KURIWAKI IKUMI (JP)
KITAMURA KAI (JP)
YAMASHITA YUMI (JP)
KAKEFUDA KENICHI (JP)
KAMIKAWA AKIO (JP)
NEGORO KENJI (JP)
SEO RYUSHI (JP)
CIAVARRI JEFFREY (US)
HAMAGUCHI WATARU (JP)
MITOBRIDGE INC (US)
| WO2021068950A1 | 2021-04-15 | |||
| WO2020150417A2 | 2020-07-23 | |||
| WO2020106741A1 | 2020-05-28 | |||
| WO2019122202A1 | 2019-06-27 | |||
| WO2019182886A1 | 2019-09-26 | |||
| WO2005115990A1 | 2005-12-08 |
| US6150413A | 2000-11-21 |
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| Claims [Claim 1] A compound of formula (I) or a salt thereof: (wherein, Ring A is phenyl which may be optionally fused with 5-membered heterocyclyl, 6- membered heteroaryl containing one or two nitrogen atoms, pyrazolyl or 6-membered saturated or partially unsaturated heterocyclyl, Ring B is phenyl which may be optionally fused with phenyl or 6-membered heteroaryl containing one or two nitrogen atoms, 6-membered heteroaryl containing one or two nitrogen atoms, pyrazolyl or imidazolyl, Ra1 and Ra2 are independently H, C1-6 alkyl, -O-C1-6 alkyl, -O-C1-6 alkylene-C2-6 alkenyl, -O-C1-6 alkylene-C2-6 alkynyl, halogen, halogeno-C1-6 alkyl, -O-halogeno-C1-6 alkyl or -OH, Rb1 and Rb2 are independently H, C1-6 alkyl, -O-C1-6 alkyl, halogeno-C1-6 alkyl, -O- halogeno-C1-6 alkyl, halogen, -C1-6 alkylene-OH, -C1-6 alkylene-NRcRd, -C(=O)-NRcRd, - NRcRd, -CN or -OH, Rc and Rd are independently H, C1-6 alkyl, C3-8 cycloalkyl, -C(=O)-C1-6 alkyl, or - S(=O)2-C1-6 alkyl, or, Rc and Rd may be optionally linked to each other to form 4- to 7-membered saturated heterocyclyl together with the nitrogen atom to which Rc and Rd are attached, wherein the heterocyclyl may be optionally substituted with one or two Re, Re is C1-6 alkyl, -O-C1-6 alkyl or halogen, R1 is H, optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted 4- to 7-membered saturated heterocyclyl, optionally substituted phenyl or optionally substituted heteroaryl, R2 is C1-6 alkyl which is substituted with one or two R3, C3-8 cycloalkyl which is substituted with one or two R4, 4- to 7- membered saturated heterocyclyl which is substituted with one or two R5, or phenyl which is substituted with one or two R6, or, R1 and R2 are linked to each other to form 4- to 7-membered saturated heterocyclyl together with the nitrogen atom to which R1 and R2 are attached, wherein the heterocyclyl may be optionally fused with phenyl, and the heterocyclyl and/or the fused phenyl may be optionally substituted with one to three R7, each R3 is independently -OH, -O-C1-6 alkyl, -C(=O)-NH2, -C(=O)-NH-C1-6 alkyl, - C(=O)-N(C1-6 alkyl)2, -NH2, -NH-C1-6 alkyl, -N(C1-6 alkyl)2, -NH-C(=O)-C1-6 alkyl, -NH- S(=O)2-C1-6 alkyl, -NH-S(=O)2-C1-6 alkylene-OH, -NH-S(=O)2-C1-6 alkylene-C(=O)-OH, - S(=O)2-NH3, -S(=O)2-C1-6 alkyl or -S(=O)(=NH)-C1-6 alkyl, each R4 is independently -OH, -O-C1-6 alkyl, -C(=O)-NH2, -C(=O)-NH-C1-6 alkyl, - C(=O)-N(C1-6 alkyl)2, -NH2, -NH-C1-6 alkyl, -N(C1-6 alkyl)2, -NH-C(=O)-C1-6 alkyl, -NH- S(=O)2-C1-6 alkyl, -S(=O)2-NH2, -S(=O)2-C1-6 alkyl or -S(=O)(=NH)-C1-6 alkyl, each R5 is independently -OH, oxo or imino, each R6 is independently -C(=O)-OH, -S(=O)2-NH2, -S(=O)2-C1-6 alkyl, -S(=O)(=NH)- C1-6 alkyl or -NH-S(=O)2-C1-6 alkyl, and each R7 is independently C1-6 alkyl, -C1-6 alkylene-OH, -C1-6 alkylene-C(=O)-OH, C3-8 cycloalkyl, -OH, -O-C1-6 alkyl, -NH2, -NH-C1-6 alkyl, -N(C1-6 alkyl)2, -NH-C(=O)-C1-6 alkyl, - NH-S(=O)2-C1-6 alkyl, -S(=O)2-C1-6 alkyl, -S(=O)(=NH)-C1-6 alkyl, -C(=O)-OH, -C(=O)-NH2, -C(=O)-NH-C1-6 alkyl, -C(=O)-N(C1-6 alkyl)2, oxo, imino or 4- to 7-membered saturated heterocyclyl which may be optionally substituted with one or two oxo, provided that the compound of formula (I) is not the compound of formula (II), (III), (IV) or (IVa)). [Claim 2] The compound or a salt thereof according to claim 1, wherein, Ring B is phenyl, 6-membered heteroaryl containing one or two nitrogen atoms or pyrazolyl, Ra1 and Ra2 are independently H, C1-6 alkyl, halogen, halogeno-C1-6 alkyl or -O- halogeno-C1-6 alkyl, Rb1 and Rb2 are independently H, halogeno-C1-6 alkyl or -C1-6 alkylene-NRcRd, Rc and Rd are independently H or C1-6 alkyl, or, Rc and Rd may be optionally linked to each other to form 4- to 7-membered saturated heterocyclyl together with the nitrogen atom to which Rc and Rd are attached, wherein the heterocyclyl may be optionally substituted with one or two Re, R1 is H, C1-6 alkyl, C3-8 cycloalkyl, 4- to 7-membered saturated heterocyclyl, optionally substituted phenyl or optionally substituted heteroaryl, R2 is C1-6 alkyl which is substituted with one or two R3, C3-8 cycloalkyl which is substituted with one or two R4, 4- to 7-membered saturated heterocyclyl which is substituted with one or two R5, or phenyl which is substituted with one or two R6, or, R1 and R2 are linked to each other to form 4- to 7-membered saturated heterocyclyl together with the nitrogen atom to which R1 and R2 are attached, wherein the heterocyclyl may be optionally fused with phenyl, and the heterocyclyl and/or the fused phenyl may be optionally substituted with one or two R7, each R3 is independently -OH, -C(=O)-NH2, -NH-C(=O)-C1-6 alkyl, -NH-S(=O)2-C1-6 alkyl or -S(=O)2-NH2, each R4 is independently -OH, -C(=O)-NH2, -NH-C(=O)-C1-6 alkyl, -NH-S(=O)2-C1-6 alkyl or -S(=O)2-NH2, each R5 is independently -OH or oxo, each R6 is independently -C(=O)-OH or -S(=O)2-NH2, and each R7 is independently C1-6 alkyl, -C1-6 alkylene-OH, -C1-6 alkylene-C(=O)-OH, C3-8 cycloalkyl, -OH, -NH2, -C(=O)-OH, -C(=O)-NH2, oxo, imino or 4- to 7-membered saturated heterocyclyl which may be optionally substituted with one or two oxo. [Claim 3] The compound or a salt thereof according to claim 2, wherein, Ring A is phenyl, 6-membered heteroaryl containing one or two nitrogen atoms, pyrazolyl or 6-membered saturated or partially unsaturated heterocyclyl, Ring B is the formula (V): X is CH or N, R1 is H, C1-6 alkyl, C3-8 cycloalkyl, 4- to 7-membered saturated heterocyclyl, phenyl or optionally substituted heteroaryl, R2 is C1-6 alkyl which is substituted with one or two R3, C3-8 cycloalkyl which is substituted with one or two R4, or 4- to 7-membered saturated heterocyclyl which is substituted with one or two R5, or, R1 and R2 are linked to each other to form 4- to 7-membered saturated heterocyclyl together with the nitrogen atom to which R1 and R2 are attached, wherein the heterocyclyl may be optionally substituted with one or two R7, R4 is -OH, provided that at least one of Ra1, Ra2, Rb1 or Rb2 are not H. [Claim 4] The compound or a salt thereof according to claim 3, wherein, Rb1 is H, Rb2 is halogeno-C1-6 alkyl, and R1 and R2 are linked to each other to form 4- to 7-membered saturated heterocyclyl together with the nitrogen atom to which R1 and R2 are attached, wherein the heterocyclyl may be optionally substituted with one or two R7. [Claim 5] The compound or a salt thereof according to claim 3, wherein, Ring A is phenyl, Ra1, Ra2 and Rb1 are H, Rb2 is halogeno-C1-6 alkyl, R1 is H, R2 is C1-6 alkyl which is substituted by one or two R3, or, R1 and R2 are linked to each other to form azetidinyl, pyrrolidinyl, piperidinyl or thiomorpholinyl together with the nitrogen atom to which R1 and R2 are attached, wherein the azetidinyl, pyrrolidinyl, piperidinyl or thiomorpholinyl may be optionally substituted with one or two R7, each R3 is independently -OH or -C(=O)-NH2, and each R7 is independently -C1-6 alkylene-OH, -OH, -C(=O)-NH2, oxo or imino. [Claim 6] The compound or a salt thereof according to claim 1, wherein the compound is a compound selected from the following group of: N2-{3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoyl}-L-serinamide, 1-[(3R,4R)-3,4-dihydroxypyrrolidin-1-yl]-3-[2-(trifluoromethyl)[1,1'-biphenyl]-4- yl]prop-2-yn-1-one, 1-{3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoyl}piperidine-4- carboxamide, 1-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-3-[2-(trifluoromethyl)[1,1'-biphenyl]-4- yl]prop-2-yn-1-one, 1-[3,3-bis(hydroxymethyl)azetidin-1-yl]-3-[2-(trifluoromethyl)[1,1'-biphenyl]-4- yl]prop-2-yn-1-one, N-[(2R)-2,3-dihydroxypropyl]-3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2- ynamide, N-[(2S)-2,3-dihydroxypropyl]-3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2- ynamide, 1-[(3S,4S)-3,4-dihydroxypyrrolidin-1-yl]-3-[2-(trifluoromethyl)[1,1'-biphenyl]-4- yl]prop-2-yn-1-one, (3R)-1-{3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoyl}pyrrolidine-3- carboxamide, 1-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-3-[6-phenyl-5-(trifluoromethyl)pyridin-3- yl]prop-2-yn-1-one, and 1-imino-4-{3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoyl}-1λ6- thiomorpholin-1-one. [Claim 7] A pharmaceutical composition comprising the compound or a salt thereof according to claim 1 and one or more pharmaceutically acceptable excipients. [Claim 8] A STING inhibitor comprising the compound or a salt thereof according to claim 1. [Claim 9] The pharmaceutical composition according to claim 7, wherein the pharmaceutical composition is a pharmaceutical composition for treatment of an autoimmune disease, a neurodegenerative disease, a type I interferonopathy and/or other STING-mediated disease. [Claim 10] Use of the compound or a salt thereof according to claim 1 for the manufacture of a pharmaceutical composition for treatment of an autoimmune disease, a neurodegenerative disease, a type I