Aryl alkyne amide derivatives

Abstract

The present inventors have discovered an aryl alkyne amide derivative having an inhibitory effect on STING. The aryl alkyne amide derivative of the present invention has an inhibitory effect on STING, and can be used as an agent for the treatment of autoimmune diseases, neurodegenerative diseases, type I interferon diseases, and / or other STING-mediated diseases.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to U.S. Provisional Application No. 63 / 314,783, filed on February 28, 2022, the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present invention relates to aryl alkyne amide derivatives, which can be used as stimulator of interferon genes (STING) inhibitors and are expected to be used as active ingredients of pharmaceutical compositions, for example, pharmaceutical compositions for treating autoimmune diseases, neurodegenerative diseases, type I interferon diseases and / or other STING-mediated diseases. Background Art

[0004] STING is an adaptor protein that is widely expressed in immune cells and participates in immune responses. When endogenous and exogenous double-stranded DNA (dsDNA) in the cytoplasm is recognized by cyclic guanosine monophosphate-adenosine monophosphate (cyclic GMP-AMP, cGAMP) synthase (cGAS), a DNA sensor, STING acts as an inflammatory mediator by producing the second messenger cGAMP, leading to the secretion of proinflammatory cytokines, such as type I interferons (IFNs) and downstream cytokines of nuclear factor kappa B (NF-kB).

[0005] The cGAS-STING pathway plays an important role in host defense against viral infections, but accumulation of endogenous dsDNA in the cytoplasm or gain-of-function mutations in STING may lead to an excessive immune response, which is known to cause type I interferonopathies, including Aicardi-Goutieres syndrome (AGS) and STING-associated vasculopathy in infancy (SAVI). In addition, activation of the cGAS-STING pathway or an increase in its ligands has been reported in a variety of diseases, such as systemic lupus erythematosus (Annals of the Rheumatic Diseases, Vol. 77, No. 10, pp. 1507-1515, 2018), Sjögren's syndrome (Journal of Autoimmunity, Vol. 108, Article No. 102381, 2020), Crohn's disease (Cell Death and Disease, Vol. 12, Article No. 815, 2021), amyotrophic lateral sclerosis (Cell, Vol. 183, No. 3, pp. 636-649, 2020) and Huntington's disease (PNAS, Vol. 117, No. 27, pp. 15989-15999, 2020).

[0006] Patent document 1 discloses a compound having inhibitory activity on the STING pathway as shown in the following formula, and the compound can be used to treat a condition, disease or disorder in which the pathology and / or symptoms and / or progression of the condition, disease or disorder of the subject are caused by increased activity of the STING pathway (please refer to the patent document for the symbols in the formula).

[0007]

Chemical formula 1

[0008]

[0009] Patent document 2 discloses a compound represented by the following formula having an inhibitory activity on STING, and the compound can be used to treat a disease, condition or disorder associated with STING (for symbols in the formula, please refer to the patent document).

[0010]

Chemical formula 2

[0011]

[0012] Patent document 3 discloses a compound having an inhibitory activity on STING represented by the following formula, and the compound can be used to treat STING-mediated diseases (for the symbols in the formula, please refer to the patent document).

[0013]

Chemical formula 3

[0014]

[0015] Patent document 4 discloses a compound having an inhibitory activity on the production of β-amyloid protein as shown in the following formula, and the compound can be used to treat neurodegenerative diseases caused by β-amyloid protein (wherein X1 represents an acetylene group, etc., and Ar1 represents an optionally substituted imidazole group, etc. For other symbols in the formula, please refer to the patent document). However, no inhibitory activity on STING is described.

[0016]

Chemical formula 4

[0017]

[0018] Patent document 5 discloses a compound having antagonistic activity on retinoic acid receptors (RAR) as shown in the following formula, and the compound can be used to treat various disease states, such as skin diseases, rheumatism, respiratory diseases, cardiovascular diseases, bone diseases and ophthalmic diseases (wherein XY represents an alkyne amide group, etc., and other symbols in the formula can be referred to in the patent document). However, no inhibitory activity on STING is described.

[0019]

Chemical formula 5

[0020]

[0021] Non-patent document 1 discloses a compound having an inhibitory activity against arylalkylamine N-acetyltransferase (AANAT) represented by the following formula (wherein R represents an amine). However, no inhibitory activity against STING is described.

[0022]

Chemical formula 6

[0023]

[0024] Non-patent document 2 discloses a compound represented by the following formula produced by an aminocarbonylation reaction. However, no inhibitory activity on STING is described.

[0025]

Chemical formula 7

[0026]

[0027] Non-patent document 3 discloses a compound represented by the following formula as a starting material for an iodine cyclization reaction. However, no inhibitory activity on STING is described.

[0028]

Chemical formula 8

[0029]

[0030] Non-patent document 4 discloses a compound represented by the following formula as a starting material for a spirotricyclization reaction. However, no inhibitory activity against STING is described.

[0031]

Chemical formula 9

[0032]

[0033] [Patent Literature]

[0034] [Patent Document 1] International Publication WO 2020 / 106741

[0035] [Patent Document 2] International Publication WO 2019 / 122202

[0036] [Patent Document 3] International Publication WO 2019 / 182886

[0037] [Patent Document 4] International Publication WO 2005 / 115990

[0038] [Patent Document 5] U.S. Patent No. 6150413

[0039]

Non-patent literature

[0040] [Non-patent document 1] Journal of Chemical Information and Modeling, Vol. 50, pp. 446-460 (2010)

[0041] [Non-patent document 2] European Journal of Organic Chemistry, pp. 2235-2243 (2015)

[0042] [Non-patent document 3] Journal of Organic Chemistry, Vol. 86, pp. 15498-15508 (2021)

[0043] [Non-patent document 4] Synthesis, Vol. 54, pp. 3105-3113 (2022) Summary of the invention

[0044] [Problems to be solved by the present invention]

[0045] The present invention provides a compound that can be used as a STING inhibitor, which is expected to be used as an active ingredient of a pharmaceutical composition, for example, a pharmaceutical composition for treating autoimmune diseases, neurodegenerative diseases, type I interferon diseases or other STING-mediated diseases.

[0046]

Methods to solve the problem

[0047] The inventors have conducted extensive research on compounds with STING inhibitory effects, and found that aryl alkyne amide derivatives have an inhibitory effect on STING and are expected to be used as active ingredients of pharmaceutical compositions for treating autoimmune diseases, neurodegenerative diseases, type I interferon diseases and / or other STING-mediated diseases, especially Sjögren's syndrome and systemic lupus erythematosus. In this way, the present invention is achieved.

[0048] The present invention relates to a compound of formula (I) or a salt thereof, and a pharmaceutical composition comprising the compound of formula (I) or a salt thereof and one or more pharmaceutically acceptable excipients.

[0049]

Chemical formula 10

[0050]

[0051] (in,

[0052] Ring A is phenyl, and the ring A may be optionally condensed with a 5-membered heterocyclic group, a 6-membered heteroaryl group containing one or two nitrogen atoms, a pyrazolyl group, or a 6-membered saturated or partially unsaturated heterocyclic group,

[0053] Ring B is phenyl, which may be optionally fused with phenyl or a 6-membered heteroaryl containing one or two nitrogen atoms, a 6-membered heteroaryl containing one or two nitrogen atoms, a pyrazolyl group or an imidazolyl group,

[0054] R a1 and R a2 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, Halo-C 1-6 Alkyl, -O-halo-C 1-6 Alkyl or -OH,

[0055] R b1 and R b2 Independently H, C 1-6 Alkyl, -OC 1-6 Alkyl, halo-C 1-6 Alkyl, -O-halo-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,

[0056] R c and R d Independently H, C 1-6 Alkyl, C 3-8 Cycloalkyl, -C(=O)-C 1-6 Alkyl or -S(=O)2-C 1-6 alkyl,

[0057] Or, R c and R d can be optionally connected to each other to form R c and R d The attached nitrogen atom together forms a 4- to 7-membered saturated heterocyclic group, wherein the heterocyclic group may be optionally substituted by one or two R e replace,

[0058] R e C 1-6 Alkyl, -OC 1-6 Alkyl or halogen,

[0059] R 1is H, optionally substituted C 1-6 Alkyl, optionally substituted C 3-8 cycloalkyl, an optionally substituted 4- to 7-membered saturated heterocyclic group, an optionally substituted phenyl group or an optionally substituted heteroaryl group,

[0060] R 2 For one or two R 3 Substituted C 1-6 Alkyl, one or two R 4 Substituted C 3-8 Cycloalkyl, with one or two R 5 substituted 4- to 7-membered saturated heterocyclic group, or one or two R 6 Substituted phenyl,

[0061] Or, R 1 and R 2 Connect to each other with R 1 and R 2 The attached nitrogen atom together forms a 4- to 7-membered saturated heterocyclic group, wherein the heterocyclic group may be optionally fused to a phenyl group, and the heterocyclic group and / or the fused phenyl group may be optionally replaced by one to three R 7 replace,

[0062] Each R 3 are 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 alkyl,

[0063] Each R 4 are 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 1-6Alkyl)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 alkyl,

[0064] Each R 5 are independently -OH, oxo or imino,

[0065] 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 Alkyl, and

[0066] Each R 7 Independently for 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 a 4- to 7-membered saturated heterocyclic group which may be optionally substituted by one or two oxo groups,

[0067] Provided that the compound of formula (I) is not a compound of formula (II), (III), (IV) or (IVa)).

[0068]

Chemical formula 11

[0069]

[0070] Furthermore, unless otherwise specifically stated, when a symbol in one formula in the present specification is also used in other formulas, the same symbol represents the same meaning.

[0071] In addition, the present invention relates to a pharmaceutical composition for treating autoimmune diseases, neurodegenerative diseases, type I interferon diseases and / or other STING-mediated diseases, which comprises a compound of formula (I) or a salt thereof.

[0072]

Chemical formula 12

[0073]

[0074] (in,

[0075] Ring A is phenyl, and the ring A may be optionally condensed with a 5-membered heterocyclic group, a 6-membered heteroaryl group containing one or two nitrogen atoms, a pyrazolyl group, or a 6-membered saturated or partially unsaturated heterocyclic group,

[0076] Ring B is phenyl, which may be optionally fused with phenyl or a 6-membered heteroaryl containing one or two nitrogen atoms, a 6-membered heteroaryl containing one or two nitrogen atoms, a pyrazolyl group or an imidazolyl group,

[0077] R a1 and R a2 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, Halo-C 1-6 Alkyl, -O-halo-C 1-6 Alkyl or -OH,

[0078] R b1 and R b2 Independently H, C 1-6 Alkyl, -OC 1-6 Alkyl, halo-C 1-6 Alkyl, -O-halo-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,

[0079] R c and R d Independently H, C 1-6 Alkyl, C 3-8 Cycloalkyl, -C(=O)-C 1-6 Alkyl or -S(=O)2-C1-6 alkyl,

[0080] Or, R c and R d can be optionally connected to each other to form R c and R d The attached nitrogen atom together forms a 4- to 7-membered saturated heterocyclic group, wherein the heterocyclic group may be optionally substituted by one or two R e replace,

[0081] R e C 1-6 Alkyl, -OC 1-6 Alkyl or halogen,

[0082] R 1 is H, optionally substituted C 1-6 Alkyl, optionally substituted C 3-8 cycloalkyl, an optionally substituted 4- to 7-membered saturated heterocyclic group, an optionally substituted phenyl group or an optionally substituted heteroaryl group,

[0083] R 2 For one or two R 3 Substituted C 1-6 Alkyl, one or two R 4 Substituted C 3-8 Cycloalkyl, with one or two R 5 substituted 4- to 7-membered saturated heterocyclic group, or one or two R 6 Substituted phenyl,

[0084] Or, R 1 and R 2 Connect to each other with R 1 and R 2 The attached nitrogen atom together forms a 4- to 7-membered saturated heterocyclic group, wherein the heterocyclic group may be optionally fused to a phenyl group, and the heterocyclic group and / or the fused phenyl group may be optionally replaced by one to three R 7 replace,

[0085] Each R 3 are 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 1-6Alkylene-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 alkyl,

[0086] Each R 4 are 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 alkyl,

[0087] Each R 5 are independently -OH, oxo or imino,

[0088] 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 Alkyl, and

[0089] Each R 7 Independently for 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(C1-6 alkyl)2, oxo, imino, or a 4- to 7-membered saturated heterocyclic group which may be optionally substituted by one or two oxo groups.

[0090] Here, the pharmaceutical composition includes an agent for treating autoimmune diseases, neurodegenerative diseases, type I interferon diseases and / or other STING-mediated diseases, wherein the agent comprises a compound of formula (I) or a salt thereof.

[0091] In addition, the present invention relates to a compound of formula (I) or a salt thereof as a STING inhibitor; a compound of formula (I) or a salt thereof used as a STING inhibitor; a STING inhibitor comprising a compound of formula (I) or a salt thereof; the use of a compound of formula (I) or a salt thereof for the manufacture of a pharmaceutical composition for treating autoimmune diseases, neurodegenerative diseases, type I interferon diseases and / or other STING-mediated diseases; the use of a compound of formula (I) or a salt thereof for treating autoimmune diseases, neurodegenerative diseases, type I interferon diseases and / or other STING-mediated diseases; a compound of formula (I) or a salt thereof for treating autoimmune diseases, neurodegenerative diseases, type I interferon diseases and / or other STING-mediated diseases; and a method for treating autoimmune diseases, neurodegenerative diseases, type I interferon diseases and / or other STING-mediated diseases, the method comprising administering an effective amount of a compound of formula (I) or a salt thereof to a subject.

[0092] Herein, a "subject" is a human or non-human animal in need of treatment, and in one embodiment, a human in need of treatment.

[0093] Effects of the Invention

[0094] The compound of formula (I) or a salt thereof has a STING inhibitory effect and can be used as a pharmaceutical agent for treating autoimmune diseases, neurodegenerative diseases, type I interferon diseases and / or other STING-mediated diseases. BRIEF DESCRIPTION OF THE DRAWINGS

[0095]

Figure 1

[0096]

Figure 2

[0097]

Figure 3

[0098] The present invention will be described in detail below. In this specification, unless otherwise indicated, the following terms have the following meanings. The following definitions are intended to illustrate but not to limit the defined terms. If a particular term used herein is not particularly defined, the term will be used in accordance with the meaning accepted by those skilled in the art.

[0099] In this manual, "C 1-6 "Alkyl" is a straight or branched chain alkyl group having 1 to 6 carbon atoms (hereinafter referred to as C 1-6 ), such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc. 1-6 In one embodiment, "alkyl" is a linear or branched C 1-4 alkyl; in another embodiment, methyl, ethyl, n-propyl, isopropyl or tert-butyl; in another embodiment, methyl, ethyl, n-propyl, isopropyl; in another embodiment, ethyl or n-propyl; in another embodiment, methyl or isopropyl; in another embodiment, methyl; or in yet another embodiment, tert-butyl.

[0100] “C 1-6 "Alkylene" is 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 C 1-4 Alkylene; in another embodiment, methylene, ethylene, or trimethylene; or in yet another embodiment, methylene.

[0101] “C 2-6 "Alkenyl" is a straight or branched chain C 2-6 Alkenyl, such as ethenyl, propenyl, butenyl, pentenyl, hexenyl, etc. 2-6 In one embodiment, the alkenyl group is C 2-4 in another embodiment, ethenyl, propenyl, or butenyl; in another embodiment, ethenyl; or in yet another embodiment, propenyl.

[0102] “C 2-6 "Alkynyl" is a straight or branched C 2-6 Alkynyl, such as ethynyl, propynyl, butynyl, pentynyl, hexynyl, etc. 2-6 In one embodiment, "alkynyl" is C 2-4 alkynyl; in another embodiment, ethynyl, propynyl or butynyl; in another embodiment, ethynyl; or in yet another embodiment, propynyl.

