2-phenyl-pyrrole compound as well as preparation method and application thereof

Abstract

The invention discloses a 2-phenyl-pyrrole compound as well as a preparation method and application thereof. Specifically, the invention provides a compound shown as a formula (I) or pharmaceutically acceptable salts thereof, and the compound has a good inhibitory effect on MPC, has a good in-vivo and in-vitro alopecia treatment effect, and has the advantages of low potential toxic and side effects and the like.

Description

TECHNICAL FIELD

[0001] The present application relates to a 2-phenyl-pyrrole compound, a preparation method thereof and an application thereof. BACKGROUND

[0002] Hair Loss, also known as Alopecia or Baldness, is a very common health problem. Studies have found that 50% of men and 25% of women will have pattern hair loss by the age of 50. Common types of hair loss include androgenetic alopecia (AGA), female pattern hair loss (FPHL), alopecia areata (AA) and hair thinning known as telogen effluvium. So far, three drugs, minoxidil, finasteride and baricitinib, have been approved by FDA for hair regeneration. All three drugs have been reported to be effective in only 30-40% of patients after repeated treatment, and there are relatively obvious side effects, such as causing increased heart rate, arrhythmia, weight gain, etc. (J Eur Acad Dermatol Venereol. 2022 Feb; 36(2): 286-294; J Am Acad Dermatol. 2021 Mar; 84(3): 737-746). Therefore, there is an urgent need for clinically efficient and low-toxicity hair loss treatment drugs with new mechanisms of action.

[0003] Hair follicle growth is cyclical. Each cycle includes a long growth phase (anagen), a short transitional phase (catagen), and a short resting phase (telogen). The ability of the hair follicle to maintain this cycle depends on the presence of hair follicle stem cells, i.e. HFSCs. HFSCs are usually inactive, but they can quickly "wake up" and actively divide when a new hair growth cycle begins. When HFSCs cannot be activated, hair loss occurs. It has been reported that the activation of HFSCs can be achieved by stimulating the activity of lactate dehydrogenase (LDH), an enzyme that catalyzes the reduction of pyruvate to lactate. Studies have found that inhibition of mitochondrial pyruvate carrier (MPC) can lead to increased LDH activity in HFSCs, and when MPC is knocked out or inhibited by drugs, cytoplasmic pyruvate cannot enter mitochondria, but is converted into other metabolites such as lactate by lactate dehydrogenase (LDH), resulting in increased LDH activity and activation of HFSCs, which ultimately promotes hair growth (Exp Dermatol. 2021 Apr; 30(4): 448-456). Currently, MPC has been shown to be a very promising therapeutic target for treating hair loss.

[0004] UK-5099 is the earliest MPC inhibitor proven to have hair growth activity (J Med Chem. 2021 Feb 25; 64(4): 2046-2063), which works similarly to Mpc1 gene knockout (Mpc1 gene is a transporter protein required for pyruvate to enter mitochondria, and its loss of function can increase the conversion of pyruvate to lactic acid), which can block pyruvate from entering mitochondria, thereby promoting lactic acid production. Increasing the production of lactic acid in the metabolic process of hair follicle stem cells can activate hair follicle stem cells in the resting phase, thereby promoting the hair follicle to enter a new growth cycle.

[0005]

[0006] At present, there are few structural types of MPC inhibitors with hair loss treatment effects, and it is urgent to find inhibitor molecules with novel structures, good physicochemical properties, good hair loss treatment effects in vivo and in vitro, and low potential toxicity. SUMMARY

[0007] The technical problem to be solved by the present application is to overcome the problems of few structural types of MPC inhibitors with hair loss treatment effects or potential toxic side effects in the prior art, and to provide a 2-phenyl-pyrrole compound, a preparation method thereof and an application thereof. The 2-phenyl-pyrrole compound of the present application satisfies one or more of the following effect advantages: novel structure, good physicochemical properties (for example, low liposolubility of the compound, easy preparation of salt, and at the same time, increased possibility of combination with protein amino acids), good inhibition effect on MPC, good hair loss treatment effect in vivo and in vitro, and low potential toxic side effects.

[0008] The present application solves the above technical problems by the following technical solutions:

[0009] The present application provides a compound as shown in formula (I) or a pharmaceutically acceptable salt thereof:

[0010]

[0011] wherein n is 0 or 1;

[0012] m is 1, 2, 3 or 4;

[0013] X is -(C1-C4 alkylene)-, -C(=O)- or -S(=O)2-;

[0014] R is independently hydrogen, halogen, cyano, C1-C6 alkyl, C1-C6 alkyl substituted by one or more R 0-1 C1-C6 alkyl, C1-C6 alkoxy or C1-C6 alkoxy substituted by one or more R 0-2 C1-C6 alkyl, C1-C6 alkoxy or C1-C6 alkoxy substituted by one or more R

[0015] R 0-1 and R 0-2 independently is C1-C6 alkyl, halogen or amino;

[0016] R 1 independently is H, 5-10 membered heterocycloalkyl, 6-10 membered aryl, 6-10 membered aryl substituted by one or more R 1-1 independently is H, 5-10 membered heterocycloalkyl, 6-10 membered aryl, 6-10 membered aryl substituted by one or more R 1-1 independently is H, 5-10 membered heterocycloalkyl, 6-10 membered aryl, 6-10 membered aryl substituted by one or more R 1-1 independently is H, 5-10 membered heterocycloalkyl, 6-10 membered aryl, 6-10 membered aryl substituted by one or more R

[0017] R 1-1 independently is C1-C6 alkyl, C1-C6 alkyl substituted by one or more halogen, C1-C6 alkoxy, halogen or amino;

[0018] R 2 is -COOR 2-1 ;

[0019] R 2-1 is hydrogen, C1-C6 alkyl or C1-C6 alkyl substituted by one or more R 2-1-1 independently is H, 5-10 membered heterocycloalkyl, 6-10 membered aryl, 6-10 membered aryl substituted by one or more R

[0020] R 2-1-1 independently is C1-C6 alkyl, halogen or amino;

[0021] R 3 is cyano.

[0022] In some preferred embodiments of the present application, some groups in the compounds of formula (I) or pharmaceutically acceptable salts thereof are defined as follows, and the groups not mentioned are as defined in any of the embodiments of the present application (simply referred to as "in some embodiments"), and the halogen is independently fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine.

[0023] In some embodiments, the C1-C4 alkylene is independently methylene.

[0024] In some embodiments, the C1-C6 alkoxy is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy, preferably ethoxy or n-butoxy.

[0025] In some embodiments, the C1-C6 alkyl groups are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, preferably ethyl.

[0026] In some embodiments, the 6-10 aryl groups are independently phenyl or naphthyl.

[0027] In some embodiments, the 5-10 heteroaryl groups are each independently a 5- or 6-membered heteroaryl group with N heteroatom and one or two heteroatoms; preferably pyridyl, for example...

[0028] In some implementations, n is 0 or 1.

[0029] In some implementations, m is 1.

[0030] In some implementations, R is independently a halogen or a cyano group.

[0031] In some implementations, R 1 Independently H, 6-10 aryl, and surrounded by one or more R 1-1 Substituted 6-10 aryl, 5-10 heteroaryl, or with one or more R 1-1 Substituted 5-10 heteroaryl groups.

[0032] In some implementations, R 1-1 It is independently a C1-C6 alkyl, a C1-C6 alkyl substituted with one or more halogens, a C1-C6 alkoxy, or a halogen.

[0033] In some implementations, R 2 -COOR 2-1 R 2-1 It is hydrogen or C1-C6 alkyl.

[0034] In some embodiments, X is independently -(C1-C4 alkylene)- or -S(=O)2-.

[0035] In some implementations, R is a halogen.

[0036] In some embodiments, X is -CH2-, -C(=O)-, or -S(=O)2-, preferably -CH2- or -S(=O)2-.

[0037] In some embodiments, m is 1, and R is independently fluorine or bromine, preferably fluorine.

[0038] In some implementations, n is 0, R 1 For H.

[0039] In some implementations, n is 1, R 1 for

[0040] In some implementations... Independently

[0041] In some embodiments, the compound represented by formula (I) is a compound represented by formula (IA) or a compound represented by formula (IB):

[0042]

[0043] Among them, R and R 1 The definition is as described above.

[0044] In some embodiments, the compound represented by formula (I) is any of the following compounds:

[0045] Table 1

[0046]

[0047]

[0048]

[0049]

[0050]

[0051]

[0052] This invention provides a compound as shown in formula (II):

[0053]

[0054] Where m, R and R 2 The definition is as described above.

[0055] This invention provides a method for preparing a compound as shown in formula (I), comprising either scheme 1 or scheme 2:

[0056] Option 1:

[0057] (1) When R 2 -COOR 2-1 ;R 2-1 It is a C1-C6 alkyl group or is composed of one or more R groups. 2-1-1When the C1-C6 alkyl group is substituted, the compound shown in formula (I) is prepared by the following steps: in a solvent, the compound shown in formula (II) is subjected to a substitution reaction with the compound shown in formula (Int-I) to obtain the compound shown in formula (I):

[0058]

[0059] Where, n, m, R, R 1 R 2 R 3 The definitions of X and X are as described above;

[0060] Y is a halogen, preferably bromine.

[0061] (2) When R 2 When the group is carboxyl, the preparation method of the compound shown in formula (I) further includes a hydrolysis reaction in addition to the above-mentioned substitution reaction.

[0062] Option 2:

[0063] In a solvent, the compound shown in formula (Ⅲ) is reacted with R. 2 -CH2-CN undergoes the addition reaction shown below to give the compound shown in formula (I);

[0064]

[0065] Where X, m, n, R, R 1 R 2 and R 3 The definition is as described above.