interferonopathy and/or other STING-mediated disease. [Claim 11] Use of the compound or a salt thereof according to claim 1 for treatment of an autoimmune disease, a neurodegenerative disease, a type I interferonopathy and/or other STING-mediated disease. [Claim 12] The compound or a salt thereof according to claim 1 for use in treatment of an autoimmune disease, a neurodegenerative disease, a type I interferonopathy and/or other STING-mediated disease. [Claim 13] A method for treatment of an autoimmune disease, a neurodegenerative disease, a type I interferonopathy and/or other STING-mediated disease comprising administering to a subject an effective amount of the compound or a salt thereof according to claim 1. [Claim 14] Use of a compound of formula (I) or a salt thereof for the manufacture of a pharmaceutical composition for treatment of an autoimmune disease, a neurodegenerative disease, a type I interferonopathy and/or other STING-mediated disease, wherein, Ring A is phenyl which may be optionally fused with 5-membered heterocyclyl, 6- membered heteroaryl containing one or two nitrogen atoms, pyrazolyl or 6-membered saturated or partially unsaturated heterocyclyl, Ring B is phenyl which may be optionally fused with phenyl or 6-membered heteroaryl containing one or two nitrogen atoms, 6-membered heteroaryl containing one or two nitrogen atoms, pyrazolyl or imidazolyl, Ra1 and Ra2 are independently H, C1-6 alkyl, -O-C1-6 alkyl, -O-C1-6 alkylene-C2-6 alkenyl, -O-C1-6 alkylene-C2-6 alkynyl, halogen, halogeno-C1-6 alkyl, -O-halogeno-C1-6 alkyl or -OH, Rb1 and Rb2 are independently H, C1-6 alkyl, -O-C1-6 alkyl, halogeno-C1-6 alkyl, -O- halogeno-C1-6 alkyl, halogen, -C1-6 alkylene-OH, -C1-6 alkylene-NRcRd, -C(=O)-NRcRd, - NRcRd, -CN or -OH, Rc and Rd are independently H, C1-6 alkyl, C3-8 cycloalkyl, -C(=O)-C1-6 alkyl, or - S(=O)2-C1-6 alkyl, or, Rc and Rd may be optionally linked to each other to form a 4- to 7-membered saturated heterocyclyl together with the nitrogen atom to which Rc and Rd are attached, wherein the heterocyclyl may be optionally substituted with one or two Re, Re is C1-6 alkyl, -O-C1-6 alkyl or halogen, R1 is H, optionally substituted C1-6 alkyl, optionally substituted C3-8 cycloalkyl, optionally substituted 4- to 7-membered saturated heterocyclyl, optionally substituted phenyl or optionally substituted heteroaryl, R2 is C1-6 alkyl which is substituted with one or two R3, C3-8 cycloalkyl which is substituted with one or two R4, 4- to 7-membered saturated heterocyclyl which is substituted with one or two R5, or phenyl which is substituted with one or two R6, or, R1 and R2 are linked to each other to form 4- to 7-membered saturated heterocyclyl together with the nitrogen atom to which R1 and R2 are attached, wherein the heterocyclyl may be optionally fused with phenyl, and the heterocyclyl and/or the fused phenyl may be optionally substituted with one to three R7, each R3 is independently -OH, -O-C1-6 alkyl, -C(=O)-NH2, -C(=O)-NH-C1-6 alkyl, - C(=O)-N(C1-6 alkyl)2, -NH2, -NH-C1-6 alkyl, -N(C1-6 alkyl)2, -NH-C(=O)-C1-6 alkyl, -NH- S(=O)2-C1-6 alkyl, -NH-S(=O)2-C1-6 alkylene-OH, -NH-S(=O)2-C1-6 alkylene-C(=O)-OH, - S(=O)2-NH2, -S(=O)2-C1-6 alkyl or -S(=O)(=NH)-C1-6 alkyl, each R4 is independently -OH, -O-C1-6 alkyl, -C(=O)-NH2, -C(=O)-NH-C1-6 alkyl, - C(=O)-N(C1-6 alkyl)2, -NH2, -NH-C1-6 alkyl, -N(C1-6 alkyl)2, -NH-C(=O)-C1-6 alkyl, -NH- S(=O)2-C1-6 alkyl, -S(=O)2-NH2, -S(=O)2-C1-6 alkyl or -S(=O)(=NH)-C1-6 alkyl, each R5 is independently -OH, oxo or imino, each R6 is independently -C(=O)-OH, -S(=O)2-NH2, -S(=O)2-C1-6 alkyl, -S(=O)(=NH)- C1-6 alkyl or -NH-S(=O)2-C1-6 alkyl, and each R7 is independently C1-6 alkyl, -C1-6 alkylene-OH, -C1-6 alkylene-C(=O)-OH, C3-8 cycloalkyl, -OH, -O-C1-6 alkyl, -NH2, -NH-C1-6 alkyl, -N(C1-6 alkyl)2, -NH-C(=O)-C1-6 alkyl, - NH-S(=O)2-C1-6 alkyl, -S(=O)2-C1-6 alkyl, -S(=O)(=NH)-C1-6 alkyl, -C(=O)-OH, -C(=O)-NH2, -C(=O)-NH-C1-6 alkyl, -C(=O)-N(C1-6 alkyl)2, oxo, imino or 4- to 7-membered saturated heterocyclyl which may be optionally substituted with one or two oxo. |
[0083] (Starting Compound Synthetic Process 2) [Chem 21] ( VIb ) ( Xb ) (in which, one of W or Z is N and the other is CH. The same applies hereinafter). This Process is a process of preparing a compound of formula (Xb) which has pyrazol- 1-yl group or imidazole-1-yl group as the Ring B among the compound of formula (X), by a reaction of a compound of formula (VIb) and a compound of formula (VIII). This reaction is carried out in the same conditions as the Starting Compound Synthetic Process 1, by using the compound of formula (VIb) and the compound of formula (VIII) instead of the compound of formula (VIa) and the compound of formula (VIIIa). [0084] (Starting Compound Synthetic Process 3) [Chem 22] This Process is a process of preparing a compound of formula (X) by a reaction between a compound of formula (VIc) and a compound of formula (VIII) to obtain a compound of formula (Xc), followed by the conversion of the amino group to halogen by the Sandmeyer reaction. [0085] (Step 1) This step is a step of preparing a compound of formula (Xc) by reaction of a compound of formula (VIc) and a compound of formula (VIII). This reaction is carried out in the same condition as the Step 2a of the Production Process 1, by using the compound of formula (VIc) instead of the compound of formula (VII). [0086] (Step 2) This step is a step of preparing a compound of formula (X) by conversion of the amino group of a compound of formula (Xc) to a halogen by Sandmeyer reaction. This reaction is carried out by adding a diazotizing reagent to a mixture of the compound of formula (Xc) and an acid in a solvent which is inactive to the reaction under cooling, preferably at 0 °C, followed by addition of halogenating reagent under cooling, preferably at 0 °C and stirring at 0 °C to room temperature, typically for 0.1 hours to 5 days. Examples of the diazotizing reagent include, but not limited to, NaNO 2 , t-butyl nitrite, isoamyl nitrite and the like. Examples of the acid include, but are not limited to, hydrochloric acid, sulfuric acid and the like. Examples of the halogenating reagent include, but are not limited to, CuCl, CuBr, KI and the like. Examples of the solvent include, but are not limited to, water, EtOH, MeOH, THF, 1,4-dioxane, CH 3 CN, acetone and a mixture thereof. It may be advantageous in some cases, for the smooth progress of the reaction, to carry out the reaction in the presence of urea. [0087] (Other Production Processes) By using a compound of formula (I) or synthetic intermediates thereof prepared by any of the above-described Production Processes as a starting material, and carrying out further chemical modification reactions typically employed by a person skilled in the art such as alkylation, amidation, acylation, sulfonylation, oxidation, reduction, reductive amination, NH- sulfoximination (Chemical Communications, 53, pp348 – 351, 2017), protection or deprotection, another compound of formula (I) or synthetic intermediates thereof can be prepared. [0088] The compound of formula (I) is isolated and purified as its free compound, or a salt, a hydrate, a solvate, or crystal polymorph substance thereof. The salt of the compound of formula (I) can also be prepared by a conventional method. Isolation and purification are carried out by employing general chemical operations such as extraction, fractional crystallization, and various types of fractional chromatography. Various isomers can be prepared by selecting appropriate starting compound, or separated by separation using differences in the physicochemical properties among the isomers. For example, the optical isomers can be obtained by means of general optical resolution methods of racemic compounds (for example, fractional crystallization introducing the compound into a diastereomer salt with an optically active base or acid; chromatography using a chiral column or the like; and others), or can also be prepared from appropriate optically active starting compound. [0089] The pharmacological activity of the compound of formula (I) can be confirmed by the following test or its modified test which is apparent to the person skilled in the art. [0090] Test Example 1: Test on the activity of IRF pathway of THP-1 0.3 uM of PMA (phorbol myristate acetate, SIGMA, P1585) was added to THP1- Dual TM cells (NF-κB-SEAP IRF-Luc Reporter Monocytes, Invivogen, thpd-nfis), and the cells were cultured at 37 °C for 1 day in RPMI1640 with 10% Fetal Bovine Serum (FBS). A compound with a known concentration was added, and the cells were incubated at room temperature for 1 hour. Mammalian (non-canonical) CDN, cyclic [G(2’,5’)pA(3’,5’)p] (2’3’- cGAMP, Invivogen, tlrl-nacga23) was added to a final concentration of 5 ug/mL, and the cells were cultured at 37 °C. On the following day, QUANTI-Luc™ (Secreted luciferase detection medium, Invivogen, rep-qlc) was added to the culture solution and the activity of IRF pathway was measured using a microplate reader. The inhibition ratio at each concentration was determined, where the activity of IRF pathway with no addition of the test compound or 2’3’- cGAMP was defined as 100% inhibition and the activity of IRF pathway with no addition of the test compound and with addition of 2’3’-cGAMP was defined as 0% inhibition. The IC 50 value was calculated