[0103] “C 3-8 "Cycloalkyl" is C 3-8 Saturated hydrocarbon ring group, and can form a bridged bicyclic or spirocyclic 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" is, in one embodiment, 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.

[0104] "Halogen" means F, Cl, Br or I. In one embodiment, "halogen" is F or Cl; in another embodiment, F; in yet another embodiment, Cl; in another embodiment, Br; or in yet another embodiment, I.

[0105] "Halogenated C 1-6 "Alkyl" is a straight or branched C 1-6 Alkyl group. "HaloC 1-6 "Alkyl" is, in one embodiment, 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.

[0106] "Heteroaryl" is a 5- to 6-membered aromatic ring having one or more heteroatoms (particularly oxygen atoms, nitrogen atoms or sulfur atoms) as constituent atoms of the ring. Examples of "heteroaryl" include, but are not limited to, pyrrolyl, furanyl, thienyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl or triazinyl. "Heteroaryl" is, in one embodiment, pyrazolyl or pyridinyl; in another embodiment, pyridinyl.

[0107] The "oxo group" is a group represented by (=O), and the "imino group" is a group represented by (=NH).

[0108] "6-membered heteroaryl containing one or two nitrogen atoms" means pyridinyl, pyrazinyl, pyrimidinyl or pyridazinyl. "6-membered heteroaryl containing one or two nitrogen atoms" is pyridinyl in one embodiment; pyrazinyl in another embodiment; pyrimidinyl in yet another embodiment; or pyridazinyl in yet another embodiment.

[0109] A "6-membered saturated or partially unsaturated heterocyclic group" is a 6-membered hydrocarbon ring which is saturated or has one double bond in the ring and has one or more heteroatoms (particularly oxygen atoms, nitrogen atoms or sulfur atoms) replacing carbon atoms as constituent atoms of the ring, and can form a bridged bicyclic or spirocyclic ring. Examples of "6-membered saturated or partially unsaturated heterocyclic groups" include, but are not limited to, tetrahydropyran, piperidine, tetrahydrothiopyran, morpholine, piperazine, thiomorpholinyl, dioxane, dihydropyran, tetrahydropyridine or dihydrothiopyran. In one embodiment, a "6-membered saturated or partially unsaturated heterocyclic group" is tetrahydropyran, dihydropyran, piperidine, tetrahydropyridine or morpholine; in another embodiment, it is tetrahydropyran or dihydropyran.

[0110] "4- to 7-membered saturated heterocyclic group" is a 4- to 7-membered saturated hydrocarbon ring having one or more heteroatoms (particularly oxygen atoms, nitrogen atoms or sulfur atoms) replacing carbon atoms as constituent atoms of the ring, and can form a bridged bicyclic or spirocyclic ring. Examples of "4- to 7-membered saturated heterocyclic group" include, but are not limited to, oxetanyl, azetidinyl, thietanyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothienyl, tetrahydropyranyl, piperidinyl, tetrahydrothiopyranyl, oxetanyl, azepanyl, thiepanyl, dioxolanyl, imidazolidinyl, pyrazolidinyl, dithiolanyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, dioxazolidinyl, dithiazolidinyl, dioxazoli ... 1-oxanyl, 1-oxa-6-azaspiro[3.3]heptyl, 2-aza-6-azaspiro[3.3]heptyl, 2-azabicyclo[2.2.1]heptyl or 6-azaspiro[2.5]octyl. "4- to 7-membered saturated heterocyclyl" is, in one embodiment, oxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydropyranyl, piperidinyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, thiomorpholinyl or 2,6-diazaspiro[3.3]heptyl; in another embodiment, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, tetrahydrothiophenyl, tetrahydropyranyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl or 2,6-diazaspiro[3.3]heptyl 2,6-diazaspiro[3.3]heptyl; in another embodiment, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl or 2,6-diazaspiro[3.3]heptyl; in another embodiment, tetrahydropyranyl; in another embodiment, tetrahydrofuranyl or pyrrolidinyl; in another embodiment, tetrahydrothiophenyl; in one embodiment, azetidinyl, pyrrolidinyl, piperidinyl or thiomorpholinyl.

[0111] “R c and R d can be optionally connected to each other to form R c and R d The "4-membered to 7-membered saturated heterocyclic group" in which the nitrogen atom attached together forms a 4-membered to 7-membered saturated heterocyclic group is a 4-membered to 7-membered saturated hydrocarbon ring having at least one nitrogen atom replacing a carbon atom in the above-mentioned "4-membered to 7-membered saturated heterocyclic group", for example, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl or thiomorpholinyl. "R c and R d can be optionally connected to each other to form R c and R dThe "4- to 7-membered saturated heterocyclic group" in the "4- to 7-membered saturated heterocyclic group" to which the nitrogen atom is attached together forms a piperidinyl group or a morpholinyl group in one embodiment.

[0112] “R 1 and R 2 Can be connected to each other with R 1 and R 2 The “4- to 7-membered saturated heterocyclic group” in “wherein the heterocyclic group may be optionally fused with a phenyl group” is a 4- to 7-membered saturated hydrocarbon ring having at least one nitrogen atom replacing a carbon atom in the above “4- to 7-membered saturated heterocyclic group”, for example, azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, thiomorpholinyl or 2,6-diazaspiro[3.3]heptyl. “The heterocyclic group may be optionally fused with a phenyl group” means that the heterocyclic group is not fused with a benzene ring, or is fused with a benzene ring to form a bicyclic ring, for example, dihydroindolinyl, isoindolinyl, tetrahydroquinolinyl or tetrahydroisoquinolinyl. “R 1 With R 2 Connect to each other with R 1 and R 2 Examples of "a 4- to 7-membered saturated heterocyclic group" are azetidinyl, pyrrolidinyl, piperidinyl, or thiomorpholinyl in one embodiment; azetidinyl, pyrrolidinyl, or piperidinyl in another embodiment; pyrrolidinyl in yet another embodiment; thiomorpholinyl in another embodiment; or indolinyl in another embodiment.

[0113] The "5-membered heterocyclic group" in the "phenyl group which may be optionally fused with a 5-membered heterocyclic group" is a 5-membered unsaturated hydrocarbon ring having one or more heteroatoms (particularly oxygen atoms, nitrogen atoms or sulfur atoms) replacing carbon atoms as constituent atoms of the ring. Examples of the "5-membered heterocyclic group" include, but are not limited to, dihydrofuranyl, furanyl, dihydropyrrolyl, pyrrolyl, dihydrothienyl, thienyl, dihydrooxazolyl, oxazolyl, dihydroimidazolyl, imidazolyl, dihydrothiazolyl, thiazolyl, dioxolyl or 2-oxodihydropyrrolyl. The "phenyl group which may be optionally fused with a 5-membered heterocyclic group" is a phenyl group, or a phenyl group which is fused with a "5-membered heterocyclic group" by sharing its double bond to form a bicyclic ring. Examples of the “phenyl group which may be optionally fused to a 5-membered heterocyclic group” include, but are not limited to, phenyl, indolyl, benzofuranyl, benzothiophenyl, indazolyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzisothiazolyl, benzothiazolyl, 1,3-benzodioxolyl or 1-oxoisoindolinyl. The “phenyl group which may be optionally fused to a 5-membered heterocyclic group” is, in one embodiment, phenyl.

[0114] The “phenyl group optionally fused to a phenyl group or a 6-membered heteroaryl group containing one or two nitrogen atoms” is a phenyl group, or a phenyl group fused to another phenyl group or a 6-membered heteroaryl group containing one or two nitrogen atoms. Examples of the “phenyl group optionally fused to a phenyl group or a 6-membered heteroaryl group containing one or two nitrogen atoms” include, but are not limited to, naphthyl, quinolyl, quinazolinyl, or quinoxalinyl. The “phenyl group optionally fused to a phenyl group or a 6-membered heteroaryl group containing one or two nitrogen atoms” is, in one embodiment, a phenyl group or a quinolyl group; in another embodiment, a phenyl group; or in yet another embodiment, a quinolyl group.

[0115] In the present specification, the expression "optionally substituted" includes "unsubstituted" or "substituted with one or more substituents (eg, substituents defined below)".

[0116] Substitution may occur anywhere on the group where a hydrogen atom would normally be present.

[0117] In one embodiment, "optionally substituted" is "optionally substituted with 1 to 5 substituents", and in another embodiment, "optionally substituted with 1 to 3 substituents".

[0118] When there are a plurality of substituents, these substituents may be the same as or different from each other.

[0119] "optionally substituted phenyl", "optionally substituted heteroaryl", "optionally substituted C 1-6 Alkyl", "optionally substituted C 3-8 Examples of substituents of "cycloalkyl" and "optionally substituted 4- to 7-membered saturated heterocyclic group" include, but are not limited to, R 3 , R 4 , R 5 , R 6 or R 7 The substituents described.

[0120] "Optionally one or two R e "Substituted" means unsubstituted or replaced by one or two R e "optionally replaced by one or two R e In one embodiment, "substituted" is by two R e In another embodiment, one R e or in another embodiment is unsubstituted. e In the case of substitution, the two R e They may be the same as or different from each other.

[0121] “Being one or two R y Replacement", where R y Represents R 3, R 4 , R 5 or R 6 , meaning that one or two R y Replaced by one or two R y In one embodiment, "substituted" is by two R y In another embodiment, one R y Replaced by two R y In the case of substitution, the two R y They may be the same as or different from each other.

[0122] "Optionally one to three R 7 "Substituted" means unsubstituted or substituted with one to three R 7 "optionally replaced by one to three R 7 In one embodiment, "substituted" is optionally replaced by 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 is unsubstituted. 7 In the case of substitution, these two or three R 7 They may be the same as or different from each other.

[0123] One or more embodiments may be combined with different embodiments even if the combination is not specifically described. That is, all embodiments may be combined in any manner.

[0124] In this specification, "treatment" includes both "therapeutic treatment" and "prophylactic treatment". "Therapeutic treatment" means relieving symptoms, changing the course of the disease, prolonging life, etc., and "prophylactic treatment" means reducing the likelihood of a subject at risk of contracting the disease. "Subject at risk of the disease" means an individual with known risk factors that make them more susceptible to the disease than the general population.

[0125] As used herein, "autoimmune disease" refers to the group of diseases including systemic lupus erythematosus, Sjögren'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 biliary cholangitis, pemphigus, pemphigoid, Hashimoto's disease, Basedow's disease, primary immune thrombocytopenia, autoimmune pulmonary alveolar proteinosis, autoimmune hemolytic anemia, Goodpasture's syndrome, and pulmonary edema. syndrome), myasthenia gravis, celiac disease and psoriasis, but "autoimmune diseases" are not limited to these diseases. "Autoimmune diseases" in one embodiment are systemic lupus erythematosus, Sjögren's syndrome, rheumatoid arthritis, Crohn's disease, ulcerative colitis, type 1 diabetes, vasculitis, systemic sclerosis, dermatomyositis, myasthenia gravis or psoriasis; in other embodiments, systemic lupus erythematosus and Sjögren's syndrome; in another embodiment, systemic lupus erythematosus; or in yet another embodiment, Sjögren's syndrome. "Systemic lupus erythematosus" herein includes several subtypes of lupus erythematosus, including but not limited to lupus nephritis, neuropsychiatric lupus erythematosus and cutaneous lupus erythematosus. "Systemic lupus erythematosus" in one embodiment is lupus nephritis; in another embodiment, neuropsychiatric lupus erythematosus; or in yet another embodiment, cutaneous lupus erythematosus. In another embodiment, "systemic lupus erythematosus" is systemic lupus erythematosus without lupus nephritis symptoms; in another embodiment, it is systemic lupus erythematosus without neuropsychiatric lupus symptoms; in another embodiment, it is systemic lupus erythematosus without lupus nephritis or neuropsychiatric lupus symptoms. In addition, "systemic lupus erythematosus" herein includes systemic lupus erythematosus complicated with Sjögren's syndrome.

[0126] "Neurodegenerative disease" herein 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-dependent macular degeneration, stroke, and traumatic brain injury, but "neurodegenerative disease" is not limited to these diseases. "Neurodegenerative disease" is multiple sclerosis in one embodiment; amyotrophic lateral sclerosis in another embodiment; Parkinson's disease, multiple system atrophy, or Lewy body dementia in other embodiments; frontotemporal lobar degeneration in yet another embodiment; Huntington's disease in yet another embodiment; stroke in other embodiments; or traumatic brain injury in other embodiments.

[0127] The "type I interferon disease" described herein refers to a group of diseases including the following: Aicardi-Guterres syndrome (AGS), STING-associated vasculopathy (SAVI) of infancy, COPA syndrome, spondylochondrodysplasia, ataxia telangiectasia and familial pernio lupus, but "type I interferon disease" is not limited to these diseases. "Type I interferon disease" is Aicardi-Guterres syndrome (AGS) or STING-associated vasculopathy (SAVI) of infancy in one embodiment; Aicardi-Guterres syndrome (AGS) in another embodiment; or STING-associated vasculopathy (SAVI) of infancy in another embodiment.

[0128] "Other STING-mediated diseases" herein refers to a group of diseases including: non-alcoholic fatty hepatitis (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. In one embodiment, "other STING-mediated diseases" are non-alcoholic fatty hepatitis (NASH) or alcoholic liver disease; in another embodiment, acute pancreatitis; in yet another embodiment, acute kidney injury; in yet another embodiment, sepsis; or in another embodiment, myocardial infarction or chronic heart failure.

[0129] Some specific embodiments of the compound of formula (I) or its salt in the present invention are shown below, including the embodiments described in (1-1) to (14-8), provided that the compound of formula (I) or its salt is not a compound or its salt of formula (II), (III), (IV) or (IVa).

[0130]

Chemical formula 13

[0131]

[0132] (1-1) A compound or a salt thereof, wherein Ring A is a phenyl group, which may be optionally condensed with a 5-membered heterocyclic group, a 6-membered heteroaryl group containing one or two nitrogen atoms, a pyrazolyl group, or a 6-membered saturated or partially unsaturated heterocyclic group.

[0133] (1-2) A compound or a salt thereof, wherein Ring A is a phenyl group, a 6-membered heteroaryl group containing one or two nitrogen atoms, a pyrazolyl group, or a 6-membered saturated or partially unsaturated heterocyclic group.

[0134] (1-3) A compound or a salt thereof, wherein Ring A is phenyl, pyrazolyl or a 6-membered saturated or partially unsaturated heterocyclic group.

[0135] (1-4) A compound or a salt thereof, wherein ring A is phenyl.

[0136] (2-1) A compound or a salt thereof, wherein Ring B is a phenyl group, which may be optionally condensed with a phenyl group or a 6-membered heteroaryl group containing one or two nitrogen atoms, a 6-membered heteroaryl group containing one or two nitrogen atoms, a pyrazolyl group or an imidazolyl group.

[0137] (2-2) A compound or a salt thereof, wherein Ring B is a phenyl group, a 6-membered heteroaryl group containing one or two nitrogen atoms, or a pyrazolyl group.

[0138] (2-3) A compound or a salt thereof, wherein Ring B is a phenyl group or a 6-membered heteroaryl group containing one or two nitrogen atoms.

[0139] (2-4) A compound or a salt thereof, wherein Ring B is represented by the formula (V) wherein X is CH or N.

[0140]

Chemical formula 14

[0141]

[0142] (2-5) A compound or a salt thereof, wherein Ring B is represented by the formula (V) wherein X is CH.

[0143] (2-6) A compound or a salt thereof, wherein Ring B is represented by the formula (V) wherein X is N.

[0144] (2-7) A compound or a salt thereof, wherein Ring B is of the formula (Va).

[0145]

Chemical formula 15

[0146]

[0147] (2-8) A compound or a salt thereof, wherein Ring B is represented by the formula (Vb).

