2-phenyl-pyrrole compound, preparation method therefor, and use thereof

Abstract

Disclosed in the present invention are a 2-phenyl-pyrrole compound, a preparation method therefor, and the use thereof. Specifically, provided in the present invention is a compound as shown in formula (I) or a pharmaceutically acceptable salt thereof. The compound of the present invention has advantages such as a good inhibitory effect on MPC, a good therapeutic effect on alopecia in-vivo and in-vitro, and potentially low toxic and side effects.

Description

2-phenyl-pyrrole compounds, methods for preparing the same and uses thereof

[0001] This application claims priority to Chinese patent application 2024106568680 with a filing date of 2024 / 5 / 24. This application incorporates the entirety of the aforementioned Chinese patent application. TECHNICAL FIELD

[0002] The present application relates to a 2-phenyl-pyrrole compound, methods for preparing the same and uses thereof. BACKGROUND

[0003] 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 thinning of hair known as telogen effluvium. Although hair loss is not a life-threatening disease, it can cause self-esteem, frustration and reduced well-being in patients with hair loss, and even lead to suicide. So far, three drugs, minoxidil, finasteride and baricitinib, have been approved by the 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 effective and low-toxicity hair loss treatment drugs with new mechanisms of action.

[0004] 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 when a new hair growth cycle begins, they can quickly "wake up" and actively divide. 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, pyruvate in the cytoplasm cannot enter the mitochondria, but is converted into other metabolites such as lactic acid by lactate dehydrogenase (LDH), thereby increasing LDH activity and activating HFSCs, which ultimately promotes hair growth (Exp Dermatol. 2021 Apr; 30(4): 448-456). Currently, MPC has been proven to be a very promising therapeutic target for treating hair loss.

[0005] UK-5099 is the earliest MPC inhibitor proven to have hair growth activity (J Med Chem. 2021 Feb 25; 64(4): 2046-2063), and its mechanism of action is similar 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 lactate), which can block pyruvate from entering mitochondria, thereby promoting the production of lactic acid. 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.

[0006] Currently, there are few structural types of MPC inhibitors with hair loss treatment effects, and there is an urgent need to discover inhibitor molecules with novel structures, good physicochemical properties, good in vitro and in vivo hair loss treatment effects, 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 (e.g. low liposolubility of the compound, easy to prepare into a salt, and at the same time increase the possibility of combining with protein amino acids), good inhibition effect on MPC, good in vitro and in vivo hair loss treatment effect, and low potential toxicity and the like.

[0008] The present application is to solve the above technical problems by the following technical solutions:

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

[0010] Wherein, n is 0 or 1;

[0011] M is 1, 2, 3 or 4;

[0012] X is -(C1-C4 alkylene)-, -C (=O)- or-S (=O) 2-;

[0013] R independently is hydrogen, halogen, cyano, C1-C6 alkyl, one or more R 0-1 Substituted C1-C6 alkyl, C1-C6 alkoxy or one or more R 0-2 Substituted C1-C6 alkoxy;When the substituent is multiple, same or different;

[0014] R 0-1 And R 0-2 Independently C1-C6 alkyl, halogen or amino;

[0015] R 1 Independently H, 5-10 membered heterocyclic alkyl, 6-10 membered aryl, one or more R 1-1 Substituted 6-10 membered aryl, 5-10 membered heteroaryl or one or more R 1-1 Substituted 5-10 membered heteroaryl;5-10 membered heteroaryl, one or more R 1-1 Substituted 5-10 membered heteroaryl and 5-10 membered heterocyclic alkyl, heteroatom is independently selected from 1, 2 or 3 in N, O and S, and the number of heteroatoms is 1, 2 or 3;When the substituent is multiple, same or different;

[0016] R 1-1 Independently C1-C6 alkyl, C1-C6 alkyl substituted by one or more halogens, C1-C6 alkoxy, halogen or amino;

[0017] R 2 -COOR 2-1 ;

[0018] R 2-1 Is hydrogen, C1-C6 alkyl or C1-C6 alkyl substituted by one or more R 2-1-1 ;When the substituent is multiple, same or different;

[0019] R 2-1-1 Independently C1-C6 alkyl, halogen or amino;

[0020] R3 is cyano.

[0021] In some preferred embodiments of the present application, certain groups in the compounds of formula (I) or pharmaceutically acceptable salts thereof are defined as follows, and the groups not mentioned are as described 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.

[0022] In some embodiments, the C1-C4 alkylene is independently methylene.

[0023] In some embodiments, the C1-C6 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably ethyl.

[0024] In some embodiments, the C1-C6 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably ethyl.

[0025] In some embodiments, the 6-10 membered aryl is independently phenyl or naphthyl.