[0066] In some embodiments, in the substitution reaction of Scheme 1, the solvent is an amide solvent, preferably DMF.

[0067] In some embodiments, the substitution reaction in Scheme 1 is carried out in the presence of a base, for example, in the presence of cesium carbonate.

[0068] In some embodiments, in the addition reaction of Scheme 2, the solvent is one or more of alcohol solvents (e.g., ethanol), ester solvents (e.g., ethyl acetate) and ether solvents (e.g., tetrahydrofuran); preferably, it is an alcohol solvent (e.g., ethanol).

[0069] In some embodiments, the addition reaction in Scheme 2 is carried out in the presence of a catalyst, for example, in the presence of L-proline.

[0070] This invention provides a pharmaceutical composition comprising:

[0071] (1) The compound shown in formula (I) above, or a pharmaceutically acceptable salt thereof, and

[0072] (2) Pharmaceutically acceptable excipients.

[0073] The present invention provides the use of the compounds shown in formula (I) above, or pharmaceutically acceptable salts thereof, in the preparation of MPC inhibitors.

[0074] In some embodiments, the MPC inhibitor can be used in mammalian organisms or in vitro (e.g., for experimental purposes, as a standard or control sample for comparison, or to prepare a kit according to conventional methods in the art to provide rapid detection of the effect of MPC inhibition).

[0075] The present invention provides the use of the compounds shown in formula (I) above or pharmaceutically acceptable salts thereof, or the pharmaceutical compositions thereof, in the preparation of medicaments for the treatment or prevention of MPC-mediated diseases or conditions.

[0076] In some implementations, the MPC-mediated disease or condition is hair loss, diabetes, metabolic disease, or inflammation, etc.

[0077] The present invention provides the use of the compound shown in formula (I) above or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition thereof, in the preparation of a medicament for promoting lactate release.

[0078] The present invention provides the use of the compound shown in formula (I) above or a pharmaceutically acceptable salt thereof, or the use of the above pharmaceutical composition in the preparation of a medicament for the treatment of hair loss.

[0079] Terminology Explanation

[0080] In this invention, the term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable acid or base. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable base in a suitable inert solvent. When a compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. See Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition) for details.

[0081] The term "ester" includes physiologically hydrolyzable esters (compounds of the present invention that can be hydrolyzed under physiological conditions to release free acids or alcohols). Alternatively, the compounds of the present invention may themselves be esters.

[0082] In this invention, the structural segments This refers to the structural segment being connected to the rest of the molecule via this bond. For example, It refers to pyridinyl.

[0083] In this invention, the term "one or more" refers to 1, 2, 3, 4, 5 or 6, for example, 1, 2 or 3.

[0084] In this invention, the term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0085] In this invention, the term "alkyl" refers to a saturated monovalent hydrocarbon group that has a specified number of carbon atoms (e.g., C1-C6), is straight-chain or branched. Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc.

[0086] In this invention, the term "alkylene" refers to a saturated divalent hydrocarbon group obtained by removing two hydrogen atoms from a saturated straight-chain or branched hydrocarbon group. Alkylenes include, but are not limited to: methylene (-CH2-), ethylene {including -CH2CH2- or -CH(CH3)-}, isopropylene {including -CH(CH3)CH2- or -C(CH3)2-}, etc.

[0087] In this invention, the term "alkoxy" refers to the group R. Y -O-,R Y The definition is the same as the term "alkyl". Alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, n-hexoxy, etc.

[0088] In this invention, the term "aryl" refers to an aryl group having a specified number of carbon atoms (e.g., C6-C). 10 Aromatic groups are cyclic, unsaturated monovalent hydrocarbon groups, which can be monocyclic or polycyclic (e.g., two). In the case of polycyclic groups, the monocyclic rings share two atoms and one bond, and each ring is aromatic. The aryl group is connected to the rest of the molecule through an aromatic ring. Aromatic groups include, but are not limited to, phenyl and naphthyl groups.

[0089] In this invention, the term "heteroaryl" refers to a cyclic, unsaturated group having a specified number of ring atoms (e.g., 5-6), a specified number of heteroatoms (e.g., 0, 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S). It is monocyclic and aromatic; the heteroaryl group is attached to the rest of the molecule via a carbon atom or a heteroatom. Heteroaryl groups include, but are not limited to, those with a specific ring number (e.g., 5-6), a specific number of heteroatoms (e.g., 0, 1, 2, or 3), and a specific type of heteroatom (one or more of N, O, and S). wait.

[0090] In this invention, the term "heterocyclic alkyl" refers to a cyclic, saturated monovalent or divalent group having a specified number of ring atoms (e.g., 3-12, 4-8, or 5-6), a specified number of heteroatoms (e.g., 1, 2, or 3), and a specified type of heteroatom (one or more of N, O, and S). It is a monocyclic alkyl group, and the heterocyclic alkyl group is attached to the rest of the molecule by a carbon atom or a heteroatom.

[0091] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0092] The reagents and raw materials used in this invention are all commercially available.

[0093] The positive and progressive effects of this invention are as follows: Compared with the prior art, the compounds disclosed in this invention have novel structures, good physicochemical properties (e.g., lipid solubility and easy preparation into salts), and good inhibitory effects on MPC. Most of them show good lactate release-promoting effects and have good in vitro and in vivo hair loss treatment effects. In addition, the preparation method of the MPC inhibitors provided by this invention is simple, the raw materials are readily available, the preparation cost is low, and the product yield is high. Detailed Implementation

[0094] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0095] Example 1: (E)-2-cyano-3-(5-(2-fluorophenyl)-1H-pyrrolo-3-yl)ethyl acrylate (compound I-11)

[0096]

[0097] Step 1:

[0098] Int.11-a (5.0 g, 26.4 mmol) was added to a 100 mL round-bottom flask and dissolved in 100 mL of ethanol. L-proline (1.22 g, 10.56 mmol) and ethyl cyanoacetate (3.89 g, 34.40 mmol) were then added. The mixture was stirred at room temperature for 12 h, during which a large amount of pale yellow solid precipitated. After the reaction was complete as monitored by TLC, 100 mL of ice water was added to the reaction mixture, and the mixture was stirred for 0.5 h. The mixture was then filtered, and the filter cake was washed 3-5 times with ice water to obtain pure I-11 (7.22 g, 96.2%).

[0099] ESI-MS (m / z): 285.2 [M+H] +

[0100] 1 H NMR(400MHz,DMSO-d6)δ12.42(s,1H),8.28(s,1H),7.94(d,J=1.7Hz,1H),7.75(m,1H), 7.40(t,J=2.2Hz,1H),7.38–7.24(m,3H),4.26(q,J=7.1Hz,2H),1.28(t,J=7.1Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ163.67,158.83,149.90,132.39,129.40,129.33,12 7.37,125.37,119.65,117.60,116.95,116.74,108.58,94.24,61.90,14.59.

[0101] Example 2: (E)-2-cyano-3-(5-(2-fluorophenyl)-1-(pyridin-2-ylmethyl)-1H-pyrrolo-3-yl)ethyl acrylate (Compound I-1)

[0102]

[0103] Step 1:

[0104] In a 100 mL round-bottom flask, Int. 11 (0.70 g, 2.46 mmol) was added and dissolved in 7 mL of DMF. Cesium carbonate (2.88 g, 8.85 mmol) was then added and the mixture was stirred for 30 min. Finally, 2-bromomethylpyridine hydrobromide (0.75 g, 2.95 mmol) was added, and the mixture was stirred overnight at room temperature. After the reaction was complete as monitored by TLC, the insoluble matter was removed by filtration. The filtrate was extracted three times with dichloromethane / water. The organic phase was then distilled under reduced pressure to obtain the crude product, which was then purified by column chromatography to obtain pure product I-1 (0.75 g, 81.2%).

[0105] ESI-MS (m / z): 376.2 [M+H]+

[0106] 1 H NMR (400MHz, DMSO-d6) δ8.44(d,J=3.9Hz,1H),8.29(s,1H),8.06(d,J=1.9Hz,1H),7.68(m,1H),7.46(m,1H),7.38–7.1 7(m,4H),7.04(d,J=1.9Hz,1H),6.87(dd,J=7.8,1.3Hz,1H),5.27(s,2H),4.27(q,J=7.1Hz,2H),1.29(t,J=7.1Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ163.56,159.88,156.17,149.71,149.54,137.48,135.14,132.55,131.64,13 1.20,125.12,123.27,121.70,119.10,118.60,117.50,116.32,110.55,94.62,61.96,53.16,14.57.

[0107] Example 3: (E)-2-cyano-3-(5-(2-fluorophenyl)-1-(pyridin-2-ylmethyl)-1H-pyrrolo-3-yl)acrylic acid (compound I-2)

[0108]

[0109] I-1 (0.45 g, 1.2 mmol) was added to a 100 mL round-bottom flask, dissolved in 8 mL of tetrahydrofuran, and then excess lithium hydroxide monohydrate (0.50 g, 12.0 mmol) was added. The mixture was hydrolyzed at room temperature for 2 h. After the reaction was completed by TLC monitoring, tetrahydrofuran was removed by vacuum distillation. Approximately 20 mL of ethyl acetate was added, and the mixture was stirred for 30 min. The mixture was separated, and the pH of the aqueous phase was adjusted to <1. A large amount of solid precipitated, which was filtered and dried to obtain the target compound I-2 (0.28 g, 67.2%).

[0110] ESI-MS (m / z): 348.2.