[0148]

Chemical formula 16

[0149]

[0150] (3-1) A compound or a salt thereof, wherein R a1 and R a2 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, Halo-C 1-6 Alkyl, -O-halo-C 1-6 Alkyl or -OH.

[0151] (3-2) A compound or a salt thereof, wherein R a1 and R a2 Independently H, C 1-6 Alkyl, halogen, halo-C 1-6 Alkyl or -O-halogenated-C 1-6 alkyl.

[0152] (3-3) A compound or a salt thereof, wherein R a1 and R a2 are independently H, halogen, halo-C 1-6 Alkyl or -O-halogenated-C 1-6 alkyl.

[0153] (3-4) A compound or a salt thereof, wherein R a1 and R a2 are independently H, halo-C 1-6 Alkyl or -O-halogenated-C 1-6 alkyl.

[0154] (3-5) A compound or a salt thereof, wherein R a1 and R a2 are independently H or -O-halo-C 1-6 alkyl.

[0155] (3-6) A compound or a salt thereof, wherein R a1 H and R a2 -O-halogenated-C 1-6 alkyl.

[0156] (3-7) A compound or a salt thereof, wherein R a1 and R a2 For H.

[0157] (4-1) A compound or a salt thereof, wherein R b1 and R b2 Independently H, C 1-6 Alkyl, -OC1-6 Alkyl, halo-C 1-6 Alkyl, -O-halo-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.

[0158] (4-2) A compound or a salt thereof, wherein R b1 and R b2 are independently H, halo-C 1-6 Alkyl or -C 1-6 Alkylene-NR c R d .

[0159] (4-3) A compound or a salt thereof, wherein R b1 and R b2 are independently H or halo-C 1-6 alkyl.

[0160] (4-4) A compound or a salt thereof, wherein R b1 H and R b2 For halogenated-C 1-6 alkyl.

[0161] (5) A compound or a salt thereof, wherein R a1 , R a2 , R b1 or R b2 At least one of them is not H.

[0162] (6-1) A compound or a salt thereof, wherein R c and R d Independently H, C 1-6 Alkyl, C 3-8 Cycloalkyl, -C(=O)-C 1-6 Alkyl or -S(=O)2-C 1-6 alkyl,

[0163] Or, R c and R d can be optionally connected to each other to form R c and R d The attached nitrogen atom together forms a 4- to 7-membered saturated heterocyclic group, wherein the heterocyclic group may be optionally substituted by one or two R e replace.

[0164] (6-2) A compound or a salt thereof, wherein R c and R d are independently H or C 1-6 alkyl,

[0165] Or, R c and R d can be optionally connected to each other to form R c and R d The attached nitrogen atom together forms a 4- to 7-membered saturated heterocyclic group, wherein the heterocyclic group may be optionally substituted by one or two R e replace,

[0166] (6-3) A compound or a salt thereof, wherein R c and R d are independently H or C 1-6 alkyl.

[0167] (6-4) A compound or a salt thereof, wherein R c and R d Connect to each other with R c and R d The attached nitrogen atom together forms a 4- to 7-membered saturated heterocyclic group, wherein the heterocyclic group may be optionally substituted by one or two R e replace.

[0168] (7-1) A compound or a salt thereof, wherein R e C 1-6 Alkyl, -OC 1-6 Alkyl or halogen.

[0169] (7-2) A compound or a salt thereof, wherein R e For-OC 1-6 alkyl.

[0170] (8-1) A compound or a salt thereof, wherein R 1 is H, optionally substituted C 1-6 Alkyl, optionally substituted C 3-8 cycloalkyl, an optionally substituted 4- to 7-membered saturated heterocyclic group, an optionally substituted phenyl group or an optionally substituted heteroaryl group,

[0171] R 2 For one or two R 3 Substituted C 1-6 Alkyl, one or two R 4 Substituted C 3-8 Cycloalkyl, with one or two R 5 substituted 4- to 7-membered saturated heterocyclic group, or one or two R 6 Substituted phenyl,

[0172] Or, R1 and R 2 Connect to each other with R 1 and R 2 The attached nitrogen atom together forms a 4- to 7-membered saturated heterocyclic group, wherein the heterocyclic group may be optionally fused to a phenyl group, and the heterocyclic group and / or the fused phenyl group may be optionally replaced by one to three R 7 replace.

[0173] (8-2) A compound or a salt thereof, wherein R 1 H, C 1-6 Alkyl, C 3-8 cycloalkyl, 4- to 7-membered saturated heterocyclic group, optionally substituted phenyl or optionally substituted heteroaryl,

[0174] R 2 For one or two R 3 Substituted C 1-6 Alkyl, one or two R 4 Substituted C 3-8 Cycloalkyl, with one or two R 5 substituted 4- to 7-membered saturated heterocyclic group, or one or two R 6 Substituted phenyl,

[0175] Or, R 1 and R 2 Connect to each other with R 1 and R 2 The attached nitrogen atom together forms a 4- to 7-membered saturated heterocyclic group, wherein the heterocyclic group may be optionally fused to a phenyl group, and the heterocyclic group and / or the fused phenyl group may be optionally replaced by one or two R 7 replace.

[0176] (8-3) A compound or a salt thereof, wherein R 1 H, C 1-6 Alkyl, C 3-8 cycloalkyl, 4- to 7-membered saturated heterocyclic group, phenyl or optionally substituted heteroaryl,

[0177] R 2 For one or two R 3 Substituted C 1-6 Alkyl, one or two R 4 Substituted C 3-8 Cycloalkyl, or one or two R 5 a substituted 4- to 7-membered saturated heterocyclic group,

[0178] Or, R 1 and R 2 Connect to each other with R 1 and R 2The attached nitrogen atom together forms a 4- to 7-membered saturated heterocyclic group, wherein the heterocyclic group may be optionally substituted by one or two R 7 replace.

[0179] (8-4) A compound or a salt thereof, wherein R 1 and R 2 Connect to each other with R 1 and R 2 The attached nitrogen atom together forms a 4- to 7-membered saturated heterocyclic group, wherein the heterocyclic group may be optionally substituted by one or two R 7 replace.

[0180] (8-5) A compound or a salt thereof, wherein R 1 For H,

[0181] R 2 For one or two R 3 Substituted C 1-6 alkyl,

[0182] Or, R 1 and R 2 Connect to each other with R 1 and R 2 The attached nitrogen atoms together form an azetidinyl, pyrrolidinyl, or piperidinyl or thiomorpholinyl group, wherein the azetidinyl, pyrrolidinyl, piperidinyl or thiomorpholinyl group may be optionally substituted by one or two R 7 replace.

[0183] (8-6) A compound or a salt thereof, wherein R 1 and R 2 Connect to each other with R 1 and R 2 The attached nitrogen atoms together form an azetidinyl, pyrrolidinyl, piperidinyl or thiomorpholinyl group, wherein the azetidinyl, pyrrolidinyl, piperidinyl or thiomorpholinyl group may be optionally substituted by one or two R 7 replace.

[0184] (8-7) A compound or a salt thereof, wherein R 1 and R 2 Connect to each other with R 1 and R 2 The attached nitrogen atoms together form a pyrrolidinyl group, wherein the pyrrolidinyl group may be optionally substituted by one or two R 7 replace.

[0185] (8-8) A compound or a salt thereof, wherein R 1 and R 2 Connect to each other with R 1 and R 2The attached nitrogen atoms together form a pyrrolidinyl group, wherein the pyrrolidinyl group is surrounded by two R 7 replace.

[0186] (8-9) A compound or a salt thereof, wherein R 1 H, C 1-6 Alkyl, C 3-8 cycloalkyl, 4- to 7-membered saturated heterocyclic group, optionally substituted phenyl or optionally substituted heteroaryl,

[0187] R 2 For one or two R 3 Substituted C 1-6 Alkyl, one or two R 4 Substituted C 3-8 Cycloalkyl, with one or two R 5 substituted 4- to 7-membered saturated heterocyclic group, or one or two R 6 Substituted phenyl,

[0188] Or, R 1 and R 2 Connect to each other with R 1 and R 2 The attached nitrogen atom together forms a 4- to 7-membered saturated heterocyclic group, wherein the heterocyclic group may be optionally fused to a phenyl group, and the heterocyclic group may be optionally substituted by one or two R 7 replace.

[0189] (9-1) A compound or a salt thereof, wherein each R 3 are 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 alkyl.

[0190] (9-2) A compound or a salt thereof, wherein each R 3 are independently -OH, -C(=O)-NH2, -NH-C(=O)-C1-6 Alkyl, -NH-S(=O)2-C 1-6 Alkyl or -S(=O)2-NH2.

[0191] (9-3) A compound or a salt thereof, wherein each R 3 is independently -OH or -C(=O)-NH2.

[0192] (10-1) A compound or a salt thereof, wherein each R 4 are 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 alkyl.

[0193] (10-2) A compound or a salt thereof, wherein each R 4 are independently -OH, -C(=O)-NH2, -NH-C(=O)-C 1-6 Alkyl, -NH-S(=O)2-C 1-6 Alkyl or -S(=O)2-NH2.

[0194] (10-3) A compound or a salt thereof, wherein R 4 It is -OH.

[0195] (11-1) A compound or a salt thereof, wherein each R 5 are independently -OH, oxo or imino.

[0196] (11-2) A compound or a salt thereof, wherein each R 5 are independently -OH or oxo.

[0197] (11-3) A compound or a salt thereof, wherein R 5 It is -OH.

[0198] (11-4) A compound or a salt thereof, wherein R 5 It is an oxo group.

[0199] (11-5) A compound or a salt thereof, wherein each R 5 are independently oxo or imino.

[0200] (12-1) A compound or a salt thereof, wherein 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 alkyl.

[0201] (12-2) A compound or a salt thereof, wherein each R 6 are independently -C(=O)-OH or -S(=O)2-NH2.

[0202] (12-3) A compound or a salt thereof, wherein R 6 It is -C(=O)-OH.

[0203] (12-4) A compound or a salt thereof, wherein R 6 It is -S(=O)2-NH2.

[0204] (13-1) A compound or a salt thereof, wherein each R 7 Independently for 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 a 4- to 7-membered saturated heterocyclic group which may be optionally substituted by one or two oxo groups.

[0205] (13-2) A compound or a salt thereof, wherein each R 7 Independently for C 1-6 Alkyl, -C 1-6 Alkylene -OH, -C 1-6 Alkylene-C(=O)-OH, C 3-8Cycloalkyl, -OH, -NH2, -C(=O)-OH, -C(=O)-NH2, oxo, imino, or a 4- to 7-membered saturated heterocyclic group which may be optionally substituted by one or two oxo groups.

[0206] (13-3) A compound or a salt thereof, wherein each R 7 Independently -C 1-6 Alkylene -OH, -OH, -C(=O)-NH2, oxo or imino.

[0207] (13-4) A compound or a salt thereof, wherein each R 7 Independently -C 1-6 Alkylene -OH, -OH or -C(=O)-NH2.

[0208] (13-5) A compound or a salt thereof, wherein R 7 It is -OH.

[0209] (14) A compound or a salt thereof obtained by combining two or more non-mutually contradictory embodiments in the embodiment group described in (1-1) to (13-5). Examples thereof include, but are not limited to, the following combinations.

[0210] (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).

[0211] (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).

[0212] (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).

[0213] (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).

[0214] (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).

[0215] (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).

[0216] (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).

[0217] (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).

[0218] Examples of specific compounds encompassed by the present invention include the following compounds or salts thereof:

[0219] N 2 -{3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynyl}-L-serinamide,

[0220] 1-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-yn-1-one,

[0221] 1-{3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynyl}piperidine-4-carboxamide,

[0222] 1-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-yn-1-one,

[0223] 1-[3,3-bis(hydroxymethyl)azetidin-1-yl]-3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-yn-1-one,

[0224] N-[(2R)-2,3-dihydroxypropyl]-3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynamide,

[0225] N-[(2S)-2,3-dihydroxypropyl]-3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynamide,

[0226] 1-[(3S,4S)-3,4-dihydroxypyrrolidin-1-yl]-3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-yn-1-one,

[0227] (3R)-1-{3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynyl}pyrrolidine-3-carboxamide,

[0228] 1-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-3-[6-phenyl-5-(trifluoromethyl)pyridin-3-yl]prop-2-yn-1-one, and

[0229] 1-Imino-4-{3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynyl}-1λ 6 -Thiomorpholinyl-1-one.

[0230] Examples of specific compounds encompassed by the present invention also include free base forms of the compounds listed in Tables 13-20 or salts thereof.

[0231] With respect to the compound of formula (I), there may be tautomers or geometric isomers thereof, depending on the type of substituents. In the present specification, in some cases, the compound of formula (I) and its salt may be described in the form of only one isomer, but the present invention includes other isomers, isolated forms of isomers or mixtures thereof.

[0232] In addition, in some cases, some compounds of formula (I) may have asymmetric carbon atoms or axial chirality, and accordingly, their enantiomers (optical isomers) may exist. The present invention includes the separation form of the single enantiomer of the compound of formula (I) or its mixture, including racemic mixture or other mixtures.

[0233] In one embodiment, the enantiomer is "stereochemically pure." "Stereochemically pure" refers to a level of stereochemical purity that one of skill in the art would consider to be substantially "pure." In another embodiment, the enantiomer is a compound having 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.

[0234] In addition, the salt of the compound of formula (I) is a pharmaceutically acceptable salt of the compound of formula (I). In some cases, the compound of formula (I) can form an acid addition salt or a salt formed with a base, depending on the type of the substituent. Specifically, examples thereof include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, acid addition salts with organic acids such as formic acid, acetic acid, propionic 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, salts formed with metal anions such as sodium, potassium, magnesium, calcium, aluminum, salts formed with organic bases such as methylamine, ethylamine, ethanolamine, lysine, ornithine, salts formed with various amino acids such as acetylleucine or amino acid derivatives, ammonium salts, etc.

[0235] In addition, the present invention also includes various hydrates or solvates and crystal polymorphs of the compound of formula (I) and its salts.

[0236] The present invention includes all pharmaceutically acceptable, isotopically-labeled compounds of the present invention having one or more radioactive or non-radioactive isotopes.

[0237] Examples of isotopes suitable for use in isotopically labeled compounds of the present invention include: isotopes of hydrogen, such as 2 H and 3 H; isotopes of carbon, such as 11 C. 13 C and 14 C; isotopes of chlorine, such as 36 Cl; isotopes of fluorine, such as 18 F; isotopes of iodine, such as 123 I and 125 I; isotopes of nitrogen, such as 13 N and 15 N; isotopes of oxygen, such as 15 O. 17 O and 18 O; isotopes of phosphorus, such as 32 P; and isotopes of sulfur, such as 35 S.

[0238] Certain isotopically labeled compounds of the invention, e.g., compounds incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. 3 H) and carbon 14 (i.e. 14 C) can be used for this purpose because they are easy to incorporate and easy to detect.

[0239] Substitution with heavier isotopes, such as deuterium (i.e. 2H) in place of hydrogen may provide certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, reduced drug-drug interference, and therefore may be used in certain circumstances.

[0240] Using positron-emitting isotopes such as 11 C. 18 F. 15 O and 13 N) can be used in positron emission tomography (PET) studies to detect the receptor occupancy of the substrate.

[0241] 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, using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously employed.

[0242] (Production Method)

[0243] The compound of formula (I) or its salt can utilize the feature based on its basic structure or substituent type, and various known synthetic methods are applied to prepare.At this moment, according to the type of functional group, in some cases, from the angle of preparation technology, in the step from starting material to intermediate, it is effective to protect functional group with suitable blocking group (group that can be easily converted into functional group).The example of blocking group includes the blocking group described in " Greene's Protective Groups in Organic Synthesis (the 4th edition, 2006) " edited by PGM Wuts and TW Greene, etc., which can be appropriately selected and used according to reaction conditions.In these methods, can react by introducing blocking group, then remove blocking group as required, thereby obtain desired compound.