[0026] In some embodiments, the 5-10 membered heteroaryl is independently a 5- or 6-membered heteroaryl with 1 or 2 heteroatoms being N; preferably pyridyl, for example

[0027] In some embodiments, n is 0 or 1.

[0028] In some embodiments, m is 1.

[0029] In some embodiments, R is independently halogen or cyano.

[0030] In some embodiments, R 1 is independently H, 6-10 membered aryl, 6-10 membered aryl substituted with one or more R 1-1 , 5-10 membered heteroaryl, 5-10 membered heteroaryl substituted with one or more R 1-1 .

[0031] In some embodiments, R 1-1 is independently C1-C6 alkyl, C1-C6 alkyl substituted with one or more halogen, C1-C6 alkoxy or halogen.

[0032] In some embodiments, R 2 is -COOR 2-1 , R 2-1 is hydrogen or C1-C6 alkyl.

[0033] In some embodiments, X is independently -(C1-C4 alkylene)- or -S(=O)2-.

[0034] In some embodiments, R is halogen.

[0035] In some embodiments, X is -CH2-, -C(=O)- or -S(=O)2-, preferably -CH2- or -S(=O)2-.

[0036] In some embodiments, m is 1, R is independently fluorine or bromine, preferably fluorine.

[0037] In some embodiments, n is 0, R 1 is H.

[0038] In some embodiments, n is 1, R 1 is

[0039] In some embodiments, is independently

[0040] In some embodiments, the compound of formula (I) is a compound of formula (I-A) or a compound of formula (I-B):

[0041] wherein R and R 1 are as defined above.

[0042] In some embodiments, the compound of formula (I) is any one of the following compounds:

[0043] Table 1

[0044] The present application provides a compound of formula (II):

[0045] wherein m, R and R 2 are as defined above.

[0046] The present application provides a method for preparing a compound of formula (I), comprising Scheme 1 or Scheme 2:

[0047] Scheme 1:

[0048] (1) when R 2 is -COOR2-1 ;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):

[0049] Where, n, m, R, R 1 R 2 R 3 The definitions of X and X are as described above;

[0050] Y is a halogen, preferably bromine.

[0051] (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.

[0052] Option 2:

[0053] 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);

[0054] Where X, m, n, R, R 1 R 2 and R 3 The definition is as described above.

[0055] In some embodiments, in the substitution reaction of Scheme 1, the solvent is an amide solvent, preferably DMF.

[0056] 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.

[0057] 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).

[0058] 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.

[0059] This invention provides a pharmaceutical composition comprising:

[0060] (1) the above-mentioned compound represented by formula (I) or a pharmaceutically acceptable salt thereof, and

[0061] (2) a pharmaceutically acceptable excipient.

[0062] The present application provides use of the above-mentioned compound represented by formula (I) or a pharmaceutically acceptable salt thereof in the preparation of an MPC inhibitor.

[0063] In some embodiments, the MPC inhibitor can be used in vivo in a mammalian organism, and can also be used in vitro (for example, as an experimental use, further for example, as a standard sample or a control sample to provide a contrast, or prepared into a kit according to a conventional method in the art to provide a rapid detection for the effect of inhibiting MPC).

[0064] The present application provides use of the above-mentioned compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition in the preparation of a drug for treating or preventing an MPC-mediated disease or disorder.

[0065] In some embodiments, the MPC-mediated disease or disorder is alopecia, diabetes, a metabolic disease, or inflammation, etc.

[0066] The present application provides use of the above-mentioned compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition in the preparation of a drug for promoting lactic acid release.

[0067] The present application provides use of the above-mentioned compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition in the preparation of a drug for treating alopecia.

[0068] Term explanation

[0069] In the present application, the term "pharmaceutically acceptable salt" refers to a salt obtained by reacting a compound with a pharmaceutically acceptable acid or base. When the compound contains a relatively acidic functional group, the 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 the compound contains a relatively basic functional group, the acid addition salt can be obtained by contacting the compound with a sufficient amount of a pharmaceutically acceptable acid in a suitable inert solvent. For specific details, please refer to Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P. Heinrich Stahl, Camille G. Wermuth, 2011, 2nd Revised Edition).

[0070] The term "ester" includes physiologically hydrolysable esters (which can be hydrolysed under physiological conditions to release the free acid or alcohol form of a compound of the application). In addition to this, the compounds of the application can themselves be esters.

[0071] In the present application, the structural fragment means that the structural fragment is attached to the remainder of the molecule via the bond. For example, means pyridyl.

[0072] In the present application, the term "one or more" means 1, 2, 3, 4, 5 or 6, for example 1, 2 or 3.