[0111] 1H NMR (400MHz, DMSO-d6) δ13.31(s,1H),8.42(m,1H),8.22(s,1H),8.00(d,J=1.9Hz,1H),7.67(td,J=7.7,1. 8Hz,1H),7.44(m,1H),7.37–7.16(m,4H),7.01(d,J=1.8Hz,1H),6.84(dt,J=7.9,1.1Hz,1H),5.25(s,2H). 13 C NMR(101MHz,DMSO-d6)δ164.95,159.87,156.27,149.69,149.00,137.49,134.47,132.56,131 .59,131.00,125.11,123.24,121.63,119.12,118.23,117.94,116.32,110.53,95.95,53.12.

[0112] Example 4: (E)-2-cyano-3-(5-(2-fluorophenyl)-1-(pyridin-3-ylmethyl)-1H-pyrrolo-3-yl)ethyl acrylate (compound I-3)

[0113] Compound I-3 was prepared using the same synthetic method as compound I-1.

[0114] ESI-MS (m / z): 376.2 [M+H] +

[0115] 1 H NMR (400MHz, DMSO-d6) δ8.43(dd,J=4.3,2.2Hz,1H),8.28(s,1H),8.12(dd,J=2.2,1.1Hz,1H),8.08(d,J=1.9Hz,1H),7 .56–7.47(m,1H),7.41–7.23(m,5H),7.04(d,J=1.9Hz,1H),5.23(s,2H),4.27(q,J=7.1Hz,2H),1.29(t,J=7.1Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ163.49,159.85,149.41,148.75,135.23,134.50,132.75,132.64,131.91,13 1.83,131.01,125.30,124.07,118.96,118.37,117.42,116.41,110.75,94.92,61.99,49.17,14.56.

[0116] Example 5: (E)-2-cyano-3-(5-(2-fluorophenyl)-1-(pyridin-3-ylmethyl)-1H-pyrrolo-3-yl)acrylic acid (compound I-4)

[0117] Following the synthetic method of compound I-2, compound I-4 was prepared using I-3 as a starting material.

[0118] ESI-MS (m / z): 348.2 [M+H] +

[0119] 1 H NMR (400MHz, DMSO-d6) δ13.38(s,1H),8.43(dd,J=4.0,2.5Hz,1H),8.21(s,1H),8.11(t,J=1.6Hz ,1H),8.03(d,J=2.0Hz,1H),7.50(m,1H),7.44–7.20(m,5H),7.02(d,J=1.9Hz,1H),5.23(s,2H). 13 C NMR(101MHz,DMSO-d6)δ164.89,159.84,149.36,148.79,148.69,135.18,133.81,132.87,132 .65,131.81,130.80,125.29,124.07,119.07,118.36,117.89,116.40,110.73,96.36,49.13.

[0120] Example 6: (E)-2-cyano-3-(5-(2-fluorophenyl)-1-(pyridin-4-ylmethyl)-1H-pyrrolo-3-yl)ethyl acrylate (compound I-5)

[0121] Compound I-5 was prepared using the same synthetic method as compound I-1.

[0122] ESI-MS (m / z): 376.2 [M+H] +

[0123] 1H NMR (600MHz, DMSO-d6) δ8.47–8.40(m,2H),8.30(s,1H),8.07(d,J=1.9Hz,1H),7.52–7.43(m,1H),7.35(td,J=7.6,1.8Hz,1H),7.29(ddd,J=9.8, 8.4,1.1Hz,1H),7.23(td,J=7.5,1.1Hz,1H),7.07(d,J=1.8Hz,1H),6.89 –6.83(m,2H),5.26(s,2H),4.28(q,J=7.1Hz,2H),1.29(t,J=7.1Hz,3H). 13 CNMR(151MHz,DMSO-d6)δ163.48,159.85,150.27,149.41,146.30,134.80,132.59,131.89,131.84,1 31.18,125.28,121.86,118.83,118.73,118.48,117.42,116.41,110.81,95.16,62.03,50.41,14.58.

[0124] Example 7: (E)-2-cyano-3-(5-(2-fluorophenyl)-1-(pyridin-4-ylmethyl)-1H-pyrrolo-3-yl)acrylic acid (compound I-6)

[0125] Following the synthetic method of compound I-2, compound I-6 was prepared using I-5 as a starting material.

[0126] ESI-MS (m / z): 348.2 [M+H] +

[0127] 1 H NMR (400MHz, DMSO-d6) δ8.43(d,J=6.1Hz,2H),8.23(s,1H),8.02(d,J=1.9Hz,1H) ,7.46(m,1H),7.38–7.18(m,3H),7.05(s,1H),6.86(d,J=6.1Hz,2H),5.25(s,2H). 13 CNMR(101MHz,DMSO-d6)δ164.86,159.83,150.23,148.70,146.43,134.05,132.58,131.82,13 1.74,130.94,125.25,121.81,118.95,118.80,118.47,117.90,116.38,110.76,96.69,50.34.

[0128] Example 8: (E)-3-(1-benzyl-5-(2-fluorophenyl)-1H-pyrrolo-3-yl)-2-cyanoacrylate (Compound I-7)

[0129] Compound I-7 was prepared using the same synthetic method as compound I-1.

[0130] ESI-MS (m / z): 375.2 [M+H] +

[0131] 1 H NMR(400MHz, DMSO-d6)δ8.26(s,1H),8.02(d,J=1.9Hz,1H),7.54–7.44(m,1H),7.40–7.27(m,2H),7.27–7.18(m,4 H),7.02(d,J=1.9Hz,1H),6.90(dd,J=7.5,2.0Hz,2H),5.16(s,2H),4.26(q,J=7.1Hz,2H),1.27(t,J=7.1Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ163.54,159.87,149.48,137.19,134.58,132.60,131.77,131.68,131.18,129.0 2,128.14,127.31,125.22,119.19,119.04,118.29,117.48,116.38,110.55,94.66,61.96,51.48,14.56.

[0132] Example 9: (E)-3-(1-benzyl-5-(2-fluorophenyl)-1H-pyrrolo-3-yl)-2-cyanoacrylate (Compound I-8)

[0133] Following the synthetic method of compound I-2, compound I-8 was prepared using I-7 as the starting material.

[0134] ESI-MS (m / z): 347.2 [M+H] +

[0135] 1 H NMR (400MHz, DMSO-d6) δ13.26 (s, 1H), 8.21 (s, 1H), 7.98 (d, J = 2.0Hz, 1H), 7.49 (m, 1H), 7. 39–7.28(m,2H),7.28–7.17(m,4H),7.02(d,J=1.9Hz,1H),6.94–6.84(m,2H),5.16(s,2H). 13C NMR(101MHz,DMSO-d6)δ164.93,159.87,148.93,137.30,133.91,132.60,131.70,131.62,130.99 ,129.01,128.10,127.25,125.21,119.29,119.14,118.27,117.91,116.37,110.54,95.98,51.41.

[0136] Example 10: (E)-2-cyano-3-(5-(2-fluorophenyl)-1-(naphth-2-ylmethyl)-1H-pyrrolo-3-yl)ethyl acrylate (compound I-9)

[0137] Compound I-9 was prepared using the same synthetic method as compound I-1.

[0138] ESI-MS (m / z): 425.2 [M+H] +

[0139] 1 H NMR(600MHz,DMSO-d6)δ8.29(s,1H),8.07(d,J=1.9Hz,1H),7.86(dd,J=6.1,3 .4Hz,1H),7.82(d,J=8.5Hz,1H),7.76(dd,J=6.1,3.4Hz,1H),7.52–7.46(m,3H ),7.42–7.36(m,2H),7.31(m,1H),7.23(m,1H),7.11(dd,J=8.4,1.8Hz,1H),7. 07(d,J=2.0Hz,1H),5.33(s,2H),4.26(q,J=7.1Hz,2H),1.28(t,J=7.1Hz,3H). 13 C NMR(151MHz,DMSO-d6)δ163.56,159.94 149.53,134.72,134.65,133.13,132.76,132.65,131.76,131.30,128.81,128.14,128.02,126.93,1 26.70,126.30,125.39,125.26,119.17,118.38,117.52,116.41,110.54,94.69,61.97,51.66,14.58.

[0140] Example 11: (E)-2-cyano-3-(5-(2-fluorophenyl)-1-(naphth-2-ylmethyl)-1H-pyrrolo-3-yl)acrylic acid (compound I-10)

[0141] Following the synthetic method of compound I-2, compound I-10 was prepared using I-9 as the starting material.

[0142] ESI-MS (m / z): 397.2 [M+H] +

[0143] 1 H NMR (400MHz, DMSO-d6) δ12.84(s,1H),8.23(s,1H),8.03(d,J=1.9Hz,1H),7.89–7.72(m,3H),7.49(m,3H),7.42–7.3 6(m,2H),7.31(m,1H),7.23(td,J=7.5,1.2Hz,1H),7.10(dd,J=8.5,1.8Hz,1H),7.05(d,J=1.9Hz,1H),5.33(s,2H). 13 C NMR(101MHz,DMSO-d6)δ172.47,164.94,159.92,148.96,134.75,134.04,133.10,132.68,131.68,131.08,128.77 ,128.06,126.91,126.66,126.17,125.33,125.23,119.26,118.34,117.94,116.38,110.52,96.00,51.59,21.51.

[0144] Example 12: (E)-2-cyano-3-(5-(2-fluorophenyl)-1H-pyrrolo-3-yl)acrylic acid (compound I-12)

[0145] Following the synthetic method of compound I-2, compound I-12 was prepared using I-11 as a starting material.

[0146] ESI-MS (m / z): 257.1 [M+H] +

[0147] 1 H NMR (400MHz, DMSO-d6) δ12.40(s,1H),8.26(s,1H),7.91(s,1H),7.77(m,1H),7.42(q,J=2.3Hz,1H),7.39–7.25(m,3H). 13C NMR (101MHz, DMSO-d6) δ165.08,158.81,149.41,131.66,129.32,129.12,127.36 125.37,119.68,119.50,118.06,116.84,108.59,95.58.