[0244] Pharmaceutically acceptable prodrug refers to a compound with such a group, which can be converted into an amino group, a hydroxyl group, a carboxyl group, etc. by solvent decomposition or under physiological conditions. The example of the group forming the prodrug includes description in Prog.Med., Vol. 5, pp. 2157-2161 (1985) or "Pharmaceutical Research and Development" (Hirokawa Publishing Co., Ltd., 1990), Vol. 7, Drug Design, pp. 163-198. In addition, the prodrug of the compound of formula (I) can be prepared by introducing a specific group in the same manner as the above-mentioned protecting group in the step from the starting material to the intermediate, or by further reacting the compound of the obtained formula (I). The reaction can be applied to methods known to those skilled in the art, such as common esterification, amidation, dehydration for preparation.

[0245] The following describes the classical preparation methods of the compounds of formula (I). Each production method can also be carried out with reference to the literature attached to the specification of this article. In addition, the preparation method of the present invention is not limited to the examples shown below.

[0246] The following abbreviations may be used herein.

[0247] AcOH: acetic acid, BOC: tert-butyloxycarbonyl, CHCl3: chloroform, CH2Cl2: dichloromethane, CH3CN: acetonitrile, COMU: (1-cyano-2-ethoxy-2-oxoethyliminooxy)dimethylamino-morpholino-carbonium 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-dimethylformamide, 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-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, (HCHO)n: paraformaldehyde, HCl: hydrochloric acid, HOBt: 1-hydroxybenzotriazole, IPA: isopropanol, IPE: diisopropyl ether, K2CO3: 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-CPBA: m-chloroperbenzoic acid, NH4HCO3: ammonium bicarbonate, NIS: N-iodosuccinimide, NMP: 1-methylpyrrolidin-2-one, P(t-Bu)3·HBF4: tritert-butyl lithium Butylphosphine 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)tripyrrolidinophosphine hexafluorophosphate, SPhos: 2-Dicyclohexylphosphino-2',6'- -dimethoxybiphenyl, TBAF: tetra-n-butylammonium fluoride, TBS: tert-butyldi(methyl)silyl, tBu: tert-butyl, Tf: trifluoromethanesulfonyl, THF: tetrahydrofuran, TFA: trifluoroacetic acid, TMS: trimethylsilyl, T3P (registered trademark): 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane-2,4,6-trioxide, EDC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, EDC·HCl: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, XPhos: 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.

[0248] (Production method 1)

[0249]

Chemical formula 17

[0250]

[0251] (where Y 1 and Y 2 R' and R" are both H, or R' and R" are connected to each other to form 4,4,5,5-tetramethyl-1,3,2-dioxaborolane together with the boronic acid residues to which R' and R" are attached. The same applies below).

[0252] (Step 1a)

[0253] This step is a step of preparing a compound of formula (VII) by reacting a compound of formula (VI) with trimethylsilyl acetylene. In this reaction, the compound of formula (VI) and trimethylsilyl acetylene are used in equal amounts, or one of the compounds is used in excess. Under cooling or heating to reflux conditions, preferably at room temperature to 190°C, in the presence of a catalyst, a co-catalyst and a base, in a solvent inert to the reaction or in the absence of a solvent, the mixture of these compounds is usually stirred for 0.1 hour to 5 days. 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 co-catalysts 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, in order to allow the reaction to proceed smoothly, it may be advantageous to react in the presence of sodium iodide. The reaction may be carried out under microwave radiation.

[0254]

References

[0255] Tetrahedron Letters, Vol. 50, pp. 4467-4470 (1975)

[0256] (Step 2a)

[0257] This step is a step of preparing a compound of formula (IX) by reacting compounds of formula (VII) and (VIII). In the reaction, the compound of formula (VII) and the compound of formula (VIII) are used in equal amounts, or one of the compounds is used in excess. Under cooling or heating to reflux conditions, preferably at room temperature to 190° C., in the presence of a catalyst and a base, in a solvent inert to the reaction or in the absence of a solvent, the mixture of these compounds is generally stirred for 0.1 hour to 5 days. 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 tert-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, xylene, and water, pyridine, CH3CN, NMP, DMF, DMSO, and mixtures thereof. In some cases, in order to facilitate the reaction, it may be advantageous to react in the presence of phosphine ligands such as SPhos, XPhos, dicyclohexyl (2', 6'-diisopropoxy-[1,1'-biphenyl]-2-yl) phosphine (RuPhos), 4,5-bis (diphenylphosphino) -9,9-dimethyloxanthene (XantPhos), P (t-Bu) 3 · HBF4, etc. The reaction may be carried out under microwave irradiation.

[0258]

References

[0259] Journal of the American Chemical Society, Vol. 127, pp. 4685-4696 (2005)

[0260] The compound of formula (IX) is also obtained from the compound of formula (VI) through step 1b and step 2b.

[0261] (Step 1b)

[0262] This step is a step of preparing a compound of formula (X) by reacting compounds of formula (VI) and (VIII). The 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).

[0263] (Step 2b)

[0264] This step is a step of preparing a compound of formula (IX) by reacting a compound of formula (X) with trimethylsilylacetylene. The reaction is carried out under the same conditions as step 1a by using a compound of formula (X) instead of a compound of formula (VI).

[0265] (Step 3)

[0266] This step is a step of preparing a compound of formula (XI) by deprotecting a compound of formula (IX). The reaction is carried out using a compound of formula (IX) and a deprotecting agent, and the method is as follows: under cooling or heating to reflux conditions, preferably at room temperature to 100° C., in a solvent inert to the reaction, the mixture is usually stirred for 0.1 hour to 5 days. Examples of deprotecting agents include, but are not limited to, bases (such as potassium carbonate, etc.) and fluorides (such as tetrabutylammonium fluoride, etc.). Examples of solvents include, but are not limited to, alcohols (such as MeOH and EtOH) and ethers (such as THF or 1,4-dioxane).

[0267] (Step 4a)

[0268] This step is a step of preparing a compound of formula (XII) by reacting a compound of formula (XI) with carbon dioxide. The reaction is carried out as follows to obtain a lithium acetylide intermediate: first, under cooling or room temperature conditions, in a solvent inert to the reaction, by using a compound of formula (XI) and an organic lithium reagent. Then, under cooling or room temperature conditions, the lithium acetylide intermediate is added to an excess of dry ice to obtain a compound of formula (XII). The entire reaction is generally carried out for 0.1 hours to 1 day. Examples of organic lithium reagents include, but are not limited to, n-butyl lithium, tert-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).

[0269] (Step 4b)

[0270] The compound of formula (XII) is also obtained from the compound of formula (X) through step 4b. This step is a step of preparing the compound of formula (XII) by reacting the compound of formula (X) with propiolic acid. The reaction is carried out under the same conditions as step 1a by using propiolic acid instead of trimethylsilyl acetylene.

[0271] (Step 5a)

[0272] This step is a step of preparing a compound of formula (I) by reacting compounds of formula (XII) and (XIII). In the 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 excess. Under cooling or heating to reflux conditions, preferably at room temperature to 100°C, in the presence of a condensing agent and a base, in a solvent inert to the reaction or in the absence of a solvent, the mixture of these compounds is usually stirred for 0.1 hour to 5 days. Examples of condensing agents include, but are not limited to, T3P (registered trademark), HATU, EDC, EDC·HCl, COMU, 2-chloro-1-methylpyridinium iodide, etc. 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), halogenated hydrocarbons (such as CH2Cl2 and CHCl3), acetonitrile, NMP, DMF, DMSO, and mixtures thereof. In some cases, in order to facilitate the reaction, it may be advantageous to carry out the reaction in the presence of HOBt.

[0273] This step can also be carried out by using a chlorinating agent as a condensing agent. The reaction is carried out as follows to obtain an acyl chloride intermediate: first, under cooling or heating to reflux conditions, preferably at 0°C to room temperature, in a solvent inert to the reaction or in the absence of a solvent, by using a compound of formula (XII) and a chlorinating agent. Then, under cooling or heating to reflux conditions, preferably at 0°C to room temperature, in a solvent inert to the reaction, the acyl chloride intermediate is added to a mixture of a base and a compound of formula (XIII). The entire reaction is generally carried out for 0.1 hours to 1 day. Examples of chlorinating agents include, but are not limited to, (COCl)2, phosphoryl chloride (POCl3) and thionyl chloride (SOCl2). Examples of bases include, but are not limited to, Na2CO3, NaHCO3, K2CO3, Et3N, DIPEA and pyridine. Examples of solvents include, but are not limited to, halogenated alkanes (such as CH2Cl2 or CHCl3) and ethers (such as THF or 1,4-dioxane). Water may be added as a co-solvent.

[0274] (Step 5b)

[0275] The compound of formula (I) is also obtained from the compound of formula (X) through step 5b. This step is a step of preparing the compound of formula (I) by reacting the compound of formula (X) with the compound (XIV). The reaction is carried out under the same conditions as step 1a by using the compound of formula (XIV) instead of trimethylsilyl acetylene.

[0276] (Production method 2)

[0277]

Chemical formula 18

[0278]

[0279] (where R'' and R z C 1-6 The same applies hereinafter).

[0280] (Step 1)

[0281] This step is a step of preparing a compound of formula (XVI) by reacting a compound of formula (VI) with a compound of formula (XV). The reaction is carried out under the same conditions as step 1a of production method 1 by using a compound of formula (XV) instead of trimethylsilylacetylene.

[0282] (Step 2)

[0283] This step is a step of preparing a compound of formula (XVII) by reacting a compound of formula (XVI) with a compound of formula (VIII). The reaction is carried out under the same conditions as step 2a of production method 1 by using a compound of formula (XVI) instead of a compound of formula (VII).

[0284] Alternatively, in this step, the compound of formula (XVII) can be obtained by using a stannyl compound of formula (VIIIb) instead of the corresponding borate compound of formula (VIII).

[0285] (Step 3)

[0286] This step is a step of preparing a compound of formula (XII) by hydrolyzing the ester group of the compound of formula (XVII). The reaction is carried out using a compound of formula (XVII) and an aqueous solution of a base, and the method is as follows: under cooling or heating to reflux conditions, preferably at room temperature to 100° C., in a solvent inert to the reaction, the mixture is usually stirred for 0.1 hour 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.

[0287] (Step 4)

[0288] 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 in step 5a of production method 1.

[0289] (Production method 3)

[0290]

Chemical formula 19

[0291]

[0292] (Step 1)

[0293] This step is a step of preparing a compound of formula (XVIII) by reacting a compound of formula (VI) with propiolic acid. The reaction is carried out under the same conditions as step 1a of production method 1 by using propiolic acid instead of trimethylsilylacetylene.

[0294] (Step 2)

[0295] This step is a step of preparing a compound of formula (XIX) by reacting a compound of formula (XVIII) with a compound of formula (XIII). The reaction is carried out under the same conditions as step 5a of production method 1 by using a compound of formula (XVIII) instead of a compound of formula (XII).

[0296] (Step 3)

[0297] This step is a step of preparing a compound of formula (I) by reacting a compound of formula (XIX) with a compound of formula (VIII). The reaction is carried out under the same conditions as step 2a of production method 1 by using a compound of formula (XIX) instead of a compound of formula (VII).

[0298] Alternatively, in this step, the compound of formula (I) can be obtained by using a stannyl compound of formula (VIIIb) instead of the corresponding borate compound of formula (VIII).

[0299] (Starting Compound Synthesis Method 1)

[0300]

Chemical formula 20

[0301]

[0302] The present method is a method for preparing a compound of formula (Xa) having a pyrazol-1-yl group as ring A in a compound of formula (X) by reacting a compound of formula (VIa) with a compound of formula (VIIIa). In the 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 excess. Under cooling or heating to reflux conditions, preferably at room temperature to 190° C., in the presence of a catalyst and a base, in a solvent inert to the reaction or in the absence of a solvent, the mixture of these compounds is usually stirred for 0.1 hour to 5 days. 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, and the like. Examples of bases used herein include, but are not limited to, Et3N, DIPEA, pyridine, and the like. Examples of solvents include, but are not limited to, CH2Cl2, CH3CN, DMF, DMSO, MeOH, EtOH, toluene, and the like. In some cases, in order to facilitate 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 a molecular sieve.

[0303] (Starting Compound Synthesis Method 2)

[0304]

Chemical formula 21

[0305]

[0306] (wherein, one of W or Z is N and the other is CH. The same applies hereinafter).

[0307] The present method is a method for preparing a compound of formula (Xb) having a pyrazol-1-yl group or an imidazol-1-yl group as ring B in a compound of formula (X) by reacting a compound of formula (VIb) with a compound of formula (VIII). The reaction is carried out under the same conditions as in the starting compound synthesis method 1, by using a compound of formula (VIb) and a compound of formula (VIII) instead of a compound of formula (VIa) and a compound of formula (VIIIa).

[0308] (Starting Compound Synthesis Method 3)

[0309]

Chemical formula 22

[0310]

[0311] The method is a method for preparing a compound of formula (X) by reacting a compound of formula (VIc) with a compound of formula (VIII) to obtain a compound of formula (Xc), and then converting the amino group into a halogen by Sandmeyer reaction.

[0312] (Step 1)

[0313] This step is a step of preparing a compound of formula (Xc) by reacting a compound of formula (VIc) with a compound of formula (VIII). The reaction is carried out under the same conditions as step 2a of production method 1 by using a compound of formula (VIc) instead of a compound of formula (VII).

[0314] (Step 2)

[0315] This step is a step of preparing a compound of formula (X) by converting the amino group of a compound of formula (Xc) into a halogen by Sandmeyer reaction. The reaction is carried out as follows: under cooling conditions, preferably at 0°C, in a solvent inert to the reaction, a diazotizing agent is added to a mixture of a compound of formula (Xc) and an acid, followed by adding a halogenating agent under cooling conditions, preferably at 0°C, and stirring at 0°C to room temperature, usually for 0.1 hours to 5 days. Examples of diazotizing agents include, but are not limited to, NaNO2, tert-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 halogenating agents 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, in order to allow the reaction to proceed smoothly, it may be advantageous to react in the presence of urea.

[0316] (Other production methods)

[0317] Another compound of formula (I) or its synthetic intermediate can be prepared by using a compound of formula (I) prepared according to any of the above production methods or its synthetic intermediate as a starting material, and performing further chemical modification reactions commonly used by those skilled in the art, such as alkylation, amidation, acylation, sulfonylation, oxidation, reduction, reductive amination, NH-decarboxylation sulfoximination (Chemical Communications, Vol. 53, pp. 348-351, 2017), protection or deprotection.

[0318] The compound of formula (I) is isolated and purified as its free compound, or its salt, hydrate, solvate or crystalline polymorph. The salt of the compound of formula (I) can also be prepared by conventional methods.

[0319] Isolation and purification are carried out using common chemical operations such as extraction, fractional crystallization and various types of fractional chromatography.

[0320] Various isomers can be prepared by selecting appropriate starting compounds, or can be separated by utilizing the differences in physicochemical properties between isomers. For example, optical isomers can be obtained by general optical resolution methods for racemic compounds (e.g., introducing a compound into a diastereomeric salt with an optically active base or acid by fractional crystallization; chromatography using a chiral column, etc.; etc.), or can also be prepared from appropriate optically active starting compounds.

[0321] The pharmacological activities of the compounds of formula (I) can be demonstrated by the following tests or modified tests thereof, which are obvious to those skilled in the art.

