[0043] As used herein, the phrase "optionally substituted" includes "unsubstituted" or "substituted with one or more substituents" (e.g., substituents defined below).

[0044] Substitution can occur wherever a hydrogen atom would normally be present on a group.

[0045] In one embodiment, "optionally substituted" is "optionally substituted with 1 to 5 substituents", and in another embodiment, "optionally substituted with 1 to 3 substituents".

[0046] In case of multiple substitutions, the substituents may be the same or different from each other.

[0047] "Optionally substituted phenyl", "optionally substituted heteroaryl", "optionally substituted C 1-6 "Alkyl", "optionally substituted C 3-8 Examples of the substituents of "cycloalkyl" and "optionally substituted 4- to 7-membered saturated heterocyclyl" include R 3 , R 4 , R 5 , R 6 , or R 7 Examples of the substituents include, but are not limited to, those described in the above.

[0048] "One or two R e "Optionally substituted with" means unsubstituted or substituted with one or two R e "One or two R e In one embodiment, "optionally substituted with" refers to two R e and in another embodiment, one R e or in another embodiment, is unsubstituted. e When replaced by two R e can be the same or different from each other.

[0049] R y But R 3 , R 4 , R 5 , or R 6 "One or two R y "Replaced by" means one or two R y "One or two R y In one embodiment, "substituted with" refers to two R y and in another embodiment, one R y It is replaced by two R y When replaced by two R y can be the same or different from each other.

[0050] "1 to 3 R 7 "Optionally substituted with" means unsubstituted or 1 to 3 R 7 It means that one to three R 7 In one embodiment, "optionally substituted with" refers to one or two R 7 In another embodiment, three R 7 In another embodiment, two R 7 In yet another embodiment, one R 7 or, in yet another embodiment, may be unsubstituted. 7When replaced by, two or three R 7 can be the same or different from each other.

[0051] One or more embodiments may be combined with different embodiments even if that combination is not specifically described, i.e., all embodiments may be combined in any manner.

[0052] As used herein, "treatment" includes both "therapeutic treatment" and "prophylactic treatment." "Therapeutic treatment" refers to alleviating symptoms, altering the course of a disease, extending life span, etc., and "prophylactic treatment" refers to reducing the likelihood of contracting a disease in a subject at risk of developing a disease. "Subject at risk of developing a disease" refers to an individual who has known risk factors that make them more likely to develop a disease than the general population.

[0053] As used herein, the term "autoimmune disease" refers to a group of diseases including systemic lupus erythematosus, Sjogren's syndrome, rheumatoid arthritis, Crohn's disease, ulcerative colitis, type 1 diabetes mellitus, vasculitis, antiphospholipid syndrome, systemic sclerosis, polymyositis, dermatomyositis, mixed connective tissue disease, IgG4-related disease, microscopic polyangiitis, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, rapidly progressive glomerulonephritis, Behcet's disease, adult-onset Still's disease, ankylosing spondylitis, autoimmune hepatitis, primary cholangitis, pemphigus, pemphigoid, Hashimoto's disease, Graves' disease, primary immune thrombocytopenia, autoimmune pulmonary arterial proteinosis, autoimmune hemolytic anemia, Goodpasture's syndrome, myasthenia gravis, celiac disease, and porosity, but "autoimmune disease" is not limited to these diseases. In one embodiment, the "autoimmune disease" is systemic lupus erythematosus, Sjogren's syndrome, rheumatoid arthritis, Crohn's disease, ulcerative colitis, type 1 diabetes, vasculitis, systemic sclerosis, dermatomyositis, myasthenia gravis, or psoriasis, in another embodiment, systemic lupus erythematosus and Sjogren's syndrome, in another embodiment, systemic lupus erythematosus, or in yet another embodiment, Sjogren's syndrome. "Systemic lupus erythematosus" as used herein includes several subtypes of lupus erythematosus, including, but not limited to, lupus nephritis, neuropsychiatric lupus erythematosus, and cutaneous lupus erythematosus. In one embodiment, the "systemic lupus erythematosus" is lupus nephritis, in another embodiment, neuropsychiatric lupus, or in yet another embodiment, cutaneous lupus erythematosus. "Systemic lupus erythematosus" refers, in a further embodiment, to systemic lupus erythematosus without symptoms of lupus nephritis, in a further embodiment, to systemic lupus erythematosus without symptoms of neuropsychiatric lupus, and in a further embodiment, to systemic lupus erythematosus without symptoms of lupus nephritis or neuropsychiatric lupus. Additionally, "systemic lupus erythematosus" as used herein includes systemic lupus erythematosus associated with Sjogren's syndrome.

[0054] As used herein, the term "neurodegenerative disease" refers to a group of diseases including multiple sclerosis, amyotrophic lateral sclerosis, frontotemporal lobar degeneration, Alzheimer's disease, Parkinson's disease, multiple system atrophy, Lewy body dementia, Huntington's disease, age-related macular degeneration, stroke, and traumatic brain injury, but "neurodegenerative disease" is not limited to these diseases. In one embodiment, the "neurodegenerative disease" is multiple sclerosis, in another embodiment, amyotrophic lateral sclerosis, in another embodiment, Parkinson's disease, multiple system atrophy, or Lewy body dementia, in yet another embodiment, frontotemporal lobar degeneration, in yet another embodiment, Huntington's disease, in another embodiment, stroke, or in another embodiment, traumatic brain injury.

[0055] As used herein, "type I interferonopathy" refers to a group of diseases including Aicardi-Goutières syndrome (AGS), STING-associated vasculopathy with infantile onset (SAVI), COPA syndrome, spondylodysplasia, telangiectasia, and familial lupus pernio, but is not limited to these diseases. In one embodiment, "type I interferonopathy" is Aicardi-Goutières syndrome (AGS) or STING-associated vasculopathy with infantile onset (SAVI), in another embodiment, Aicardi-Goutières syndrome (AGS), or in yet another embodiment, STING-associated vasculopathy (SAVI).

[0056] "Other STING-mediated diseases" in this specification refers to a group of diseases including non-alcoholic steatohepatitis (NASH), alcoholic liver disease, acute pancreatitis, acute kidney injury, sepsis, myocardial infarction, and chronic heart failure, but "other STING-mediated diseases" are not limited to these diseases. "Other STING-mediated diseases" are, in one embodiment, non-alcoholic steatohepatitis (NASH) or alcoholic liver disease, in another embodiment, acute pancreatitis, in yet another embodiment, acute kidney injury, in yet another embodiment, sepsis, or in a further embodiment, myocardial infarction or chronic heart failure.

[0057] Some embodiments of the compound of formula (I) or a salt thereof of the present invention, including the embodiments described in (1-1) to (14-8), are shown below, with the proviso that the compound of formula (I) or a salt thereof is not a compound of formula (II), (III), (IV), or (IVa) or a salt thereof.

[0058] [ka]

[0059] (1-1) A compound or a salt thereof, wherein ring A is phenyl optionally fused with a 5-membered heterocyclyl, a 6-membered heteroaryl containing 1 or 2 nitrogen atoms, pyrazolyl, or a 6-membered saturated or partially unsaturated heterocyclyl. (1-2) A compound or a salt thereof, wherein ring A is phenyl, a 6-membered heteroaryl containing 1 or 2 nitrogen atoms, pyrazolyl, or a 6-membered saturated or partially unsaturated heterocyclyl. (1-3) A compound or a salt thereof, wherein ring A is phenyl, pyrazolyl, or a 6-membered saturated or partially unsaturated heterocyclyl. (1-4) A compound or a salt thereof, wherein ring A is phenyl. (2-1) A compound or a salt thereof, wherein ring B is phenyl which may be fused with phenyl or with a 6-membered heteroaryl containing 1 or 2 nitrogen atoms, a 6-membered heteroaryl containing 1 or 2 nitrogen atoms, pyrazolyl, or imidazolyl. (2-2) A compound or a salt thereof, wherein Ring B is phenyl, a 6-membered heteroaryl containing 1 or 2 nitrogen atoms, or pyrazolyl. (2-3) A compound or a salt thereof, wherein Ring B is phenyl or a 6-membered heteroaryl containing 1 or 2 nitrogen atoms. (2-4) A compound or a salt thereof, wherein ring B is formula (V), and X is CH or N. [ka] (2-5) A compound or a salt thereof, wherein ring B is formula (V), and X is CH. (2-6) A compound or a salt thereof, wherein ring B is formula (V) and X is N. (2-7) A compound or a salt thereof, wherein ring B is formula (Va): [ka] (2-8) A compound or a salt thereof, wherein ring B is formula (Vb). [ka] (3-1)R a1 and R a2 However, independently, H, C 1-6 Alkyl, -OC 1-6 Alkyl, -OC 1-6 Alkylene-C 2-6 Alkenyl, -OC 1-6 Alkylene-C 2-6 Alkynyl, halogen, halogeno-C 1-6 Alkyl, -O-halogeno-C 1-6 A compound or a salt thereof, wherein the compound is -alkyl, or -OH. (3-2)R a1 and R a2 However, independently, H, C 1-6 Alkyl, halogen, halogeno-C 1-6 Alkyl or -O-halogeno-C 1-6 The compound or a salt thereof, (3-3)R a1 and R a2 are independently H, halogen, halogeno-C 1-6 Alkyl or -O-halogeno-C 1-6 The compound or a salt thereof, (3-4)R a1 and R a2 Independently, H, halogeno-C 1-6 Alkyl or -O-halogeno-C 1-6 The compound or a salt thereof, (3-5)R a1 and R a2 are independently H or -O-halogeno-C 1-6 The compound or a salt thereof, (3-6)Ra1 is H and R a2 But -O-halogeno-C 1-6 The compound or a salt thereof, (3-7)R a1 and R a2 is H, or a salt thereof. (4-1)R b1 and R b2 However, independently, H, C 1-6 Alkyl, -OC 1-6 Alkyl, halogeno-C 1-6 Alkyl, -O-halogeno-C 1-6 Alkyl, halogen, -C 1-6 Alkylene -OH, -C 1-6 Alkylene-NR c R d , -C(=O)-NR c R d , -NR c R d , -CN, or -OH, or a salt thereof. (4-2)R b1 and R b2 independently, H, halogeno-C 1-6 Alkyl or -C 1-6 Alkylene-NR c R d or a salt thereof. (4-3)R b1 and R b2 are independently H or halogeno-C 1-6 The compound or a salt thereof, (4-4)R b1 is H and R b2 But, halogeno-C 1-6 The compound or a salt thereof, (5)R a1 , R a2 , R b1 , or R b2 At least one of the following is not H: (6-1)R c and R d However, independently, H, C 1-6 Alkyl, C 3-8 Cycloalkyl, -C(=O)-C1-6 Alkyl or -S(=O)2-C 1-6 Is it an alkyl group? or R c and R d are connected to each other, R c and R d may form a 4- to 7-membered saturated heterocyclyl together with the nitrogen atom to which it is attached, and the heterocyclyl may be one or two R e The compound or a salt thereof, which may be substituted with (6-2)R c and R d are independently H or C 1-6 Is it an alkyl group? or R c and R d are connected to each other, R c and R d may form a 4- to 7-membered saturated heterocyclyl together with the nitrogen atom to which it is attached, and the heterocyclyl may be one or two R e The compound or a salt thereof, which may be substituted with (6-3)R c and R d are independently H or C 1-6 The compound or a salt thereof, (6-4)R c and R d are connected to each other, R c and R d together with the nitrogen atom to which it is attached, form a 4- to 7-membered saturated heterocyclyl, the heterocyclyl being one or two R e The compound or a salt thereof, which may be substituted with (7-1)R e But, C 1-6 Alkyl, -OC 1-6 A compound or a salt thereof, wherein the compound is an alkyl, or a halogen. (7-2)R e But, -OC 1-6 The compound or a salt thereof, (8-1)R 1 is H, optionally substituted C 1-6 Alkyl, optionally substituted C 3-8cycloalkyl, optionally substituted 4- to 7-membered saturated heterocyclyl, optionally substituted phenyl, or optionally substituted heteroaryl; R 2 But one or two R 3 C replaced with 1-6 Alkyl, one or two R 4 C replaced with 3-8 Cycloalkyl, one or two R 5 or one or two R 6 or Or R 1 and R 2 are connected to each other, R 1 and R 2 together with the nitrogen atom to which it is attached form a 4-7 membered saturated heterocyclyl, the heterocyclyl may be fused to a phenyl, and the heterocyclyl and / or the fused phenyl may be fused to one or more of R 7 The compound or a salt thereof, which may be substituted with (8-2)R 1 But, H, C 1-6 Alkyl, C 3-8 cycloalkyl, 4-7 membered saturated heterocyclyl, optionally substituted phenyl, or optionally substituted heteroaryl; R 2 But one or two R 3 C replaced with 1-6 Alkyl, one or two R 4 C replaced with 3-8 Cycloalkyl, one or two R 5 or one or two R 6 or Or R 1 and R 2 are connected to each other, R 1 and R 2together with the nitrogen atom to which it is attached, form a 4- to 7-membered saturated heterocyclyl, the heterocyclyl may be fused with a phenyl, and the heterocyclyl and / or the fused phenyl may be one or two R 7 The compound or a salt thereof, which may be substituted with (8-3)R 1 But, H, C 1-6 Alkyl, C 3-8 cycloalkyl, 4-7 membered saturated heterocyclyl, phenyl, or optionally substituted heteroaryl; R 2 But one or two R 3 C replaced with 1-6 Alkyl, one or two R 4 C replaced with 3-8 Cycloalkyl, or one or two R 5 or a 4- to 7-membered saturated heterocyclyl substituted with Or R 1 and R 2 are connected to each other, R 1 and R 2 together with the nitrogen atom to which it is attached, form a 4- to 7-membered saturated heterocyclyl, the heterocyclyl being one or two R 7 The compound or a salt thereof, which may be substituted with (8-4)R 1 and R 2 are connected to each other, R 1 and R 2 together with the nitrogen atom to which it is attached, form a 4- to 7-membered saturated heterocyclyl, the heterocyclyl being one or two R 7 The compound or a salt thereof, which may be substituted with (8-5)R 1 is H or R 2 But one or two R 3 C replaced by 1-6 Is it an alkyl group? Or R 1 and R 2 are connected to each other, R 1 and R 2together with the nitrogen atom to which it is attached form an azetidinyl, pyrrolidinyl, piperidinyl, or thiomorpholinyl, and the azetidinyl, pyrrolidinyl, piperidinyl, or thiomorpholinyl is selected from the group consisting of one or two R 7 The compound or a salt thereof, which may be substituted with (8-6)R 1 and R 2 are connected to each other, R 1 and R 2 together with the nitrogen atom to which it is attached form an azetidinyl, pyrrolidinyl, piperidinyl, or thiomorpholinyl, and the azetidinyl, pyrrolidinyl, piperidinyl, or thiomorpholinyl is selected from the group consisting of one or two R 7 The compound or a salt thereof, which may be substituted with (8-7)R 1 and R 2 are connected to each other, R 1 and R 2 together with the nitrogen atom to which it is attached to form a pyrrolidinyl, the pyrrolidinyl being 7 The compound or a salt thereof, which may be substituted with (8-8)R 1 and R 2 are connected to each other, and R 1 and R 2 together with the nitrogen atom to which it is attached to form a pyrrolidinyl, which is a group consisting of two R 7 or a salt thereof, wherein (8-9)R 1 But, H, C 1-6 Alkyl, C 3-8 cycloalkyl, 4-7 membered saturated heterocyclyl, optionally substituted phenyl, or optionally substituted heteroaryl; R 2 But one or two R 3 C replaced with 1-6 Alkyl, one or two R 4 C replaced with 3-8 Cycloalkyl, one or two R 5 or one or two R 6or Or R 1 and R 2 are connected to each other, R 1 and R 2 together with the nitrogen atom to which it is attached form a 4- to 7-membered saturated heterocyclyl, the heterocyclyl being optionally fused with a phenyl, the heterocyclyl being optionally fused with one or two R 7 The compound or a salt thereof, which may be substituted with (9-1)Each R 3 Independently, -OH, -OC 1-6 Alkyl, -C(=O)-NH2, -C(=O)-NH-C 1-6 Alkyl, -C(=O)-N(C 1-6 alkyl)2, -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH-C(=O)-C 1-6 Alkyl, -NH-S(=O)2-C 1-6 Alkyl, -NH-S(=O)2-C 1-6 Alkylene-OH, -NH-S(=O)2-C 1-6 Alkylene-C(=O)-OH, -S(=O)2-NH2, -S(=O)2-C 1-6 Alkyl, or -S(=O)(=NH)-C 1-6 The compound or a salt thereof, (9-2)Each R 3 are independently -OH, -C(=O)-NH2, -NH-C(=O)-C 1-6 Alkyl, -NH-S(=O)2-C 1-6 A compound or a salt thereof, which is -S(=O)2-NH2. (9-3)Each R 3 are independently -OH or -C(=O)-NH2, or a salt thereof. (10-1)Each R 4 Independently, -OH, -OC 1-6 Alkyl, -C(=O)-NH2, -C(=O)-NH-C 1-6 Alkyl, -C(=O)-N(C 1-6 alkyl)2, -NH2, -NH-C 1-6 Alkyl, -N(C1-6 Alkyl)2, -NH-C(=O)-C 1-6 Alkyl, -NH-S(=O)2-C 1-6 Alkyl, -S(=O)2-NH2, -S(=O)2-C 1-6 Alkyl, or -S(=O)(=NH)-C 1-6 The compound or a salt thereof, (10-2)Each R 4 are independently -OH, -C(=O)-NH2, -NH-C(=O)-C 1-6 Alkyl, -NH-S(=O)2-C 1-6 A compound or a salt thereof, which is -S(=O)2-NH2. (10-3)R 4 is -OH, or a salt thereof. (11-1)Each R 5 is independently -OH, oxo, or imino, or a salt thereof. (11-2)Each R 5 are independently -OH or oxo, or a salt thereof. (11-3)R 5 is -OH, or a salt thereof. (11-4)R 5 is oxo, or a salt thereof. (11-5)Each R 5 is independently oxo or imino, or a salt thereof. (12-1)Each R 6 are independently -C(=O)-OH, -S(=O)2-NH2, -S(=O)2-C 1-6 Alkyl, -S(=O)(=NH)-C 1-6 Alkyl, or -NH-S(=O)2-C 1-6 The compound or a salt thereof, (12-2)Each R 6 are independently -C(=O)-OH or -S(=O)2-NH2, or a salt thereof. (12-3)R 6 is -C(=O)-OH, or a salt thereof. (12-4)R 6is -S(=O)2-NH2, or a salt thereof. (13-1)Each R 7 But independently, C 1-6 Alkyl, -C 1-6 Alkylene -OH, -C 1-6 Alkylene-C(=O)-OH, C 3-8 Cycloalkyl, -OH, -OC 1-6 Alkyl, -NH2, -NH-C 1-6 Alkyl, -N(C 1-6 Alkyl)2, -NH-C(=O)-C 1-6 Alkyl, -NH-S(=O)2-C 1-6 Alkyl, -S(=O)2-C 1-6 Alkyl, -S(=O)(=NH)-C 1-6 Alkyl, -C(=O)-OH, -C(=O)-NH2, -C(=O)-NH-C 1-6 Alkyl, -C(=O)-N(C 1-6 A compound or a salt thereof, which is a 4- to 7-membered saturated heterocyclyl optionally substituted by alkyl, oxo, imino, or one or two oxo. (13-2) Each R 7 But independently, C 1-6 Alkyl, -C 1-6 Alkylene -OH, -C 1-6 Alkylene-C(=O)-OH, C 3-8 A compound or a salt thereof which is a 4- to 7-membered saturated heterocyclyl optionally substituted by cycloalkyl, -OH, -NH2, -C(=O)-OH, -C(=O)-NH2, oxo, imino, or one or two oxo. (13-3)Each R 7 But independently, -C 1-6 A compound or a salt thereof which is alkylene-OH, -OH, -C(=O)-NH2, oxo, or imino. (13-4)Each R 7 But independently, -C 1-6 A compound or a salt thereof, which is alkylene-OH, -OH, or -C(=O)-NH2. (13-5)R 7 is -OH, or a salt thereof. (14) A compound or a salt thereof which is a combination of two or more mutually non-inconsistent embodiments among the embodiments of the groups described in (1-1) to (13-5). Examples thereof include, but are not limited to, the following combinations: (14-1) A compound or a salt thereof which is a combination of (1-1), (2-1), (3-1), (4-1), (6-1), (7-1), (8-1), (9-1), (10-1), (11-1), (12-1), and (13-1). (14-2) A compound or a salt thereof which is a combination of (1-1), (2-2), (3-2), (4-2), (6-2), (7-1), (8-2), (9-2), (10-2), (11-2), (12-2), and (13-2). (14-3) A compound or a salt thereof which is a combination of (1-2), (2-4), (3-2), (4-2), (5), (6-2), (7-1), (8-3), (9-2), (10-3), (11-2), and (13-2). (14-4) A compound or a salt thereof which is a combination of (1-2), (2-4), (3-2), (4-4), (8-4), and (13-2). (14-5) A compound or a salt thereof which is a combination of (1-4), (2-4), (3-7), (4-4), (8-5), (9-3), and (13-3). (14-6) A compound or a salt thereof which is a combination of (1-4), (2-4), (3-7), (4-4), (8-6), and (13-3). (14-7) A compound or a salt thereof which is a combination of (1-4), (2-5), (3-7), (4-4), (8-8), and (13-5). (14-8) A compound or a salt thereof which is a combination of (1-1), (2-2), (3-2), (4-2), (6-2), (7-1), (8-9), (9-2), (10-2), (11-2), (12-2), and (13-2).