by sigmoid Exam model non-linear regression analysis. Table 1 and Table 2 show the results. It was confirmed that the example compounds inhibited the activity of IRF pathway. [Table 1] [Table 2] [0091] Test Example 2: Test on IFNβ production in mice plasma Male C57BL/6J mice (8–12-weeks-old) were administered orally either vehicle or 1 mg/kg of test compounds. After 1 hour, 5,6-Dimethylxanthenone-4-acetic acid (DMXAA) (BLD Pharmatech Ltd, BD126695) was administered intraperitoneally at a dose of 20 mg/kg. Four hours later, the mice were euthanized, and the plasma was collected. Plasma concentration of IFNβ was measured by an enzyme-linked immunosorbent assay method using an AlphaLISA Mouse IFNβ Detection Kit (Parkin Elmer, AL586C), and the inhibition ratio to the vehicle administration group was calculated. Table 3 shows the inhibition ratio of the production of IFNβ to the vehicle administration group. It was confirmed that these compounds inhibit the production of IFNβ in vivo. [Table 3] [0092] Test Example 3: Test on drug-induced Sjogren's syndrome-like salivary dysfunction in mice Female C57BL/6J mice (8–10-weeks-old) were injected subcutaneously with 20 mg/kg of DMXAA or its vehicle, 5% NaHCO 3 , four times at weekly intervals. From the day after the last DMXAA challenge, mice were orally administered the test compound or its vehicle once a day for 8 days. On the following day, saliva was collected from mice using a cotton swab under awake conditions, and saliva weight during 15 min was measured and evaluated as an indicator of salivary gland function. The results of the evaluation of the Example 33, 34 and 99 are shown in Figures 1-3. These compounds significantly improved saliva production in mice drug-induced Sjogren's syndrome-like model. From this, it was confirmed that these compounds showed an improving effect on salivary disfunction. [0093] Test Example 4: Trex1 KO mice model of autoimmune disease C57BL/6N-Trex1 em1Aiwsk /J mice (Trex1 KO mice : strain number 032213) were purchased from The Jackson Laboratory. Male Trex1 KO mice and their wild-type (WT) littermates (4–6-weeks-old) were orally administered the test compound or its vehicle once daily for 4 to 9 weeks. Blood, kidneys and other affected tissues were collected for further analysis. Kidneys were stored in RNA protect Tissue Reagent (Qiagen, 76106) and RNA purified using RNeasy Plus Mini Kit (Qiagen, 74134). Reverse transcription and real-time PCR reactions were performed using SuperScript VILO cDNA Synthesis Kit (Life Technologies, 11754250) and TaqMan Gene Expression Master Mix (Life Technologies, 4369016), respectively. Real-time PCR reactions were performed using the equipment in Quant Studio12K Flex (Thermo Fisher Scientific). Probes used were Cxcl10 (Mm00445235_m1), Cd68 (Mm03047343_m1) and Gapdh (Mm99999915_g1), and relative quantification was performed using the ΔΔCT method with Gapdh as the housekeeping gene. A specific compound of formula (I) or a salt thereof significantly reduced Cxcl10 and Cd68 gene expression, which were elevated in the kidneys of Trex1 KO mice. [0094] As a result of the tests above, it was confirmed that some compounds of the formula (I) shown in Table 1 have STING inhibitory action. Moreover, some compounds of formula (I) were demonstrated to inhibit the production of IFNβ induced by DMXAA in mice (Test Example 2). Accordingly, the compound of formula (I) can be used for treating an autoimmune disease, a neurodegenerative disease, a type I interferonopathy and/or other STING-mediated disease. [0095] A pharmaceutical composition comprising one or two or more kinds of the compound of formula (I) as an active ingredient can be prepared using an excipient which is usually used in the art, that is, an excipient for a pharmaceutical preparation, a carrier for a pharmaceutical preparation, and the like, according to a method usually used. Administration can be accomplished either by oral administration via tablets, pills, capsules, granules, powders, solutions, and the like, or parenteral administration via injections, such as intraarticular, intravenous, and intramuscular injections, suppositories, ophthalmic solution, ophthalmic ointments, transdermal liquid preparations, ointments, transdermal patches, transmucosal liquid preparations, transmucosal patches, inhalers, and the like. [0096] As a solid composition for oral administration, tablets, powders, granules, and the like are used. In such a solid composition, one kind or two or more kinds of the active ingredients are mixed with at least one excipient. In a conventional method, the composition may contain excipients such as a lubricant, a disintegrating agent, a stabilizer, or a solubilization assisting agent. If necessary, tablets, powders and granule may be coated with a wax, a sugar or with a film of a gastric or enteric coating substance. The liquid composition for oral administration includes pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, or the like, and also includes generally used diluents, for example, purified water or ethanol. The liquid composition may also include excipients such as a solubilization assisting agent, a moistening agent, a suspending agent, sweeteners, flavors, aromatics, and antiseptics. [0097] The injections for parenteral administration include sterile aqueous or non-aqueous solution preparations, suspensions, or emulsions. The aqueous solvent includes, for example, distilled water for injection and saline. Examples of the non-aqueous solvent include alcohols such as ethanol. Such a composition may further include a tonicity agent, an antiseptic, a moistening agent, an emulsifying agent, a dispersing agent, a stabilizing agent, or a solubilizing assisting agent. These are sterilized, for example, by filtration through a bacteria retaining filter, blending of a bactericide, or irradiation. In addition, these can also be used by preparing a sterile solid composition and dissolving or suspending it in sterile water or a sterile solvent for injection prior to its use. [0098] Examples of the vehicle for external use include ointments, hard plasters, creams, jellies, cataplasms, sprays, lotions, ophthalmic solution, ophthalmic ointments, and the like. The vehicle further contains generally used ointment bases, lotion bases, aqueous or non- aqueous liquid preparations, suspensions, emulsions, and the like. [0099] As the transmucosal agents such as an inhaler and a transnasal agent, those in the form of a solid, liquid, or semi-solid state are used, and can be prepared in accordance with a method known in the related art. For example, a known excipient, and also a pH adjusting agent, an antiseptic, a surfactant, a lubricant, a stabilizing agent, a thickening agent, and the like may be appropriately added thereto. For the administration, an appropriate device for inhalation or blowing can be used. For example, a compound may be administered alone or as a powder of formulated mixture, or as a solution or suspension in combination with a pharmaceutically acceptable carrier, using a known device or sprayer such as a metered administration inhalation device. A dry powder inhaler and the like may be for single or multiple administration use, and a dry powder or a powder-containing capsule may be used. Alternatively, this may be in a form such as a pressurized aerosol spray that uses an appropriate propellant agent, for example, a suitable gas such as chlorofluoroalkanes, carbon dioxide, or other forms. [0100] Usually, in the case of oral administration, the daily dose is from about 0.001 mg/kg to 100 mg/kg, as an embodiment from 0.1 mg/kg to 30 mg/kg, and as another embodiment from 0.1 mg/kg to 10 mg/kg, per body weight, administered in one portion or in 2 to 4 divided portions. In the case of intravenous administration, the daily dose is suitably administered from about 0.0001 mg/kg to 10 mg/kg per body weight, once a day or two or more times a day. In addition, a transmucosal agent is administered at a dose from about 0.001 mg/kg to 100 mg/kg per body weight, once or plural times a day. The dose is appropriately decided in response to the individual case by taking the symptoms, the age, and the gender, and the like into consideration. [0101] Although there are differences depending on a route of administration, a dosage form, an administration site, and a type of the excipient or additive, a pharmaceutical composition of the present invention comprises 0.01% by weight to 100% by weight of, as an embodiment, 0.01% by weight to 50% by weight of, one or more of the compound of formula (I) or a salt thereof which is the active ingredient. [0102] The compound of formula (I) may be used in combination with various agents for treating diseases on which the compound of formula (I) is considered to show the effect. Such combined preparations may be administered simultaneously, or separately and consecutively, or at a desired time interval. The preparations to be co-administered may be a blend, or may be prepared individually. [Examples] [0103] Hereinbelow, the production process for the compound of formula (I) will be described in more detail with reference to Examples. The present invention is not limited to the compounds described in the Examples below. Further, the production processes for the starting compounds will be described in