[0322] Test Example 1: IRF pathway activity test of THP-1

[0323] 0.3 μM PMA (phorbol myristate, SIGMA, P1585) was added to THP1-Dual TM cells (NF-κB-SEAP IRF-Luc reporter monocytes, Invivogen, thpd-nfis) and cultured in RPMI1640 containing 10% fetal bovine serum (FBS) at 37°C for 1 day. Compounds of known concentrations were added and the cells were incubated at room temperature for 1 hour. Mammalian (atypical) CDN, cyclic [G(2',5')pA(3',5')p] (2'3'-cGAMP, Invivogen, tlrl-nacga23) was added to a final concentration of 5 μg / mL and the cells were cultured at 37°C. The next day, QUANTI-Luc TM (Secreted luciferase assay medium, Invivogen, rep-qlc) was added to the culture solution, and the activity of the IRF pathway was measured using a microplate reader. The inhibition rate at each concentration was determined, where the activity of the IRF pathway without the addition of the test compound or 2'3'-cGAMP was defined as 100% inhibition, and the activity of the IRF pathway without the addition of the test compound but with the addition of 2'3'-cGAMP was defined as 0% inhibition. The IC was calculated using the sigmoid Exam model nonlinear regression analysis 50 value.

[0324] The results are shown in Tables 1 and 2. This confirmed that the exemplary compounds inhibited the activity of the IRF pathway.

[0325]

Table 1

[0326] Ex <![CDATA[IC 50 (nM)]]> Ex <![CDATA[IC 50 (nM)]]> Ex <![CDATA[IC 50 (nM)]]> Ex <![CDATA[IC 50 (nM)]]> 1 13413 28 95 55 83 82 239 2 1090 29 153 56 256 83 430 3 155 30 159 57 381 84 435 4 236 31 115 58 441 85 224 5 950 32 178 59 444 86 8038 6 4823 33 136 60 528 87 1611 7 2061 34 230 61 611 88 5550 8 7752 35 466 62 594 89 1692 9 116 36 615 63 422 90 471 10 182 37 195 64 448 91 600 11 146 38 88 65 340 92 767 12 385 39 351 66 48 93 919 13 1545 40 422 67 38 94 11774 14 374 41 792 68 64 95 1442 15 237 42 158 69 190 96 80 16 229 43 201 70 35 97 4611 17 233 44 174 71 43 98 2566 18 1407 45 89 72 1212 99 102 19 1390 46 150 73 99 100 125 20 244 47 277 74 48 101 190 21 295 48 91 75 73 102 842 22 210 49 231 76 76 103 402 23 91 50 48 77 91 104 1789 24 121 51 184 78 51 105 620 25 158 52 442 79 185 106 358 26 299 53 550 80 539 107 489 27 216 54 66 81 37 108 263

[0327]

Table 2

[0328]

[0329] Test Example 2: IFNβ production test in mouse plasma

[0330] Male C57BL / 6J mice (8 to 12 weeks old) were orally administered with vehicle or 1 mg / kg test compound. One hour later, 5,6-dimethylxanthone-4-acetic acid (DMXAA) (BLD Pharmatech Ltd, BD126695) was intraperitoneally administered at a dose of 20 mg / kg. Four hours later, mice were euthanized and plasma was collected. The plasma concentration of IFNβ was measured by enzyme-linked immunosorbent assay using the AlphaLISA Mouse IFNβ detection kit (Parkin Elmer, AL586C), and the inhibition rate relative to the vehicle administration group was calculated.

[0331] The inhibition rate of the produced IFNβ relative to the vehicle-administered group is shown in Table 3. This confirmed that these compounds inhibited the production of IFNβ in vivo.

[0332]

Table 3

[0333] Ex Inh(%) 33 92 34 90 35 83 36 85 43 87 44 82 46 69 99 68

[0334] Test Example 3: Drug-induced salivary dysfunction test in Sjögren's syndrome-like mice

[0335] Female C57BL / 6J mice (8 to 10 weeks old) were subcutaneously injected with 20 mg / kg DMXAA or its solvent 5% NaHCO3 at intervals of four times a week. Starting from the second day of the last DMXAA challenge, the mice were orally administered with the test compound or its solvent once a day for 8 days. On the second day, the mouse saliva was collected with a cotton swab under the condition that the mouse was awake, and the saliva weight within 15 minutes was measured, and the saliva weight was evaluated as an indicator of salivary gland function.

[0336] The evaluation results of Examples 33, 34 and 99 are shown in Figures 1 to 3 These compounds significantly improved saliva production in drug-induced Sjögren's syndrome-like model mice, thus confirming that these compounds have an improving effect on salivary dysfunction.

[0337] Test Example 4: Trex1 KO Mouse Model of Autoimmune Disease

[0338] C57BL / 6N-Trex1 em1Aiwsk / J mice (Trex1 KO mice: strain number 032213) were purchased from Jackson Laboratory. Male Trex1 KO mice and their wild-type (WT) littermates (4 to 6 weeks old) were orally administered with the test compound or its vehicle once a day for 4 to 9 weeks. Blood, kidneys and other affected tissues were collected for further analysis. The kidneys were stored in an RNA protection tissue kit (Qiagen, 76106) and RNA was purified using an 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 the equipment of Quant Studio 12K Flex (Thermo Fisher Scientific). The probes used were Cxcl10 (Mm00445235_m1), Cd68 (Mm03047343_m1) and Gapdh (Mm99999915_g1), and Gapdh was used as a housekeeping gene, and the ΔΔCT method was used for relative quantification. The specific compound of formula (I) or a salt thereof significantly reduced the expression of Cxcl10 and Cd68 genes, the expression of which was increased in the kidney of Trex1 KO mice.

[0339] The results of the above test confirmed that some of the compounds of formula (I) shown in Table 1 have STING inhibitory effects. In addition, some compounds of formula (I) were shown to be able to 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 interferon diseases and / or other STING-mediated diseases.

[0340] Pharmaceutical compositions containing one or two or more compounds of formula (I) as active ingredients can be prepared using excipients commonly used in the art (ie, excipients for pharmaceutical preparations, carriers for pharmaceutical preparations, etc.) according to commonly used methods.

[0341] Administration can be carried out orally via tablets, pills, granules, granules, powders, solutions, etc., or parenterally via injection (such as intra-articular injection, intravenous injection, intramuscular injection), suppositories, ophthalmic solutions, ophthalmic ointments, transdermal liquid preparations, ointments, transdermal patches, transmucosal liquid preparations, transmucosal patches, inhalants, etc.

[0342] As solid compositions for oral administration, tablets, powders, granules, etc. are used. In such solid compositions, one or two or more active ingredients are mixed with at least one excipient. According to a conventional method, excipients such as lubricants, disintegrants, stabilizers or solubilizers may be contained in the composition. If necessary, tablets, powders and granules may be coated with wax, sugar or gastric soluble or enteric coating material films.

[0343] Liquid compositions for oral administration include pharmaceutically 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 solubilizers, wetting agents, suspending agents, sweeteners, flavoring agents, aromatics, and preservatives.

[0344] Injections for parenteral administration include sterile aqueous or non-aqueous solution preparations, suspensions or emulsions. Aqueous solvents include, for example, distilled water and saline for injection. Examples of non-aqueous solvents include alcohols, such as ethanol. Such compositions may also contain tonicity agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers or solubilizers. For example, they may be sterilized by filtering through a bacteria-retaining filter, mixing with a bactericide or irradiating. In addition, they may be used in the following manner: they may be made into sterile solid compositions and dissolved or suspended in sterile water or a sterile solvent for injection before use.

[0345] Examples of vehicles for external use include ointments, plasters, creams, gels, pastes, sprays, lotions, eye solutions, eye ointments, etc. The vehicle also contains commonly used ointment bases, lotion bases, aqueous or non-aqueous liquid preparations, suspensions, emulsions, etc.

[0346] Transmucosal agents such as inhalants and nasal agents can be used in the form of solid, liquid or semi-solid states, and can be prepared according to methods known in the prior art. For example, known excipients and pH regulators, preservatives, surfactants, lubricants, stabilizers, thickeners, etc. can be appropriately added. For administration, a suitable inhalation or insufflation device can be used. For example, the compound can be administered alone using a known device or a sprayer (such as a metered administration inhalation device), or as a powder for preparing a mixture, or as a solution or suspension combined with a pharmaceutically acceptable carrier. Dry powder inhalers, etc. can be used for single or multiple administrations, and dry powders or capsules containing powders can be used. Alternatively, this can be in the form of a pressurized aerosol spray using a suitable propellant, such as a suitable gas, such as chlorofluorocarbons, carbon dioxide or other forms.

[0347] Typically, in the case of oral administration, the daily dose is about 0.001 mg / kg to 100 mg / kg per body weight, 0.1 mg / kg to 30 mg / kg as one embodiment, and 0.1 mg / kg to 10 mg / kg as another embodiment, a one-time application or 2 to 4 applications. In the case of intravenous administration, the daily dose is appropriately applied with about 0.0001 mg / kg to 10 mg / kg per body weight, applied once a day or twice a day or more. In addition, transmucosal agents are applied with about 0.001 mg / kg to 100 mg / kg per body weight, applied once or multiple times a day. Dosage is appropriately determined according to individual circumstances by considering symptoms, age and sex, etc.

[0348] Although there are differences depending on the administration route, dosage form, administration site, type of excipients or additives, the pharmaceutical composition of the present invention contains 0.01% to 100% by weight (0.01% to 50% by weight as one embodiment) of one or more compounds of formula (I) or salts thereof as active ingredients.

[0349] The compounds of formula (I) can be used in combination with various medicaments to treat diseases that are believed to be effective for the compounds of formula (I). Such combined preparations can be administered simultaneously, or respectively and continuously, or at desired time intervals. The co-administered preparations can be blends, or can be prepared separately.

[0350] [Example]

[0351] The production method of the compound of formula (I) will be described in more detail below with respect to the examples. The present invention is not limited to the compounds described in the examples below. In addition, the production method of the starting compound will be described in the preparation examples, and the production method of the known compound will be described in the reference examples. In addition, the production method of the compound of formula (I) is not limited to the production method of the specific examples shown below, but can be prepared by the combination of these production methods or methods obvious to those skilled in the art. The compound of formula (I)

[0352] The onset temperatures of the endothermic peak and the exothermic peak were measured using DSC Q2000 (manufactured by TA Instruments) with an open aluminum sample pan under the following conditions: temperature range: 25°C to 300°C, heating rate: 10°C / min, nitrogen flow rate: 50 mL / min.

[0353] Powder X-ray diffraction was measured using Empyrean (manufactured by Malvern Panalytical) under the following conditions, tube: Cu, tube current: 40 mA, tube voltage: 45 kV, step size: 0.013°, wavelength: The diffraction angle range (2θ) is 2.5°-40°. Due to the nature of the data, the lattice spacing and the overall pattern of powder X-ray diffraction are critical to determining the identity of the crystal. The error range of the diffraction angle (2θ(°)) in powder X-ray diffraction is typically ±0.2°, but the diffraction angle and diffraction intensity should not be strictly understood, and they may vary to a certain extent depending on the crystal growth direction, particle size and measurement conditions.

[0354] Furthermore, in some cases, the following abbreviations are used in the following Examples, Preparation Examples and Tables.

[0355] PEx: Production Example No., Ex: Example No., PSyn: Production Example No., wherein the compound is produced by the same method (in the case where the number in the PSyn column has E as the first letter, the compound is prepared by using the corresponding starting materials in the same manner as the compound with the number of the Example compound. For example, the compound wherein the PSyn column is E95 means that it is prepared in the same manner as the compound of Example 95. And in the case where the Production Example compound forms a salt, the salt can be formed by a conventional method), Syn: Example No., wherein the compound is produced by the same method (in the case where the number in the Syn column has P as the first letter, the compound is prepared by using the corresponding starting materials in the same manner as the compound with the number of the Production Example compound. The compound is prepared in the same manner as the compound of Example 10. For example, the compound in the Syn column is P10, which means that it is prepared in the same manner as the compound of Production Example 10. And in the case where the Example compound forms a salt, the salt can be formed by a conventional method), Str: chemical structural formula, DAT: physicochemical data, CI+: m / z value in mass spectrum (unless otherwise specified, the ionization method is CI, [M+H]+), EI+: m / z value in mass spectrum (unless otherwise specified, the ionization method is EI, M+), ESI+: m / z value in mass spectrum (unless otherwise specified, the ionization method is ESI, [M+H]+), ESI-: m / z value in mass spectrum (unless otherwise specified, the ionization method is ESI, [MH]-), 1 H-NMR (CDCl3, 400MHz): 1 δ (ppm) of H NMR signal, 1 H-NMR (CDCl3, 500MHz): 1 δ (ppm) of H NMR signal, 1 H-NMR (DMSO-d6, 400 MHz): 1 δ (ppm) of H NMR signal, 1 H-NMR (DMSO-d6, 500 MHz):1 δ (ppm) of H NMR signal, 1 H-NMR (CD3OD, 400MHz): 1 δ (ppm) of HNMR signal, J: coupling constant, s: singlet, d: doublet, t: triplet, q: quartet, dd: double of doublets, dt: double of triplet, dq: double of quartets, ddd: double of doublets, br: broad peak (e.g. br s), m: multiplet, aq.: aqueous solution, sat.: saturated, rt: room temperature, DSC 1 : The starting temperature of the endothermic peak in DSC measurement, DSC 2 : the onset temperature of the exothermic peak in DSC measurement, 2θ: the diffraction angle of the peak in powder X-ray diffraction.

[0356] In this specification, naming software such as ACD / Name (registered trademark; Advanced Chemistry Development, Inc.) may be used in some cases.

[0357] Compounds with "rac" in front of their names are racemates.

[0358] In addition, for the sake of convenience, the concentration of mol / L is expressed as M. For example, 1M sodium hydroxide aqueous solution means 1 mol / L sodium hydroxide aqueous solution.

[0359] Preparation Example 1

[0360] Under argon flow and room temperature, CuI (55 mg), PdCl2(PPh3)2 (201 mg), Et3N (4 mL) and trimethylsilyl acetylene (0.47 mL) were added to a solution of 1-bromo-4-iodo-2-(trifluoromethyl)benzene (1 g) in THF (5 mL), and the mixture was stirred at room temperature for 1 hour and 15 minutes. The mixture was treated with water at room temperature and then extracted with CH2Cl2. 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 obtain {[4-bromo-3-(trifluoromethyl)phenyl]ethynyl}(trimethyl)silane (936 mg) as an oil.

[0361] Preparation Example 6

[0362] To a mixture of 4-iodo[1,1'-biphenyl]-2-carboxaldehyde (11.2 g) and Pd(PPh3)4 (2.11 g) in DMSO (150 mL) was added dropwise prop-2-ynoic acid (3.08 g) and DBU (14.9 g) under nitrogen and 25 to 35°C. The mixture was stirred for 1.5 hours under nitrogen and 40°C. The mixture was diluted with an aqueous solution of NaHCO3 and extracted with EtOAc. The separated aqueous phase was adjusted to pH 2-3 with a cold 1M HCl aqueous solution to obtain a suspension. The suspension was filtered and the filter cake was concentrated to obtain 3-(2-formyl[1,1'-biphenyl]-4-yl)prop-2-ynoic acid (7.2 g) as a solid.

[0363] Preparation Example 7

[0364] 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) under argon flow and room temperature, and the mixture was stirred at 100°C for 3 hours 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.

[0365] Preparation Example 10

[0366] 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 under microwave irradiation and 130 ° C for 1 hour and 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 carbon powder was added), then filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / EtOAc=100 / 0 to 90 / 10) to give trimethyl{[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]ethynyl}silane (87 mg) as an oil.

[0367] Preparation Example 11

[0368] 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. under an argon stream for 1 hour 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 carbon 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.

[0369] Preparation Example 21

[0370] 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 hours. The mixture was treated with water at room temperature and extracted with CH2Cl2. 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.

[0371] Preparation Example 22

[0372] To a solution of 2-phenyl-3-(trifluoromethyl)-5-[(trimethylsilyl)ethynyl]pyridine (887 mg) in MeOH (14 mL) was added KCO (580 mg) at room temperature, and the mixture was stirred at room temperature for 1 hour. The mixture was treated with water at room temperature and extracted with CHCl. ​​The organic layer was washed with brine, dried over anhydrous MgSO, 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.