[0060] Examples of specific compounds encompassed by the present invention include the following compounds or salts thereof: N 2-{3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoyl}-L-serinamide, 1-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-yn-1-one, 1-{3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoyl}piperidine-4-carboxamide, 1-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-yn-1-one, 1-[3,3-bis(hydroxymethyl)azetidin-1-yl]-3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-yn-1-one, N-[(2R)-2,3-dihydroxypropyl]-3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynamide, N-[(2S)-2,3-dihydroxypropyl]-3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynamide, 1-[(3S,4S)-3,4-dihydroxypyrrolidin-1-yl]-3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-yn-1-one, (3R)-1-{3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoyl}pyrrolidine-3-carboxamide, 1-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-3-[6-phenyl-5-(trifluoromethyl)pyridin-3-yl]prop-2-yn-1-one, and 1-Imino-4-{3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoyl}-1λ 6 -Thiomorpholin-1-one Examples include:

[0061] Examples of specific compounds encompassed by the present invention also include those compounds listed in Tables 13-20, either in free base form or as a salt thereof.

[0062] Regarding the compound of formula (I), depending on the type of the substituent, its tautomer or geometric isomer may exist. In this specification, the compound of formula (I) and its salts may be described in some cases only in one form of isomer, but the present invention includes other isomers, isolated form of isomers, or mixtures thereof.

[0063] Furthermore, some of the compounds of formula (I) may in some cases have asymmetric carbon atoms or axial chirality and, correspondingly, their enantiomers (optical isomers) may exist. The present invention includes the individual enantiomers of the compounds of formula (I) in isolated form or mixtures thereof, including racemic mixtures or otherwise.

[0064] In one embodiment, an enantiomer is "stereochemically pure." "Stereochemically pure" refers to a level of stereochemical purity that is recognized by those of skill in the art as essentially "pure." In another embodiment, an enantiomer is a compound that has a stereochemical purity of greater than 90% ee (enantiomeric excess), greater than 95% ee, greater than 98% ee, greater than 99% ee, or greater than 99.5% ee.

[0065] Furthermore, the salts of the compounds of formula (I) are pharma- ceutically acceptable salts of the compounds of formula (I), which in some cases may form acid addition salts or salts with bases depending on the types of substituents. Specific examples include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, as well as with organic acids such as formic acid, acetic acid, propanoic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, mandelic acid, tartaric acid, dibenzoyltartaric acid, ditolyltartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, aspartic acid, and glutamic acid, as well as salts with metal anions such as sodium, potassium, magnesium, calcium, and aluminum, as well as salts with organic bases such as methylamine, ethylamine, ethanolamine, lysine, and ornithine, salts with various amino acids such as acetylleucine, or derivatives of amino acids, ammonium salts, and others.

[0066] In addition, the present invention also includes various hydrates or solvates, as well as crystalline polymorphic substances, of the compounds of formula (I) and their salts.

[0067] The present invention includes all pharma- ceutically acceptable isotopically labeled compounds of the present invention that contain one or more radioactive or non-radioactive isotopes.

[0068] Examples of isotopes suitable for isotopically labeled compounds of the present invention include: 2 H and 3 Hydrogen such as H 11 C. 13 C, and 14 Carbon, such as C 36 Chlorine such as Cl, 18 Fluorine such as F 123 I and 125 Iodine, such as I 13 N and 15 Nitrogen such as N 15 O. 17 O, and 18 Oxygen, such as O 32 Phosphorus such as P, 35Examples of sulfur include S.

[0069] Certain isotopically labeled compounds of the invention, for example those incorporating a radioactive isotope, may be useful in drug and / or substrate tissue distribution studies. The radioactive isotope tritium, i.e. 3 H, and carbon-14, i.e. 14 C may be used for this purpose given their ease of incorporation and ready means of detection.

[0070] Substitution of a heavier isotope, e.g., deuterium for hydrogen, i.e. 2 Substitution with H may provide certain therapeutic advantages due to greater metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements, reduced drug-drug interference, and therefore may be used in some situations.

[0071] 11 C. 18 F, 15 O, and 13 Substitution with positron emitting isotopes, such as N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy.

[0072] Isotopically labeled compounds of the present invention 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 an appropriate isotopically labeled reagent for the non-labeled reagent previously employed.

[0073] (Production Process) The compounds of formula (I) or their salts can be prepared by applying various known synthesis methods using the characteristics based on their basic structure or the type of substituents. At this time, depending on the type of functional group, in some cases, it is effective from the viewpoint of preparation technology to protect the functional group with a suitable protecting group (a group that can be easily converted into a functional group) during the step from the starting material to the intermediate. Examples of protecting groups include those described in "Greene's Protective Groups in Organic Synthesis (4th edition, 2006)" edited by PG M Huts and TW Greene, etc., which can be appropriately selected and used depending on the reaction conditions. In these methods, the desired compound can be obtained by introducing a protecting group to carry out the reaction, and then removing the protecting group as necessary.

[0074] A pharma- ceutically acceptable prodrug refers to a compound having a group that can be converted to an amino group, a hydroxyl group, a carboxyl group, etc., by solvent decomposition or under physiological conditions. Examples of groups that form prodrugs include those described in Prog. Med., 5, 2157-2161 (1985) or “Pharmaceutical Research and Development” (Hirokawa Publishing Company, 1990), vol. 7, Drug Design, 163-198. In addition, prodrugs of the compound of formula (I) can be prepared by introducing a specific group in the same manner as the above-mentioned protective group during the steps from the starting material to the intermediate, or by carrying out further reactions using the obtained compound of formula (I). The reactions can be carried out by applying methods known to those skilled in the art, such as general esterification, amidation, and dehydration.

[0075] The following describes typical preparation methods of the compound of formula (I). Each of the production processes can also be carried out with reference to the documents attached to the description of this specification. Furthermore, the preparation method of the present invention is not limited to the examples shown below.

[0076] The following abbreviations may be used herein: AcOH: acetic acid, BOC: t-butoxycarbonyl, CHCl3: chloroform, CH2Cl2: dichloromethane, CH3CN: acetonitrile, COMU: (1-cyano-2-ethoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate, (COCl)2: oxalyl chloride, CuI: copper(I) iodide, Cu(OAc)2: copper(II) acetate, DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene, DIBAL-H: diisobutylaluminum hydride, DMF: N,N-dimethylphosphite amide, DMSO: dimethyl sulfoxide, DIPEA: N,N-diisopropylethylamine, Et3N: triethylamine, EtOH: ethanol, Et2O: diethyl ether, EtOAc: ethyl acetate, HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolol[4,5-b]pyridinium 3-oxide hexafluorophosphate, (HCHO)n: paraformaldehyde, HCl: hydrochloric acid, HOBt: 1-hydroxybenzotriazole, IPA: isopropyl alcohol, IPE: diisopropyl ether, K 2CO3: Potassium carbonate, K3PO4: Potassium phosphate, LiBH4: Lithium borohydride, LiCl: Lithium chloride, LiOH·H2O: Lithium hydroxide monohydrate, Me: Methyl, MeOH: Methanol, MgSO4: Magnesium sulfate, MnO2: Manganese(IV) oxide, NaBH4: Sodium borohydride, NaBH3CN: Sodium cyanoborohydride, Na2CO3: Sodium carbonate, NaHCO3: Sodium bicarbonate, NaNO2: Sodium nitrite, NaOH: Sodium hydroxide, nBuLi: n-butyl lithium, m-C PBA: m-chloroperbenzoic acid, NH4HCO3: ammonium bicarbonate, NIS: N-iodosuccinimide, NMP: 1-methylpyrrolidin-2-one, P(t-Bu)3·HBF4: tri-t-butylphosphonium tetrafluoroborate, Pd / C: palladium on carbon, PdCl2(PPh3)2: bis(triphenylphosphine)palladium(II) dichloride, PdCl2(dppf) / CH2Cl2: [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride / dichloromethane adduct, Pd2(dba)3: (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one / palladium (3:2), Pd(OAc)2: palladium(II) acetate, Pd(PPh3)4: tetrakis(triphenylphosphine)palladium, PyBOP: (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate, SPhos: 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl, TBAF: tetra-n-butylammonium fluoride, TBS: tert-butyldi(methyl)silyl, tBu: tert-butyl ethyl ether, Tf: trifluoromethanesulfonyl, THF: tetrahydrofuran, TFA: trifluoroacetic acid, TMS: trimethylsilyl, T3P®: 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide, EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, EDC·HCl: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, XPhos: 2-dicycloxylphosphosphino-2',4',6'-triisopropylbiphenyl,

[0077] (Production Process 1) [ka] (In the formula, Y 1 and Y 2 are independently Cl, Br, I, or OTf. Both R' and R'' are H, or R' and R'' are linked together to form 4,4,5,5-tetramethyl-1,3,2-dioxaborane together with the boronic acid residue to which R' and R'' are attached. The same applies below.)