Preparation Examples, and the production processes for the known compounds will be described in Reference Examples. In addition, the production processes for the compound of formula (I) are not limited to the production processes of the specific Examples shown below, but the compound of formula (I) can be prepared by a combination of these production processes or a method that is apparent to a person skilled in the art. [0104] The onset temperatures of endothermic peak and 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. [0105] 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 width: 0.013°, wavelength: 1.5418 Å, measurement diffraction angle range (2θ): 2.5- 40°. Due to the nature of the data, the crystal lattice spacing and overall pattern of the powder X-ray diffraction are important in determining crystal identity. The error range of the diffraction angle (2θ (°)) in powder X-ray diffraction is usually ± 0.2°, but the diffraction angle and diffraction intensity should not be strictly understood, which may vary to some extent depending on direction of crystal growth, particle size, and measurement conditions. [0106] Moreover, the following abbreviations may be used in Examples, Preparation Examples, and Tables below in some cases. PEx: Production Example No., Ex: Example No., PSyn: Production Example No. where compounds are produced by the same method (In the case that the number in the PSyn column has E as an initial letter, the compound was produced by using the corresponding starting material in the same manner as the compound having the number of Example compound. For example, the compound in which the PSyn column is E95 means that it was prepared in the same manner as the compound of Example 95. And in the case that the Production Example compound forms a salt, the salt can be formed by a conventional method), Syn: Example No. where compounds are produced by the same method (In the case that the number in the Syn column has P as an initial letter, the compound was produced by using the corresponding starting material in the same manner as the compound having the number of Production Example compound. For example, the compound in which the Syn column is P10 means that it was prepared in the same manner as the compound of Production Example 10. And in the case that 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 spectrometry (ionization method CI, [M+H]+ unless otherwise specified), EI+: m/z value in mass spectrometry (ionization method EI, M+ unless otherwise specified), ESI+: m/z value in mass spectrometry (ionization method ESI, [M+H]+ unless otherwise specified), ESI-: m/z value in mass spectrometry (ionization method ESI, [M-H]- unless otherwise specified), 1 H- NMR (CDCl 3 , 400 MHz): δ (ppm) of signals in 1 H NMR in CDCl 3 , 1 H-NMR (CDCl 3 , 500 MHz): δ (ppm) of signals in 1 H NMR in CDCl 3 , 1 H-NMR (DMSO-d 6 , 400 MHz): δ (ppm) of signals in 1 H NMR in DMSO-d 6 , 1 H-NMR (DMSO-d 6 , 500 MHz): δ (ppm) of signals in 1 H NMR in DMSO-d 6 , 1 H-NMR (CD 3 OD, 400 MHz): δ (ppm) of signals in 1 H NMR in CD 3 OD, J: coupling constant, s: singlet, d: doublet, t: triplet, q: quartet, dd: double doublet, dt: double triplet, dq: double quartet, ddd: double double doublet, br: broad (e.g. br s), m: multiplet, aq.: aqueous solution, sat.: saturated, rt: room temperature, DSC 1 : onset temperatures of endothermic peaks in DSC measurement, DSC 2 : onset temperatures of exothermic peaks in DSC measurement, 2θ: diffraction angle of peaks in powder X-ray diffraction. [0107] In the present specification, a naming software such as ACD/Name (registered trademark; Advanced Chemistry Development, Inc.) may be used in some cases. [0108] Compounds whose names are preceded by "rac" are racemates. [0109] In addition, for the sake of convenience, a concentration of mol/L is represented by M. For example, a 1 M aqueous sodium hydroxide solution means a 1 mol/L aqueous sodium hydroxide solution. [0110] Preparation Example 1 Under an argon flow, to a solution of 1-bromo-4-iodo-2-(trifluoromethyl)benzene (1 g) in THF (5 mL) were added CuI (55 mg), PdCl 2 (PPh 3 ) 2 (201 mg), Et 3 N (4 mL) and trimethylsilylacetylene (0.47 mL) at rt and the mixture was stirred at rt for 1 hour 15 min. The mixture was treated with water at rt, then extracted with CH 2 Cl 2 . The organic layer was dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc = 100/0 to 90/10) to give {[4- bromo-3-(trifluoromethyl)phenyl]ethynyl}(trimethyl)silane (936 mg) as oil. [0111] Preparation Example 6 To a mixture of 4-iodo[1,1'-biphenyl]-2-carbaldehyde (11.2 g) and Pd(PPh 3 ) 4 (2.11 g) in DMSO (150 mL) were added prop-2-ynoic acid (3.08 g) and DBU (14.9 g) dropwise at 25- 35 °C under nitrogen. The mixture was stirred at 40 °C for 1.5 hours under nitrogen. The mixture was diluted with NaHCO 3 aq., extracted with EtOAc. The separated aqueous phase was adjusted pH to 2-3 with cold 1 M HCl aq. to give the suspension. The suspension was filtered and the filtered cake was concentrated to give 3-(2-formyl[1,1'-biphenyl]-4-yl)prop-2- ynoic acid (7.2 g) as a solid. [0112] Preparation Example 7 Under an argon flow, to a solution of 4-bromo-1-(4-fluorophenyl)-5-(trifluoromethyl)- 1H-pyrazole (760 mg) in DMF (16 mL) were added Pd(OAc) 2 (30 mg), XPhos (122 mg), Et 3 N (1.1 mL) and trimethylsilylacetylene (0.52 mL) at rt, and the mixture was stirred at 100 °C for 3 hours, then cooled to rt. The mixture was treated with water and brine at rt, then extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO 4 , 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 oil. [0113] Preparation Example 10 A mixture of {[4-bromo-3-(trifluoromethyl)phenyl]ethynyl}(trimethyl)silan e (100 mg), phenylboronic acid (57 mg), SPhos (13 mg), Pd(OAc) 2 (4 mg), K 3 PO 4 (200 mg), toluene (2 mL) and water (0.5 mL) was stirred at 130 °C for 1 hour under microwave irradiation, then cooled to rt. The mixture was treated with water (10 mL) and EtOAc (10 mL) at rt and extracted with EtOAc. The organic layer was dried over anhydrous MgSO 4 (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 oil. [0114] Preparation Example 11 Under an argon flow, 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), K 3 PO 4 (1.98 g), toluene (16 mL) and water (3.5 mL) was stirred at 100 °C for 1 hour, then cooled to rt. The mixture was treated with water and EtOAc at rt and extracted with EtOAc. The organic layer was dried over anhydrous MgSO 4 (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 oil. [0115] Preparation Example 21 To a solution of trimethyl{[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]ethynyl}s ilane (9.19 g) in MeOH (150 mL) was added K 2 CO 3 (6 g) at rt, and the mixture was stirred at rt for 1.5 hours. The mixture was treated with water at rt and extracted with CH 2 Cl 2 . The organic layer was dried over anhydrous MgSO 4 , 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 oil. [0116] Preparation Example 22 To a solution of 2-phenyl-3-(trifluoromethyl)-5-[(trimethylsilyl)ethynyl]pyri dine (887 mg) in MeOH (14 mL) was added K 2 CO 3 (580 mg) at rt, and the mixture was stirred at rt for 1 hour. The mixture was treated with water at rt and extracted with CHCl 3 . The organic layer was washed with brine, dried over anhydrous MgSO 4 , 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 oil. [0117] Preparation Example 23 To a mixture of 1-phenyl-5-(trifluoromethyl)-4-[(trimethylsilyl)ethynyl]-1H- pyrazole (980 mg) in THF (10 mL) was added TBAF (1 M in THF, 4.9 mL). The mixture was stirred at 25-30 °C for 4 hours. The reaction mixture was concentrated and the residue was diluted with water, extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give 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 oil. [0118] Preparation Example 31 Under an argon flow, to an ice-water-bath cooled solution of 4-ethynyl-2- (trifluoromethyl)-1,1'-biphenyl (7.1 g) in THF (100 mL) was added nBuLi (26 mL, 1.57M in hexane) dropwise, and the mixture was stirred at rt for 0.5 hours. The mixture was poured into dry-ice in a 1000 mL beaker quickly, then stirred at rt in water bath for 0.5 hours. To the mixture was added 0.5 M HCl aq. (150 mL) slowly at rt, then stirred at rt for 10 min. The mixture was extracted with EtOAc. The organic layer was dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure to give the crude product as a solid. The obtained solid was treated with IPE and hexane at rt. The solution was extracted with 0.5 M NaOH aq. solution. The aqueous layer was treated with 1 M HCl aq. at rt, then extracted with EtOAc. The organic layer was dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure to give the product. The obtained solid was treated with hexane and IPE at rt, then stirred at rt for 5 min. 