[0373] Preparation Example 23

[0374] 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° C. to 30° C. for 4 hours. 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 a 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.

[0375] Preparation Example 31

[0376] Under argon flow, nBuLi (26mL, 1.57M hexane solution) was added dropwise to a solution of 4-ethynyl-2-(trifluoromethyl)-1,1'-biphenyl (7.1g) in THF (100mL) cooled in an ice-water bath, and the mixture was stirred at room temperature for 0.5 hours. The mixture was quickly poured into dry ice in a 1000mL beaker and then stirred in a water bath at room temperature for 0.5 hours. 0.5M HCl aqueous solution (150mL) was slowly added to the mixture at room temperature, and then stirred at room temperature for 10 minutes. The mixture was extracted with EtOAc. The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to obtain a crude product as a solid. The obtained solid was treated with IPE and hexane at room temperature. The solution was extracted with a 0.5M NaOH aqueous solution. The water layer was treated with a 1MHCl aqueous solution at room temperature and then extracted with EtOAc. The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to obtain the product. The obtained solid was treated with hexane and IPE at room temperature and then stirred at room temperature for 5 minutes. The solid was collected by filtration, washed with hexane and dried in vacuo to give 3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoic 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 to 70 / 30) to give 3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoic acid (2.81 g) as a solid.

[0377] Preparation Example 32

[0378] Under argon gas flow, nBuLi (1.8mL, 1.57M hexane solution) was added dropwise to THF (10mL) solution of 5-ethynyl-2-phenyl-3-(trifluoromethyl) pyridine (582mg) cooled by dry ice-acetone bath, and the mixture was stirred for 20 minutes at the same temperature. Dry ice was added to the mixture, and then the mixture was warmed to room temperature and kept for 0.5 hour. At room temperature, 1M NaOH aqueous solution and water were added to the mixture, and then the mixture was washed with Et2O. The organic layer was extracted with water twice. At room temperature, the combined water layer was treated with 10% citric acid aqueous solution, and then extracted with CHCl3-IPA (5:1, v / v). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to obtain 3-[6-phenyl-5-(trifluoromethyl) pyridine-3-yl] prop-2-ynoic acid (544mg), which was solid.

[0379] In Preparation Examples 33 to 36, the reactions were carried out in a similar manner to Preparation Example 31. After stirring with dry ice, the reaction mixture was concentrated, and the lithium salt of the target carboxylic acid was obtained without further treatment.

[0380] Preparation Example 43

[0381] To a mixture of 3-(4-bromophenyl)prop-2-ynoic acid (500 mg) and 1-methylpiperazine (267 mg) in THF (10 mL) was added DIPEA (1.2 mL) and T3P (registered trademark) (1.70 g, 50% in EtOAc). The mixture was stirred for 16 hours at 20°C. 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 fluid was concentrated to remove CH3CN, and the aqueous phase was 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 to give 3-(4-bromophenyl)-1-(4-methylpiperazin-1-yl)prop-2-yn-1-one (970 mg) as a solid.

[0382] Preparation Example 45

[0383] To a solution of tert-butyl 4-(3-{1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}prop-2-ynyl)piperazine-1-carboxylate (108 mg) in CH2Cl2 (2 mL) was added TFA (100 μL). The mixture was stirred at 28°C to 32°C for 1 hour. The reaction mixture was concentrated to give 1-(piperazine-1-yl)-3-{1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}prop-2-yn-1-one monotrifluoroacetate (157 mg) as a solid.

[0384] Preparation Example 47

[0385] At room temperature, 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 for 13 hours. The mixture was treated with EtOAc and water at room temperature, and then extracted with EtOAc. The organic layer was washed with 10% citric acid aqueous solution, saturated NaHCO3 aqueous solution 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 obtain methyl 3-({3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoyl}amino)benzoate (47 mg) as a solid.

[0386] Preparation Example 48

[0387] To a mixture of 3-(4-bromophenyl)prop-2-ynoic acid (2 g) in DMF (20 mL) was added 2-anilino-1-ethanol (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 hour. 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-ynoic acid amide (2.72 g) as a solid.

[0388] Preparation Example 50

[0389] To a solution of 4-iodo-3-(trifluoromethyl)-1H-pyrazole (1g) in CH2Cl2 (20mL) was added phenylboronic acid (1g), Cu(OAc)2 (600mg) and pyridine (600μL), then the reaction mixture was stirred for 12 hours under an oxygen atmosphere at 25°C to 30°C. 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 a 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 (1.28g) as an oil.

[0390] Preparation Example 51

[0391] To a mixture of 1-(piperazine-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-bromobutyrate (239 mg), and the reaction mixture was stirred at 25°C to 35°C for 48 hours. The 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 a crude product. The crude product was purified by reverse phase column chromatography (C18, 50%-60% CH3CN in water / 0.05% HCl) and lyophilized to give ethyl 4-(4-{3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynyl}piperazin-1-yl)butanoate monohydrochloride (260 mg) as a solid.

[0392] Preparation Example 52

[0393] 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 1 M NaOH aqueous solution (5 mL) at room temperature. The mixture was stirred at room temperature for 1 hour and washed with Et2O. 1 M HCl aqueous solution (5 mL) and EtOH were added to the separated aqueous extract. The mixture was concentrated in vacuo. EtOH was added to the residue, and the mixture was then 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.

[0394] Preparation Example 56

[0395] DIBAL-H (156 mL, 1.0 M toluene solution) was added to a CH2Cl2 solution (150 mL) of methyl 4-iodo[1,1'-biphenyl]-2-carboxylate (14.7 g) and reacted under nitrogen at -78°C for 0.5 hours. The mixture was stirred for another 3 hours under nitrogen at 25°C to 30°C. The mixture was poured into water and diluted with a 2M HCl aqueous solution until the mixture became clear. The mixture was extracted with CH2Cl2. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give a 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.

[0396] Preparation Example 57

[0397] MnO2 (30 g) was added to a solution of (4-iodo[1,1'-biphenyl]-2-yl)methanol (12.2 g) in CH2Cl2 (150 mL), and the reaction mixture was stirred at 50°C for 12 hours. After cooling to room temperature, the reaction mixture was filtered through Celite (registered trademark). The filtrate was concentrated to give 4-iodo[1,1'-biphenyl]-2-carboxaldehyde (11.2 g) as an oil.

[0398] Preparation Example 58

[0399] To a solution of 3-(2-formyl[1,1'-biphenyl]-4-yl)prop-2-ynoic acid (1 g) in CH2Cl2 (15 mL) was added DMF (29.2 mg) and (COCl)2 (420 μL) at 0°C and stirred at 0°C for 0.5 hours. The mixture was added to a mixture of (2S)-3-aminopropane-1,2-diol (728 mg) and Na2CO3 (1.69 g) in water (20 mL) and CH2Cl2 (20 mL). The reaction mixture was stirred at 0°C for 1 hour, diluted with water, and extracted with CHCl3 / IPA (3 / 1, v / v). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give a crude product. The crude product 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.

[0400] Preparation Example 59

[0401] To a solution of 3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoic acid (100 mg) in CH2Cl2 (1.02 mL) at 0°C was added Et3N (130 μL), racemic-methyl (3R)-pyrrolidine-3-carboxylate monohydrochloride (68 mg) and COMU (192 mg). The mixture was stirred at room temperature for 1 hour. After the addition of saturated aqueous NaHCO3, 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 chromatographed on a silica gel column (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-ynyl}-(3R)-pyrrolidine-3-carboxylate (96.6 mg) as an oil.

[0402] Preparation Example 60

[0403] Pd / C (260 mg, 10%) was added to a solution of 4-(3,6-dihydro-2H-pyran-4-yl)-3-(trifluoromethyl)phenol (2.6 g) in MeOH (25 mL) under a hydrogen atmosphere. The mixture was stirred at room temperature for 24 hours. The reaction mixture was filtered through a Celite (registered trademark) pad. The filtrate was concentrated under reduced pressure to give 4-(oxacyclohexane-4-yl)-3-(trifluoromethyl)phenol (2.51 g) as a solid.

[0404] Preparation Example 61

[0405] To a solution of 4-(oxacyclohexane-4-yl)-3-(trifluoromethyl)phenol (2.5 g) and 1,1,1-trifluoro-N-phenyl-N-((trifluoromethyl)-sulfonyl)methanesulfonamide (7.26 g) in CH2Cl2 (30 mL) was added DIPEA (2.6 g). The mixture was stirred at room temperature for 3 hours. The reactants were concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0%-9% EtOAc in hexane) to give 4-(oxacyclohexane-4-yl)-3-(trifluoromethyl)phenyl trifluoromethanesulfonate (3.56 g) as an oil.

[0406] Preparation Example 63

[0407] Under argon flow and room temperature, CuI (63 mg), PdCl2(PPh3)2 (137 mg), Et3N (4.6 mL) and trimethylsilyl acetylene (0.54 mL) were added to a solution of 2-chloro-5-iodo-3-(trifluoromethyl) pyridine (1 g) in THF (10 mL), and the mixture was stirred at room temperature for 1 hour. 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 obtain 2-chloro-3-(trifluoromethyl)-5-[(trimethylsilyl)ethynyl]pyridine (867 mg) as an oil.

[0408] Preparation Example 92

[0409] 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, then stirred at 90° C. for 2 hours under a nitrogen atmosphere. The mixture was combined with another batch (using 400 mg of 8-chloro-5-[(trimethylsilyl)ethynyl]quinoline for the same reaction). 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 to 13 / 87) to give 5-ethynyl-8-[2-(trifluoromethyl)phenyl]quinoline (580 mg) as a solid.

[0410] Preparation Example 127

[0411] At 20 ℃, a mixture of K2CO3 (2.77 g) and 5-bromo-2-iodophenol (2 g) in DMF (10 mL) was stirred for 1 hour. 2-iodopropane (3.41 g) was added to the mixture, and the mixture was stirred for 3 hours at 70 ℃. 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 obtain 4-bromo-1-iodo-2-[(propyl-2-yl)oxy]benzene (2 g), which was an oil.

[0412] Preparation Example 135

[0413] In an ice-water bath, Et3N (120 μL), 2-(methylsulfanyl)ethyl-1-amine (39 μL) and PyBOP (233 mg) were added to a solution of 3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoic acid (100 mg) in CH2Cl2 (3 mL). The mixture was stirred at room temperature for 15 hours, treated with saturated NaHCO3 aqueous solution, and extracted with CHCl3. The organic layer was washed with saturated NaHCO3 aqueous solution, 1M HCl aqueous solution and water, and 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-ynoic acid amide (103 mg) as a solid.

[0414] Preparation Example 136

[0415] Under nitrogen, microwave and 150 ℃, by 3-[4-bromo-3-(trifluoromethyl) phenyl] prop-2-ynoic acid methyl esters (500mg), 2-(tributyl stannyl) pyridine (780mg) and Pd(PPh ) 4 (94mg) mixture in toluene (10mL) is stirred 3 hours.This mixture is merged with other 4 batches (each batch uses 500mg of 3-[4-bromo-3-(trifluoromethyl) phenyl] prop-2-ynoic acid ester to carry out four identical reactions) and concentrated.The crude product is purified by silica gel column chromatography (EtOAc / petroleum ether=15 / 85) to obtain 3-[4-(pyridin-2-yl)-3-(trifluoromethyl) phenyl] prop-2-ynoic acid methyl esters (1.43g), which is an oil.

[0416] Preparation Example 137

[0417] 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 hours 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.

[0418] Preparation Example 138

[0419] In an ice-water bath, 1-chloro-N,N,2-trimethylprop-1-ene-1-amine (85 μL) was added to a solution of 3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoic acid (155 mg) in CH2Cl2 (2 mL), and the mixture was stirred for 15 minutes. In an ice-water bath, 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 NaHCO3 aqueous solution (2.0 mL). The mixture was stirred for 45 minutes at the same temperature. The resulting mixture was treated with water and extracted with CHCl3. 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-[(methylsulfonyl)amino]propyl}-3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynamide (322 mg) as an oil.

[0420] Preparation Example 139

[0421] At room temperature, to a mixture of N-(3-aminopropyl)methanesulfonamide (100 mg) in MeOH (3 mL) was added {[tert-butyldi(methyl)silyl]oxy}acetaldehyde (126 mg). The mixture was stirred at room temperature for 1 hour. At room temperature, NaBH4 (27.1 mg) was added to the mixture. The mixture was stirred at room temperature for 2 hours, treated with water, CHCl3 and NH4Cl aqueous solution, 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 to 80 / 20) to give N-{3-[(2-{[tert-butyldi(methyl)silyl]oxy}ethyl)amino]propyl}methanesulfonamide (168 mg) as an oil.

[0422] Preparation Example 141

[0423] A mixture of 4-amino-2'-(trifluoromethyl)[1,1'-biphenyl]-2-carboxylic acid methyl ester (11.4 g) and 3M HCl aqueous solution (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 for 1 hour at 0 ° C. 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 for 1 hour at 0 ° C. The mixture was stirred for 1 hour at 15 ° C to 20 ° C. 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 to 10 / 90) to give methyl 4-iodo-2'-(trifluoromethyl)[1,1'-biphenyl]-2-carboxylate (8.2 g) as an oil.

[0424] Preparation Example 142

[0425] At 0 ° C, to a mixture of tert-butyl (2-aminoethyl) carbamate (500 mg) in CH2Cl2 (15 mL), Et3N (1.30 mL) was added, followed by (chlorosulfonyl) methyl acetate (648 mg), and stirred at 15 ° C to 20 ° C for 1 hour. 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 to 60 / 40) to obtain 10,10-dimethyl-3,3,8-trioxo-9-oxa-3λ 6 -thia-4,7-diazaundecane-1-oic acid methyl ester (310 mg) as a gum.

[0426] Preparation Example 143

[0427] At 0°C to 4°C, 10,10-dimethyl-3,3,8-trioxo-9-oxa-3λ 6 To a solution of methyl-thia-4,7-diazaundecane-1-yl ester (310 mg) in THF (5 mL) was added LiBH4 (46 mg). The mixture was stirred at 0°C to 4°C for 1.5 hours. The mixture was poured into a saturated aqueous NH4Cl solution and 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.

[0428] Preparation Example 144

[0429] NIS (7.0 g) was added to a solution of 1-(4-fluorophenyl)-2-(trifluoromethyl)-1H-imidazole (1.2 g) in H2SO4 (12 mL) and water (12 mL) at 0°C. The mixture was stirred at 0°C for 10 minutes and then at 70°C for 16 hours. The reaction mixture was adjusted to pH 8-9 with 30% aqueous NaOH solution 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.

[0430] Preparation Example 145

[0431] At -40 ° C, 1- (4-fluorophenyl) -4,5- diiodo-2- (trifluoromethyl) -1H-imidazole (1.35g) in THF (14mL) solution was added dropwise ethylmagnesium bromide (945μL, 3M Et2O solution). The mixture was stirred for 30 minutes at -40 ° C. The reaction mixture was quickly poured into an NH4Cl aqueous solution 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 obtain 1- (4-fluorophenyl) -4- iodo-2- (trifluoromethyl) -1H-imidazole (0.8g) as a solid.

[0432] Example 1

[0433] At 0°C, T3P (registered trademark) (2.58 g, 50% EtOAc solution) was added to a solution of 1-methylpiperazine (180 μL), 3-([1,1'-biphenyl]-2-yl)prop-2-ynoic acid (300 mg) and DIPEA (1.05 g) in THF (15 mL). The mixture was stirred at room temperature for 16 hours. The mixture was concentrated under reduced pressure to obtain a residue. The crude product was purified by reverse phase column chromatography (C18, 5%-55% CH3CN in water / 0.1% NH3.H2O) to obtain 3-([1,1'-biphenyl]-2-yl)-1-(4-methylpiperazine-1-yl)prop-2-yn-1-one (110 mg) as a solid.