[0078] (Step 1a) This step is the preparation of a compound of formula (VII) by the reaction of a compound of formula (VI) with trimethylsilylacetylene. In this reaction, the compound of formula (VI) and trimethylsilylacetylene are used in equal amounts, or one of the compounds is used in an excess amount. A mixture of these compounds is stirred in a solvent inert to the reaction or without a solvent, in the presence of a catalyst, a cocatalyst, and a base, typically for 0.1 hours to 5 days, under cooling or under reflux, preferably at room temperature to 190°C. Examples of catalysts used herein include, but are not limited to, Pd(PPh3)4, PdCl2(PPh3)2, PdCl2(dppf) / CH2Cl2, Pd2(dba)3, Pd(OAc)2, and combinations thereof. Examples of cocatalysts used herein include, but are not limited to, CuI. Examples of bases include, but are not limited to, DBU, Et3N, and DIPEA. Examples of solvents include, but are not limited to, ethers such as THF, 2-methyltetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane, CH3CN, NMP, DMF, DMSO, and mixtures thereof. In some cases, it may be advantageous to carry out the reaction in the presence of sodium iodide for smooth progress of the reaction. This reaction may be carried out under microwave irradiation. [References] Tetrahedron Letters,50,pp 4467-4470(1975)

[0079] (Step 2a) This step is the preparation of a compound of formula (IX) by the reaction of compounds of formula (VII) and (VIII). In this reaction, the compounds of formula (VII) and formula (VIII) are used in equal amounts, or one of the compounds is used in an excess amount. A mixture of these compounds is stirred in a solvent inert to the reaction or without a solvent in the presence of a catalyst and a base, typically for 0.1 hours to 5 days, under cooling or under reflux, preferably at room temperature to 190°C. Examples of catalysts used herein include, but are not limited to, Pd(PPh3)4, PdCl2(PPh3)2, PdCl2(dppf) / CH2Cl2, Pd2(dba)3, and Pd(OAc)2. Examples of bases include, but are not limited to, K3PO4, Na2CO3, K2CO3, cesium carbonate (Cs2CO3), NaOH, and sodium t-butoxide. Examples of solvents include, but are not limited to, ethers such as diethyl ether, THF, 1,4-dioxane, and 1,2-dimethoxyethane, aromatic hydrocarbons such as benzene, toluene, and xylene, as well as water, pyridine, CH3CN, NMP, DMF, DMSO, and mixtures thereof. In some cases, for smooth progress of the reaction, it may be advantageous to carry out the reaction in the presence of a phosphine ligand such as SPhos, XPhos, dicyclohexyl(2',6'-diisopropoxy-[1,1'-biphenyl]-2-yl)phosphine (RuPhos), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (XantPhos), P(t-Bu)3·HBF4, etc. This reaction may be carried out under microwave irradiation. [References] Journal of the American Chemical Society,127,pp 4685-4696(2005)

[0080] The compound of formula (IX) can also be obtained from the compound of formula (VI) via step 1b and step 2b.

[0081] (Step 1b) This step is the preparation of a compound of formula (X) by the reaction of compounds of formula (VI) and (VIII). This reaction is carried out under the same conditions as step 2a, by using a compound of formula (VI) instead of a compound of formula (VII).

[0082] (Step 2b) This step is the preparation of a compound of formula (IX) by the reaction of a compound of formula (X) with trimethylsilylacetylene. This reaction is carried out under the same conditions as step 1a, except that a compound of formula (X) is used instead of a compound of formula (VI).

[0083] (Step 3) This step is a step of preparing a compound of formula (XI) by deprotecting a compound of formula (IX). This reaction is carried out by using a compound of formula (IX) and a deprotecting reagent, by stirring the mixture in a solvent inert to the reaction under cooling or under heating and reflux, preferably at room temperature to 100° C., typically for 0.1 hours to 5 days. Examples of deprotecting reagents include, but are not limited to, bases such as potassium carbonate, and fluorides such as tetrabutylammonium fluoride. Examples of solvents include, but are not limited to, alcohols such as MeOH and EtOH, and ethers such as THF or 1,4-dioxane.

[0084] (Step 4a) This step is a step of preparing a compound of formula (XII) by the reaction of a compound of formula (XI) with carbon dioxide. This reaction is first carried out by using a compound of formula (XI) and an organolithium reagent in a solvent inert to the reaction under cooling or at room temperature to obtain an acetylated lithium intermediate. The acetylated lithium intermediate is then added to an excess of dry ice under cooling or at room temperature to obtain a compound of formula (XII). The entire reaction is typically carried out for 0.1 hours to 1 day. Examples of organolithium reagents include, but are not limited to, n-butyl lithium, t-butyl lithium, and lithium diisopropylamide. Examples of solvents include, but are not limited to, hydrocarbons such as n-hexane or n-pentane, and ethers such as THF or 1,4-dioxane.

[0085] (Step 4b) The compound of formula (XII) can also be obtained from the compound of formula (X) via step 4b, which is a step of preparing the compound of formula (XII) by reacting the compound of formula (X) with propiolic acid. This reaction is carried out under the same conditions as step 1a, except that propiolic acid is used instead of trimethylsilylacetylene.

[0086] (Step 5a) This step is a step of preparing a compound of formula (I) by the reaction of compounds of formula (XII) and (XIII). In this reaction, the compound of formula (XII) and the compound of formula (XIII) are used in equal amounts, or one of the compounds is used in an excess amount. A mixture of these compounds is stirred in a solvent inert to the reaction or without a solvent in the presence of a condensing agent and a base, typically for 0.1 hours to 5 days, under cooling or under reflux, preferably at room temperature to 100°C. Examples of condensing agents include, but are not limited to, T3P®, HATU, EDC, EDC·HCl, COMU, 2-chloro-1-methylpyridinium iodide, and the like. Examples of bases include, but are not limited to, Et3N and DIPEA. Examples of solvents include, but are not limited to, ethers such as THF, 2-methyltetrahydrofuran, 1,4-dioxane, and 1,2-dimethoxyethane, halocarbons such as CH2Cl2 and CHCl3, acetonitrile, NMP, DMF, DMSO, and mixtures thereof. In some cases, it may be advantageous to carry out the reaction in the presence of HOBt for smooth progress of the reaction.

[0087] This step can also be carried out by using a chlorinating agent as a condensing agent. The reaction is first carried out by using a compound of formula (XII) and a chlorinating agent in a reaction-inert solvent or without a solvent, under cooling or heating to reflux, preferably at 0° C. to room temperature, to obtain an acyl chloride intermediate. The acyl chloride intermediate is then added to a mixture of a base and a compound of formula (XIII), in a reaction-inert solvent, under cooling or heating to reflux, preferably at 0° C. to room temperature. The entire reaction is typically carried out for 0.1 hours to 1 day. Examples of chlorinating agents include, but are not limited to, (COCl) 2 , phosphoryl chloride (POCl 3 ), and thionyl chloride (SOCl 2 ). Examples of bases include, but are not limited to, Na 2 CO 3 , NaHCO 3 , K 2 CO 3 , Et 3 N, DIPEA, and pyridine. Examples of solvents include, but are not limited to, haloalkanes such as CH 2 Cl 2 or CHCl 3 , and ethers such as THF or 1,4-dioxane. Water may be added as a co-solvent.

[0088] (Step 5b) The compound of formula (I) can also be obtained from the compound of formula (X) via step 5b, which is a step of preparing the compound of formula (I) by the reaction of the compound of formula (X) with the compound of formula (XIV). This reaction is carried out under the same conditions as step 1a, except that the compound of formula (XIV) is used instead of trimethylsilylacetylene.

[0089] (Production Process 2) [ka] (Wherein, R′′ and R z is C 1-6 It is an alkyl group. The same applies below.)

[0090] (Step 1) This step is a step of preparing a compound of formula (XVI) by the reaction of a compound of formula (VI) with a compound of formula (XV). This reaction is carried out under the same conditions as step 1a of production process 1, by using a compound of formula (XV) instead of trimethylsilylacetylene.

[0091] (Step 2) This step is to prepare a compound of formula (XVII) by reacting a compound of formula (XVI) with a compound of formula (VIII). This reaction is carried out under the same conditions as step 2a of production process 1, by using a compound of formula (XVI) instead of a compound of formula (VII).

[0092] Alternatively, in this step, compounds of formula (XVII) can also be obtained by using stannyl compounds of formula (VIIIb) instead of the corresponding boronate compounds of formula (VIII).

[0093] (Step 3) This step is to prepare a compound of formula (XII) by hydrolyzing the ester group of the compound of formula (XVII). This reaction is carried out by using an aqueous solution of the compound of formula (XVII) and a base, by stirring the mixture in a solvent inert to the reaction under cooling or under reflux, preferably at room temperature to 100°C, typically for 0.1 hours to 5 days. Examples of bases include, but are not limited to, LiOH·H2O, NaOH, KOH, K2CO3, etc. Examples of solvents include, but are not limited to, alcohols such as MeOH or EtOH, ethers such as THF or 1,4-dioxane, and mixtures thereof.

[0094] (Step 4) This step is a step of preparing a compound of formula (I) by reacting a compound of formula (XII) with a compound of formula (XIII). This reaction is carried out under the same conditions as step 5a of production process 1.

[0095] (Production process 3) [ka]

[0096] (Step 1) This step is to prepare a compound of formula (XVIII) by reacting a compound of formula (VI) with propiolic acid. This reaction is carried out under the same conditions as step 1a of production process 1, except that propiolic acid is used instead of trimethylsilylacetylene.

[0097] (Step 2) This step is to prepare a compound of formula (XIX) by the reaction of a compound of formula (XVIII) with a compound of formula (XIII). This reaction is carried out under the same conditions as step 5a of production process 1, by using a compound of formula (XVIII) instead of a compound of formula (XII).

[0098] (Step 3) This step is to prepare the compound of formula (I) by the reaction of the compound of formula (XIX) with the compound of formula (VIII). This reaction is carried out under the same conditions as step 2a of production process 1, by using the compound of formula (XIX) instead of the compound of formula (VII).

[0099] Alternatively, in this step, compounds of formula (I) can also be obtained by using stannyl compounds of formula (VIIIb) instead of the corresponding boronate compounds of formula (VIII).

[0100] (Starting compound synthesis process 1) [ka] This process is a process for preparing a compound of formula (Xa) having a pyrazol-1-yl group as ring A among compounds of formula (X) by reacting a compound of formula (VIa) with a compound of formula (VIIIa). In this reaction, the compound of formula (VIa) and the compound of formula (VIIIa) are used in equal amounts, or one of the compounds is used in an excess amount. A mixture of these compounds is stirred in a solvent inert to the reaction or without a solvent in the presence of a catalyst and a base, typically for 0.1 hours to 5 days, under cooling or under heating at reflux, preferably at room temperature to 190°C. Examples of catalysts used herein include, but are not limited to, Cu(OAc)2, copper(I) oxide (Cu2O), copper(I) chloride (CuCl), copper(II) bromide (CuBr2), CuI, etc. Examples of bases used herein include, but are not limited to, Et3N, DIPEA, pyridine, etc. Examples of solvents include, but are not limited to, CH2Cl2, CH3CN, DMF, DMSO, MeOH, EtOH, toluene, etc. In some cases, for smooth progress of the reaction, it may be advantageous to carry out the reaction in the presence of a bidentate ligand such as 1,10-phenanthroline or N,N,N',N'-tetramethylethylenediamine, and / or molecular sieves.

[0101] (Start of compound synthesis process 2) [ka] (In the formula, one of W and Z is N, and the other is CH. The same applies below.)

[0102] This process is a process for preparing a compound of formula (Xb) having a pyrazol-1-yl group or an imidazol-1-yl group as ring B of a compound of formula (X) by reacting a compound of formula (VIb) with a compound of formula (VIII). This reaction is carried out under the same conditions as the starting compound synthesis process 1, except that a compound of formula (VIb) and a compound of formula (VIII) are used instead of a compound of formula (VIa) and a compound of formula (VIIIa).

[0103] (Starting compound synthesis process 3) [ka] This process involves the preparation of a compound of formula (X) by the reaction between a compound of formula (VIc) and a compound of formula (VIII) to give a compound of formula (Xc), followed by conversion of the amino group to a halogen by a Sandmeyer reaction.

[0104] (Step 1) This step is to prepare a compound of formula (Xc) by the reaction of a compound of formula (VIc) with a compound of formula (VIII). This reaction is carried out under the same conditions as step 2a of production process 1, by using a compound of formula (VIc) instead of a compound of formula (VII).

[0105] (Step 2) This step is a step of preparing a compound of formula (X) by converting the amino group of the compound of formula (Xc) to a halogen by Sandmeyer reaction. This reaction is carried out by adding a diazotization reagent to a mixture of the compound of formula (Xc) and an acid under cooling, preferably at 0° C., in a solvent inert to the reaction, followed by adding a halogenation reagent under cooling, preferably at 0° C., and stirring at 0° C. to room temperature, typically for 0.1 hours to 5 days. Examples of diazotization reagents include, but are not limited to, NaNO2, t-butyl nitrite, isoamyl nitrite, and the like. Examples of acids include, but are not limited to, hydrochloric acid, sulfuric acid, and the like. Examples of halogenation reagents include, but are not limited to, CuCl, CuBr, KI, and the like. Examples of solvents include, but are not limited to, water, EtOH, MeOH, THF, 1,4-dioxane, CH3CN, acetone, and mixtures thereof. In some cases, it may be advantageous to carry out the reaction in the presence of urea for smooth progress of the reaction.

[0106] (Other production processes) A compound of formula (I) or a synthetic intermediate thereof prepared by any of the above-mentioned production processes can be used as a starting material to prepare another compound of formula (I) or a synthetic intermediate thereof by carrying out further chemical modification reactions typically employed by a person skilled in the art, such as alkylation, amidation, acylation, sulfonylation, oxidation, reduction, reductive amination, NH-sulfoximination (Chemical Communications, 53, pp348-351, 2017), protection, or deprotection.

[0107] The compound of formula (I) is isolated and purified as the free compound or as a salt, hydrate, solvate, or polymorphic substance thereof. Salts of the compound of formula (I) can also be prepared by conventional methods.

[0108] Isolation and purification are carried out by employing common chemical procedures such as extraction, fractional crystallization, and various types of fractional chromatography.

[0109] Various isomers can be prepared by selecting appropriate starting compounds, or can be separated by separation utilizing the differences in physicochemical properties between isomers. For example, optical isomers can be obtained by conventional optical resolution methods of racemates (e.g., fractional crystallization using optically active bases or acids to induce diastereomeric salts of compounds, chromatography using chiral columns, etc.), or can be prepared from appropriate optically active starting compounds.

[0110] The pharmacological activity of the compounds of formula (I) can be confirmed by the following tests or modifications thereof which will be apparent to those skilled in the art.