[0148] Example 13: (E)-2-cyano-3-(1-(2-fluorobenzyl)-5-(2-fluorophenyl)-1H-pyrrolo-3-yl)ethyl acrylate (Compound I-13)

[0149] Compound I-13 was prepared using the same synthetic method as compound I-1.

[0150] ESI-MS (m / z): 393.2 [M+H] +

[0151] 1 H NMR(400MHz, DMSO-d6)δ8.28(s,1H),8.02(d,J=1.9Hz,1H),7.50(m,1H),7.42–7.21(m,4H),7.15–7.04(m, 2H),7.02(d,J=1.9Hz,1H),6.86(m,1.7Hz,1H),5.22(s,2H),4.26(q,J=7.1Hz,2H),1.28(t,J=7.1Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ163.51,160.12,159.92,149.48,134.53,132.56,131.79,131.13,130.65,129.8 9,125.15,123.92,119.03,118.88,118.27,117.45,116.34,115.78,110.56,94.81,61.97,45.61,14.56.

[0152] Example 14: (E)-2-cyano-3-(1-(2-fluorobenzyl)-5-(2-fluorophenyl)-1H-pyrrolo-3-yl)acrylic acid (compound I-14)

[0153] Following the synthetic method of compound I-2, compound I-14 was prepared using I-13 as a starting material.

[0154] ESI-MS (m / z): 365.2 [M+H] +

[0155] 1H NMR (400MHz, DMSO-d6) δ13.39(s,1H),8.19(s,1H),7.95(d,J=1.9Hz,1H),7.55–7.42(m,1 H),7.40–7.17(m,4H),7.15–7.03(m,2H),6.99(d,J=1.9Hz,1H),6.83(m,1H),5.21(s,2H). 13 C NMR(101MHz,DMSO-d6)δ164.94,160.07,159.92,148.63,133.68,132.56,131.71,130.87,130.58 ,129.79,125.21,125.08,124.06,119.09,118.27,118.01,116.33,115.75,110.55,96.61,45.53.

[0156] Example 15: (E)-2-cyano-3-(1-(3-fluorobenzyl)-5-(2-fluorophenyl)-1H-pyrrolo-3-yl)ethyl acrylate (Compound I-15)

[0157] Compound I-15 was prepared using the same synthetic method as compound I-1.

[0158] ESI-MS (m / z): 393.2 [M+H] +

[0159] 1 H NMR(600MHz,DMSO-d6)δ8.28(s,1H),8.05(d,J=1.9Hz,1H),7.50(m,1H),7.37(m,1H),7.35–7.23(m, 3H),7.10–7.02(m,2H),6.75–6.69(m,2H),5.20(s,2H),4.26(t,J=7.1Hz,2H),1.29(t,J=7.1Hz,3H). 13 C NMR(151MHz,DMSO-d6)δ163.51,162.54,159.89,149.46,140.04,134.65,132.62,131.82,131.09,12 5.27,123.34,118.99,118.35,117.45,116.40,114.97,114.20,110.66,94.89,62.00,50.92,14.58.

[0160] Example 16: (E)-2-cyano-3-(1-(3-fluorobenzyl)-5-(2-fluorophenyl)-1H-pyrrolo-3-yl)acrylic acid (compound I-16)

[0161] Following the synthetic method of compound I-2, compound I-16 was prepared using I-15 as a starting material.

[0162] ESI-MS (m / z): 365.2 [M+H] +

[0163] 1 H NMR (400MHz, DMSO-d6) δ13.34(s,1H),8.22(s,1H),8.00(d,J=1.9Hz,1H),7.49 (m,1H),7.43–7.20(m,4H),7.14–6.96(m,2H),6.80–6.64(m,2H),5.19(s,2H). 13 C NMR (101MHz, DMSO-d6) δ164.89,162.52,159.87,148.88,140.14,133.97,132.61,131.74,131.06 130.90,125.24,123.27,119.08,118.32,117.87,116.37,114.93,114.12,110.63,96.20,50.85.

[0164] Example 17: (E)-2-cyano-3-(1-(4-fluorobenzyl)-5-(2-fluorophenyl)-1H-pyrrolo-3-yl)ethyl acrylate (Compound I-17)

[0165] Compound I-17 was prepared using the same synthetic method as compound I-1.

[0166] ESI-MS (m / z): 393.2 [M+H] +

[0167] 1 H NMR(400MHz, DMSO-d6)δ8.27(s,1H),8.02(d,J=1.9Hz,1H),7.50(m,1H),7.40–7.18(m,3H),7.12–7.04(m ,2H),7.02(d,J=1.9Hz,1H),6.99–6.89(m,2H),5.15(s,2H),4.27(q,J=7.1Hz,2H),1.28(t,J=7.1Hz,3H). 13C NMR(101MHz,DMSO-d6)δ163.52,161.97,159.87,149.45,134.49,133.34,132.61,131.78,131.0 7,129.57,125.24,119.08,118.28,117.45,116.37,115.84,110.63,94.72,61.97,50.80,14.56.

[0168] Example 18: (E)-2-cyano-3-(1-(4-fluorobenzyl)-5-(2-fluorophenyl)-1H-pyrrolo-3-yl)acrylic acid (compound I-18)

[0169] Following the synthetic method of compound I-2, compound I-18 was prepared using I-17 as a starting material.

[0170] ESI-MS (m / z): 365.2 [M+H] +

[0171] 1 H NMR (400MHz, DMSO-d6) δ8.03(s,1H),7.82(d,J=1.9Hz,1H),7.47(m,1H),7.37–7.17(m,3H),7.11–7.01(m,2H),6.93(m,3H),5.12(s,2H). 13 C NMR(101MHz,DMSO-d6)δ165.21,161.88,159.84,145.63,133.80,132.61,131.67,131.48,130 .13,129.40,129.32,125.18,119.60,119.42,118.61,116.33,115.77,110.50,50.58,49.05.

[0172] Example 19: (E)-2-cyano-3-(5-(2-fluorophenyl)-1-(2-(trifluoromethyl)benzyl)-1H-pyrrolo-3-yl)ethyl acrylate (Compound I-19)

[0173] Compound I-19 was prepared using the same synthetic method as compound I-1.

[0174] ESI-MS (m / z): 443.2 [M+H] +

[0175] 1H NMR (600MHz, DMSO-d6) δ8.31(s,1H),8.03(d,J=2.0Hz,1H),7.66(d,J=7.8Hz,1H),7.60(d,J=7.7Hz,1H),7.51–7.39(m,2H),7.32–7.24 (m,2H),7.17(t,J=7.5Hz,1H),7.10(d,J=1.9Hz,1H),6.74(d,J=7.8Hz,1H),5.40(s,2H),4.28(q,J=7.1Hz,2H),1.29(t,J=7.1Hz,3H). 13 C NMR(151MHz,DMSO-d6)δ163.47,159.86,149.45,135.40,135.07,133.57,132.57,131.86,131.27,128.74,12 8.30,126.43,125.23,125.15,118.64,118.54,118.36,117.42,116.28,110.93,95.20,62.03,48.20,14.58.

[0176] Example 20: (E)-2-cyano-3-(5-(2-fluorophenyl)-1-(2-(trifluoromethyl)benzyl)-1H-pyrrolo-3-yl)acrylic acid (compound I-20)

[0177] Following the synthetic method of compound I-2, compound I-20 was prepared using I-19 as a starting material.

[0178] ESI-MS (m / z): 415.2 [M+H] +

[0179] 1 H NMR (400MHz, DMSO-d6) δ13.01(s,1H),8.25(s,1H),8.00(d,J=1.9Hz,1H),7.71–7.57(m,2H),7.52–7.38(m,2 H),7.34–7.21(m,2H),7.17(td,J=7.5,1.1Hz,1H),7.09(d,J=1.8Hz,1H),6.72(d,J=7.8Hz,1H),5.40(s,2H). 13C NMR(101MHz,DMSO-d6)δ164.84,159.85,148.85,134.02,131.78,131.06,128.66,128.16,126.38 ,126.08,125.78,125.13,125.10,123.09,118.67,118.34,117.83,116.25,110.91,96.51,48.12.

[0180] Example 21: (E)-2-cyano-3-(5-(2-fluorophenyl)-1-(3-(trifluoromethyl)benzyl)-1H-pyrrolo-3-yl)ethyl acrylate (Compound I-21)

[0181] Compound I-21 was prepared using the same synthetic method as compound I-1.

[0182] ESI-MS (m / z): 443.2 [M+H] +

[0183] 1 H NMR (400MHz, DMSO-d6) δ8.28(s,1H),8.09(d,J=1.9Hz,1H),7.59(d,J=7.8Hz,1H),7.49(m,2H),7.34(td,J=7.6, 1.9Hz,1H),7.32–7.15(m,4H),7.04(d,J=1.9Hz,1H),5.30(s,2H),4.27(q,J=7.1Hz,2H),1.29(t,J=7.1Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ163.48,159.88,149.42,138.54,134.58,132.59,131.82,131.52,130.97,130.16,12 9.59,125.21,124.93,124.85,124.10,118.98,118.33,117.42,116.35,110.79,94.96,61.98,51.03,14.55.

[0184] Example 22: (E)-2-cyano-3-(5-(2-fluorophenyl)-1-(3-(trifluoromethyl)benzyl)-1H-pyrrolo-3-yl)acrylic acid (compound I-22)

[0185] Following the synthetic method of compound I-2, compound I-22 was prepared using I-21 as a starting material.