[0434] Embodiment 20

[0435] To a solution of 3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoic acid (100 mg) in CH2Cl2 (1 mL) was added Et3N (130 μL), (3R)-pyrrolidine-3-carboxamide monohydrochloride (62 mg) and COMU (192 mg) at 0°C. The mixture was stirred at room temperature for 1 hour. Saturated aqueous NaHCO3 solution was added to the mixture, and the mixture was extracted with EtOAc. The separated organic extract was washed with saturated aqueous NaHCO3 solution, 1M aqueous HCl solution 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 to 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.

[0436] Embodiment 33

[0437] A mixture of (3R,4S)-pyrrolidine-3,4-diol monohydrochloride (63 mg), 3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoic acid (99.7 mg), DIPEA (183 mg) and HATU (327 mg) in DMF (2 mL) was stirred at room temperature for 13 hours. 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 to 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.

[0438] Embodiment 34

[0439] A mixture of piperidine-4-carboxamide (61 mg), 3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoic acid (99.6 mg), DIPEA (93 mg) and HATU (196 mg) in DMF (2 mL) was stirred for 4 hours at room temperature. The mixture was treated with EtOAc and water at room temperature, and then extracted with EtOAc. The organic layer was washed with saturated NaHCO3 aqueous solution 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 to 90 / 10) to obtain the desired product. The resulting product was treated with IPE and hexane at room temperature, and then ground. The solid was collected by filtration, washed with hexanes and dried in vacuo at 50 °C to give 1-{3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynyl}piperidine-4-carboxamide (76 mg) as a solid.

[0440] Embodiment 35

[0441] A mixture of (2S)-3-aminopropane-1,2-diol (43 mg), 3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoic acid (99.8 mg), DIPEA (96 mg) and HATU (198 mg) in DMF (2 mL) was stirred for 2 hours at room temperature. The mixture was treated with EtOAc and water at room temperature, and then extracted with EtOAc. The organic layer was washed with saturated NaHCO3 aqueous solution 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 to 90 / 10) to give N-[(2S)-2,3-dihydroxypropyl]-3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoic acid amide (29 mg) as a syrup.

[0442] Embodiment 36

[0443] A mixture of (2R)-3-aminopropane-1,2-diol (43 mg), 3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoic acid (99.8 mg), DIPEA (95 mg) and HATU (196 mg) in DMF (2 mL) was stirred for 4 hours at room temperature. The mixture was treated with EtOAc and water at room temperature, and then extracted with EtOAc. The organic layer was washed with saturated NaHCO3 aqueous solution 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 to 90 / 10) to give N-[(2R)-2,3-dihydroxypropyl]-3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoic acid amide (14 mg) as a syrup.

[0444] Embodiment 43

[0445] 2-Chloro-1-methylpyridinium iodide (1.4 mL) (0.33 M DMF solution) and DIPEA (64 mg) were added to a mixture of 3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoic acid (90 mg) and (3R, 4R)-pyrrolidine-3,4-diol (39 mg), and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc, washed with saturated NaHCO3 aqueous solution and brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by preparative LC / MS (XBridgePrep C18 5μm OBD TM 30×150 mm column: MeOH / 10 mM NH 4 HCO 3 aqueous solution, 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.

[0446] Embodiment 44

[0447] 2-Chloro-1-methylpyridinium iodide (1.5 mL) (0.35 M DMF solution) and DIPEA (77 mg) were added to a mixture of 3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoic acid (100 mg) and (3S,4S)-pyrrolidine-3,4-diol (43 mg), and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc, washed with saturated NaHCO3 aqueous solution and brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by preparative LC / MS (XBridgePrep C18 5 μm OBD TMThe product was purified by 30×150 mm column: MeOH / 10 mM NH4HCO3 aqueous solution, 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 ultrasound for a while. 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.

[0448] Embodiment 45

[0449] 2-Chloro-1-methylpyridinium iodide (1 mL) (0.45 M DMF solution) and DIPEA (102 mg) were added to a mixture of 3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoic acid (90 mg) and L-serinamide monohydrochloride (54 mg), and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc, washed with saturated NaHCO3 aqueous solution and brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The residue was purified by preparative LC / MS (XBridgePrep C18 5 μm OBD TM 30×150 mm column: MeOH / 10 mM NH4HCO3 aqueous solution, 10 / 90 to 95 / 5) and lyophilized to obtain N 2 -{3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynyl}-L-serinamide (16 mg) as a solid.

[0450] Embodiment 46

[0451] 2-Chloro-1-methylpyridinium iodide (1 mL) (0.45 M DMF solution) and DIPEA (103 mg) were added 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), and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc, washed with saturated NaHCO3 aqueous solution 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 TMThe mixture was purified by lyophilization with 100% NH4HCO3 (30×150 mm column: MeOH / 10 mM aqueous NH4HCO3, 10 / 90 to 95 / 5) 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.

[0452] Embodiment 47

[0453] A mixture of (3R, 4S)-pyrrolidine-3,4-diol monohydrochloride (226 mg), 3-[6-phenyl-5-(trifluoromethyl)pyridin-3-yl]prop-2-ynoic 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 for 2 hours at room temperature. The mixture was treated with EtOAc and water 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 (CHCl3 / MeOH=100 / 0 to 90 / 10) to obtain the desired product as a solid. The resulting solid was treated with IPE (1 mL) and hexane (5 mL) at room temperature, and then ground. The solid was collected by filtration, washed with hexanes and dried in vacuo 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.

[0454] Embodiment 87

[0455] Under argon atmosphere, microwave radiation and 100 ℃, a mixture of 3-(4-bromophenyl)-N-(2-hydroxyethyl)-N-phenylprop-2-ynamide (100 mg), trimethyl(2-pyridyl)tin (75 μL) and PdCl2(PPh3)2(20 mg) in toluene (1 mL) was stirred for 2 hours. Aqueous potassium fluoride solution was added to the mixture, and the resulting mixture was stirred and extracted with CHCl3. The organic layer was concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane / EtOAc=50 / 50 to 0 / 100) to obtain the desired product. The solid was ground with EtOAc, filtered and dried in vacuo to obtain N-(2-hydroxyethyl)-N-phenyl-3-[4-(pyridin-2-yl)phenyl]prop-2-ynamide (18 mg) as a solid.

[0456] Embodiment 88

[0457] A mixture of 3-(4-bromophenyl)-1-(4-methylpiperazine-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) and water (0.8 mL) was degassed and purged with nitrogen, and then the reaction mixture was stirred at nitrogen and 85°C for 16 hours. The mixture was treated with water (30 mL) and extracted three times with EtOAc. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated to dryness. The residue was purified by silica gel column chromatography eluting with 0%-10% EtOAc / petroleum ether, followed by reverse phase column chromatography (C18, 0%-50% CH3CN in water / 0.05% NH3.H2O) 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.

[0458] Embodiment 90

[0459] At room temperature, 1M NaOH aqueous solution (0.5mL) was added to a solution of methyl 3-({3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynyl}amino)benzoate (47mg) in THF (1mL) and MeOH (1mL), and the mixture was stirred at room temperature for 1.5 hours. 1M NaOH aqueous solution (0.5mL) was added to the mixture at room temperature, and the mixture was stirred at room temperature for 5 hours. The mixture was treated with 1M HCl aqueous solution (1.0mL) 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 to 80 / 20) to obtain the desired product. The resulting solid was treated with IPE (1mL) and hexane (5mL) and ground at room temperature. The solid was collected by filtration, washed with hexanes and dried in vacuo at 50°C to give 3-({3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynyl}amino)benzoic acid (28 mg) as a solid.

[0460] Embodiment 91

[0461] A mixture of ethyl 3-(piperazine-1-yl)propanoate dihydrochloride (175 mg), 3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoic acid (150 mg), DIPEA (0.32 mL), HOBt (7 mg) and EDC·HCl (297 mg) in DMF (3 mL) was stirred for 15 hours at room temperature. The mixture was treated with EtOAc and water at room temperature, and then extracted with EtOAc. The organic layer was washed with saturated NaHCO3 aqueous solution 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 obtain the desired intermediate as a slurry. The obtained intermediate (114 mg) was dissolved with THF (1 mL) and MeOH (1 mL) at room temperature, and then 1M NaOH aqueous solution (1 mL) was added to the solution at room temperature. The mixture was stirred for 0.5 hours at room temperature. The mixture was treated with 1M HCl aqueous solution (1mL) and water (10mL) at room temperature, and then extracted with CHCl3-IPA (5:1, v / v). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to obtain the desired product, which was a solid. The obtained solid was dissolved with THF (3mL) at room temperature, and 4M HCl / dioxane (1mL) was then added thereto. The mixture was concentrated under reduced pressure. The residue was treated with IPE (5mL) and ground at room temperature. The solid was collected by filtration, washed with IPE and dried in vacuo at 50°C to obtain 3-(4-{3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoyl}piperazine-1-yl)propionic acid monohydrochloride (79mg), which was a solid.

[0462] Embodiment 92

[0463] A mixture of methyl 2,3-dihydro-1H-indole-6-carboxylate (120 mg), 3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoic acid (150 mg), DIPEA (0.32 mL) and HATU (393 mg) in DMF (3 mL) was stirred for 3 hours at room temperature. The mixture was treated with EtOAc and water at room temperature and then extracted with EtOAc. The organic layer was washed with saturated aqueous NaHCO3 solution 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 obtain the desired intermediate. The intermediate was treated with concentrated aqueous HCl solution (2 mL) and dioxane (2 mL) at room temperature, and the mixture was stirred at 100°C for 0.5 hours and then cooled to room temperature. Since the reaction did not proceed, it was decided to stop the reaction and recover the intermediate. The mixture was treated with water and extracted with CHCl3. The organic layer is dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (CHCl3 / MeOH=100 / 0 to 90 / 10) to obtain the recovered intermediate. The intermediate is dissolved with THF (4mL) and H2O (2mL) at room temperature, and then LiOH·H2O (100mg) is added to the solution. The mixture is stirred at room temperature for 4 hours and stirred for 6 hours at 50°C (oil bath temperature). The mixture is treated with 1M HCl aqueous solution (5mL) at room temperature and extracted with CHCl3. The organic layer is dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (CHCl3 / MeOH=100 / 0 to 90 / 10) to obtain the desired product, which is treated with IPE and hexane at room temperature and then ground. The solid was collected by filtration, washed with hexanes and dried in vacuo at 50 °C to give 1-{3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynyl}-2,3-dihydro-1H-indole-6-carboxylic acid (10 mg) as a solid.

[0464] Embodiment 95

[0465] To a mixture of 1-(piperazine-1-yl)-3-{1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}prop-2-yn-1-one monotrifluoroacetate (157 mg) in MeOH (10 mL) were added (HCHO)n (37 mg), Et3N (34 μL) and AcOH (28 μL). The mixture was stirred at 25°C to 30°C for 0.5 hours, then NaBH3CN (31 mg) was added, and the resulting mixture was stirred for 0.5 hours. The mixture was heated to 50°C and stirred for 12 hours. The mixture was concentrated in vacuo. The crude product was purified by preparative HPLC (column: Phenomenex (registered trademark) C18 80*40mm*3μm; mobile phase: water (NH3H2O) / CH3CN=58 / 42 to 28 / 72). 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.

[0466] Embodiment 96

[0467] 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 μL). The reaction mixture was stirred at 60° C. for 4 hours. NaBH3CN (41 mg) was then added to the above mixture and stirred at 25° C. for another 3 hours. The mixture was combined with another batch and purified by reverse phase column chromatography (C18, 80%-100% MeOH in water / 0.1% NH3.H2O) 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.

[0468] Embodiment 99

[0469] Iodophenyl diacetate (295 mg) and ammonium carbamate (57 mg) were added to a solution of 1-(thiomorpholin-4-yl)-3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-yn-1-one (137 mg) in MeOH (1 mL) and CH2Cl2 (0.25 mL). The mixture was stirred at room temperature for 30 minutes and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (EtOAc / hexane: 30 / 70 to 100 / 0, then CHCl3 / MeOH=90 / 10) to give 1-imino-4-{3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynyl}-1λ6 -thiomorpholin-1-one (134 mg) as a solid.

[0470] Embodiment 100

[0471] At room temperature, a mixture of (3S)-tert-butyl pyrrolidin-3-ylcarbamate (77 mg), 3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoic acid (99.8 mg), 2-chloro-1-methylpyridinium iodide (0.28M DMF solution, 2 mL) and DIPEA (95 mg) in DMF (2 mL) was stirred for 12 hours. The mixture was treated with EtOAc and water at room temperature, and then extracted with EtOAc. The organic layer was washed with saturated NaHCO3 aqueous solution 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 obtain an intermediate as a slurry. The obtained intermediate was dissolved with CH2Cl2 (2 mL) at room temperature, and TFA (1 mL) was added to the solution at room temperature. The mixture was stirred for 1 hour at room temperature and concentrated under reduced pressure. The residue was treated with saturated NaHCO3 aqueous solution (10mL) and water at room temperature, and then extracted with CHCl3-IPA (5:1, v / v). The organic layer was dried over anhydrous MgSO4, filtered and concentrated under reduced pressure to obtain the desired product as a slurry. The resulting product was dissolved with THF (2mL), IPE (2mL) and hexane (5mL) at room temperature, and oxalic acid (17mg) was then added thereto. The mixture was stirred for 0.5 hours at room temperature. The solid was collected by filtration, washed with hexane and dried in vacuo at 50°C to obtain 1-[(3S)-3-aminopyrrolidin-1-yl]-3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-yn-1-one monooxalate (54mg), which was a solid.

[0472] Embodiment 106

[0473] To a solution of 3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoic acid (208 mg) in DMF (10 mL) was added EDC·HCl (187 mg), HOBt (163 mg) and DIPEA (244 mg) under nitrogen atmosphere and 0°C. The mixture was stirred for 1 hour, followed by the addition of (1R,2S,4r)-4-aminocyclopentane-1,2-diol (100 mg). The reaction was stirred at room temperature for 16 hours and then concentrated under reduced pressure. The residue was purified by preparative TLC (CH2Cl2:MeOH=10:1) to give N-[(1r,3R,4S)-3,4-dihydroxycyclopentyl]-3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoamide (64.6 mg) as a solid.

[0474] Embodiment 119

[0475] 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 μL), and the mixture was stirred at 50° C. for 16 hours. The mixture was combined with another batch (using 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 for the same reaction), diluted with 4% aqueous LiCl solution, 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 in water / 0.1% NH3.H2O). The resulting product was purified by reverse phase column (C18, 45%-55% MeOH in water / 0.1% NH3.H2O). The crude product was purified by preparative HPLC (column: Phenomenex C18; mobile phase: 20%-40% MeCN in water (HCl)) and lyophilized 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.

[0476] Embodiment 127

[0477] A mixture of tert-butyl methyl [(3R)-1-{3-[4-(pyridin-2-yl)-3-(trifluoromethyl)phenyl]prop-2-ynyl}pyrrolidin-3-yl]carbamate (257 mg) and TFA (1 mL) in CH2Cl2 (5 mL) was stirred for 2 h at 10° C. to 20° C. The mixture was concentrated to give a crude product, which was purified by reverse phase column (C18, 50%-60% MeOH in water / 0.1% NH3.H2O) and lyophilized 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.

[0478] Embodiment 128

[0479] 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 CH2Cl2 (8 mL) was added m-CPBA (319 mg), and the reaction mixture was stirred at 10°C to 15°C for 12 hours. The reaction mixture was quenched by the addition of saturated aqueous Na2SO3 solution, 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 (NH3.H2O) / MeCN=60 / 40 to 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-ynyl}-1λ 6 -thiomorpholine-1,1-dione (107 mg) as a solid.