[0111] Test Example 1: Testing the activity of the IRF pathway in THP-1 0.3uM PMA (phorbol myristate acetate, SIGMA, P1585) was added to THP1-Dual™ cells (NF-κB-SEAP IRF-Luc Reporter Monocytes, Invivogen, thpd-nfis) and cells were cultured in RPMI1640 with 10% fetal bovine serum (FBS) at 37°C for 1 day. Known concentrations of compounds were added and cells were incubated at room temperature for 1 hour. Mammalian (non-canonical) CDN, cyclic [G(2',5')pA(3',5')p] (2'3'-cGAMP, Invivogen, tlrl-nacga23) was added to a final concentration of 5ug / mL and cells were cultured at 37°C. The next day, QUANTI-Luc™ (Secreted Luciferase Detection Medium, Invivogen, rep-qlc) was added to the culture medium, and the activity of the IRF pathway was measured using a microplate reader. The inhibition rate at each concentration was determined, and the activity of the IRF pathway without the addition of test compound or 2'3'-cGAMP was defined as 100% inhibition, and the activity of the IRF pathway without the addition of test compound and with the addition of 2'3'-cGAMP was defined as 0% inhibition. IC 50 Values ​​were calculated by sigmoidal test model nonlinear regression analysis.

[0112] The results are shown in Tables 1 and 2. It was determined that the exemplary compounds inhibited the activity of the IRF pathway.

[0113] [Table 1]

[0114] [Table 2]

[0115] Test Example 2: Test for IFNβ production in mouse plasma Male C57BL / 6J mice (8-12 weeks old) were orally administered either vehicle or 1 mg / kg of test compound. One hour later, 5,6-dimethylxanthenone-4-acetic acid (DMXAA) (BLD Pharmatech Ltd, BD126695) was administered intraperitoneally at a dose of 20 mg / kg. Four hours later, mice were euthanized and plasma was collected. Plasma concentrations of IFNβ were measured by enzyme-linked immunosorbent assay using the AlphaLISA Mouse IFNβ Detection Kit (Parkin Elmer, AL586C), and the inhibition rate relative to the vehicle-treated group was calculated.

[0116] Table 3 shows the inhibition rate of IFNβ production relative to the vehicle administration group. It was confirmed that these compounds inhibited IFNβ production in vivo.

[0117] [Table 3]

[0118] Test Example 3: Test for drug-induced Sjögren's syndrome-like salivary dysfunction in mice Female C57BL / 6J mice (8-10 weeks old) were subcutaneously injected with 20 mg / kg DMXAA or its vehicle, 5% NaHCO3, four times at weekly intervals. From the day after the final DMXAA challenge, the mice were orally administered the test compound or its vehicle once a day for 8 days. On the following day, saliva was collected from the mice using a cotton swab under awake conditions, and the weight of saliva for 15 minutes was measured and evaluated as an index of salivary gland function.

[0119] The evaluation results of Examples 33, 34, and 99 are shown in Figures 1 to 3. These compounds significantly improved saliva production in a mouse drug-induced Sjogren's syndrome-like model. This confirmed that these compounds showed an improving effect on salivary dysfunction.

[0120] Test Example 4: Trex1 KO mouse model of autoimmune disease C57BL / 6N-Trex1 em1Aiwsk / J mice (Trex1 KO mice: strain number 032213) were purchased from The Jackson Laboratory. Male Trex1 KO mice and their wild-type (WT) littermates (4-6 weeks old) were orally administered the test compound or its vehicle once a day for 4-9 weeks. Blood, kidneys, and other diseased tissues were collected for further analysis. Kidneys were preserved in RNAProtect Tissue Reagent (Qiagen, 76106), and RNA was purified using RNeasy Plus Mini Kit (Qiagen, 74134). Reverse transcription and real-time PCR reactions were performed using SuperScript VILO cDNA Synthesis Kit (Life Technologies, 11754250) and TaqMan Gene Expression Master Mix (Life Technologies, 4369016), respectively. Real-time PCR reactions were performed using a Quant Studio12K Flex (Thermo Fisher Scientific) instrument. The probes used were Cxcl10 (Mm00445235_m1), Cd68 (Mm03047343_m1), and Gapdh (Mm99999915_g1), and relative quantification was performed using the ΔΔCT method with Gapdh as the housekeeping gene. Certain compounds of formula (I) or salts thereof significantly reduced the elevated Cxcl10 and Cd68 gene expression in the kidneys of Trex1 KO mice.

[0121] As a result of the above test, it was confirmed that some compounds of formula (I) shown in Table 1 have STING inhibitory activity. Furthermore, it was demonstrated that some compounds of formula (I) inhibit the production of IFNβ induced by DMXAA in mice (Test Example 2). Therefore, the compounds of formula (I) can be used to treat autoimmune diseases, neurodegenerative diseases, type I interferonopathy, and / or other STING-mediated diseases.

[0122] Pharmaceutical compositions containing one or more types of compounds of formula (I) as active ingredients can be prepared according to commonly used methods using excipients commonly used in the art, i.e., excipients for pharmaceutical preparations, carriers for pharmaceutical preparations, etc.

[0123] Administration can be accomplished either orally via tablets, pills, capsules, granules, powders, solutions and the like, or parenterally via injection, such as intra-articular, intravenous and intramuscular injections, suppositories, ophthalmic solutions, ophthalmic ointments, transdermal liquid preparations, ointments, transdermal patches, transmucosal liquid preparations, transmucosal patches, inhalers and the like.

[0124] As the solid composition for oral administration, tablets, powders, granules, etc. are used. In such solid compositions, one or more active ingredients are mixed with at least one excipient. In a conventional manner, the composition may contain excipients such as lubricants, disintegrants, stabilizers, or solubilizing aids. If necessary, tablets, powders, and granules may be coated with wax, sugar, or with a film of gastric or enteric coating material.

[0125] Liquid compositions for oral administration include pharma- ceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and also include commonly used diluents such as purified water or ethanol. Liquid compositions may also include excipients such as solubilizing aids, moisturizing agents, suspending agents, sweeteners, flavors, aromatics, and disinfectants.

[0126] Injections for parenteral administration include sterile aqueous or non-aqueous preparations, suspensions, or emulsions. Aqueous solvents include, for example, distilled water for injection and physiological saline. Examples of non-aqueous solvents include alcohols such as ethanol. Such compositions may further include tonicity agents, preservatives, moisturizing agents, emulsifying agents, dispersing agents, stabilizers, or solubilizing aids. These are sterilized, for example, by filtration through a bacteria-retaining filter, blending with a sterilizing agent, or irradiation. In addition, they can also be used by preparing a sterile solid composition and dissolving or suspending it in sterile water or a sterile solvent for injection before its use.

[0127] Examples of topical vehicles include ointments, anhydrite, creams, jellies, poultices, sprays, lotions, ophthalmic solutions, ophthalmic ointments, etc. Vehicles further include commonly used ointment bases, lotion bases, aqueous or non-aqueous liquid preparations, suspensions, emulsions, etc.

[0128] For transmucosal agents such as inhalants and nasal agents, those in the form of solid, liquid, or semi-solid state are used and can be prepared according to methods known in the relevant technical field. For example, known excipients, pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners, etc. can be appropriately added. For administration, a suitable device for inhalation or insufflation can be used. For example, the compound can be administered using a known device such as a metered dose inhaler or a nebulizer, either alone or as a powder of a formulated mixture, or as a solution or suspension combined with a pharma-ceutically acceptable carrier. Dry powder inhalers and the like can be for single or multiple doses, and can use dry powder or powder-containing capsules. Alternatively, it can be in the form of a pressurized aerosol spray, etc., using a suitable propellant, for example, a suitable gas such as chlorofluoroalkane, carbon dioxide, or other form.

[0129] In general, in the case of oral administration, the daily dose is 0.001 mg / kg to 100 mg / kg, in one embodiment, 0.1 mg / kg to 30 mg / kg, and in another embodiment, 0.1 mg / kg to 10 mg / kg per body weight, administered once or in 2 to 4 divided doses. In the case of intravenous administration, it is preferably administered once a day or more than twice a day at a daily dose of about 0.0001 mg / kg to 10 mg / kg per body weight. In addition, transmucosal agents are administered at a dose of about 0.001 mg / kg to 100 mg / kg per body weight once or multiple times a day. The dose is appropriately determined according to the individual case, taking into consideration symptoms, age, sex, etc.

[0130] Although there are differences depending on the route of administration, dosage form, site of administration, and type of excipient or additive, the pharmaceutical composition of the present invention contains 0.01% by weight to 100% by weight, and in one embodiment, 0.01% by weight to 50% by weight, of one or more of the compounds of formula (I) or salts thereof as active ingredients.

[0131] The compound of formula (I) may be used in combination with various drugs to treat diseases for which the compound of formula (I) is believed to be effective. Such combined preparations may be administered simultaneously or separately, consecutively or at desired intervals. The preparations to be administered simultaneously may be blended or prepared separately. EXAMPLES

[0132] The production process of the compound of formula (I) is described in more detail below with reference to examples. The present invention is not limited to the compounds described in the following examples. Furthermore, the production process of the starting compound is described in Preparation Examples, and the production process of the known compound is described in Reference Examples. In addition, the production process of the compound of formula (I) is not limited to the production process of the specific examples shown below, but the compound of formula (I) can be prepared by a combination of these production processes or a method obvious to a person skilled in the art.

[0133] The onset temperatures of the endothermic and exothermic peaks were measured using an open aluminum sample pan using a DSC Q2000 (manufactured by TA Instruments) under the following conditions: temperature range: 25°C to 300°C, heating rate: 10°C / min, nitrogen flow rate: 50 mL / min.

[0134] Powder X-ray diffraction was measured using an Empyrean (manufactured by Malvern Panalytical) under the following conditions: tube: Cu, tube current: 40 mA, tube voltage: 45 kV, step width: 0.013°, wavelength: 1.5418 Å, measured diffraction angle range (2θ): 2.5-40°. Due to the nature of the data, the crystal lattice spacing and overall pattern of powder X-ray diffraction are important in determining crystal identity. The error range of the diffraction angle (2θ (°)) in powder X-ray diffraction is usually ±0.2°, but the diffraction angle and diffraction intensity should not be strictly understood, and these may vary to some extent depending on the crystal growth direction, particle size, and measurement conditions.

[0135] Additionally, the following abbreviations may be used in some instances in the examples, preparations, and tables below: PEx: Production Example Number, Ex: Example Number, PSyn: Production Example Number, where the compound is produced in the same manner (if the PSyn column number has E as the initial letter, the compound was produced in the same manner as the compound with the Example Compound Number using the corresponding starting material. For example, the compound with PSyn column E95 means that it was prepared in the same manner as the compound of Example 95. Also, if the Production Example Compound forms a salt, the salt can be formed by conventional methods), Syn: Example Number, where the compound is produced in the same manner (if the Syn column number has P as the initial letter, the compound was produced in the same manner as the Production Example Compound Number using the corresponding starting material. For example, a compound having a Syn column of P10 means that it was prepared in the same manner as the compound of Production Example 10. In addition, when the example compound forms a salt, the salt can be formed by a conventional method), Str: chemical structure, DAT: physical chemical data, CI+: m / z value in mass spectrometry (unless otherwise specified, ionization method CI, [M+H]+), EI+: m / z value in mass spectrometry (unless otherwise specified, ionization method EI, M+), ESI+: m / z value in mass spectrometry (unless otherwise specified, ionization method ESI, [M+H]+), ESI-: m / z value in mass spectrometry (ionization method ESI, [MH]- unless otherwise specified), 1 H-NMR (CDCl3, 400MHz): 1 δ (ppm) of signals in H NMR, 1 H-NMR (CDCl3, 500MHz): 1 δ (ppm) of signals in H NMR, 1 H-NMR (DMSO-d6, 400MHz): 1 δ (ppm) of signals in H NMR, 1 H-NMR (DMSO-d6, 500MHz): 1 δ (ppm) of signals in H NMR, 1 H-NMR (CD3OD, 400MHz): 1Signals in H NMR, J: coupling constant, s: singlet, d: doublet, t: triplet, q: quartet, dd: double doublet, dt: double triplet, dq: double quartet, ddd: double doublet, br: broad (e.g. br s), m: multiplet, aq.: aqueous solution, sat.: saturated, rt: room temperature, DSC 1 : Endothermic peak onset temperature in DSC measurement, DSC 2 : Onset temperature of exothermic peak in DSC measurement, 2θ: Diffraction angle of peak in powder X-ray diffraction.

[0136] Herein, naming software such as ACD / Name (registered trademark, Advanced Chemistry Development, Inc.) may be used in some cases.

[0137] Compounds with "rac" in front of their names are racemic.

[0138] Additionally, for convenience, concentrations in mol / L are expressed as M. For example, 1M sodium hydroxide solution means 1 mol / L of sodium hydroxide solution.

[0139] Preparation Example 1 Under argon flow, CuI (55 mg), PdCl2(PPh3)2 (201 mg), Et3N (4 mL), and trimethylsilylacetylene (0.47 mL) were added to a solution of 1-bromo-4-iodo-2-(trifluoromethyl)benzene (1 g) in THF (5 mL) at room temperature, and the mixture was stirred at room temperature for 1 h 15 min. The mixture was treated with water at room temperature and then extracted with CHCl2. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / EtOAc = 100 / 0 to 90 / 10) to give {[4-bromo-3-(trifluoromethyl)phenyl]ethynyl}(trimethyl)silane (936 mg) as an oil.

[0140] Preparation Example 6 To a mixture of 4-iodo[1,1'-biphenyl]-2-carbaldehyde (11.2 g) and Pd(PPh3)4 (2.11 g) in DMSO (150 mL) was added prop-2-inoic acid (3.08 g) and DBU (14.9 g) dropwise at 25-35 °C under nitrogen. The mixture was stirred at 40 °C under nitrogen for 1.5 h. The mixture was diluted with aqueous NaHCO3 and extracted with EtOAc. The pH of the separated aqueous phase was adjusted to 2-3 with cold 1 M aqueous HCl to give a suspension. The suspension was filtered and the filter cake was concentrated to give 3-(2-formyl[1,1'-biphenyl]-4-yl)prop-2-inoic acid (7.2 g) as a solid.

[0141] Preparation Example 7 Under argon flow, to a solution of 4-bromo-1-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazole (760 mg) in DMF (16 mL) was added Pd(OAc)2 (30 mg), XPhos (122 mg), Et3N (1.1 mL), and trimethylsilylacetylene (0.52 mL) at room temperature, and the mixture was stirred at 100°C for 3 h and then cooled to room temperature. The mixture was treated with water and brine at room temperature and then extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / EtOAc = 100 / 0 to 90 / 10) to give 1-(4-fluorophenyl)-5-(trifluoromethyl)-4-[(trimethylsilyl)ethynyl]-1H-pyrazole (723 mg) as an oil.