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 (CHCl 3 /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. [0119] Preparation Example 32 Under an argon flow, to a dry-ice-acetone-bath cooled solution of 5-ethynyl-2-phenyl- 3-(trifluoromethyl)pyridine (582 mg) in THF (10 mL) was added nBuLi (1.8 mL, 1.57 M in hexane) dropwise, and the mixture was stirred at the same temperature for 20 minutes. To the mixture was added dry-ice, then the mixture was warmed up to rt for 0.5 hours. To the mixture were added 1M NaOH aq. and water at rt, then the mixture was washed with Et 2 O. The organic layer was extracted with water twice. The combined aqueous layer was treated with 10% citric acid aq. at rt, then extracted with CHCl 3 -IPA (5:1, v/v). The organic layer was dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure to give 3-[6-phenyl-5- (trifluoromethyl)pyridin-3-yl]prop-2-ynoic acid (544 mg) as a solid. [0120] In Preparation Examples 33-36, a reaction was conducted in the similar manner to that of Preparation Example 31. The reaction mixture was concentrated after the stirring with dry- ice, and no further treatment was conducted to give a lithium salt of a target carboxylic acid. [0121] Preparation Example 43 To a mixture of 3-(4-bromophenyl)prop-2-ynoic acid (500 mg) and 1-methylpiperazine (267 mg) in THF (10 mL) were added DIPEA (1.2 mL) and T3P (registered trademark) (1.70 g, 50% in EtOAc). The mixture was stirred at 20 °C for 16 hours. The mixture was combined with another batch. The combined mixture was treated with water and extracted with EtOAc three times. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness. The residue was purified by reversed phase column chromatography [C18, 10-20% CH 3 CN in water (0.05% NH 3 .H 2 O)]. The combined flows were concentrated to remove CH 3 CN, and the aqueous phase was extracted with EtOAc three times. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated to dryness to give 3- (4-bromophenyl)-1-(4-methylpiperazin-1-yl)prop-2-yn-1-one (970 mg) as a solid. [0122] Preparation Example 45 To a solution of tert-butyl 4-(3-{1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}prop- 2-ynoyl)piperazine-1-carboxylate (108 mg) in CH 2 Cl 2 (2 mL) was added TFA (100 uL). The mixture was stirred at 28-32 °C for 1 hour. The reaction mixture was concentrated to give 1- (piperazin-1-yl)-3-{1-[4-(trifluoromethyl)phenyl]-1H-pyrazol -4-yl}prop-2-yn-1-one monotrifluoroacetate (157 mg) as a solid. [0123] Preparation Example 47 A mixture of methyl 3-aminobenzoate (102 mg), 3-[2-(trifluoromethyl)[1,1'-biphenyl]- 4-yl]prop-2-ynoic acid (150 mg), DIPEA (242 mg) and HATU (491 mg) in DMF (3 mL) was stirred at rt for 13 hours. The mixture was treated with EtOAc and water at rt, then extracted with EtOAc. The organic layer was washed with 10% citric acid aq., sat. NaHCO 3 aq. and brine, and dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography twice (hexane/EtOAc = 90/10 to 50/50) to give methyl 3-({3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2- ynoyl}amino)benzoate (47 mg) as a solid. [0124] Preparation Example 48 To a mixture of 3-(4-bromophenyl)prop-2-ynoic acid (2 g) in DMF (20 mL) were added 2-anilinoethan-1-ol (1.34 mL), 2-chloro-1-methylpyridinium iodide (3.4 g) and DIPEA (2.28 mL). The mixture was stirred at rt for 1 hour. After addition of water, the mixture was extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO 4 , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography twice (hexane/EtOAc = 75/25 to 0/100) to give 3-(4-bromophenyl)-N-(2-hydroxyethyl)-N- phenylprop-2-ynamide (2.72 g) as a solid. [0125] Preparation Example 50 To a solution of 4-iodo-3-(trifluoromethyl)-1H-pyrazole (1 g) in CH 2 Cl 2 (20 mL) were added phenylboronic acid (1 g), Cu(OAc) 2 (600 mg) and pyridine (600 uL), then the reaction mixture was stirred at 25-30 °C for 12 hours under oxygen atmosphere. The mixture was concentrated, and the residue was diluted with water, extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give crude product. The crude product was purified by silica gel column chromatography (0.9% EtOAc in petroleum ether) to give 4-iodo-1-phenyl-3-(trifluoromethyl)-1H-pyrazole (1.28 g) as oil. [0126] Preparation Example 51 To a mixture of 1-(piperazin-1-yl)-3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-y l]prop-2- yn-1-one monotrifluoroacetate (480 mg) in DMF (10 mL) was added K 2 CO 3 (336 mg) and ethyl 4-bromobutanoate (239 mg), then the reaction mixture was stirred at 25-35°C for 48 hours. This mixture was combined with another batch, diluted with water, extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude. The crude was purified by reversed phase column chromatography (C18, 50-60% CH 3 CN in water/0.05% HCl) and lyophilized to give ethyl 4- (4-{3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoyl} piperazin-1-yl)butanoate monohydrochloride (260 mg) as a solid. [0127] Preparation Example 52 To a mixture of methyl 3-[3'-(difluoromethoxy)-2-(trifluoromethyl)[1,1'-biphenyl]-4 - yl]prop-2-ynoate (1.2 g), THF (5 mL) and MeOH (5 mL) was added 1 M NaOH aq. (5 mL) at rt. The mixture was stirred at rt for 1 hour and washed with Et 2 O. To the separated aqueous extract was added 1 M HCl aq. (5 mL) and EtOH. The mixture was concentrated in vacuo. To the residue was added EtOH and then the mixture was filtered to remove the 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. [0128] Preparation Example 56 To a solution of methyl 4-iodo[1,1'-biphenyl]-2-carboxylate (14.7 g) in CH 2 Cl 2 (150 mL) was added DIBAL-H (156 mL, 1.0 M in toluene) at -78 °C for 0.5 hours under nitrogen. The mixture was stirred at 25-30°C for another 3 hours under nitrogen. The mixture was poured into water and diluted with 2 M HCl aq. until the mixture was turned to clear. The mixture was extracted with CH 2 Cl 2 . The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated to give the crude. The crude 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 oil. [0129] Preparation Example 57 To a solution of (4-iodo[1,1'-biphenyl]-2-yl)methanol (12.2 g) in CH 2 Cl 2 (150 mL) was added MnO 2 (30 g) and the reaction mixture was stirred at 50 °C for 12 hours. After cooled to room temperature, the reaction mixture was filtered through Celite (registered trademark). The filtrate was concentrated to give 4-iodo[1,1'-biphenyl]-2-carbaldehyde (11.2 g) as oil. [0130] Preparation Example 58 To a solution of 3-(2-formyl[1,1'-biphenyl]-4-yl)prop-2-ynoic acid (1 g) in CH 2 Cl 2 (15 mL) were added DMF (29.2 mg) and (COCl) 2 (420 uL) 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 Na 2 CO 3 (1.69 g) in water (20 mL) and CH 2 Cl 2 (20 mL). The reaction mixture was stirred at 0 °C for 1 hour, diluted with water, and extracted with CHCl 3 /IPA (3/1, v/v). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated to give the crude. The crude was purified by silica gel column chromatography (5% MeOH in CH 2 Cl 2 ) to give N-[(2S)-2,3- dihydroxypropyl]-3-(2-formyl[1,1'-biphenyl]-4-yl)prop-2-ynam ide (738 mg) as a solid. [0131] Preparation Example 59 A solution of 3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoic acid (100 mg) in CH 2 Cl 2 (1.02 mL) were added Et 3 N (130 uL), rac-methyl (3R)-pyrrolidine-3-carboxylate monohydrochloride (68 mg) and COMU (192 mg) at 0 °C. The mixture was stirred at rt for 1 hour. After addition of sat. NaHCO 3 aq., the mixture was extracted with EtOAc. The separated organic extracts were washed with sat. NaHCO 3 aq., 1 M HCl aq. and brine, filtered through a phase-separator and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (EtOAc/hexane: 50/50 to 100/0, then CHCl 3 /MeOH = 90/10) to give rac-methyl 1-{3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoyl}- (3R)- pyrrolidine-3-carboxylate (96.6 mg) as oil. [0132] Preparation Example 60 To a solution of 4-(3,6-dihydro-2H-pyran-4-yl)-3-(trifluoromethyl)phenol (2.6 g) in MeOH (25 mL) was added Pd/C (260 mg, 10%) under hydrogen atmosphere. The mixture was stirred at rt for 24 hours. The reaction mixture was filtered through a pad of Celite (registered trademark). The filtrate was concentrated under reduced pressure to give 4-(oxan-4-yl)-3- (trifluoromethyl)phenol (2.51 g) as a solid. [0133] Preparation Example 61 To a solution of 4-(oxan-4-yl)-3-(trifluoromethyl)phenol (2.5 g) and 1,1,1-trifluoro-N- phenyl-N-((trifluoromethyl)-sulfonyl) methanesulfonamide (7.26 g) in CH 2 Cl 2 (30 mL) was added DIPEA (2.6 g). The mixture was stirred at rt for 3 hours. The reaction was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-9% EtOAc in hexane) to afford 4-(oxan-4-yl)-3-(trifluoromethyl)phenyl trifluoromethanesulfonate (3.56 g) as oil. [0134] Preparation Example 63 Under an argon flow, to a solution of 2-chloro-5-iodo-3-(trifluoromethyl)pyridine (1 g) in THF (10 mL) were added CuI (63 mg), PdCl 2 (PPh 3 ) 2 (137 mg), Et 3 N (4.6 mL) and trimethylsilylacetylene (0.54 mL) at rt and the mixture was stirred at rt for 1 hour. The mixture was treated with water, then extracted with CHCl 3 . The organic layer was dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc = 100/0 to 95/5) to give 2-chloro-3- (trifluoromethyl)-5-[(trimethylsilyl)ethynyl]pyridine (867 mg) as oil. [0135] Preparation Example 92 A mixture of 8-chloro-5-[(trimethylsilyl)ethynyl]quinoline (400 mg), [2- (trifluoromethyl)phenyl]boronic acid (460 mg), Pd(OAc) 2 (36 mg), K 2 CO 3 (440 mg) and XPhos (148 mg) in dioxane (40 mL) and water (13.3 mL) was degassed and purged with nitrogen, and then the mixture was stirred at 90 °C for 2 hours under nitrogen atmosphere. The mixture was combined with another batch (the same reaction was conducted with 400 mg of 8-chloro-5-[(trimethylsilyl)ethynyl]quinoline). The mixture was treated with water, extracted with EtOAc, washed with brine, dried over anhydrous sodium sulfate and filtered.The filtrate was concentrated. The crude product was purified by silica gel column