[0186] ESI-MS (m / z): 415.2 [M+H]+

[0187] 1 H NMR (400MHz, DMSO-d6) δ13.34(s,1H),8.22(s,1H),8.05(d,J=1.9Hz,1H),7.59(d,J=7.8Hz,1H),7.53–7.43(m,2H),7. 34(td,J=7.6,1.8Hz,1H),7.31–7.27(m,1H),7.27–7.21(m,1H),7.21–7.16(m,2H),7.02(d,J=1.8Hz,1H),5.29(s,2H). 13 C NMR(101MHz,DMSO-d6)δ164.87,159.87,148.86,138.65,133.94,132.59,131.76,131.46,130.78,130 .15,129.57,125.72,125.19,124.87,124.07,119.09,118.32,117.86,116.34,110.76,96.27,50.97.

[0188] Example 23: (E)-2-cyano-3-(5-(2-fluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo-3-yl)ethyl acrylate (Compound I-23)

[0189] Compound I-23 was prepared using the same synthetic method as compound I-1.

[0190] ESI-MS (m / z): 443.2 [M+H] +

[0191] 1 H NMR (400MHz, DMSO-d6) δ8.29(s,1H),8.06(d,J=1.9Hz,1H),7.63(d,J=8.1Hz,2H),7.49(m,1H),7.36(m,1H),7.33–7 .19(m,2H),7.11(d,J=8.0Hz,2H),7.05(d,J=1.9Hz,1H),5.30(s,2H),4.27(q,J=7.1Hz,2H),1.29(t,J=7.1Hz,3H). 13C NMR(101MHz,DMSO-d6)δ163.47,159.86,149.40,142.03,134.66,132.59,131.85,131.18,128.65,12 7.95,125.90,125.26,123.17,118.89,118.46,117.41,116.37,110.70,95.01,62.00,50.95,14.55.

[0192] Example 24: (E)-2-cyano-3-(5-(2-fluorophenyl)-1-(4-(trifluoromethyl)benzyl)-1H-pyrrolo-3-yl)acrylic acid (compound I-24)

[0193] Following the synthetic method of compound I-2, compound I-24 was prepared using I-23 as a starting material.

[0194] ESI-MS (m / z): 415.2 [M+H] +

[0195] 1 H NMR (400MHz, DMSO-d6) δ13.35(s,1H),8.22(s,1H),8.01(d,J=1.9Hz,1H),7.63(d,J =8.1Hz,2H),7.48(m,J=7.5,1H),7.41–7.19(m,3H),7.18–6.98(m,3H),5.29(s,2H). 13 C NMR(101MHz,DMSO-d6)δ164.86,159.86,148.85,142.15,134.02,132.59,131.79,130.99,12 8.61,127.88,125.90,125.25,118.98,118.44,117.84,116.37,110.68,96.31,50.91,25.09.

[0196] Example 25: (E)-2-cyano-3-(5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrolo-3-yl)ethyl acrylate (Compound I-25)

[0197]

[0198] Step 1:

[0199] I-11 (1.0 g, 3.52 mmol) and DMAP (21.5 mg, 0.18 mmol) were added to a 50 mL round-bottom flask and dissolved in 5 mL of LACN. DIPEA (454.6 mg, 3.52 mmol) was then added and stirred for 10 min. ACN solution of pyridine-3-sulfonyl chloride (937.7 mg, 5.28 mmol) (1 mL) was added and the mixture was heated in an oil bath at 40 °C for about 5 hours. After the reaction was completed by TLC monitoring, acetonitrile was removed by vacuum distillation, and the mixture was extracted three times with dichloromethane / water. The organic phase was then distilled under reduced pressure to obtain the crude product, which was then purified by column chromatography to obtain pure I-25 (0.93 g, 62.1%).

[0200] ESI-MS (m / z): 426.1 [M+H] +

[0201] 1 H NMR (400MHz, DMSO-d6) δ8.93(dd,J=4.9,1.6Hz,1H),8.64(d,J=1.9Hz,1H),8.59(dd,J=2.6,0.7Hz,1H),8.36(s,1H),7.95(m ,1H),7.65(m,1H),7.61–7.53(m,1H),7.27–7.15(m,3H),7.04(d,J=1.9Hz,1H),4.29(q,J=7.1Hz,2H),1.29(t,J=7.1Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ162.39,160.66 156.10,147.79,147.63,135.77,133.82,133.48,133.12,132.98,130.24,12 5.29,124.54,120.99,117.48,116.34,115.85,114.57,100.96,62.60,14.45.

[0202] Example 26: (E)-3-(1-((6-chloropyridin-3-yl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrolo-3-yl)-2-cyanoacrylate (Compound I-26)

[0203] Compound I-26 was prepared using the same method as compound I-25.

[0204] ESI-MS (m / z): 460.1 [M+H] +

[0205] 1H NMR (400MHz, DMSO-d6) δ8.63(d,J=1.9Hz,1H),8.46(d,J=2.6Hz,1H),8.36(s,1H),8.00(dd,J=8.6,2.7Hz,1H),7.81( d,J=8.6Hz,1H),7.60(m,1H),7.34–7.21(m,3H),7.06(d,J=1.9Hz,1H),4.30(q,J=7.1Hz,2H),1.30(t,J=7.1Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ162.37,160.67,156.95,148.81,147.56,138.91,133.50,133.12 ,130.23,126.30,124.64,121.13,117.50,116.30,115.87,114.67,101.07,62.63,14.46.

[0206] Example 27: (E)-2-cyano-3-(5-(2-fluorophenyl)-1-((2-methoxypyridin-3-yl)sulfonyl)-1H-pyrrolo-3-yl)ethyl acrylate (compound I-27)

[0207] Compound I-27 was prepared using the same synthetic method as compound I-25.

[0208] ESI-MS (m / z): 456.2 [M+H] +

[0209] 1 H NMR (400MHz, DMSO-d6) δ8.62(d,J=1.9Hz,1H),8.53(dd,J=4.9,1.8Hz,1H),8.47(s,1H),7.56(dd,J=7.8,1 .9Hz,1H),7.53–7.44(m,1H),7.22–6.97(m,5H),4.31(q,J=7.1Hz,2H),3.89(s,3H),1.31(t,J=7.1Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ162.59,160.45,159.56,154.99,148.32,140.72,134.30,133.62,132.68,12 9.44,124.32,119.33,117.77,117.41,116.63,115.66,114.01,100.07,62.50,55.37,55.10,14.49.

[0210] Example 28: (E)-3-(1-((5-bromopyridin-3-yl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrolo-3-yl)-2-cyanoacrylate (Compound I-28)

[0211] Compound I-28 was prepared using the same method as compound I-25.

[0212] ESI-MS (m / z): 504.1 [M+H] +

[0213] 1 H NMR(400MHz, DMSO-d6)δ9.11(d,J=2.1Hz,1H),8.62(dd,J=12.5,2.0Hz,2H),8.36(s,1H),8.11(t,J=2.1Hz ,1H),7.61(m,1H),7.33–7.17(m,3H),7.07(d,J=1.9Hz,1H),4.31(q,J=7.1Hz,2H),1.30(t,J=7.1Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ162.38,160.67,157.08,147.59,146.38,137.87,134.64,133.72,133.17 ,129.97,124.56,121.20,120.91,117.39,117.23,116.30,115.89,114.71,101.06,62.63,14.46.

[0214] Example 29: (E)-3-(1-((2-chloropyridin-3-yl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrolo-3-yl)-2-cyanoacrylate (Compound I-29)

[0215] Compound I-29 was prepared using the same method as compound I-25.

[0216] ESI-MS (m / z): 460.1 [M+H] +

[0217] 1H NMR (400MHz, DMSO-d6) δ8.80–8.66(m,2H),8.45(s,1H),7.72(dd,J=8.0,1.8Hz,1H),7.49(td,J=8.4,4 .0Hz,2H),7.16(dd,J=5.2,2.9Hz,2H),7.12–7.03(m,2H),4.31(q,J=7.1Hz,2H),1.31(t,J=7.1Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ162.44,160.49,155.88,147.91,147.58,141.44,134.24,133.85,133.07 ,131.72,129.46,124.58,124.28,119.78,116.78,116.47,115.80,114.32,100.82,62.57,14.48.

[0218] Example 30: (E)-2-cyano-3-(5-(2-fluorophenyl)-1-(benzenesulfonyl)-1H-pyrrolo-3-yl)ethyl acrylate (Compound I-30)

[0219] Compound I-30 was prepared using the same synthetic method as compound I-25.

[0220] ESI-MS (m / z): 425.1 [M+H] +

[0221] 1 H NMR (400MHz, DMSO-d6) δ8.80–8.66(m,2H),8.45(s,1H),7.72(dd,J=8.0,1.8Hz,1H),7.49(td,J=8.4,4 .0Hz,2H),7.16(dd,J=5.2,2.9Hz,2H),7.12–7.03(m,2H),4.31(q,J=7.1Hz,2H),1.31(t,J=7.1Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ162.44,160.49,155.88,147.91,147.58,141.44,134.24,133.85,133.07 ,131.72,129.46,124.58,124.28,119.78,116.78,116.47,115.80,114.32,100.82,62.57,14.48.

[0222] Example 31: (E)-2-cyano-3-(1-((4-ethoxyphenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrolo-3-yl)ethyl acrylate (Compound I-31)

[0223] Compound I-31 was prepared using the same synthetic method as compound I-25.

[0224] ESI-MS (m / z): 469.2 [M+H] +

[0225] 1 H NMR (400MHz, DMSO-d6) δ8.80–8.66(m,2H),8.45(s,1H),7.72(dd,J=8.0,1.8Hz,1H),7.49(td,J=8.4,4 .0Hz,2H),7.16(dd,J=5.2,2.9Hz,2H),7.12–7.03(m,2H),4.31(q,J=7.1Hz,2H),1.31(t,J=7.1Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ162.44,160.49,155.88,147.91,147.58,141.44,134.24,133.85,133.07 ,131.72,129.46,124.58,124.28,119.78,116.78,116.47,115.80,114.32,100.82,62.57,14.48.