[0142] Preparation Example 10 A mixture of {[4-bromo-3-(trifluoromethyl)phenyl]ethynyl}(trimethyl)silane (100 mg), phenylboronic acid (57 mg), SPhos (13 mg), Pd(OAc)2 (4 mg), K3PO4 (200 mg), toluene (2 mL), and water (0.5 mL) was stirred at 130° C. for 1 h under microwave irradiation, then cooled to room temperature. The mixture was treated with water (10 mL) and EtOAc (10 mL) at room temperature and extracted with EtOAc. The organic layer was dried over anhydrous MgSO4 (activated charcoal powder was added), then filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / EtOAc=100 / 0-90 / 10) to give trimethyl{[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]ethynyl}silane (87 mg) as an oil.

[0143] Preparation Example 11 Under a stream of argon, a mixture of 2-chloro-3-(trifluoromethyl)-5-[(trimethylsilyl)ethynyl]pyridine (862 mg), phenylboronic acid (568 mg), Pd(OAc)2 (35 mg), SPhos (128 mg), K3PO4 (1.98 g), toluene (16 mL), and water (3.5 mL) was stirred at 100°C for 1 h and then cooled to room temperature. The mixture was treated with water and EtOAc at room temperature and extracted with EtOAc. The organic layer was dried over anhydrous MgSO4 (activated charcoal powder was added), then filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / EtOAc = 100 / 0 to 75 / 25) to give 2-phenyl-3-(trifluoromethyl)-5-[(trimethylsilyl)ethynyl]pyridine (890 mg) as an oil.

[0144] Preparation Example 21 To a solution of trimethyl{[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]ethynyl}silane (9.19 g) in MeOH (150 mL) was added K2CO3 (6 g) at room temperature, and the mixture was stirred at room temperature for 1.5 h. The mixture was treated with water at room temperature and extracted with CHCl2. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane) to give 4-ethynyl-2-(trifluoromethyl)-1,1'-biphenyl (7.1 g) as an oil.

[0145] Preparation Example 22 To a solution of 2-phenyl-3-(trifluoromethyl)-5-[(trimethylsilyl)ethynyl]pyridine (887 mg) in MeOH (14 mL) was added K2CO3 (580 mg) at room temperature, and the mixture was stirred at room temperature for 1 h. The mixture was treated with water at room temperature and extracted with CHCl3. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / EtOAc = 100 / 0 to 75 / 25) to give 5-ethynyl-2-phenyl-3-(trifluoromethyl)pyridine (493 mg) as an oil.

[0146] Preparation Example 23 To a mixture of 1-phenyl-5-(trifluoromethyl)-4-[(trimethylsilyl)ethynyl]-1H-pyrazole (980 mg) in THF (10 mL) was added TBAF (1M in THF, 4.9 mL). The mixture was stirred at 25-30 °C for 4 h. The reaction mixture was concentrated, and the residue was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (2.5% EtOAc in petroleum ether) to give 4-ethynyl-1-phenyl-5-(trifluoromethyl)-1H-pyrazole (750 mg) as an oil.

[0147] Preparation Example 31 To an ice-water bath cooled solution of 4-ethynyl-2-(trifluoromethyl)-1,1'-biphenyl (7.1 g) in THF (100 mL) under a stream of argon, nBuLi (26 mL, 1.57 M in hexane) was added dropwise, and the mixture was stirred at room temperature for 0.5 h. The mixture was quickly poured onto dry ice in a 1000 mL beaker, then stirred in a water bath at room temperature for 0.5 h. To the mixture, 0.5 M aqueous HCl (150 mL) was slowly added at room temperature, then stirred at room temperature for 10 min. The mixture was extracted with EtOAc. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give the crude product as a solid. The resulting solid was treated with IPE and hexane at room temperature. The solution was extracted with 0.5 M aqueous NaOH. The aqueous layer was treated with 1 M aqueous HCl at room temperature, then extracted with EtOAc. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give the product. The resulting solid was treated with hexane and IPE at room temperature, then stirred at room temperature for 5 minutes. The solid was collected by filtration, washed with hexane, and dried in vacuum to give 3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-inoic acid (3.35 g) as a solid. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / MeOH=100 / 0-70 / 30) to give 3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-inoic acid (2.81 g) as a solid.

[0148] Preparation Example 32 Under argon flow, nBuLi (1.8 mL, 1.57 M in hexane) was added dropwise to a dry ice acetone bath cooled solution of 5-ethynyl-2-phenyl-3-(trifluoromethyl)pyridine (582 mg) in THF (10 mL) and stirred at the same temperature for 20 min. Dry ice was added to the mixture and the mixture was allowed to warm to room temperature for 0.5 h. 1 M aqueous NaOH and water were added to the mixture at room temperature, and then the mixture was washed with Et2O. The organic layer was extracted twice with water. The combined aqueous layers were treated with 10% aqueous citric acid at room temperature, then extracted with CHCl3-IPA (5:1, v / v). The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give 3-[6-phenyl-5-(trifluoromethyl)pyridin-3-yl]prop-2-inoic acid (544 mg) as a solid.

[0149] In Preparation Examples 33 to 36, the reactions were carried out in the same manner as in Preparation Example 31. The reaction mixtures were stirred with dry ice and then concentrated to give the lithium salts of the target carboxylic acids without further treatment.

[0150] Preparation Example 43 To a mixture of 3-(4-bromophenyl)prop-2-inoic acid (500 mg) and 1-methylpiperazine (267 mg) in THF (10 mL) was added DIPEA (1.2 mL) and T3P® (1.70 g, 50% in EtOAc). The mixture was stirred at 20° C. for 16 h. The mixture was combined with another batch. The combined mixture was treated with water and extracted three times with EtOAc. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was purified by reverse phase column chromatography [C18, 10-20% CH3CN in water (0.05% NH3.H2O)]. The combined streams were concentrated to remove CH3CN and the aqueous phase was extracted three times with EtOAc. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to give 3-(4-bromophenyl)-1-(4-methylpiperazin-1-yl)prop-2-yn-1-one (970 mg) as a solid.

[0151] Preparation Example 45 To a solution of tert-butyl 4-(3-{1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}prop-2-ynoyl)piperazine-1-carboxylate (108 mg) in CHCl (2 mL) was added TFA (100 uL). The mixture was stirred at 28-32 °C for 1 h. The reaction mixture was concentrated to give 1-(piperazin-1-yl)-3-{1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}prop-2-yn-1-one monotrifluoroacetate (157 mg) as a solid.

[0152] Preparation Example 47 A mixture of methyl 3-aminobenzoate (102 mg), 3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoic acid (150 mg), DIPEA (242 mg), and HATU (491 mg) in DMF (3 mL) was stirred at room temperature for 13 h. The mixture was treated with EtOAc and water at room temperature, then extracted with EtOAc. The organic layer was washed with 10% aqueous citric acid, saturated aqueous NaHCO3, and brine, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified twice by silica gel column chromatography (hexane / EtOAc = 90 / 10 to 50 / 50) to give methyl 3-({3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoyl}amino)benzoate (47 mg) as a solid.

[0153] Preparation Example 48 To a mixture of 3-(4-bromophenyl)prop-2-inoic acid (2 g) in DMF (20 mL) was added 2-anilinoethan-1-ol (1.34 mL), 2-chloro-1-methylpyridinium iodide (3.4 g), and DIPEA (2.28 mL). The mixture was stirred at room temperature for 1 h. After adding water, the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified twice by silica gel column chromatography (hexane / EtOAc = 75 / 25 to 0 / 100) to give 3-(4-bromophenyl)-N-(2-hydroxyethyl)-N-phenylprop-2-ynamide (2.72 g) as a solid.

[0154] Preparation Example 50 To a solution of 4-iodo-3-(trifluoromethyl)-1H-pyrazole (1 g) in CHCl (20 mL) was added phenylboronic acid (1 g), Cu(OAc) (600 mg), and pyridine (600 uL), and then the reaction mixture was stirred at 25-30° C. for 12 h under oxygen atmosphere. The mixture was concentrated, and the residue was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (0.9% EtOAc in petroleum ether) to give 4-iodo-1-phenyl-3-(trifluoromethyl)-1H-pyrazole (1.28 g) as an oil.

[0155] Preparation Example 51 To a mixture of 1-(piperazin-1-yl)-3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-yn-1-one monotrifluoroacetate (480 mg) in DMF (10 mL) was added K2CO3 (336 mg) and ethyl 4-bromobutanoate (239 mg), then the reaction mixture was stirred at 25-35 °C for 48 h. This mixture was combined with another batch, diluted with water, and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude material was purified by reverse-phase column chromatography (C18, 50-60% CHCN / 0.05% HCl in water) and lyophilized to give ethyl 4-(4-{3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoyl}piperazin-1-yl)butanoate monohydrochloride (260 mg) as a solid.

[0156] Preparation Example 52 To a mixture of methyl 3-[3'-(difluoromethoxy)-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoate (1.2 g), THF (5 mL), and MeOH (5 mL) was added 1M aqueous NaOH (5 mL) at room temperature. The mixture was stirred at room temperature for 1 h and washed with Et2O. To the separated aqueous extract was added 1M aqueous HCl (5 mL) and EtOH. The mixture was concentrated in vacuo. To the residue was added EtOH, and then the mixture was filtered to remove insoluble material. The filtrate was concentrated in vacuo to give 3-[3'-(difluoromethoxy)-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoic acid (1.15 g) as a solid.

[0157] Preparation Example 56 To a solution of methyl 4-iodo[1,1'-biphenyl]-2-carboxylate (14.7 g) in CHCl (150 mL) was added DIBAL-H (156 mL, 1.0 M in toluene) at −78 °C under nitrogen for 0.5 h. The mixture was stirred at 25-30 °C under nitrogen for another 3 h. The mixture was poured into water and diluted with 2 M aqueous HCl until the mixture became clear. The mixture was extracted with CHCl. ​​The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by silica gel column chromatography (8-15% EtOAc in petroleum ether) to give (4-iodo[1,1'-biphenyl]-2-yl)methanol (12.2 g) as an oil.

[0158] Preparation Example 57 To a solution of (4-iodo[1,1'-biphenyl]-2-yl)methanol (12.2 g) in CHCl (150 mL) was added MnO (30 g) and the reaction mixture was stirred at 50° C. for 12 h. After cooling to room temperature, the reaction mixture was filtered through Celite®. The filtrate was concentrated to give 4-iodo[1,1'-biphenyl]-2-carbaldehyde (11.2 g) as an oil.

[0159] Preparation Example 58 To a solution of 3-(2-formyl[1,1'-biphenyl]-4-yl)prop-2-inoic acid (1 g) in CHCl (15 mL) was added DMF (29.2 mg) and (COCl) (420 uL) at 0° C. and stirred at 0° C. for 0.5 h. The mixture was added to a mixture of (2S)-3-aminopropane-1,2-diol (728 mg) and NaCO (1.69 g) in water (20 mL) and CHCl (20 mL). The reaction mixture was stirred at 0° C. for 1 h, diluted with water and extracted with CHCl / IPA (3 / 1, v / v). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude material was purified by silica gel column chromatography (5% MeOH in CH2Cl2) to give N-[(2S)-2,3-dihydroxypropyl]-3-(2-formyl[1,1'-biphenyl]-4-yl)prop-2-ynamide (738 mg) as a solid.

[0160] Preparation Example 59 To a solution of 3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-inoic acid (100 mg) in CHCl (1.02 mL) was added EtN (130 uL), rac-methyl (3R)-pyrrolidine-3-carboxylate monohydrochloride (68 mg), and COMU (192 mg) at 0° C. The mixture was stirred at room temperature for 1 h. After addition of saturated aqueous NaHCO3, the mixture was extracted with EtOAc. The separated organic extract was washed with saturated aqueous NaHCO3, 1 M aqueous HCl, and brine, filtered through a phase separator, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc / hexane: 50 / 50 to 100 / 0, then CHCl3 / MeOH=90 / 10) to give rac-methyl 1-{3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoyl}-(3R)-pyrrolidine-3-carboxylate (96.6 mg) as an oil.

[0161] Preparation Example 60 To a solution of 4-(3,6-dihydro-2H-pyran-4-yl)-3-(trifluoromethyl)phenol (2.6 g) in MeOH (25 mL) was added Pd / C (260 mg, 10%) under hydrogen atmosphere. The mixture was stirred at room temperature for 24 h. The reaction mixture was filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to give 4-(oxan-4-yl)-3-(trifluoromethyl)phenol (2.51 g) as a solid.

[0162] Preparation Example 61 To a solution of 4-(oxan-4-yl)-3-(trifluoromethyl)phenol (2.5 g) and 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)-sulfonyl)methanesulfonamide (7.26 g) in CHCl (30 mL) was added DIPEA (2.6 g). The mixture was stirred at room temperature for 3 h. The reaction was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-9% EtOAc in hexanes) to give 4-(oxan-4-yl)-3-(trifluoromethyl)phenyl trifluoromethanesulfonate (3.56 g) as an oil.

[0163] Preparation Example 63 Under argon flow, CuI (63 mg), PdCl2(PPh3)2 (137 mg), Et3N (4.6 mL), and trimethylsilylacetylene (0.54 mL) were added to a solution of 2-chloro-5-iodo-3-(trifluoromethyl)pyridine (1 g) in THF (10 mL) at room temperature, and the mixture was stirred at room temperature for 1 h. The mixture was treated with water and then extracted with CHCl3. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / EtOAc = 100 / 0 to 95 / 5) to give 2-chloro-3-(trifluoromethyl)-5-[(trimethylsilyl)ethynyl]pyridine (867 mg) as an oil.

[0164] Preparation Example 92 A mixture of 8-chloro-5-[(trimethylsilyl)ethynyl]quinoline (400 mg), [2-(trifluoromethyl)phenyl]boronic acid (460 mg), Pd(OAc)2 (36 mg), K2CO3 (440 mg), and XPhos (148 mg) in dioxane (40 mL) and water (13.3 mL) was degassed and purged with nitrogen, and the mixture was then stirred at 90° C. for 2 h under nitrogen atmosphere. The mixture was combined with another batch (the same reaction was carried out with 400 mg of 8-chloro-5-[(trimethylsilyl)ethynyl]quinoline). The mixture was treated with water, extracted with EtOAc, washed with brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated. The crude product was purified by silica gel column chromatography (EtOAc / petroleum ether=12 / 88-13 / 87) to give 5-ethynyl-8-[2-(trifluoromethyl)phenyl]quinoline (580 mg) as a solid.

[0165] Preparation Example 127 A mixture of K2CO3 (2.77 g) and 5-bromo-2-iodophenol (2 g) in DMF (10 mL) was stirred at 20° C. for 1 h. To the mixture, 2-iodopropane (3.41 g) was added and the mixture was stirred at 70° C. for 3 h. The reaction mixture was diluted with water and extracted with EtOAc. The separated organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 4-bromo-1-iodo-2-[(propan-2-yl)oxy]benzene (2 g) as an oil.

[0166] Preparation Example 135 To a solution of 3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-inoic acid (100 mg) in CHCl (3 mL) was added EtN (120 uL), 2-(methylsulfanyl)ethan-1-amine (39 uL), and PyBOP (233 mg) in an ice-water bath. The mixture was stirred at room temperature for 15 h, treated with saturated aqueous NaHCO3, and extracted with CHCl3. The organic layer was washed with saturated aqueous NaHCO3, 1 M aqueous HCl, and water, then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EtOAc / Hexane = 10 / 90 to 50 / 50) to give N-[2-(methylsulfanyl)ethyl]-3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynamide (103 mg) as a solid.