chromatography (EtOAc/petroleum ether = 12/88 to 13/87) to give 5-ethynyl-8-[2- (trifluoromethyl)phenyl]quinoline (580 mg) as a solid. [0136] Preparation Example 127 A mixture of K 2 CO 3 (2.77 g) and 5-bromo-2-iodophenol (2 g) in DMF (10 mL) was stirred at 20 °C for 1 hour. To the mixture was added 2-iodopropane (3.41 g) and the mixture was stirred at 70 °C for 3 hours. The reaction mixture was diluted with water and extracted with EtOAc. The separated organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 4-bromo-1-iodo-2-[(propan-2- yl)oxy]benzene (2 g) as oil. [0137] Preparation Example 135 To a solution of 3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoic acid (100 mg) in CH 2 Cl 2 (3 mL) were added Et 3 N (120 uL), 2-(methylsulfanyl)ethan-1-amine (39 uL) and PyBOP (233 mg) in ice-water bath. The mixture was stirred at rt for 15 hours, treated with sat. NaHCO 3 aq., and extracted with CHCl 3 . The organic layer was washed with sat. NaHCO 3 aq., 1 M HCl aq. and water, then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (EtOAc/hexane = 10/90 to 50/50) to give N-[2- (methylsulfanyl)ethyl]-3-[2-(trifluoromethyl)[1,1'-biphenyl] -4-yl]prop-2-ynamide (103 mg) as a solid. [0138] Preparation Example 136 A mixture of methyl 3-[4-bromo-3-(trifluoromethyl)phenyl]prop-2-ynoate (500 mg), 2- (tributylstannyl)pyridine (780 mg) and Pd(PPh 3 ) 4 (94 mg) in toluene (10 mL) was stirred at 150 °C for 3 hours under nitrogen on microwave. The mixture was combined with 4 other batches (the same reaction was conducted four times with 500 mg of 3-[4-bromo-3- (trifluoromethyl)phenyl]prop-2-ynoate for each batch) and concentrated. The crude product was purified by silica gel column chromatography (EtOAc/petroleum ether = 15/85) to give methyl 3-[4-(pyridin-2-yl)-3-(trifluoromethyl)phenyl]prop-2-ynoate (1.43 g) as oil. [0139] Preparation Example 137 A mixture of 3-[2'-(benzyloxy)-2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]-1 -[(3R,4S)- 3,4-dihydroxypyrrolidin-1-yl]prop-2-yn-1-one (280 mg) in TFA (5 mL) was stirred at 80 °C for 16 hours and concentrated. The crude product was purified by reversed 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. [0140] Preparation Example 138 To a solution of 3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoic acid (155 mg) in CH 2 Cl 2 (2 mL) was added 1-chloro-N,N,2-trimethylprop-1-en-1-amine (85 uL) in an ice- water bath and the mixture was stirred for 15 min. The above solution was added dropwise to a mixture of N-{3-[(2-{[tert- butyldi(methyl)silyl]oxy}ethyl)amino]propyl}methanesulfonami de (166 mg) and sat. NaHCO 3 aq. (2.0 mL) in an ice-water bath. The mixture was stirred at the same temperature for 45 min. The resultant mixture was treated with water and extracted with CHCl 3 . 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-[(methanesulfony l)amino]propyl}-3-[2- (trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynamide (322 mg) as oil. [0141] Preparation Example 139 To a mixture of N-(3-aminopropyl)methanesulfonamide (100 mg) in MeOH (3 mL) was added {[tert-butyldi(methyl)silyl]oxy}acetaldehyde (126 mg) at rt. The mixture was stirred at rt for 1 hour. To the mixture was added NaBH 4 (27.1 mg) at rt. The mixture was stirred at rt for 2 hours, treated with water, CHCl 3 and NH 4 Cl aq., and extracted with CHCl 3 . 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 (CHCl 3 /MeOH = 100/0 to 80/20) to give N-{3-[(2-{[tert- butyldi(methyl)silyl]oxy}ethyl)amino]propyl}methanesulfonami de (168 mg) as oil. [0142] Preparation Example 141 A mixture of methyl 4-amino-2'-(trifluoromethyl)[1,1'-biphenyl]-2-carboxylate (11.4 g) and 3 M HCl aq. (39.2 mL) in acetone (300 mL) was cooled to 0 °C and a solution of NaNO 2 (2.94 g) in water (50 mL) was added dropwise. The mixture was stirred at 0 °C for 1 hour. Urea (881 mg) was added followed by a solution of KI (11.2 g) in water (50 mL) at 0 °C. The mixture was stirred at 0 °C for 1 hour. The mixture was stirred at 15-20 °C for 1 hour. The mixture was diluted with water, 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 oil. [0143] Preparation Example 142 To a mixture of tert-butyl (2-aminoethyl)carbamate (500 mg) in CH 2 Cl 2 (15 mL) was added Et 3 N (1.30 mL) followed by methyl (chlorosulfonyl)acetate (648 mg) at 0 °C and stirred at 15-20 °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 give methyl 10,10-dimethyl-3,3,8-trioxo-9-oxa- 3λ 6 -thia-4,7-diazaundecan-1-oate (310 mg) as a gum. [0144] Preparation Example 143 To a solution of methyl 10,10-dimethyl-3,3,8-trioxo-9-oxa-3λ 6 -thia-4,7-diazaundecan- 1-oate (310 mg) in THF (5 mL) was added LiBH 4 (46 mg) at 0-4 °C. The mixture was stirred at 0-4 °C for 1.5 hours. The mixture was poured into sat. NH 4 Cl aq. and extracted with EtOAc, dried over anhydrous sodium sulfate, filtered, concentrated to give tert-butyl {2-[(2- hydroxyethanesulfonyl)amino]ethyl}carbamate (250 mg) as oil. [0145] Preparation Example 144 To a solution of 1-(4-fluorophenyl)-2-(trifluoromethyl)-1H-imidazole (1.2 g) in H 2 SO 4 (12 mL) and water (12 mL) was added NIS (7.0 g) at 0 °C. The mixture was stirred for 10 min at 0 °C, then the mixture was stirred at 70 °C for 16 hours. The reaction mixture was adjusted pH to 8-9 with 30% NaOH aq. 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-imidazo le (1.35 g) as a solid. [0146] Preparation Example 145 To a solution of 1-(4-fluorophenyl)-4,5-diiodo-2-(trifluoromethyl)-1H-imidazo le (1.35 g) in THF (14 mL) was added dropwise ethylmagnesium bromide (945 uL, 3 M in Et 2 O) at - 40 °C. The mixture was stirred at -40 °C for 30 min. The reaction mixture was quickly poured into NH 4 Cl aq. and extracted with EtOAc. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel column chromatography (EtOAc/petroleum ether = 18/82) to give 1-(4- fluorophenyl)-4-iodo-2-(trifluoromethyl)-1H-imidazole (0.8 g) as a solid. [0147] Example 1 To a solution of 1-methylpiperazine (180 uL), 3-([1,1'-biphenyl]-2-yl)prop-2-ynoic acid (300 mg), DIPEA (1.05 g) in THF (15 mL) was added T3P (registered trademark) (2.58 g, 50% in EtOAc) at 0 °C. The mixture was stirred at rt for 16 hours. The mixture was concentrated under reduced pressure to give a residue. The crude product was purified by reversed phase column chromatography (C18, 5~55% CH 3 CN in water/0.1% NH 3 .H 2 O) to give 3-([1,1'- biphenyl]-2-yl)-1-(4-methylpiperazin-1-yl)prop-2-yn-1-one (110 mg) as a solid. [0148] Example 20 To a solution of 3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoic acid (100 mg) in CH 2 Cl 2 (1 mL) were added Et 3 N (130 uL), (3R)-pyrrolidine-3-carboxamide monohydrochloride (62 mg) and COMU (192 mg) at 0 °C. The mixture was stirred at rt for 1 hour. To the mixture was added sat. NaHCO 3 aq. and the mixture was extracted with EtOAc. The separated organic extracts were washed with sat. NaHCO 3 aq., 1 M HCl aq. and brine, filtered through a phase separator and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl 3 /MeOH = 100/0 to 90/10) to give (3R)- 1-{3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoyl}p yrrolidine-3-carboxamide (98.3 mg) as a solid. [0149] Example 33 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 rt for 13 hours. The mixture was treated with EtOAc and water at rt, then extracted with EtOAc. The organic layer was washed with 10% aq. citric acid, sat. NaHCO 3 aq., brine, and dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography twice (CHCl 3 /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. [0150] Example 34 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 at rt for 4 hours. The mixture was treated with EtOAc and water at rt, then extracted with EtOAc. The organic layer was washed with sat. NaHCO 3 aq. and brine, dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl 3 /MeOH = 100/0 to 90/10) to give the desired product. The obtained product was treated with IPE and hexane at rt, then triturated. The solid was collected by filtration, washed with hexane and dried in vacuo at 50 °C to give 1-{3-[2- (trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoyl}piperidin e-4-carboxamide (76 mg) as a solid. [0151] Example 35 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 at rt for 2 hours. The mixture was treated with EtOAc and water at rt, then extracted with EtOAc. The organic layer was washed with sat. NaHCO 3 aq. and brine, dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography twice (CHCl 3 /MeOH = 100/0 to 90/10) to give N-[(2S)-2,3-dihydroxypropyl]-3-[2-(trifluoromethyl)[1,1'-bip henyl]-4-yl]prop-2-ynamide (29 mg) as syrup. [0152] Example 36 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 at rt for 4 hours. The mixture was treated with EtOAc and water at rt, then extracted with EtOAc. The organic layer was washed with sat. NaHCO 3 aq. and brine, dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography twice (CHCl 3 /MeOH = 100/0 to 90/10) to give N-[(2R)-2,3-dihydroxypropyl]-3-[2-(trifluoromethyl)[1,1'-bip henyl]-4-yl]prop-2-ynamide (14 mg) as syrup. [0153] Example 43 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) were added 2-chloro-1-methylpyridinium iodide (1.4 mL) (0.33 M in DMF) and DIPEA (64 mg), and the mixture was stirred at rt for 2 hours. The mixture was diluted with EtOAc and washed with sat. NaHCO 3 aq. and brine, dried over anhydrous MgSO 4 , filtered and concentrated in vacuo. The residue was purified by preparative LC/MS (XBridge Prep C18 5 µm OBD TM 30 x150 mm Column: MeOH/10 mM NH 4 HCO 3 aq.