[0226] Example 32: (E)-3-(1-((4-butoxyphenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrolo-3-yl)-2-cyanoacrylate (Compound I-32)

[0227] Compound I-32 was prepared using the same method as compound I-25.

[0228] ESI-MS (m / z): 497.2 [M+H] +

[0229] 1H NMR(400MHz,DMSO-d6)δ8.57(d,J=1.9Hz,1H),8.36(s,1H),7.57(m,1H),7. 43–7.36(m,2H),7.30–7.21(m,2H),7.17(td,J=7.4,1.8Hz,1H),7.10–7.03( m,2H),6.99(d,J=1.9Hz,1H),4.29(q,J=7.1Hz,2H),4.07(t,J=6.5Hz,2H),1 .70(m,2H),1.48–1.36(m,2H),1.29(t,J=7.1Hz,3H),0.93(t,J=7.4Hz,3H). 13 C NMR(101MHz,DMSO-d6)δ164.30,162.52,160.78,147.97,133.46,133.06,132.69,132.61,130.18,127.72,124.33,1 20.39,118.06,117.90,116.49,115.95,115.84,115.63,114.00,100.17,68.66,62.51,30.80,19.02,14.47,14.06.

[0230] Example 33: (E)-2-cyano-3-(1-((4-ethylphenyl)sulfonyl)-5-(2-fluorophenyl)-1H-pyrrolo-3-yl)ethyl acrylate (Compound I-33)

[0231] Compound I-33 was prepared using the same synthetic method as compound I-25.

[0232] ESI-MS (m / z): 453.2 [M+H] +

[0233] 1 H NMR (400MHz, DMSO-d6) δ8.60(d,J=1.9Hz,1H),8.37(s,1H),7.57(m,1H),7.42(s,4H),7.24(t,J=8.9Hz,2H),7.15(td,J=7.5, 1.8Hz,1H),7.01(d,J=1.8Hz,1H),4.30(q,J=7.1Hz,2H),2.69(q,J=7.6Hz,2H),1.29(t,J=7.1Hz,3H),1.17(t,J=7.6Hz,3H). 13C NMR(101MHz,DMSO-d6)δ162.48,160.76,152.76,147.88,134.24,133.40,133.13,132.67,130.31,129.71,12 7.74,124.34,120.60,117.98,117.82,116.45,115.84,115.62,114.13,100.40,62.53,28.57,15.35,14.46.

[0234] Example 34: (E)-3-(1-benzoyl-5-(2-fluorophenyl)-1H-pyrrolo-3-yl)-2-cyanoacrylate (Compound I-34)

[0235] Step 1: Synthesis of intermediate Int.I-34

[0236]

[0237] Step 1:

[0238] In a 50 mL round-bottom flask, add Int.I-11-a (1.0 g, 5.3 mmol), DMAP (32.4 mg, 0.3 mmol), and triethylamine (0.64 g, 6.4 mmol). Dissolve in 20 mL of dichloromethane, and under nitrogen protection, add Int.I-34-a (0.89 g, 6.3 mmol) at 0 °C. Stir overnight at room temperature. Extract three times with dichloromethane / water. Dry the organic phase and distill under reduced pressure to obtain the crude product. Analyze by column chromatography to obtain pure Int.I-34 (0.8 g, 51.5%).

[0239] ESI-MS (m / z): 294.1 [M+H] +

[0240] Step 2: Synthesis of compound I-34

[0241]

[0242] Step 1:

[0243] Int. I-34 (0.7 g, 2.4 mmol) was added to a 50 mL round-bottom flask and dissolved in 20 mL of ethanol. L-proline (0.35 g, 3.12 mmol) and ethyl cyanoacetate (0.35 g, 3.12 mmol) were then added. The mixture was stirred at room temperature for 6 h, resulting in the precipitation of a large amount of pale yellow solid. After the reaction was complete as monitored by TLC, 20 mL of ice water was added to the reaction solution, and the mixture was stirred for 0.5 h. The mixture was then filtered, and the filter cake was washed 3-5 times with ice water to obtain pure I-1 (0.83 g, 89.1%).

[0244] ESI-MS (m / z): 389.1 [M+H] +

[0245] 1 H NMR(500MHz,Chloroform-d)δ8.06(m,2H),8.00(s,1H),7.87(m,1H),7.57–7.48(m,4H),7.39(m,1H ),7.19(td,J=8.2,1.5Hz,1H),6.40(t,J=1.9Hz,1H),4.33(q,J=7.1Hz,2H),1.29(t,J=7.1Hz,3H). 13 C NMR(125MHz,Chloroform-d)δ167.56,164.59,161.14,159.15,146.20,135.21,132.31,132.24,131.88,131.34,131.29,129.98,129. 94,129.66,128.78,128.41,125.34,125.31,122.41,122.30,119.30,117.00,116.83,115.95,115.91,115.47,103.68,62.27,14.07.

[0246] Example 35: (E)-3-(1-benzoyl-5-(2-fluorophenyl)-1H-pyrrolo-3-yl)-2-cyanoacrylate (Compound I-35)

[0247] Following the synthetic method of compound I-2, compound I-35 was prepared using I-34 as a starting material.

[0248] ESI-MS (m / z): 361.1 [M+H] +

[0249] 1 H NMR(500MHz,Chloroform-d)δ8.06(m,2H),7.97(s,1H),7.87(m,1H),7.57–7.48(m,4H),7.39(m,1H),7.19(td,J=8.3,1.4Hz,1H),6.40(t,J=1.9Hz,1H). 13C NMR(125MHz,Chloroform-d)δ167.56,163.77,161.14,159.15,135.21,134.17,132.31,132.24,131.88,131.34,131.29,129.9 8,129.94,129.66,128.78,128.41,125.34,125.31,122.41,122.30,119.30,117.00,116.83,115.95,115.91,115.60,107.03.

[0250] Example 36: (E)-3-(5-(2-bromophenyl)-1-(pyridin-2-ylmethyl)-1H-pyrrolo-3-yl)-2-cyanoacrylate (Compound I-36)

[0251] Compound I-36 was prepared using the same synthetic method as compound I-1.

[0252] ESI-MS (m / z): 436.1 [M+H] +

[0253] 1 H NMR(500MHz,Chloroform-d)δ8.39(dd,J=4.2,1.6Hz,1H),8.00(s,1H),7.64( dd,J=7.8,1.3Hz,1H),7.53(m,1H),7.48–7.40(m,2H),7.36(m,1H),7.27–7.21 (m,1H),7.09(dq,J=6.7,1.1Hz,1H),6.28(dq,J=1.6,0.9Hz,1H),6.10(d,J=1 .7Hz,1H),5.82(t,J=0.9Hz,2H),4.33(q,J=7.1Hz,2H),1.29(t,J=7.1Hz,3H). 13 C NMR(125MHz,Chloroform-d)δ164.59,156.20,149.92,146.20,137.32,135.20,134.19,133.25,131.01, 129.90,128.87,126.43,125.15,122.93,122.30,122.22,115.47,109.87,103.68,62.27,53.57,14.07.

[0254] Example 37: (E)-3-(5-(2-bromophenyl)-1-(pyridin-2-ylmethyl)-1H-pyrrolo-3-yl)-2-cyanoacrylate (Compound I-37)

[0255] Following the synthetic method of compound I-2, compound I-37 was prepared using I-36 as the starting material.

[0256] ESI-MS (m / z): 408.1 [M+H] +

[0257] 1 H NMR(500MHz,Chloroform-d)δ8.39(dd,J=4.1,1.6Hz,1H),7.97(s,1H),7.64(dd,J=7.8,1.4Hz,1H),7.53(ddd,J=7.3,6.5,1.6Hz,1H),7.48–7.40(m,2H),7. 36(ddd,J=7.5,6.6,1.3Hz,1H),7.27–7.21(m,1H),7.09(dq,J=6.6,1.1Hz,1H) ,6.30–6.26(m,1H),6.10(d,J=1.7Hz,1H),5.82(s,1H),5.82(d,J=1.9Hz,1H). 13 C NMR(125MHz,Chloroform-d)δ163.77,156.20,149.92,137.32,135.20,134.19,134.17,133.25,1 31.01,129.90,128.87,126.43,125.15,122.93,122.30,122.22,115.60,109.87,107.03,53.57.

[0258] Example 38: (E)-2-cyano-3-(5-(3-fluorophenyl)-1-(pyridin-2-ylmethyl)-1H-pyrrolo-3-yl)ethyl acrylate (Compound I-38)

[0259] Compound I-38 was prepared using the same synthetic method as compound I-1.

[0260] ESI-MS (m / z): 376.1 [M+H] +

[0261] 1H NMR(500MHz,Chloroform-d)δ8.39(dd,J=4.2,1.6Hz,1H),8.00(s,1H),7.86(m,1H),7.56–7.45(m,2H),7.28–7.21(m,2H),7.1 7(m,1H),7.09(m,1H),6.28(m,1H),6.10(d,J=1.7Hz,1H),5.82(t,J=0.9Hz,2H),4.33(q,J=7.1Hz,2H),1.29(t,J=7.1Hz,3H). 13 C NMR(125MHz,Chloroform-d)δ164.59,164.03,162.05,156.20,149.92,146.20,137.32,134.15,134.10,132.60,132.54,129.84,129 .76,128.87,125.15,123.36,123.33,122.93,122.30,117.59,117.41,115.47,114.48,114.29,110.50,103.68,62.27,53.57,14.07.

[0262] Example 39: (E)-2-cyano-3-(5-(3-fluorophenyl)-1-(pyridin-2-ylmethyl)-1H-pyrrolo-3-yl)acrylic acid (compound I-39)

[0263] Following the synthetic method of compound I-2, compound I-39 was prepared using I-38 as the starting material.