[0167] Preparation Example 136 A mixture of methyl 3-[4-bromo-3-(trifluoromethyl)phenyl]prop-2-ynoate (500 mg), 2-(tributylstannyl)pyridine (780 mg), and Pd(PPh3)4 (94 mg) in toluene (10 mL) was stirred at 150° C. under nitrogen in a microwave for 3 h. The mixture was combined with four other batches (the same reaction was carried out four times with 500 mg of 3-[4-bromo-3-(trifluoromethyl)phenyl]prop-2-ynoate for each batch) and concentrated. The crude product was purified by silica gel column chromatography (EtOAc / petroleum ether=15 / 85) to give methyl 3-[4-(pyridin-2-yl)-3-(trifluoromethyl)phenyl]prop-2-ynoate (1.43 g) as an oil.

[0168] Preparation Example 137 A mixture of 3-[2'-(benzyloxy)-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-1-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]prop-2-yn-1-one (280 mg) in TFA (5 mL) was stirred at 80° C. for 16 h and concentrated. The crude product was purified by reverse phase column (C18, 50-70% MeOH in water / 0.05% TFA) to give 1-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-3-[2'-hydroxy-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-yn-1-one as a solid.

[0169] Preparation Example 138 To a solution of 3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-inoic acid (155 mg) in CHCl (2 mL) was added 1-chloro-N,N,2-trimethylprop-1-en-1-amine (85 uL) in ice-water bath, and the mixture was stirred for 15 min. The above solution was added dropwise to a mixture of N-{3-[(2-{[tert-butyldi(methyl)silyl]oxy}ethyl)amino]propyl}methanesulfonamide (166 mg) and saturated aqueous NaHCO (2.0 mL) in ice-water bath. The mixture was stirred at the same temperature for 45 min. The resulting mixture was treated with water and extracted with CHCl. ​​The separated organic layer was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EtOAc / hexane=20 / 80 to 67 / 33) to give N-(2-{[tert-butyldi(methyl)silyl]oxy}ethyl)-N-{3-[(methanesulfonyl)amino]propyl}-3-[2-(trifluoromethyl)[1,1′-biphenyl]-4-yl]prop-2-ynamide (322 mg) as an oil.

[0170] Preparation Example 139 To a mixture of N-(3-aminopropyl)methanesulfonamide (100 mg) in MeOH (3 mL) was added {[tert-butyldi(methyl)silyl]oxy}acetaldehyde (126 mg) at room temperature. The mixture was stirred at room temperature for 1 h. To the mixture was added NaBH4 (27.1 mg) at room temperature. The mixture was stirred at room temperature for 2 h, treated with water, CHCl3, and aqueous NH4Cl, and extracted with CHCl3. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (CHCl3 / MeOH=100 / 0-80 / 20) to give N-{3-[(2-{[tert-butyldi(methyl)silyl]oxy}ethyl)amino]propyl}methanesulfonamide (168 mg) as an oil.

[0171] Preparation Example 141 A mixture of 4-amino-2'-(trifluoromethyl)[1,1'-biphenyl]-2-carboxylate (11.4 g) and 3M aqueous HCl (39.2 mL) in acetone (300 mL) was cooled to 0°C and a solution of NaNO2 (2.94 g) in water (50 mL) was added dropwise. The mixture was stirred at 0°C for 1 h. Urea (881 mg) was added, followed by a solution of KI (11.2 g) in water (50 mL) at 0°C. The mixture was stirred at 0°C for 1 h. The mixture was stirred at 15-20°C for 1 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (EtOAc / petroleum ether=5 / 95-10 / 90) to give methyl 4-iodo-2′-(trifluoromethyl)[1,1′-biphenyl]-2-carboxylate (8.2 g) as an oil.

[0172] Preparation Example 142 To a mixture of tert-butyl (2-aminoethyl)carbamate (500 mg) in CHCl (15 mL), EtN (1.30 mL) was added followed by methyl (chlorosulfonyl)acetate (648 mg) at 0° C. and stirred at 15-20° C. for 1 h. The mixture was diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (EtOAc / petroleum ether=50 / 50-60 / 40) to give methyl 10,10-dimethyl-3,3,8-trioxo-9-oxa-3λ. 6 -Thia-4,7-diazaundecane-1-oat (310 mg) was obtained as a gum.

[0173] Preparation Example 143 Methyl 10,10-dimethyl-3,3,8-trioxo-9-oxa-3λ in THF (5 mL) 6 To a solution of 4,7-thia-4,7-diazaundecane-1-oate (310 mg) was added LiBH4 (46 mg) at 0-4 °C. The mixture was stirred at 0-4 °C for 1.5 h. The mixture was poured into saturated aqueous NH4Cl solution, extracted with EtOAc, dried over anhydrous sodium sulfate, filtered, and concentrated to give tert-butyl {2-[(2-hydroxyethanesulfonyl)amino]ethyl}carbamate (250 mg) as an oil.

[0174] Preparation Example 144 To a solution of 1-(4-fluorophenyl)-2-(trifluoromethyl)-1H-imidazole (1.2 g) in H2SO4 (12 mL) and water (12 mL) was added NIS (7.0 g) at 0°C. The mixture was stirred at 0°C for 10 min, then the mixture was stirred at 70°C for 16 h. The reaction mixture was adjusted to pH 8-9 with 30% aqueous NaOH and filtered. The filtrate was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (EtOAc / petroleum ether=20 / 80) to give 1-(4-fluorophenyl)-4,5-diiodo-2-(trifluoromethyl)-1H-imidazole (1.35 g) as a solid.

[0175] Preparation Example 145 To a solution of 1-(4-fluorophenyl)-4,5-diiodo-2-(trifluoromethyl)-1H-imidazole (1.35 g) in THF (14 mL) was added dropwise ethylmagnesium bromide (945 uL, 3M in Et2O) at -40°C. The mixture was stirred at -40°C for 30 min. The reaction mixture was quickly poured into aqueous NH4Cl and extracted with EtOAc. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (EtOAc / petroleum ether = 18 / 82) to give 1-(4-fluorophenyl)-4-iodo-2-(trifluoromethyl)-1H-imidazole (0.8 g) as a solid.

[0176] Example 1 To a solution of 1-methylpiperazine (180 uL), 3-([1,1'-biphenyl]-2-yl)prop-2-inoic acid (300 mg), DIPEA (1.05 g) in THF (15 mL) was added T3P® (2.58 g, 50% in EtOAc) at 0° C. The mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reverse phase column chromatography (C18, 5-55% CH3CN / 0.1% NH3.H2O in water) to give 3-([1,1'-biphenyl]-2-yl)-1-(4-methylpiperazin-1-yl)prop-2-yn-1-one (110 mg) as a solid.

[0177] Example 20 To a solution of 3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-inoic acid (100 mg) in CHCl (1 mL) was added EtN (130 uL), (3R)-pyrrolidine-3-carboxamide monohydrochloride (62 mg) and COMU (192 mg) at 0°C. The mixture was stirred at room temperature for 1 h. To the mixture was added saturated aqueous NaHCO3 and the mixture was extracted with EtOAc. The separated organic extract was washed with saturated aqueous NaHCO3, 1M aqueous HCl and brine, filtered through a phase separator and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / MeOH=100 / 0-90 / 10) to give (3R)-1-{3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoyl}pyrrolidine-3-carboxamide (98.3 mg) as a solid.

[0178] Example 33 A mixture of (3R,4S)-pyrrolidine-3,4-diol monohydrochloride (63 mg), 3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-inoic acid (99.7 mg), DIPEA (183 mg), and HATU (327 mg) in DMF (2 mL) was stirred at room temperature for 13 h. The mixture was treated with EtOAc and water at room temperature, then extracted with EtOAc. The organic layer was washed with 10% aqueous citric acid, saturated aqueous NaHCO3, brine, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified twice by silica gel column chromatography (CHCl3 / MeOH=100 / 0-90 / 10) to give 1-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-yn-1-one (42 mg) as a solid.

[0179] Example 34 A mixture of piperidine-4-carboxamide (61 mg), 3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-inoic acid (99.6 mg), DIPEA (93 mg), and HATU (196 mg) in DMF (2 mL) was stirred at room temperature for 4 h. The mixture was treated with EtOAc and water at room temperature, then extracted with EtOAc. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / MeOH=100 / 0-90 / 10) to give the desired product. The resulting product was treated with IPE and hexane at room temperature, then triturated. The solid was collected by filtration, washed with hexane, and dried in vacuum at 50° C. to give 1-{3-[2-(trifluoromethyl)[1,1′-biphenyl]-4-yl]prop-2-ynoyl}piperidine-4-carboxamide (76 mg) as a solid.

[0180] Example 35 A mixture of (2S)-3-aminopropane-1,2-diol (43 mg), 3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-inoic acid (99.8 mg), DIPEA (96 mg), and HATU (198 mg) in DMF (2 mL) was stirred at room temperature for 2 h. The mixture was treated with EtOAc and water at room temperature, then extracted with EtOAc. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified twice by silica gel column chromatography (CHCl3 / MeOH=100 / 0-90 / 10) to give N-[(2S)-2,3-dihydroxypropyl]-3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynamide (29 mg) as a syrup.

[0181] Example 36 A mixture of (2R)-3-aminopropane-1,2-diol (43 mg), 3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-inoic acid (99.8 mg), DIPEA (95 mg), and HATU (196 mg) in DMF (2 mL) was stirred at room temperature for 4 h. The mixture was treated with EtOAc and water at room temperature, then extracted with EtOAc. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified twice by silica gel column chromatography (CHCl3 / MeOH=100 / 0-90 / 10) to give N-[(2R)-2,3-dihydroxypropyl]-3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynamide (14 mg) as a syrup.

[0182] Example 43 To a mixture of 3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-inoic acid (90 mg) and (3R,4R)-pyrrolidine-3,4-diol (39 mg), 2-chloro-1-methylpyridinium iodide (1.4 mL) (0.33 M in DMF) and DIPEA (64 mg) were added, and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The residue was purified by preparative LC / MS (XBridge Prep C18 5 μm OBD™ 30×150 mm column: MeOH / 10 mM aqueous NH4HCO3 10 / 90 to 95 / 5) and lyophilized to give 1-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-3-[2-(trifluoromethyl)[1,1′-biphenyl]-4-yl]prop-2-yn-1-one (48 mg) as a solid.

[0183] Example 44 To a mixture of 3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-inoic acid (100 mg) and (3S,4S)-pyrrolidine-3,4-diol (43 mg), 2-chloro-1-methylpyridinium iodide (1.5 mL) (0.35 M in DMF) and DIPEA (77 mg) were added and the mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by preparative LC / MS (XBridge Prep C18 5 μm OBD™ 30×150 mm column: MeOH / 10 mM aqueous NH4HCO3 10 / 90 to 95 / 5) and MeOH was removed under reduced pressure. The residue was extracted with CHCl3, and the organic layer was washed with water, dried over anhydrous MgSO4, filtered, and concentrated in vacuo to give a solid, which was treated with IPE and briefly sonicated. The mixture was concentrated in vacuo to give 1-[(3S,4S)-3,4-dihydroxypyrrolidin-1-yl]-3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-yn-1-one (42 mg) as a solid.

[0184] Example 45 To a mixture of 3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoic acid (90 mg) and L-serinamide monohydrochloride (54 mg), 2-chloro-1-methylpyridinium iodide (1 mL) (0.45 M in DMF) and DIPEA (102 mg) were added and the mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by preparative LC / MS (XBridge Prep C18 5 μm OBD™ 30×150 mm column: MeOH / 10 mM aqueous NH4HCO3 10 / 90 to 95 / 5), lyophilized and purified by N 2 -{3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoyl}-L-serinamide (16 mg) was obtained as a solid.

[0185] Example 46 To a mixture of 3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoic acid (90 mg) and (azetidine-3,3-diyl)dimethanol monohydrochloride (58 mg), 2-chloro-1-methylpyridinium iodide (1 mL) (0.45 M in DMF) and DIPEA (103 mg) were added and the mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by preparative LC / MS (XBridge Prep C18 5 μm OBD™ 30×150 mm column: MeOH / 10 mM aqueous NH4HCO3 10 / 90 to 95 / 5) and lyophilized to give an oil, which was treated with a small amount of CH2Cl2. The mixture was concentrated in vacuo to give 1-[3,3-bis(hydroxymethyl)azetidin-1-yl]-3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-yn-1-one (37 mg) as a solid.

[0186] Example 47 A mixture of (3R,4S)-pyrrolidine-3,4-diol monohydrochloride (226 mg), 3-[6-phenyl-5-(trifluoromethyl)pyridin-3-yl]prop-2-inoic acid (235 mg), 2-chloro-1-methylpyridinium iodide (3.3 mL) (0.5 M in DMF), DIPEA (523 mg), and DMF (2 mL) was stirred at room temperature for 2 h. The mixture was treated with EtOAc and water at room temperature, then extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / MeOH=100 / 0-90 / 10) to give the desired product as a solid. The resulting solid was treated with IPE (1 mL) and hexane (5 mL) at room temperature, then triturated. The solid was collected by filtration, washed with hexanes, and dried in vacuum to give 1-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-3-[6-phenyl-5-(trifluoromethyl)pyridin-3-yl]prop-2-yn-1-one (42 mg) as a solid.

[0187] Example 87 Under argon atmosphere, a mixture of 3-(4-bromophenyl)-N-(2-hydroxyethyl)-N-phenylprop-2-ynamide (100 mg), trimethyl(2-pyridyl)tin (75 uL) and PdCl2(PPh3)2 (20 mg) in toluene (1 mL) was stirred at 100°C for 2 hours under microwave irradiation. Aqueous potassium fluoride was added to the mixture, and the resulting mixture was stirred and extracted with CHCl3. The organic layer was concentrated in vacuum. The residue was purified by silica gel column chromatography (hexane / EtOAc = 50 / 50 to 0 / 100) to give the desired product. The solid was triturated with EtOAc, filtered and dried in vacuum to give N-(2-hydroxyethyl)-N-phenyl-3-[4-(pyridin-2-yl)phenyl]prop-2-ynamide (18 mg) as a solid.

[0188] Example 88 A mixture of 3-(4-bromophenyl)-1-(4-methylpiperazin-1-yl)prop-2-yn-1-one (200 mg), 4-pyridylboronic acid (96.0 mg), Na2CO3 (138 mg), and Pd(PPh3)4 (76 mg) in 1,4-dioxane (4 mL) with water (0.8 mL) was degassed and purged with nitrogen gas, and the reaction mixture was then stirred at 85° C. under nitrogen gas for 16 hours. The mixture was treated with water (30 mL) and extracted three times with EtOAc. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was purified by silica gel column chromatography eluted with 0-10% EtOAc / petroleum ether followed by reverse phase column chromatography (C18, 0-50% CH3CN / 0.05% NH3.H2O in water) to give 1-(4-methylpiperazin-1-yl)-3-[4-(pyridin-4-yl)phenyl]prop-2-yn-1-one (67.9 mg) as a solid after lyophilization.