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-o ne (48 mg) as a solid. [0154] Example 44 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) were added 2-chloro-1-methylpyridinium iodide (1.5 mL) (0.35 M in DMF) and DIPEA (77 mg), and the mixture was stirred at rt for 2 hours. The mixture was diluted with EtOAc and washed with sat. NaHCO 3 aq. and brine, dried over anhydrous MgSO 4 , filtered and concentrated in vacuo. The residue was purified by preparative LC/MS (XBridge Prep C18 5 µm OBD TM 30 x150 mm Column: MeOH/10 mM NH 4 HCO 3 aq.10/90 to 95/5), and MeOH was removed under reduced pressure. The residue was extracted with CHCl 3 and the organic layer was washed with water, dried over anhydrous MgSO 4 , filtered and concentrated in vacuo to give a solid, which was treated with IPE and sonicated for a while. The mixture was concentrated in vacuo to give 1-[(3S,4S)-3,4- dihydroxypyrrolidin-1-yl]-3-[2-(trifluoromethyl)[1,1'-biphen yl]-4-yl]prop-2-yn-1-one (42 mg) as a solid. [0155] Example 45 To a mixture of 3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoic acid (90 mg) and L-serinamide monohydrochloride (54 mg) were added 2-chloro-1-methylpyridinium iodide (1 mL) (0.45 M in DMF) and DIPEA (102 mg), and the mixture was stirred at rt for 2 hours. The mixture was diluted with EtOAc and washed with sat. NaHCO 3 aq. and brine, dried over anhydrous MgSO 4 , filtered and concentrated in vacuo. The residue was purified by preparative LC/MS (XBridge Prep C18 5 µm OBD TM 30 x150 mm Column: MeOH/10 mM NH 4 HCO 3 aq.10/90 to 95/5), and lyophilized to give N 2 -{3-[2-(trifluoromethyl)[1,1'- biphenyl]-4-yl]prop-2-ynoyl}-L-serinamide (16 mg) as a solid. [0156] Example 46 To a mixture of 3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoic acid (90 mg) and (azetidine-3,3-diyl)dimethanol monohydrochloride (58 mg) were added 2-chloro-1- methylpyridinium iodide (1 mL) (0.45 M in DMF) and DIPEA (103 mg), and the mixture was stirred at rt for 2 hours. The mixture was diluted with EtOAc and washed with sat. NaHCO 3 aq. and brine, dried over anhydrous MgSO 4 , filtered and concentrated in vacuo. The residue was purified by preparative LC/MS (XBridge Prep C185 µm OBD TM 30 x150 mm Column: MeOH/10 mM NH 4 HCO 3 aq.10/90 to 95/5) and lyophilized to give oil, which was treated with small amount of CH 2 Cl 2 . 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. [0157] Example 47 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 at rt for 2 hours. The mixture was treated with EtOAc and water at rt, then extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl 3 /MeOH = 100/0 to 90/10) to give the desired product as a solid. The obtained solid was treated with IPE (1 mL) and hexane (5 mL) at rt, then triturated. The solid was collected by filtration, washed with hexane 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. [0158] Example 87 Under argon atmosphere, a mixture of 3-(4-bromophenyl)-N-(2-hydroxyethyl)-N- phenylprop-2-ynamide (100 mg), trimethyl(2-pyridyl)tin (75 uL) and PdCl 2 (PPh 3 ) 2 (20 mg) in toluene (1 mL) was stirred for 2 hours at 100 °C under microwave irradiation. To the mixture was added potassium fluoride aq. and the resultant mixture was stirred and extracted with CHCl 3 . The organic layer was concentrated in vacuo. The residue was purified by silica gel column chromatography (hexane/EtOAc = 50/50 to 0/100) to give the desired product. The solid was triturated with EtOAc, filtered and dried in vacuo to give N-(2-hydroxyethyl)-N- phenyl-3-[4-(pyridin-2-yl)phenyl]prop-2-ynamide (18 mg) as a solid. [0159] Example 88 A mixture of 3-(4-bromophenyl)-1-(4-methylpiperazin-1-yl)prop-2-yn-1-one (200 mg), 4-pyridylboronic acid (96.0 mg), Na 2 CO 3 (138 mg) and Pd(PPh 3 ) 4 (76 mg) in 1,4-dioxane (4 mL) and water (0.8 mL) was degassed and purged with nitrogen gas, then the reaction mixture was stirred at 85 °C for 16 hours under nitrogen gas. The mixture was treated with water (30 mL) and extracted with EtOAc three times. The combined organic phase was 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 eluted with 0~10% EtOAc/petroleum ether followed by reversed phase column chromatography (C18, 0-50% CH 3 CN in water/0.05% NH 3 .H 2 O) to give the 1-(4-methylpiperazin-1-yl)-3-[4-(pyridin-4- yl)phenyl]prop-2-yn-1-one (67.9 mg) as a solid after lyophilization. [0160] Example 90 A solution of methyl 3-({3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2- ynoyl}amino)benzoate (47 mg) in THF (1 mL) and MeOH (1 mL) was added 1 M NaOH aq. (0.5 mL) at rt, and the mixture was stirred at rt for 1.5 hours. To the mixture was added 1 M NaOH aq. (0.5 mL) at rt, and the mixture was stirred at rt for 5 hours. The mixture was treated with 1 M HCl aq. (1.0 mL) and water at rt, then extracted with CHCl 3 . The organic layer was dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl 3 /MeOH = 100/0 to 80/20) to give the desired product. The obtained solid was treated with IPE (1 mL) and hexane (5 mL) at rt, and triturated. The solid was collected by filtration, washed with hexane and dried in vacuo at 50 °C to give 3-({3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoyl} amino)benzoic acid (28 mg) as a solid. [0161] Example 91 A mixture of ethyl 3-(piperazin-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 at rt for 15 hours. The mixture was treated with EtOAc and water at rt, then extracted with EtOAc. The organic layer was washed with sat. NaHCO 3 aq. and brine, dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl 3 /EtOAc = 100/0 to 50/50) to give the desired intermediate as syrup. The obtained intermediate (114 mg) was dissolved with THF (1 mL) and MeOH (1 mL) at rt, then to the solution was added 1 M NaOH aq. (1 mL) at rt. The mixture was stirred at rt for 0.5 hours. The mixture was treated with 1 M HCl aq. (1 mL) and water (10 mL) at rt, then extracted with CHCl 3 -IPA (5:1, v/v). The organic layer was dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure to give the desired product as a solid. The obtained solid was dissolved with THF (3 mL) at rt, then 4 M HCl/dioxane (1 mL) was added to it. The mixture was concentrated under reduced pressure. The residue was treated with IPE (5 mL) at rt, and triturated. The solid was collected by filtration, washed with IPE and dried in vacuo at 50 °C to give 3-(4-{3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoy l}piperazin-1- yl)propanoic acid monohydrochloride (79 mg) as a solid. [0162] Example 92 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 at rt for 3 hours. The mixture was treated with EtOAc and water at rt, then extracted with EtOAc. The organic layer was washed with sat. NaHCO 3 aq. and brine and dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc = 95/5 to 50/50) to give the desired intermediate. The intermediate was treated with concentrated HCl aq. (2 mL) and dioxane (2 mL) at rt, and the mixture was stirred at 100 °C for 0.5 hours, then cooled to rt. 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 CHCl 3 . The organic layer was dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl 3 /MeOH = 100/0 to 90/10) to give the recovered intermediate. The intermediate was dissolved with THF (4 mL) and H 2 O (2 mL) at rt, then LiOH·H 2 O (100 mg) was added to the solution. The mixture was stirred at rt for 4 hours and at 50 °C (oil bath temperature) for 6 hours. The mixture was treated with 1 M HCl aq. (5 mL) at rt and extracted with CHCl 3 . The organic layer was dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (CHCl 3 /MeOH = 100/0 to 90/10) to give the desired product, which was treated with IPE and hexane at rt, then triturated. The solid was collected by filtration, washed with hexane and dried in vacuo at 50 °C to give 1-{3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoyl}- 2,3-dihydro-1H- indole-6-carboxylic acid (10 mg) as a solid. [0163] Example 95 To a mixture of 1-(piperazin-1-yl)-3-{1-[4-(trifluoromethyl)phenyl]-1H-pyraz ol-4- yl}prop-2-yn-1-one monotrifluoroacetate (157 mg) in MeOH (10 mL) were added (HCHO)n (37 mg), Et 3 N (34 uL) and AcOH (28 uL). The mixture was stirred at 25-30 °C for 0.5 hours, then NaBH 3 CN (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*3um; mobile phase: water (NH 3 H 2 O)/CH 3 CN = 58/42 to 28/72). Fractions containing the desired compounds 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. [0164] Example 96 To a mixture of N-[(2R)-2,3-dihydroxypropyl]-3-(2-formyl[1,1'-biphenyl]-4-yl )-N- phenylprop-2-ynamide (95 mg) and piperidine (0.05 mL) in MeOH (2 mL) was added AcOH (30 uL). The reaction mixture was stirred at 60 °C for 4 hours. Then to the above mixture was added NaBH 3 CN (41 mg) and stirred at 25 °C for another 3 hours. The mixture was combined with another batch and purified by reversed phase column chromatography (C18, 80-100% MeOH in water/0.1% NH 3 .H 2 O) 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. [0165] Example 99 To a solution of 1-(thiomorpholin-4-yl)-3-[2-(trifluoromethyl)[1,1'-biphenyl] -4- yl]prop-2-yn-1-one (137 mg) in MeOH (1 mL) and CH 2 Cl 2 (0.25 mL) were added iodobenzene diacetate (295 mg) and ammonium carbamate (57 mg). The mixture was stirred at rt for 30 min and concentrated under reduced