[0480] Embodiment 129

[0481] 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 μL). The reaction mixture was stirred at 60°C for 1.5 hours. The reaction mixture was combined with 2 batches (each batch using 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 the same reaction). The resulting mixture was purified by reverse phase column (C18, water (0.1% NH3.H2O) / MeCN = 50 / 50 to 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.

[0482] Embodiment 130

[0483] In an ice-water bath, TBAF (1M in THF, 1 mL) was added to a mixture of N-(2-{[tert-butyldi(methyl)silyl]oxy}ethyl)-N-{3-[(methylsulfonyl)amino]propyl}-3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynamide (317 mg) and THF (5 mL). The mixture was stirred for 1.5 hours at the same temperature. The mixture was treated with saturated aqueous NH4Cl solution 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 obtained oil was sonicated with a mixture of EtOAc, IPE and hexane. The obtained mixture was concentrated under reduced pressure. The obtained solid was dissolved with CH2Cl2. Hexane was added to the solution, and the mixture was concentrated to give N-(2-hydroxyethyl)-N-{3-[(methylsulfonyl)amino]propyl}-3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynamide (209 mg) as a solid.

[0484] Embodiment 131

[0485] To a solution of 3-[2'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoic acid (32 mg) in CH2Cl2 (1 mL) was added Et3N (42 μL), (3R,4S)-pyrrolidine-3,4-diol monohydrochloride (23 mg) and PyBOP (74 mg). The mixture was stirred at room temperature for 4 hours, treated with 1M HCl aqueous solution 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 (CHCl3 / MeOH=100 / 0 to 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.

[0486] Embodiment 133

[0487] To a mixture of dimethylamine hydrochloride (37 mg) and MeOH (2 mL) was added Et3N (52 μL), and the mixture was stirred at 30°C for 10 minutes. 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 μL) were added to the mixture, and the resulting mixture was stirred at 60°C for 3 hours. NaBH3CN (39 mg) was added, and stirred at 30°C for 30 minutes. The mixture was concentrated to give a crude product, which was purified by reverse phase column (C18, 40%-50% MeCN in water / 0.1% NH3.H2O) 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.

[0488] Embodiment 134

[0489] 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 minutes. 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.

[0490] Embodiment 135

[0491] A mixture of 1-{3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynyl}piperidine-4-carboxamide (100 mg) and EtOH (6 mL) was stirred at 50 ° C for 2 hours. 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-ynyl}piperidine-4-carboxamide (22 mg) as a solid.

[0492] Embodiment 136

[0493] The 1-imino-4-{3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynyl}-1λ 6 -Thiomorpholine-1-one (134 mg) and a vial of EtOAc (500 μL to 1000 μL) were placed in a large bottle containing hexane (5 mL to 10 mL). The outer vial was sealed and left overnight at room temperature. The precipitate was collected by filtration and rinsed 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) as a solid.

[0494] The compounds of Preparation Examples and Examples shown in the following table were prepared in the same manner as the methods in the above-mentioned Preparation Examples or Examples.

[0495]

Table 4

[0496]

[0497]

[0498]

Table 5

[0499]

[0500]

[0501]

Table 6

[0502]

[0503]

[0504]

Table 7

[0505]

[0506]

Table 8

[0507]

[0508]

[0509]

Table 9

[0510]

[0511]

[0512]

Table 10

[0513]

[0514]

[0515]

Table 11

[0516]

[0517]

[0518]

Table 12

[0519]

[0520]

Table 13

[0521]

[0522]

[0523]

Table 14

[0524]

[0525]

[0526]

[0527]

Table 15

[0528]

[0529]

[0530]

Table 16

[0531]

[0532]

[0533]

Table 17

[0534]

[0535]

[0536]

Table 18

[0537]

[0538]

[0539]

Table 19

[0540]

[0541]

[0542]

Table 20

[0543]

[0544]

[0545]

Table 21

[0546]

[0547]

[0548]

Table 22

[0549]

[0550]

[0551]

Table 23

[0552]

[0553]

[0554]

Table 24

[0555]

[0556]

Table 25

[0557]

[0558]

Table 26

[0559]

[0560]

[0561]

Table 27

[0562]

[0563]

[0564]

Table 28

[0565]

[0566]

[0567]

Table 29

[0568]

[0569]

[0570]

Table 30

[0571]

[0572]

[0573]

Table 31

[0574]

[0575]

[0576]

Table 32

[0577]

[0578]

[0579]

Table 33

[0580]

[0581]

[0582]

Table 34

[0583] Ex Syn DAT 109 1 ESI+;410.1 110 1 ESI+;419.0 111 1 ESI+;406.1 112 1 ESI+;390.1 113 33 ESI+;362.4 114 33 ESI+;441.1 115 33 ESI+; 372.0 116 33 ESI+; 378.1 117 33 ESI+;427.1 118 33 ESI+;378.1 119 - ESI+;419.0 120 88 ESI+;333.1 121 88 ESI+;324.1 122 88 ESI+;408.4 123 96 ESI+;459.6 124 96 ESI+;483.2 125 99 ESI+; 395.3 126 106 ESI+;434.0 127 - ESI+; 374.0 128 - ESI+;438.1 129 - ESI+;430.1 130 - ESI+;469.2 131 - ESI+; 376.2 132 131 ESI+;443.2 133 - ESI+;406.0

[0584]

Table 35

[0585]

[0586] [Industrial Applicability]

[0587] The compound of formula (I) or a salt thereof has an inhibitory effect on STING and is expected to be used as a therapeutic drug for autoimmune diseases, neurodegenerative diseases, type I interferon diseases and / or other STING-mediated diseases.

Claims

1. A compound of formula (I) or a salt thereof: (in, Ring A is phenyl, and the ring A may be optionally condensed with a 5-membered heterocyclic group, a 6-membered heteroaryl group containing one or two nitrogen atoms, a pyrazolyl group, or a 6-membered saturated or partially unsaturated heterocyclic group, Ring B is phenyl, and the ring B may be optionally fused with phenyl or a 6-membered heteroaryl containing one or two nitrogen atoms, a 6-membered heteroaryl containing one or two nitrogen atoms, a pyrazolyl group or an imidazolyl group, R a1 and R a2 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, Halo-C 1-6 Alkyl, -O-halo-C 1-6 Alkyl or -OH, R b1 and R b2 Independently H, C 1-6 Alkyl, -OC 1-6 Alkyl, halo-C 1-6 Alkyl, -O-halo-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 Independently H, C 1-6 Alkyl, C 3-8 Cycloalkyl, -C(=O)-C 1-6 Alkyl or -S(=O)2-C 1-6 alkyl, Or, R c and R d can be optionally connected to each other to form R c and R d The attached nitrogen atom together forms a 4- to 7-membered saturated heterocyclic group, wherein the heterocyclic group may be optionally substituted by one or two R e replace, R e 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, an optionally substituted 4- to 7-membered saturated heterocyclic group, an optionally substituted phenyl group or an optionally substituted heteroaryl group, R 2 For one or two R 3 Substituted C 1-6 Alkyl, one or two R 4 Substituted C 3-8 Cycloalkyl, with one or two R 5 substituted 4- to 7-membered saturated heterocyclic group, or one or two R 6 Substituted phenyl, Or, R 1 and R 2 Connect to each other with R 1 and R 2 The attached nitrogen atom together forms a 4- to 7-membered saturated heterocyclic group, wherein the heterocyclic group may be optionally fused to a phenyl group, and the heterocyclic group and / or the fused phenyl group may be optionally replaced by one to three R 7 replace, Each R 3 are 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 alkyl, Each R 4 are 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 alkyl, Each R 5 are 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 Alkyl, and Each R 7 Independently for 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 a 4- to 7-membered saturated heterocyclic group which may be 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. The compound according to claim 1 or a salt thereof, in, Ring B is phenyl, a 6-membered heteroaryl containing one or two nitrogen atoms, or pyrazolyl, R a1 and R a2 Independently H, C 1-6 Alkyl, halogen, halo-C 1-6 Alkyl or -O-halogenated-C 1-6 Alkyl, R b1 and R b2 are independently H, halo-C 1-6 Alkyl or -C 1-6 Alkylene-NR c R d , R c and R d independently H or C 1-6 alkyl, Or, R c and R d can be optionally connected to each other to form R c and R d The attached nitrogen atom together forms a 4- to 7-membered saturated heterocyclic group, wherein the heterocyclic group may be optionally substituted by one or two R e replace, R 1 H, C 1-6 Alkyl, C 3-8 cycloalkyl, 4- to 7-membered saturated heterocyclic group, optionally substituted phenyl or optionally substituted heteroaryl, R 2 For one or two R 3 Substituted C 1-6 Alkyl, one or two R 4 Substituted C 3-8 Cycloalkyl, with one or two R 5 substituted 4- to 7-membered saturated heterocyclic group, or one or two R 6 Substituted phenyl, Or, R 1 and R 2 Connect to each other with R 1 and R 2 The attached nitrogen atom together forms a 4- to 7-membered saturated heterocyclic group, wherein the heterocyclic group may be optionally fused to a phenyl group, and the heterocyclic group and / or the fused phenyl group may be optionally substituted by one or two R 7 replace, Each R 3 are independently -OH, -C(=O)-NH2, -NH-C(=O)-C 1-6 Alkyl, -NH-S(=O)2-C 1-6 Alkyl or -S(=O)2-NH2, Each R 4 are independently -OH, -C(=O)-NH2, -NH-C(=O)-C 1-6 Alkyl, -NH-S(=O)2-C 1-6 Alkyl or -S(=O)2-NH2, Each R 5 are independently -OH or oxo, Each R 6 are independently -C(=O)-OH or -S(=O)2-NH2, and Each R 7 Independently for C 1-6 Alkyl, -C 1-6 Alkylene -OH, -C 1-6 Alkylene-C(=O)-OH, C 3-8 Cycloalkyl, -OH, -NH2, -C(=O)-OH, -C(=O)-NH2, oxo, imino, or a 4- to 7-membered saturated heterocyclic group which may be optionally substituted by one or two oxo groups.

3. The compound or salt thereof according to claim 2, in, Ring A is phenyl, a 6-membered heteroaryl containing one or two nitrogen atoms, pyrazolyl, or a 6-membered saturated or partially unsaturated heterocyclic group, Ring B is of formula (V): X is CH or N, R 1 H, C 1-6 Alkyl, C 3-8 cycloalkyl, 4- to 7-membered saturated heterocyclic group, phenyl or optionally substituted heteroaryl, R 2 For one or two R 3 Substituted C 1-6 Alkyl, one or two R 4 Substituted C 3-8 Cycloalkyl, or one or two R 5 a substituted 4- to 7-membered saturated heterocyclic group, Or, R 1 and R 2 Connect to each other with R 1 and R 2 The attached nitrogen atom together forms a 4- to 7-membered saturated heterocyclic group, wherein the heterocyclic group may be optionally substituted by one or two R 7 replace, R 4 is -OH, The prerequisite is R a1 , R a2 , R b1 or R b2 At least one of them is not H.

4. The compound or salt thereof according to claim 3, in, R b1 For H, R b2 For halogenated-C 1-6 Alkyl, and R 1 and R 2 Connect to each other with R 1 and R 2 The attached nitrogen atom together forms a 4- to 7-membered saturated heterocyclic group, wherein the heterocyclic group may be optionally substituted by one or two R 7 replace.

5. The compound or a salt thereof according to claim 3, in, Ring A is phenyl, R a1 , R a2 and R b1 For H, R b2 For halogenated-C 1-6 alkyl, R 1 For H, R 2 For one or two R 3 Substituted C 1-6 alkyl, Or, R 1 and R 2 Connect to each other with R 1 and R 2 The attached nitrogen atoms together form an azetidinyl, pyrrolidinyl, piperidinyl or thiomorpholinyl group, wherein the azetidinyl, pyrrolidinyl, piperidinyl or thiomorpholinyl group may be optionally substituted by one or two R 7 replace, Each R 3 are independently -OH or -C(=O)-NH2, and Each R 7 Independently -C 1-6 Alkylene -OH, -OH, -C(=O)-NH2, oxo or imino.

6. The compound or a salt thereof according to claim 1, wherein the compound is a compound selected from the following group: N 2 -{3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynyl}-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-ynyl}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-ynyl}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-ynyl}-1λ 6 -Thiomorpholin-1-one.

7. A pharmaceutical composition comprising the compound or a salt thereof according to claim 1 and one or more pharmaceutically acceptable excipients.

8. A STING inhibitor, comprising the compound according to claim 1 or a salt thereof.

9. The pharmaceutical composition according to claim 7, wherein the pharmaceutical composition is a pharmaceutical composition for treating autoimmune diseases, neurodegenerative diseases, type I interferon diseases and / or other STING-mediated diseases.

10. Use of the compound or salt thereof according to claim 1 for preparing a pharmaceutical composition for treating autoimmune diseases, neurodegenerative diseases, type I interferon diseases and / or other STING-mediated diseases.

11. Use of the compound or salt thereof according to claim 1 for treating autoimmune diseases, neurodegenerative diseases, type I interferon diseases and / or other STING-mediated diseases.

12. The compound or salt thereof according to claim 1 is used for treating autoimmune diseases, neurodegenerative diseases, type I interferon diseases and / or other STING-mediated diseases.

13. A method for treating autoimmune diseases, neurodegenerative diseases, type I interferon diseases and / or other STING-mediated diseases, comprising administering an effective amount of the compound or a salt thereof according to claim 1 to a subject.

14. Use of a compound of formula (I) or a salt thereof for preparing a pharmaceutical composition for treating autoimmune diseases, neurodegenerative diseases, type I interferon diseases and / or other STING-mediated diseases, in, Ring A is phenyl, and the ring A may be optionally condensed with a 5-membered heterocyclic group, a 6-membered heteroaryl group containing one or two nitrogen atoms, a pyrazolyl group, or a 6-membered saturated or partially unsaturated heterocyclic group, Ring B is phenyl, and the ring B may be optionally fused with phenyl or a 6-membered heteroaryl containing one or two nitrogen atoms, a 6-membered heteroaryl containing one or two nitrogen atoms, a pyrazolyl group or an imidazolyl group, R a1 and R a2 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, Halo-C 1-6 Alkyl, -O-halo-C 1-6 Alkyl or -OH, R b1 and R b2 Independently H, C 1-6 Alkyl, -OC 1-6 Alkyl, halo-C 1-6 Alkyl, -O-halo-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 Independently H, C 1-6 Alkyl, C 3-8 Cycloalkyl, -C(=O)-C 1-6 Alkyl or -S(=O)2-C 1-6 alkyl, Or, R c and R d can be optionally connected to each other to form R c and R d The attached nitrogen atom together forms a 4- to 7-membered saturated heterocyclic group, wherein the heterocyclic group may be optionally substituted by one or two R e replace, R e 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, an optionally substituted 4- to 7-membered saturated heterocyclic group, an optionally substituted phenyl group or an optionally substituted heteroaryl group, R 2 For one or two R 3 Substituted C 1-6 Alkyl, one or two R 4 Substituted C 3-8 Cycloalkyl, with one or two R 5 substituted 4- to 7-membered saturated heterocyclic group, or one or two R 6 Substituted phenyl, Or, R 1 and R 2 Connect to each other with R 1 and R 2 The attached nitrogen atom together forms a 4- to 7-membered saturated heterocyclic group, wherein the heterocyclic group may be optionally fused to a phenyl group, and the heterocyclic group and / or the fused phenyl group may be optionally replaced by one to three R 7 replace, Each R 3 are 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 alkyl, Each R 4 are 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 alkyl, Each R 5 are 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 Alkyl, and Each R 7 Independently for 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 a 4- to 7-membered saturated heterocyclic group which may be optionally substituted by one or two oxo groups.

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