[0189] Example 90 To a solution of methyl 3-({3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoyl}amino)benzoate (47 mg) in THF (1 mL) and MeOH (1 mL), 1M aqueous NaOH solution (0.5 mL) was added at room temperature, and the mixture was stirred at room temperature for 1.5 h. To the mixture, 1M aqueous NaOH solution (0.5 mL) was added at room temperature, and the mixture was stirred at room temperature for 5 h. The mixture was treated with 1M aqueous HCl solution (1.0 mL) and water at room temperature, and then extracted with CHCl3. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / MeOH=100 / 0-80 / 20) to give the desired product. The obtained solid was treated with IPE (1 mL) and hexane (5 mL) at room temperature and triturated. The solid was collected by filtration, washed with hexane, and dried in vacuum at 50° C. to give 3-({3-[2-(trifluoromethyl)[1,1′-biphenyl]-4-yl]prop-2-ynoyl}amino)benzoic acid (28 mg) as a solid.

[0190] Example 91 A mixture of ethyl 3-(piperazin-1-yl)propanoate dihydrochloride (175 mg), 3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-inoate (150 mg), DIPEA (0.32 mL), HOBt (7 mg), and EDC·HCl (297 mg) in DMF (3 mL) was stirred at room temperature for 15 h. The mixture was treated with EtOAc and water at room temperature, then extracted with EtOAc. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / EtOAc = 100 / 0 to 50 / 50) to give the desired intermediate as a syrup. The obtained intermediate (114 mg) was dissolved in THF (1 mL) and MeOH (1 mL) at room temperature, and then 1M aqueous NaOH solution (1 mL) was added to the solution at room temperature. The mixture was stirred at room temperature for 0.5 h. The mixture was treated with 1M aqueous HCl (1 mL) and water (10 mL) at room temperature, then extracted with CHCl3-IPA (5:1, v / v). The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give the desired product as a solid. The obtained solid was dissolved in THF (3 mL) at room temperature, then 4M HCl / dioxane (1 mL) was added to it. The mixture was concentrated under reduced pressure. The residue was treated with IPE (5 mL) at room temperature and triturated. The solid was collected by filtration, washed with IPE, and dried under vacuum at 50° C. to give 3-(4-{3-[2-(trifluoromethyl)[1,1′-biphenyl]-4-yl]prop-2-ynoyl}piperazin-1-yl)propanoic acid monohydrochloride (79 mg) as a solid.

[0191] Example 92 A mixture of 2,3-dihydro-1H-indole-6-carboxylate (120 mg), 3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-inoic acid (150 mg), DIPEA (0.32 mL), and HATU (393 mg) in DMF (3 mL) was stirred at room temperature for 3 h. The mixture was treated with EtOAc and water at room temperature, then extracted with EtOAc. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / EtOAc = 95 / 5 to 50 / 50) to give the desired intermediate. The intermediate was treated with concentrated aqueous HCl (2 mL) and dioxane (2 mL) at room temperature, and the mixture was stirred at 100 °C for 0.5 h, then cooled to room temperature. Since the reaction did not proceed, it was decided to stop the reaction and collect the intermediate. The mixture was treated with water and extracted with CHCl3. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / MeOH=100 / 0~90 / 10) to give the recovered intermediate. The intermediate was dissolved in THF (4 mL) and H2O (2 mL) at room temperature, and then LiOH·H2O (100 mg) was added to the solution. The mixture was stirred at room temperature for 4 h and at 50°C (oil bath temperature) for 6 h. The mixture was treated with 1M aqueous HCl (5 mL) at room temperature and extracted with CHCl3. The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl3 / MeOH=100 / 0~90 / 10) to give the desired product, which was treated with IPE and hexane at room temperature and then triturated. The solid was collected by filtration, washed with hexane, and dried in vacuum at 50° C. to give 1-{3-[2-(trifluoromethyl)[1,1′-biphenyl]-4-yl]prop-2-ynoyl}-2,3-dihydro-1H-indole-6-carboxylic acid (10 mg) as a solid.

[0192] Example 95 To a mixture of 1-(piperazin-1-yl)-3-{1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}prop-2-yn-1-one monotrifluoroacetate (157 mg) in MeOH (10 mL) was added (HCHO)n (37 mg), Et3N (34 uL), and AcOH (28 uL). The mixture was stirred at 25-30°C for 0.5 h, then NaBH3CN (31 mg) was added, and the resulting mixture was stirred for 0.5 h. The mixture was heated to 50°C and stirred for 12 h. The mixture was concentrated in vacuo. The crude product was purified by preparative HPLC (column: Phenomenex® C18 80*40 mm*3 um, mobile phase: water (NH3H2O) / CH3CN=58 / 42-28 / 72). The fractions containing the desired compound were lyophilized to give 1-(4-methylpiperazin-1-yl)-3-{1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}prop-2-yn-1-one (40.4 mg) as a solid.

[0193] Example 96 To a mixture of N-[(2R)-2,3-dihydroxypropyl]-3-(2-formyl[1,1'-biphenyl]-4-yl)-N-phenylprop-2-ynamide (95 mg) and piperidine (0.05 mL) in MeOH (2 mL) was added AcOH (30 uL). The reaction mixture was stirred at 60° C. for 4 h. NaBH3CN (41 mg) was then added to the above mixture and stirred at 25° C. for another 3 h. The mixture was combined with another batch and purified by reverse phase column chromatography (C18, 80-100% MeOH / 0.1% NH3.H2O in water) to give N-[(2R)-2,3-dihydroxypropyl]-N-phenyl-3-{2-[(piperidin-1-yl)methyl][1,1'-biphenyl]-4-yl}prop-2-ynamide (64.5 mg) as a solid.

[0194] Example 99 To a solution of 1-(thiomorpholin-4-yl)-3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-yn-1-one (137 mg) and CHCl (0.25 mL) in MeOH (1 mL), iodobenzene diacetate (295 mg) and ammonium carbamate (57 mg) were added. The mixture was stirred at room temperature for 30 min and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (EtOAc / hexane: 30 / 70 to 100 / 0, then CHCl / MeOH = 90 / 10) to give 1-imino-4-{3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-yn-1-one (137 mg) and CHCl (0.25 mL). 6 -Thiomorpholin-1-one (134 mg) was obtained as a solid.

[0195] Example 100 A mixture of Tert-butyl (3S)-pyrrolidin-3-ylcarbamate (77 mg), 3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-inoic acid (99.8 mg), 2-chloro-1-methylpyridinium iodide (0.28 M in DMF, 2 mL) and DIPEA (95 mg) in DMF (2 mL) was stirred at room temperature for 12 h. The mixture was treated with EtOAc and water at room temperature, then extracted with EtOAc. The organic layer was washed with saturated aqueous NaHCO3 and brine, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / EtOAc = 100 / 0 to 50 / 50) to give the intermediate as a syrup. The obtained intermediate was dissolved in CH2Cl2 (2 mL) at room temperature, and TFA (1 mL) was added to the solution at room temperature. The mixture was stirred at room temperature for 1 h and concentrated under reduced pressure. The residue was treated with saturated aqueous NaHCO3 (10 mL) and water at room temperature, then extracted with CHCl3-IPA (5:1, v / v). The organic layer was dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure to give the desired product as a syrup. The obtained product was dissolved in THF (2 mL), IPE (2 mL), and hexane (5 mL) at room temperature, and then oxalic acid (17 mg) was added to it. The mixture was stirred at room temperature for 0.5 h. The solid was collected by filtration, washed with hexane, and dried in vacuum at 50 °C to give 1-[(3S)-3-aminopyrrolidin-1-yl]-3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-yn-1-one monooxalate (54 mg) as a solid.

[0196] Example 106 To a solution of 3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynonic acid (208 mg) in DMF (10 mL) was added EDC·HCl (187 mg), HOBt (163 mg), and DIPEA (244 mg) at 0 °C under nitrogen atmosphere. The mixture was stirred for 1 h, followed by the addition of (1R,2S,4r)-4-aminocyclopentane-1,2-diol (100 mg). The reaction was stirred at room temperature for 16 h and then concentrated under reduced pressure. The residue was purified by preparative TLC (CHCl:MeOH=10:1) to give N-[(1r,3R,4S)-3,4-dihydroxycyclopentyl]-3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynamide (64.6 mg) as a solid.

[0197] Example 119 To a mixture of 4-{3-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-3-oxoprop-1-yn-1-yl}-2'-(trifluoromethyl)[1,1'-biphenyl]-2-carboxylic acid (135 mg), NH4Cl (21 mg), and HATU (245 mg) in DMF (3 mL) was added DIPEA (168 uL), and the mixture was then stirred at 50° C. for 16 h. The mixture was combined with another batch (the same reaction was performed with 20 mg of 4-{3-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-3-oxoprop-1-yn-1-yl}-2'-(trifluoromethyl)[1,1'-biphenyl]-2-carboxylic acid), diluted with 4% aqueous LiCl, and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by reverse phase column (C18, 50-60% MeOH / 0.1% NH3.H2O in water). The obtained product was purified by reverse phase column (C18, 45-55% MeOH / 0.1% NH3.H2O in water). The crude product was purified by preparative HPLC (column: Phenomenex C18, mobile phase: 20-40% MeCN in water (HCl)) to give 4-{3-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-3-oxoprop-1-yn-1-yl}-2'-(trifluoromethyl)[1,1'-biphenyl]-2-carboxamide (45.7 mg) as a solid by lyophilization.

[0198] Example 127 A mixture of tert-butyl methyl[(3R)-1-{3-[4-(pyridin-2-yl)-3-(trifluoromethyl)phenyl]prop-2-ynoyl}pyrrolidin-3-yl]carbamate (257 mg) and TFA (1 mL) in CHCl (5 mL) was stirred for 2 h at 10-20° C. The mixture was concentrated to give the crude product, which was purified by reverse phase column (C18, 50-60% MeOH / 0.1% NH.H0 in water) to give 1-[(3R)-3-(methylamino)pyrrolidin-1-yl]-3-[4-(pyridin-2-yl)-3-(trifluoromethyl)phenyl]prop-2-yn-1-one (128 mg) as a solid by lyophilization.

[0199] Example 128 To a mixture of rac-1-[(3R)-3-(hydroxymethyl)thiomorpholin-4-yl]-3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-yn-1-one (308 mg) in CHCl (8 mL) was added m-CPBA (319 mg) and the reaction mixture was stirred at 10-15 °C for 12 h. The reaction mixture was quenched by addition of saturated aqueous NaSO, diluted with water and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex C18, mobile phase: water (NH.H2O) / MeCN=60 / 40-30 / 70). The fractions containing the desired compound were lyophilized to give rac-(3R)-3-(hydroxymethyl)-4-{3-[2-(trifluoromethyl)[1,1′-biphenyl]-4-yl]prop-2-ynoyl}-1λ 6 -Thiomorpholine-1,1-dione (107 mg) was obtained as a solid.

[0200] Example 129 To a mixture of 1-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-3-[2'-hydroxy-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-yn-1-one (20 mg) and K2CO3 (22 mg) in DMF (1 mL) was added 3-bromoprop-1-yne (7 uL). The reaction mixture was stirred at 60°C for 1.5 h. The reaction mixture was combined into two batches (the same reaction was carried out with 30 mg and 85 mg of 1-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-3-[2'-hydroxy-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-yn-1-one for each batch). The resulting mixture was purified by a reverse phase column (C18, water (0.1% NH3.H2O) / MeCN=50 / 50-40 / 60) to give 1-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-3-{2'-[(prop-2-yn-1-yl)oxy]-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl}prop-2-yn-1-one (85.2 mg) as a solid.

[0201] Example 130 To a mixture of N-(2-{[tert-butyldi(methyl)silyl]oxy}ethyl)-N-{3-[(methanesulfonyl)amino]propyl}-3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynamide (317 mg) and THF (5 mL) was added TBAF (1M in THF, 1 mL) in an ice-water bath. The mixture was stirred at the same temperature for 1.5 h. The mixture was treated with saturated aqueous NH4Cl and CHCl3. The separated organic layer was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (CHCl3 / MeOH=100:0 to 92:8). The resulting oil was sonicated with a mixture of EtOAc, IPE, and hexane. The resulting mixture was concentrated under reduced pressure. The resulting solid was dissolved in CHCl2. Hexane was added to the solution and the mixture was concentrated to give N-(2-hydroxyethyl)-N-{3-[(methanesulfonyl)amino]propyl}-3-[2-(trifluoromethyl)[1,1′-biphenyl]-4-yl]prop-2-ynamide (209 mg) as a solid.

[0202] Example 131 To a solution of 3-[2'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-inoic acid (32 mg) in CHCl (1 mL) was added EtN (42 uL), (3R,4S)-pyrrolidine-3,4-diol monohydrochloride (23 mg) and PyBOP (74 mg). The mixture was stirred at room temperature for 4 h, treated with 1M aqueous HCl and water, and then extracted with EtOAc. The separated organic layer was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (CHCl / MeOH=100 / 0-90 / 10) to give 1-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-3-[2'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-yn-1-one (36.4 mg) as a solid.

[0203] Example 133 To a mixture of dimethylamine hydrochloride (37 mg) and MeOH (2 mL), Et3N (52 uL) was added and the mixture was stirred at 30° C. for 10 min. To the mixture, 4-{3-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-3-oxoprop-1-yn-1-yl}-2'-(trifluoromethyl)[1,1'-biphenyl]-2-carbaldehyde (150 mg) and AcOH (26 uL) were added and the resulting mixture was stirred at 60° C. for 3 h. NaBH3CN (39 mg) was added and the mixture was stirred at 30° C. for 30 min. The mixture was concentrated to give the crude product, which was purified by reverse phase column (C18, 40-50% MeCN / 0.1% NH3.H2O in water) to give 1-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-3-[2-(hydroxymethyl)-2'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-yn-1-one (82.2 mg) as a solid.

[0204] Example 134 A mixture of 1-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-yn-1-one (300 mg) and EtOAc (3 mL) was stirred at 60° C. for 20 min. The solution was cooled to room temperature and stirred overnight. The precipitate was collected by filtration and dried under reduced pressure at 40° C. to give 1-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-yn-1-one (145 mg) as a solid.

[0205] Example 135 A mixture of 1-{3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoyl}piperidine-4-carboxamide (100 mg) and EtOH (6 mL) was stirred at 50° C. for 2 h. The solution was cooled to room temperature and the precipitate was collected by filtration. The resulting solid was dried under reduced pressure at 50° C. to give 1-{3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoyl}piperidine-4-carboxamide (22 mg) as a solid.

[0206] Example 136 1-Imino-4-{3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoyl}-1λ 6 A small vial containing -thiomorpholin-1-one (134 mg) and EtOAc (500-1000 uL) was placed into a lager vial (5-10 mL) containing hexane. The outer vial was sealed and left at room temperature overnight. The precipitate was collected by filtration and washed with EtOAc / hexane (1 / 1) to give 1-imino-4-{3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoyl}-1λ 6 -Thiomorpholin-1-one (104 mg) was obtained as a solid.

[0207] The compounds of the Preparations and Examples shown in the following tables were produced in the same manner as the Preparations or Examples described above.