pressure. The resultant residue was purified by silica gel column chromatography (EtOAc/hexane: 30/70 to 100/0 then CHCl 3 /MeOH = 90/10) to give 1-imino-4-{3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2 -ynoyl}-1λ 6 -thiomorpholin-1- one (134 mg) as a solid. [0166] Example 100 A mixture of tert-butyl (3S)-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 (0.28 M in DMF, 2mL) and DIPEA (95 mg) in DMF (2 mL) was stirred at rt for 12 hours. The mixture was treated with EtOAc and water at rt, then extracted with EtOAc. The organic layer was washed with sat. NaHCO 3 aq. and brine, and dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/EtOAc = 100/0 to 50/50) to give the intermediate as syrup. The obtained intermediate was dissolved with CH 2 Cl 2 (2 mL) at rt and to the solution was added TFA (1 mL) at rt. The mixture was stirred at rt for 1 hour and concentrated under reduced pressure. The residue was treated with sat. NaHCO 3 aq. (10 mL) and water at rt, then extracted with CHCl 3 -IPA (5:1, v/v). The organic layer was dried over anhydrous MgSO 4 , filtered and concentrated under reduced pressure to give the desired product as syrup. The obtained product was dissolved with THF (2 mL), IPE (2 mL) and hexane (5 mL) at rt, then oxalic acid (17 mg) was added to it. The mixture was stirred at rt for 0.5 hours. The solid was collected by filtration, washed with hexane and dried in vacuo at 50 °C to give 1-[(3S)-3- aminopyrrolidin-1-yl]-3-[2-(trifluoromethyl)[1,1'-biphenyl]- 4-yl]prop-2-yn-1-one monooxalate (54 mg) as a solid. [0167] Example 106 To a solution of 3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoic acid (208 mg) in DMF (10 mL) were added EDC ·HCl (187 mg), HOBt (163 mg) and DIPEA (244 mg) under nitrogen atmosphere at 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 rt for 16 hours and then concentrated under reduced pressure. The residue was purified by preparative TLC (CH 2 Cl 2 :MeOH = 10:1) to give N-[(1r,3R,4S)-3,4-dihydroxycyclopentyl]-3-[2- (trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynamide (64.6 mg) as a solid. [0168] Example 119 To the 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), NH 4 Cl (21 mg) and HATU (245 mg) in DMF (3 mL) was added DIPEA (168 uL), and then the mixture was stirred at 50 °C for 16 hours. The mixture was combined with another batch (the same reaction was conducted with 20 mg of 4-{3-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-3-oxoprop-1-yn-1 -yl}- 2'-(trifluoromethyl)[1,1'-biphenyl]-2-carboxylic acid), diluted with 4% LiCl aq. 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 reversed-phase column (C18, 50- 60% MeOH in water/0.1% NH 3 .H 2 O). The obtained product was purified by reversed-phase column (C18, 45-55% MeOH in water/0.1% NH 3 .H 2 O). The crude product was purified by preparative HPLC (column: Phenomenex C18; mobile phase: 20-40% MeCN in water (HCl)) to give 4-{3-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-3-oxoprop-1-yn-1 -yl}-2'- (trifluoromethyl)[1,1'-biphenyl]-2-carboxamide (45.7 mg) as a solid by lyophilization. [0169] Example 127 A mixture of tert-butyl methyl[(3R)-1-{3-[4-(pyridin-2-yl)-3- (trifluoromethyl)phenyl]prop-2-ynoyl}pyrrolidin-3-yl]carbama te (257 mg) and TFA (1 mL) in CH 2 Cl 2 (5 mL) was stirred at 10-20 °C for 2 hours. The mixture was concentrated to give the crude, which was purified by reversed-phase column (C18, 50-60 % MeOH in water/0.1% NH 3 .H 2 O) to afford 1-[(3R)-3-(methylamino)pyrrolidin-1-yl]-3-[4-(pyridin-2-yl)- 3- (trifluoromethyl)phenyl]prop-2-yn-1-one (128 mg) as a solid by lyophilization. [0170] Example 128 To a mixture of rac-1-[(3R)-3-(hydroxymethyl)thiomorpholin-4-yl]-3-[2- (trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-yn-1-one (308 mg) in CH 2 Cl 2 (8 mL) was added m-CPBA (319 mg) and the reaction mixture was stirred at 10-15 °C for 12 hours. The reaction mixture was quenched by addition of sat. Na 2 SO 3 aq., diluted with water, and extracted with EtOAc. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Phenomenex C18; mobile phase: water (NH 3 .H 2 O)/MeCN = 60/40 to 30/70). Fractions containing the desired compounds were lyophilized to give rac-(3R)-3- (hydroxymethyl)-4-{3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-y l]prop-2-ynoyl}-1λ 6 - thiomorpholine-1,1-dione (107 mg) as a solid. [0171] Example 129 To a mixture of 1-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-3-[2'-hydroxy-2- (trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-yn-1-one (20 mg) and K 2 CO 3 (22 mg) in DMF (1 mL) was added 3-bromoprop-1-yne (7 uL). The reaction mixture was stirred at 60 °C for 1.5 hours. The reaction mixture was combined with 2 batches (the same reaction was conducted with 30 mg and 85 mg of 1-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-3-[2'-hydroxy-2- (trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-yn-1-one for each batch). The resultant mixture was purified by reversed phase column (C18, water (0.1% NH 3 .H 2 O)/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. [0172] Example 130 To a mixture of N-(2-{[tert-butyldi(methyl)silyl]oxy}ethyl)-N-{3- [(methanesulfonyl)amino]propyl}-3-[2-(trifluoromethyl)[1,1'- biphenyl]-4-yl]prop-2-ynamide (317 mg) and THF (5 mL) was added TBAF (1 M in THF, 1 mL) in ice-water bath. The mixture was stirred at the same temperature for 1.5 hours. The mixture was treated with sat. NH 4 Cl aq. and CHCl 3 . The separated organic layer was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (CHCl 3 /MeOH = 100:0 to 92:8). The obtained oil was sonicated with a mixture of EtOAc, IPE and hexane. The resultant mixture was concentrated under reduced pressure. The obtained solid was dissolved with CH 2 Cl 2 . To the solution was added hexane, and the mixture was concentrated to give N-(2-hydroxyethyl)- N-{3-[(methanesulfonyl)amino]propyl}-3-[2-(trifluoromethyl)[ 1,1'-biphenyl]-4-yl]prop-2- ynamide (209 mg) as a solid. [0173] Example 131 To a solution of 3-[2'-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoic acid (32 mg) in CH 2 Cl 2 (1 mL) were added Et 3 N (42 uL), (3R,4S)-pyrrolidine-3,4-diol monohydrochloride (23 mg) and PyBOP (74 mg). The mixture was stirred at rt for 4 hours, treated with 1 M HCl aq. and water, then extracted by EtOAc. The separated organic layer was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (CHCl 3 /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. [0174] Example 133 To a mixture of dimethylamine hydrochloride (37 mg) and MeOH (2 mL) was added Et 3 N (52 uL) and the mixture was stirred at 30 °C for 10 min. To the mixture were added 4-{3- [(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-3-oxoprop-1-yn-1-yl}- 2'-(trifluoromethyl)[1,1'- biphenyl]-2-carbaldehyde (150 mg) and AcOH (26 uL), and the resultant mixture was stirred at 60 °C for 3 hours. NaBH 3 CN (39 mg) was added and stirred at 30 °C for 30 min. The mixture was concentrated to give the crude product, which was purified by reversed phase column (C18, 40-50% MeCN in water/0.1%NH 3 .H 2 O) 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. [0175] Example 134 A mixture of 1-[(3R,4S)-3,4-dihydroxypyrrolidin-1-yl]-3-[2-(trifluorometh yl)[1,1'- biphenyl]-4-yl]prop-2-yn-1-one (300 mg) and EtOAc (3 mL) was stirred at 60 °C for 20 min. The solution was cooled to rt and stirred overnight. The precipitates were collected by filtration and dried at 40 °C under reduced pressure 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. [0176] Example 135 A mixture of 1-{3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2-ynoyl}p iperidine-4- carboxamide (100 mg) and EtOH (6 mL) was stirred at 50 °C for 2 hours. The solution was cooled to rt and the precipitates were collected by filtration. The obtained solid was dried at 50 °C under reduced pressure to give 1-{3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2- ynoyl}piperidine-4-carboxamide (22 mg) as a solid. [0177] Example 136 A small vial containing 1-imino-4-{3-[2-(trifluoromethyl)[1,1'-biphenyl]-4-yl]prop-2 - ynoyl}-1λ 6 -thiomorpholin-1-one (134 mg) and EtOAc (500-1000 uL) was placed in a lager vial containing hexane (5-10 mL). The outside vial was sealed and left to stand at rt overnight. The precipitates were 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-y noyl}-1λ 6 -thiomorpholin-1-one (104 mg) as solid. [0178] The compounds of Preparation Examples and Examples shown in Tables below were produced in the same manner as the methods in Preparation Examples or Examples as described above.
[0179] [Table 4] [0180] [Table 5] [0181] [Table 7]
[0183] [0184] [0185] [0186] [0187] [Table 12]
[0188] [Table 13] [0189] [Table 14] [0190] [Table 15] [0191] [Table 16] [0192] [Table 17] [0193] [Table 18]
[0194] [Table 19] [0195] [Table 20]
[0196] [Table 21]
[0197] [Table 22] [0198] [Table 23]
[0199] [Table 24] [0200] [Table 25]
[0201] [Table 26]
[0202] [Table 27] [0203] [Table 28]
[0204] [Table 29] [0205] [Table 30] [0206] [Table 31] [0207] [Table 32] [0208] [Table 33]
[0209] [Table 34]
[0210] [Table 35] [Industrial Applicability] [0211] A compound of formula (I) or a salt thereof has an inhibitory action on STING and is expected to be useful as a therapeutic drug for an autoimmune disease, a neurodegenerative disease, a type I interferonopathy and/or other STING-mediated disease.
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