[0264] ESI-MS (m / z): 348.1 [M+H] +

[0265] 1 H NMR(500MHz,Chloroform-d)δ8.39(dd,J=4.1,1.7Hz,1H),7.97(s,1H),7.86(m,1H),7.56–7.45(m,2H),7.28–7.2 1(m,2H),7.17(m,1H),7.09(m,1H),6.30–6.26(m,1H),6.10(d,J=1.6Hz,1H),5.82(s,1H),5.82(d,J=1.9Hz,1H). 13C NMR(125MHz,Chloroform-d)δ164.03,163.77,162.05,156.20,149.92,137.32,134.17,134.14,134.10,132.60,132.54,129. 84,129.76,128.87,125.15,123.36,123.33,122.93,122.30,117.59,117.41,115.60,114.48,114.29,110.50,107.03,53.57.

[0266] Example 1: In vitro lactate release experiment of the compound

[0267] 1) Instruments and reagents

[0268] The experimental equipment and main reagents for the in vitro lactic acid release experiment are as follows (see Table 2):

[0269] Table 2

[0270] Name Manufacturer Model MCF-10A cells Promocell CL-0525 MCF-10A cell-specific medium Promocell CM-0525 Cell incubator Thermo Scientific 51032719 Enzyme-free centrifuge tube Servicebio EP-150-M Shaking table Servicebio TSY-B Vortex mixer Servicebio MX-F Pipette Dragon KE0003087 / KA0056573 Refrigerator Qingdao Haier Co., Ltd. BCD-192TGN Microscope CIC XSP-C204 Constant temperature box LABOTERY DS-U3 6 cm cell culture dish LABSELECT 12211 6-well cell culture plate LABSELECT 11110

[0271] The main experimental reagents for the in vitro lactic acid release experiment are shown in Table 3:

[0272] Table 3

[0273]

[0274] 2) Experimental Operation

[0275] Step 1: MCF-10A cell passage

[0276] (1) Remove the original culture medium;

[0277] (2) Add about 2 mL of PBS, gently shake the culture flask to rinse the cells, and then aspirate and discard the PBS.

[0278] (3) Add about 1 mL of trypsin and gently shake the culture flask to infiltrate all cells;

[0279] Note: MCF-10A cells are relatively difficult to digest. Please extend the digestion time until the cells shrink and become round. Gently tap the side of the culture flask and the cells can slide off. This digestion can be stopped at this time. It usually takes 10 to 15 minutes.

[0280] (4) Place the culture flask in an incubator for digestion. When you see the cells in the middle of the cell block become obviously rounded and have gaps under a microscope, you can stop the process. Do not tap the culture flask throughout the process.

[0281] (5) Add 3 mL of serum-containing culture medium to stop digestion, pipette the cells to detach them from the cell wall, and repeatedly pipette the cells in the liquid to make them as much as possible a single-cell suspension.

[0282] (6) Collect the cell suspension and centrifuge at 1200 rpm / min for 3 minutes. After centrifugation, aspirate and discard the supernatant.

[0283] (7) Add fresh culture medium, blow a few times to mix the cells, inoculate into new culture flasks according to the ratio, replenish the culture medium, loosen the bottle cap or use a breathable bottle cap for culture.

[0284] Step 2: Determining the maximum lactate release rate concentration of UK-5099

[0285] (1) Cells were treated with the positive control drug UK-5099, and the amount of LA released was detected. Different concentrations were set: 0, 2.5, 5, 10, 20, 50, and 100 μM.

[0286] (2) MCF-10A cells were cultured and, after reaching confluence, were digested and collected. The cells were then cultured at a concentration of 1×10⁻⁶ cells / cells. 6 Cells were seeded at a rate of 100 cells / dish in 6cm culture dishes and cultured overnight for 12 hours. Then, different concentrations of UK-5099 were added, with each concentration repeated twice, and the mixture was cultured for 36 hours.

[0287] (3) Take out the cells to be tested, add 0.8 mL of extraction solution one, and lyse at room temperature for 30 min. Centrifuge at 12000 g for 10 min at 4℃, take 0.8 mL of supernatant, add 0.15 mL of extraction solution two, centrifuge at 12000 g for 10 min at 4℃, and take the supernatant for testing.

[0288] (4) Sample addition table (see Table 4):

[0289] Table 4

[0290]

[0291] (5) Calculated based on standard products

[0292] LA content (mM / 10) 6 cell) = (A 测定 -A 空白 ) / (A 标准 -A 空白 )×C 标准

[0293] C 标准 =Concentration of the standard, 3mM

[0294] The obtained data were processed, and the concentration at which the positive control drug UK-5099 achieved the maximum lactic acid release rate was calculated to be 10 μM.

[0295] Step 3: Lactic acid (LA) content detection

[0296] (1) The concentration of 10 μM at which the maximum lactic acid release rate of the positive drug UK-5099 is achieved.

[0297] (2) MCF-10A cells were cultured until they reached confluence. The cells were then digested and collected at a concentration of 1×10⁻⁶. 6 Cells were seeded at a rate of 100 cells / dish in 6cm culture dishes and cultured overnight for 12 hours. Then, 10μM of different compounds were added and the cells were cultured for 36 hours.

[0298] (3) Take out the cells to be tested, add 0.8 mL of extraction solution one, and lyse at room temperature for 30 min. Centrifuge at 12000 g for 10 min at 4℃, take 0.8 mL of supernatant, add 0.15 mL of extraction solution two, centrifuge at 12000 g for 10 min at 4℃, and take the supernatant for testing.

[0299] (4) Sample addition table (see Table 5):

[0300] Table 5

[0301]

[0302]

[0303] (5) Calculate the relative expression level of LA in cells after the addition of the compound: take the absorbance of the DMSO group as a unit and calculate the ratio of each group to the DMSO group.

[0304] 3) Results of the compound's lactate release experiment (see Table 6)

[0305] Table 6

[0306] Compound Relative expression of lactic acid release UK-5099 1.219 I-1 1.255 I-2 1.417 I-3 1.324 I-4 1.308 I-5 1.109 I-6 1.336 I-7 1.202 I-8 1.178 I-9 0.870 I-10 0.943 I-11 1.012 I-12 1.437 I-13 1.233 I-14 1.240 I-15 1.209 I-16 1.248 I-17 1.171 I-18 1.109 I-19 1.062 I-20 1.295 I-21 1.023 I-22 1.147 I-23 1.101 I-24 1.287 I-25 1.442 I-26 1.225 I-27 1.147 I-28 1.163 I-29 1.411 I-30 1.163 I-31 0.922 I-32 1.171 I-33 1.008

[0307] The experimental results shown in Table 6 above indicate that there is no significant structure-activity relationship between the compound structure and the lactate release-promoting effect. In the tests of this invention, some compounds of this invention, such as I-1, I-2, I-3, I-4, I-6, I-12, I-13, I-14, I-16, I-20, I-24, I-25, I-26, and I-29, showed better lactate release-promoting effects compared with the positive control (UK-5099).

[0308] Example 2: Hair growth experiment of C57BL / 6J mice

[0309] 1) Experimental conditions

[0310] (1) Laboratory animals

[0311] Species: C57BL / 6J mouse, grade: SPF, weight: male mouse 18g (purchased from Shanghai Slack Laboratory Animal Co., Ltd.);

[0312] (2) Environmental adaptation

[0313] Environmental acclimatization for 7 days prior to the experiment;

[0314] (3) Feeding conditions

[0315] Stocking density: 10 birds / cage; Cage space movement frequency: once / week;

[0316] (4) Rearing environment conditions

[0317] Standards for breeding environment conditions: National Standard of the People's Republic of China GB14925-2010;

[0318] (5) Feed

[0319] Feeding method: Free access;

[0320] Standard nutritional components: crude protein, crude fat, crude fiber, crude ash, moisture, calcium, and phosphorus.

[0321] (6) Drinking water

[0322] Type: Drinking water for laboratory animals (autoclaved tap water);

[0323] Water supply method: Water is provided in bottles and can be consumed freely;

[0324] 2) Experimental methods

[0325] (1) Route of administration: Topical application; Volume of administration: 20 μM 300 μL; Dosage: Distilled water, anhydrous ethanol and polyethylene 400 (5:3:2).

[0326] (2) Trial period: The drug was administered once a day and observed for 16 days after administration.

[0327] (3) Observation indicators:

[0328] General symptoms:

[0329] Observe the growth of the mouse's skin and fur daily, record the time it takes for the skin of each mouse's shaved area to change from pink to gray, and from gray to full fur growth, take photos, record the data, and score the data.

[0330] The scoring criteria are as follows (see Table 7):

[0331] Table 7

[0332] Score Description 1 point Mouse back smooth, no hair or a few 2 points Sparse hair, soft texture not in pieces 3 points Sparse hair, soft texture, connected in pieces 4 points Pieces of soft hair cover 5 points Pieces of hair, texture is hard, thick

[0333] System autopsy:

[0334] After 16 days of drug administration, the animals were euthanized by anesthesia and bloodletting with 3% sodium pentobarbital, and their hair growth was examined.

[0335] 3) The experimental results are as follows (see Table 8):

[0336] Table 8

[0337] Compound Hair growth score UK-5099 3 Minoxidil 2 I-1 4 I-2 4 I-3 4 I-4 4 I-6 5 I-11 5 I-12 4 I-13 4 I-14 4 I-16 4 I-20 4 I-22 4 I-24 5 I-25 5 I-26 5 I-29 5 I-34 3

[0338] The experimental results shown in Table 8 above indicate that, compared with the positive control (UK-5099), the compounds of the present invention all showed superior or comparable hair growth-promoting effects, and all compounds were superior to the marketed drug minoxidil.