[0208] [Table 4]

[0209] [Table 5]

[0210] [Table 6]

[0211]

Table 7

[0212]

Table 8

[0213]

Table 9

[0214]

Table 10

[0215]

Table 11

[0216]

Table 12

[0217]

Table 13

[0218]

Table 14

[0219]

Table 15

[0220]

Table 16

[0221]

Table 17

[0222]

Table 18

[0223]

Table 19

Table 20

Table 21

[0224]

Table 22

[0225]

Table 23

[0226]

Table 24

[0227]

Table 25

[0228]

Table 26

[0229]

Table 27

[0230]

Table 28

[0231] [Table 29]

[0232] [Table 30]

[0233] [Table 31]

[0234] [Table 32]

[0235] [Table 33]

[0236] [Table 34]

[0237] [Table 35]

[0238] [Industrial Applicability] The compounds of formula (I) or salts thereof have an inhibitory effect on STING and are expected to be useful as therapeutic agents for the treatment of autoimmune diseases, neurodegenerative diseases, type I interferonopathies, and / or other STING-mediated diseases.

Claims

1. A compound of formula (I) or a salt thereof: (In the formula, Ring A is phenyl optionally fused with a 5-membered heterocyclyl, a 6-membered heteroaryl containing 1 or 2 nitrogen atoms, pyrazolyl, or a 6-membered saturated or partially unsaturated heterocyclyl; Ring B is phenyl optionally fused to phenyl or to a 6-membered heteroaryl containing 1 or 2 nitrogen atoms, pyrazolyl, or imidazolyl; R ａ１ and R ａ２ However, independently, H, C １－６ Alkyl, —O—C １－６ Alkyl, —O—C １－６ Alkylene-C ２－６ Alkenyl, —O—C １－６ Alkylene-C ２－６ Alkynyl, halogen, halogeno-C １－６ Alkyl, —O-halogeno-C １－６ alkyl, or —OH; R ｂ１ and R ｂ２ However, independently, H, C １－６ Alkyl, —O—C １－６ Alkyl, halogeno-C １－６ Alkyl, —O-halogeno-C １－６ Alkyl, halogen, -C １－６ Alkylene -OH, -C １－６ Alkylene -NR ｃ R ｄ , -C(=O)-NR ｃ R ｄ , -NR ｃ R ｄ , —CN, or —OH; R ｃ and R ｄ However, independently, H, C １－６ Alkyl, C ３－８ Cycloalkyl, —C(═O)—C １－６ Alkyl, or -S(=O) ２ -C １－６ Is it alkyl? Or R ｃ and R ｄ are connected to each other, R ｃ and R ｄ may be joined together with the nitrogen atom to which they are attached to form a 4- to 7-membered saturated heterocyclyl, wherein the heterocyclyl is selected from one or two R ｅ may be substituted with R ｅ But C １－６ Alkyl, —O—C １－６ alkyl, or halogen; R １ is H, optionally substituted C １－６ Alkyl, optionally substituted C ３－８ cycloalkyl, optionally substituted 4- to 7-membered saturated heterocyclyl, optionally substituted phenyl, or optionally substituted heteroaryl; R ２ But one or two R ３ C substituted with １－６ alkyl, one or two R ４ C substituted with ３－８ cycloalkyl, one or two R ５ or one or two R ６ or a phenyl substituted with Or R １ and R ２ are connected to each other, R １ and R ２ together with the nitrogen atom to which it is attached to form a 4- to 7-membered saturated heterocyclyl, said heterocyclyl being optionally fused with a phenyl, and said heterocyclyl and / or the fused phenyl being optionally fused with 1 to 3 R ７ may be substituted with Each R ３ are independently —OH, —O—C １－６ Alkyl, —C(═O)—NH ２ , -C(=O)-NH-C １－６ Alkyl, —C(═O)—N(C １－６ alkyl) ２ , -NH ２ , —NH—C １－６ Alkyl, —N(C １－６ alkyl) ２ , -NH-C(=O)-C １－６ Alkyl, —NH—S(═O) ２ -C １－６ Alkyl, —NH—S(═O) ２ -C １－６ Alkylene -OH, -NH-S(=O) ２ -C １－６ Alkylene -C(=O)-OH, -S(=O) ２ -NH ２ , -S(=O) ２ -C １－６ Alkyl, or -S(=O)(=NH)-C １－６ is alkyl, Each R ４ are independently —OH, —O—C １－６ Alkyl, —C(═O)—NH ２ , -C(=O)-NH-C １－６ Alkyl, —C(═O)—N(C １－６ alkyl) ２ , -NH ２ , —NH—C １－６ Alkyl, —N(C １－６ alkyl) ２ , -NH-C(=O)-C １－６ Alkyl, —NH—S(═O) ２ -C １－６ Alkyl, —S(═O) ２ -NH ２ , -S(=O) ２ -C １－６ Alkyl, or -S(=O)(=NH)-C １－６ is alkyl, Each R ５ is independently —OH, oxo, or imino; Each R ６ are independently —C(═O)—OH, —S(═O) ２ -NH ２ , -S(=O) ２ -C １－６ Alkyl, —S(═O)(═NH)—C １－６ Alkyl, or —NH—S(═O) ２ -C １－６ is alkyl, Each R ７ But independently, C １－６ Alkyl, —C １－６ Alkylene -OH, -C １－６ Alkylene-C(=O)-OH, C ３－８ Cycloalkyl, —OH, —O—C １－６ Alkyl, —NH ２ , —NH—C １－６ Alkyl, —N(C １－６ alkyl) ２ , -NH-C(=O)-C １－６ Alkyl, —NH—S(═O) ２ -C １－６ Alkyl, —S(═O) ２ -C １－６ Alkyl, —S(═O)(═NH)—C １－６ Alkyl, —C(═O)—OH, —C(═O)—NH ２ , -C(=O)-NH-C １－６ Alkyl, —C(═O)—N(C １－６ alkyl) ２ , oxo, imino, or 4- to 7-membered saturated heterocyclyl optionally substituted by one or two oxo groups, provided that the compound of formula (I) is not a compound of formula (II), (III), (IV), or (IVa). ）。

2. During the ceremony, Ring B is phenyl, a 6-membered heteroaryl containing 1 or 2 nitrogen atoms, or pyrazolyl; R ａ１ and R ａ２ However, independently, H, C １－６ Alkyl, halogen, halogeno-C １－６ Alkyl, or -O-halogeno-C １－６ is alkyl, R ｂ１ and R ｂ２ are independently H, halogeno-C １－６ Alkyl, or -C １－６ Alkylene -NR ｃ R ｄ and R ｃ and R ｄ are independently H or C １－６ Is it alkyl? Or R ｃ and R ｄ are connected to each other, R ｃ and R ｄ may be joined together with the nitrogen atom to which they are attached to form a 4- to 7-membered saturated heterocyclyl, wherein the heterocyclyl is selected from one or two R ｅ may be substituted with R １ But H, C １－６ Alkyl, C ３－８ cycloalkyl, 4- to 7-membered saturated heterocyclyl, optionally substituted phenyl, or optionally substituted heteroaryl; R ２ But one or two R ３ C substituted with １－６ alkyl, one or two R ４ C substituted with ３－８ cycloalkyl, one or two R ５ or one or two R ６ or a phenyl substituted with Or R １ and R ２ are connected to each other, R １ and R ２ together with the nitrogen atom to which it is attached to form a 4- to 7-membered saturated heterocyclyl, said heterocyclyl being optionally fused with a phenyl, and said heterocyclyl and / or said fused phenyl being optionally fused with one or two R ７ may be substituted with Each R ３ are independently —OH, —C(═O)—NH ２ , -NH-C(=O)-C １－６ Alkyl, —NH—S(═O) ２ -C １－６ Alkyl, or -S(=O) ２ -NH ２ and Each R ４ are independently —OH, —C(═O)—NH ２ , -NH-C(=O)-C １－６ Alkyl, —NH—S(═O) ２ -C １－６ Alkyl, or -S(=O) ２ -NH ２ and Each R ５ is independently —OH or oxo; Each R ６ are independently —C(═O)—OH or —S(═O) ２ -NH ２ and Each R ７ But independently, C １－６ Alkyl, —C １－６ Alkylene -OH, -C １－６ Alkylene-C(=O)-OH, C ３－８ Cycloalkyl, —OH, —NH ２ , -C(=O)-OH, -C(=O)-NH ２ , oxo, imino, or 4- to 7-membered saturated heterocyclyl optionally substituted by one or two oxo groups; The compound or salt thereof according to claim 1.

3. During the ceremony, Ring A is phenyl, a 6-membered heteroaryl containing 1 or 2 nitrogen atoms, pyrazolyl, or a 6-membered saturated or partially unsaturated heterocyclyl; Ring B is formula (V), X is CH or N; R １ But H, C １－６ Alkyl, C ３－８ cycloalkyl, 4- to 7-membered saturated heterocyclyl, phenyl, or optionally substituted heteroaryl; R ２ But one or two R ３ C substituted with １－６ alkyl, one or two R ４ C substituted with ３－８ cycloalkyl, or one or two R ５ or a 4- to 7-membered saturated heterocyclyl substituted with Or R １ and R ２ are connected to each other, R １ and R ２ together with the nitrogen atom to which it is attached to form a 4- to 7-membered saturated heterocyclyl, wherein the heterocyclyl is ７ may be substituted with R ４ is -OH, However, R ａ１ , R ａ２ , R ｂ１ , or R ｂ２ is not H. The compound or salt thereof according to claim 2.

4. During the ceremony, R ｂ１ is H, R ｂ２ But halogeno-C １－６ is alkyl, R １ and R ２ are connected to each other, R １ and R ２ together with the nitrogen atom to which it is attached to form a 4- to 7-membered saturated heterocyclyl, wherein the heterocyclyl is ７ optionally substituted with, The compound or salt thereof according to claim 3.

5. During the ceremony, Ring A is phenyl; R ａ１ , R ａ２ , and R ｂ１ is H, R ｂ２ But halogeno-C １－６ is alkyl, R １ is H or R ２ But one or two R ３ C substituted by １－６ Is it alkyl? Or R １ and R ２ are connected to each other, R １ and R ２ together with the nitrogen atom to which it is attached to form an azetidinyl, pyrrolidinyl, piperidinyl, or thiomorpholinyl, and the azetidinyl, pyrrolidinyl, piperidinyl, or thiomorpholinyl is selected from the group consisting of one or two R ７ may be substituted with Each R ３ are independently —OH or —C(═O)—NH ２ and Each R ７ But independently, -C １－６ Alkylene -OH, -OH, -C(=O)-NH ２ , oxo, or imino; The compound or salt thereof according to claim 3.

6. The compound is selected from the group: N ２ -{3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoyl}-L-serinamide, 1-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-3-[2-(trifluoromethyl)[1,1′-biphenyl]-4-yl]prop-2-yn-1-one, 1-{3-[2-(trifluoromethyl)[1,1′-biphenyl]-4-yl]prop-2-ynoyl}piperidine-4-carboxamide, 1-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-3-[2-(trifluoromethyl)[1,1′-biphenyl]-4-yl]prop-2-yn-1-one, 1-[3,3-bis(hydroxymethyl)azetidin-1-yl]-3-[2-(trifluoromethyl)[1,1′-biphenyl]-4-yl]prop-2-yn-1-one, N-[(2R)-2,3-dihydroxypropyl]-3-[2-(trifluoromethyl)[1,1′-biphenyl]-4-yl]prop-2-ynamide, N-[(2S)-2,3-dihydroxypropyl]-3-[2-(trifluoromethyl)[1,1′-biphenyl]-4-yl]prop-2-ynamide, 1-[(3S,4S)-3,4-dihydroxypyrrolidin-1-yl]-3-[2-(trifluoromethyl)[1,1′-biphenyl]-4-yl]prop-2-yn-1-one, (3R)-1-{3-[2-(trifluoromethyl)[1,1′-biphenyl]-4-yl]prop-2-ynoyl}pyrrolidine-3-carboxamide, 1-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-3-[6-phenyl-5-(trifluoromethyl)pyridin-3-yl]prop-2-yn-1-one, 1-Imino-4-{3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoyl}-1λ ６ -thiomorpholin-1-one, and 1-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-3-[2-methoxy-2'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-yn-1-one is a compound selected from The compound or salt thereof according to claim 1.

7. The compound or salt thereof according to claim 6, wherein the compound is N 2 -{3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoyl}-L-serinamide.

8. The compound or salt thereof according to claim 6, wherein the compound is 1-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-yn-1-one.

9. The compound or salt thereof according to claim 6, wherein the compound is 1-{3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoyl}piperidine-4-carboxamide.

10. The compound or salt thereof according to claim 6, wherein the compound is 1-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-yn-1-one.

11. The compound or salt thereof according to claim 6, wherein the compound is 1-[3,3-bis(hydroxymethyl)azetidin-1-yl]-3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-yn-1-one.

12. The compound or salt thereof according to claim 6, wherein the compound is N-[(2R)-2,3-dihydroxypropyl]-3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynamide.

13. The compound or salt thereof according to claim 6, wherein the compound is N-[(2S)-2,3-dihydroxypropyl]-3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynamide.

14. The compound or salt thereof according to claim 6, wherein the compound is 1-[(3S,4S)-3,4-dihydroxypyrrolidin-1-yl]-3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-yn-1-one.

15. The compound or salt thereof according to claim 6, wherein the compound is (3R)-1-{3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoyl}pyrrolidine-3-carboxamide.

16. The compound or salt thereof according to claim 6, wherein the compound is 1-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-3-[6-phenyl-5-(trifluoromethyl)pyridin-3-yl]prop-2-yn-1-one.

17. The compound or salt thereof according to claim 6, wherein the compound is 1-imino-4-{3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoyl}-1λ 6 -thiomorpholin-1-one.

18. The compound or salt thereof according to claim 6, wherein the compound is 1-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-3-[2-methoxy-2'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-yn-1-one.

19. The compound or salt thereof according to claim 10, wherein the compound is crystalline and has an X-ray powder diffraction spectrum including angles 2θ (°): 4.0, 8.0, 12.0, 12.7, 15.1, 16.7, 18.1, 18.9, 19.6, 22.

2.

20. The compound or salt thereof according to claim 9, wherein the compound is crystalline and has an X-ray powder diffraction spectrum including angles 2θ (°): 5.7, 7.7, 13.4, 14.2, 15.4, 16.0, 16.6, 18.3, 23.7, 25.

7.

21. The compound or salt thereof according to claim 17, wherein the compound is crystalline and has an X-ray powder diffraction spectrum including angles 2θ (°): 4.2, 12.5, 14.4, 14.9, 16.7, 17.1, 18.6, 19.7, 22.0, 25.

4.

22. A pharmaceutical composition comprising the compound according to any one of claims 1 to 21 or a salt thereof and one or more pharmaceutically acceptable excipients.

23. 23. The pharmaceutical composition of claim 22 for use in the treatment of autoimmune diseases, neurodegenerative diseases, type I interferonopathies, and / or other STING-mediated diseases.

24. A STING inhibitor comprising the compound according to any one of claims 1 to 21 or a salt thereof.

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