[0339] Example 3: Experiment on the effect of compounds on hERG potassium channels

[0340] The potential cardiotoxic side effects of some compounds of this invention were preliminarily investigated in vitro using the hERG potassium channel inhibition assay. The experimental procedure is as follows:

[0341] 1) Cell preparation

[0342] CHO-hERG cells (Millipore Precision) TM hERG-CHO Recombinant Cell Line (Cat#CYL3038) cultured at 175 cm⁻¹ 2 In the culture flask, when the cell density grows to 60-80%, remove the culture medium, wash once with 7 mL PBS, and then add 3 mL Detachin (Yaji Biotechnology, A1110501) for digestion.

[0343] After complete digestion, add 7 mL of culture medium to neutralize, then centrifuge, aspirate the supernatant, and resuspend in 5 mL of culture medium to ensure a cell density of 2–5 × 10⁻⁶ cells / mL. 6 / mL.

[0344] 2) Electrophysiological recording process

[0345] The single-cell high-impedance sealing and whole-cell pattern formation processes were all automated by the Qpatch instrument. After obtaining the whole-cell recording pattern, the cells were clamped at -80 mV. Before applying a 5-second +20 mV depolarization stimulus, a 50-millisecond -50 mV pre-voltage was applied, followed by repolarization to -50 mV for 5 seconds, and then back to -80 mV. This voltage stimulus was applied every 15 seconds. After recording for 2 minutes, extracellular fluid was applied for another 2 minutes of recording, and then the drug administration process began. The compound concentration started from the lowest test concentration of 0.1 μM, and each test concentration was administered for 2 minutes. After all concentrations were administered, a positive control compound of 10 μM UK-5099 was administered. At least 3 cells (n≥3) were tested for each concentration.

[0346] 3) Compound preparation

[0347] The stock solution of the compound was diluted with extracellular fluid. 2 μL of the stock solution was added to 998 μL of extracellular fluid, and then the solution was serially diluted 5-fold in extracellular fluid containing 0.2% DMSO to obtain the final concentration to be tested. Experimental data were analyzed using XLFit software.

[0348] The experimental results are shown in Table 9:

[0349] Table 9

[0350] Compound hERG IC 50 (μM) I-1 >10 I-2 >10 I-3 >10 I-4 >10 I-6 >10 I-11 >10 I-12 >10 I-13 >10 I-14 >10 I-16 >10 I-20 >10 I-22 >10 I-24 >10 I-25 >10 I-26 >10 I-29 >10 I-34 >10 I-35 >10 I-36 >10 I-37 >10 I-38 >10 I-39 >10

[0351] The experimental results shown in Table 9 above demonstrate that the compound hERG IC of this invention... 50 The values ​​were all greater than 10 μM, indicating relatively low potential cardiotoxicity.

[0352] While specific embodiments of the present invention have been described above, those skilled in the art should understand that these are merely illustrative examples, and the scope of protection of the present invention is defined by the appended claims. Those skilled in the art can make various changes or modifications to these embodiments without departing from the principles and essence of the present invention, but all such changes and modifications fall within the scope of protection of the present invention.

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof: in, n is 0 or 1; m can be 1, 2, 3, or 4; X is -(C1-C4 alkylene)-, -C(=O)-, or -S(=O)2-; R is independently hydrogen, halogen, cyano, C1-C6 alkyl, or is contained in one or more R groups. 0-1 Substituted C1-C6 alkyl, C1-C6 alkoxy, or substituted with one or more R 0-2 Substituted C1-C6 alkoxy groups; when there are multiple substituents, they may be the same or different; R 0-1 and R 0-2 It is independently C1-C6 alkyl, halogen, or amino; R 1 Independently H, 5-10 membered heterocyclic alkyl, 6-10 membered aryl, surrounded by one or more R 1-1 Substituted 6-10 aryl, 5-10 heteroaryl, or substituted with one or more R 1-1 Substituted 5-10 heteroaryl groups; the 5-10 heteroaryl group, substituted with one or more R groups 1 -1 In the substituted 5-10-membered heteroaryl and 5-10-membered heterocyclic alkyl groups, the heteroatoms are independently selected from one, two, or three of N, O, and S, and the number of heteroatoms is one, two, or three; when there are multiple substituents, they may be the same or different; R 1-1 Independently, it is a C1-C6 alkyl, a C1-C6 alkyl substituted with one or more halogens, a C1-C6 alkoxy, a halogen, or an amino; R 2 -COOR 2-1 ; R 2-1 It is hydrogen, C1-C6 alkyl, or composed of one or more R 2-1-1 Substituted C1-C6 alkyl groups; when there are multiple substituents, they may be the same or different; R 2-1-1 It is independently C1-C6 alkyl, halogen, or amino; R 3 It is a cyano group.

2. The compound of formula (I) as claimed in claim 1, characterized in that, It meets one or more of the following conditions: (1) The halogen is independently fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine; (2) Each of the C1-C4 alkylene groups is independently methylene; (3) The C1-C6 alkoxy groups are independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy or tert-butoxy, preferably ethoxy or n-butoxy; (4) The C1-C6 alkyl groups are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably ethyl; (5) The 6-10 aryl groups are independently phenyl or naphthyl; and (6) The 5-10 aryl groups are each independently a 5- or 6-aryl group with N heteroatom and 1 or 2 heteroatoms; preferably pyridyl, for example 3. The compound of formula (I) as claimed in claim 1, characterized in that, It meets one or more of the following conditions: (1) n is 0 or 1; (2) m is 1; (3) R is independently a halogen or a cyano group, preferably a halogen; (4)R 1 Independently H, 6-10 aryl, and surrounded by one or more R 1-1 Substituted 6-10 aryl, 5-10 heteroaryl, or with one or more R 1-1 Substituted 5-10 heteroaryl groups; (5)R 1-1 Independently, it is a C1-C6 alkyl, a C1-C6 alkyl substituted with one or more halogens, a C1-C6 alkoxy, or a halogen; (6)R 2 -COOR 2-1 R 2-1 It is hydrogen or C1-C6 alkyl; and (7) X is independently -(C1-C4 alkylene)- or -S(=O)2-.

4. The compound of formula (I) as claimed in claim 1, characterized in that, It meets one or two of the following conditions: (1) X is -CH2-, -C(=O)- or -S(=O)2-, preferably -CH2- or -S(=O)2-; (2) m is 1, and R is independently fluorine or bromine, preferably fluorine; (3) n is 0, R 1 For H; or, n is 1, R 1 for and (4) Independently 5. The compound of formula (I) as claimed in claim 11, or a pharmaceutically acceptable salt thereof, characterized in that, The compound represented by formula (I) is either the compound represented by formula (IA) or the compound represented by formula (IB): Among them, R and R 1 The definition is as described in claim 1.

6. The compound of formula (I) as claimed in claim 1, characterized in that, The compound represented by formula (I) is any of the following compounds:

7. A compound as shown in formula (II), in, m, R and R 2 The definition is as described in any one of claims 1-4.

8. A method for preparing a compound as shown in formula (I), characterized in that, It includes Option 1 or Option 2: Option 1: (1) When R 2 -COOR 2-1 ;R 2-1 It is a C1-C6 alkyl group or is composed of one or more R groups. 2-1-1 When the C1-C6 alkyl group is substituted, the compound shown in formula (I) is prepared by the following steps: in a solvent, the compound shown in formula (II) is subjected to a substitution reaction with the compound shown in formula (Int-I) to obtain the compound shown in formula (I): Where, n, m, R, R 1 R 2 R 3 X is defined as described in any one of claims 1-4; Y is a halogen, preferably bromine; And / or, (2) when R 2 When the group is carboxyl, the preparation method of the compound shown in formula (I) further includes a hydrolysis reaction in addition to the above-mentioned substitution reaction; Alternatively, Option 2: In a solvent, the compound shown in formula (Ⅲ) is reacted with R. 2 -CH2-CN undergoes the addition reaction shown below to give the compound shown in formula (I); Where X, m, n, R, R 1 R 2 and R 3 The definition is as described in any one of claims 1-4; Preferably, the method for preparing the compound as shown in formula (I) satisfies one or more of the following conditions: (1) In the substitution reaction described in Scheme 1, the solvent is an amide solvent, preferably DMF; (2) In the substitution reaction described in Scheme 1, the substitution reaction is carried out in the presence of a base, for example, in the presence of cesium carbonate; (3) In the addition reaction described in Scheme 2, the solvent is one or more of alcohol solvents, ester solvents, and ether solvents. For example, the alcohol solvent may be ethanol, the ester solvent may be ethyl acetate, and the ether solvent may be tetrahydrofuran; and (4) In the addition reaction of Scheme 2, the addition reaction is carried out in the presence of a catalyst, for example, in the presence of L-proline.

9. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises: (1) The compound of formula (I) as described in any one of claims 1-6, or a pharmaceutically acceptable salt thereof, and (2) Pharmaceutically acceptable excipients.

10. The use of the compound of formula (I) as described in any one of claims 1-6, or a pharmaceutically acceptable salt thereof, or the use of the pharmaceutical composition as described in claim 9 in the preparation of an MPC inhibitor.

11. The use of a compound of formula (I) as claimed in any one of claims 1-6, or a pharmaceutically acceptable salt thereof, or the use of a pharmaceutical composition as claimed in claim 9 in the preparation of a medicament, characterized in that, The drug meets one or more of the following conditions: (1) The drug is used to treat or prevent MPC-mediated diseases or conditions; for example, the MPC-mediated diseases or conditions are hair loss, diabetes, metabolic diseases or inflammation; (2) The drug is used to promote lactate release; and (3) The drug is used to treat hair loss.

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