[0073] In the present application, the term "halogen" means fluorine, chlorine, bromine or iodine.

[0074] In the present application, the term "alkyl" means a straight or branched chain, saturated, monovalent hydrocarbon radical having the indicated number of carbon atoms (e.g., C1-C6). Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl, n-hexyl, and the like.

[0075] In the present application, the term "alkylene" means a saturated, divalent hydrocarbon radical obtained by removing two hydrogen atoms from a straight or branched chain hydrocarbon radical. Alkylene groups include, but are not limited to, methylene (-CH2-), ethylene {including -CH2CH2- or -CH(CH3)-}, isopropylene {including -CH(CH3)CH2- or -C(CH3)2-}, and the like.

[0076] In the present application, the term "alkoxy" means the group R Y -O-, R Y is defined as the term "alkyl". Alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, s-butyloxy, t-butyloxy, n-pentyloxy, n-hexyloxy, and the like.

[0077] In the present application, the term "aryl" means a cyclic, unsaturated, monovalent hydrocarbon radical having the indicated number of carbon atoms (e.g., C6-C 10 ), which is monocyclic or polycyclic (e.g., 2), which, if polycyclic, shares two atoms and one bond between the rings, and each ring of which is aromatic. The aryl group is attached to the remainder of the molecule via the ring having aromaticity. Aryl groups include, but are not limited to, phenyl, naphthyl, and the like.

[0078] In the present application, the term "heteroaryl" refers to a cyclic, unsaturated, monovalent group having a specified number of ring atoms (e.g., 5-6 membered), a specified number of heteroatoms (e.g., 0, 1, 2, or 3), a specified type of heteroatoms (one or more of N, O, and S), which is monocyclic, and aromatic; the heteroaryl group is attached to the remainder of the molecule through a carbon atom or a heteroatom. Heteroaryl groups include, but are not limited to etc.

[0079] In the present application, the term "heteroaryl" refers to a cyclic, unsaturated, monovalent group having a specified number of ring atoms (e.g., 5-6 membered), a specified number of heteroatoms (e.g., 0, 1, 2, or 3), a specified type of heteroatoms (one or more of N, O, and S), which is monocyclic, and aromatic; the heteroaryl group is attached to the remainder of the molecule through a carbon atom or a heteroatom. Heteroaryl groups include, but are not limited to

[0080] The above-mentioned preferred conditions can be combined in any manner without departing from the common general knowledge in the art, thereby obtaining preferred embodiments of the present application.

[0081] The reagents and raw materials used in the present application are commercially available.

[0082] The positive progress effect of the present application is that, compared with the prior art, the compound disclosed in the present application has novel structure, good physicochemical properties (e.g., the compound is fat-soluble and easy to be prepared into a salt), good inhibitory effect on MPC, good lactic acid release promoting effect, and good in-vivo and in-vitro hair loss treatment effect. In addition, the preparation method of the MPC inhibitor provided in the present application has simple conditions, easy-to-obtain raw materials, low preparation cost, and high product yield. DETAILED DESCRIPTION

[0083] The present application will be further described by way of examples, but the present application is not limited to the scope of the examples. In the following examples, the experimental methods not specified in the examples are selected according to conventional methods and conditions, or according to the instructions of the commercial products.

[0084] Example 1: (E)-2-cyano-3-(5-(2-fluorophenyl)-1H-pyrrol-3-yl)acrylic acid ethyl ester (Compound I-11)

[0085] Step 1:

[0086] In a 100 mL round bottom flask, Int. 11-a (5.0 g, 26.4 mmol) was dissolved in 100 mL of ethanol, then L-proline (1.22 g, 10.56 mmol) and ethyl cyanoacetate (3.89 g, 34.40 mmol) were added, and the reaction was stirred at room temperature for 12 h. A large amount of light yellow solid was precipitated. After the reaction was completed by TLC monitoring, 100 mL of ice water was added to the reaction solution, stirred for 0.5 h, then filtered, and the filter cake was washed with ice water for 3-5 times to obtain the pure product I-11 (7.22 g, 96.2%).

[0087] ESI-MS (m / z): 285.2 [M+H] +

[0088] 1 H NMR (400 MHz, DMSO-d6) δ 12.42 (s, 1H), 8.28 (s, 1H), 7.94 (d, J = 1.7 Hz, 1H), 7.75 (m, 1H), 7.40 (t, J = 2.2 Hz, 1H), 7.38 - 7.24 (m, 3H), 4.26 (q, J = 7.1 Hz, 2H), 1.28 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 163.67, 158.83, 149.90, 132.39, 129.40, 129.33, 127.37, 125.37, 119.65, 117.60, 116.95, 116.74, 108.58, 94.24, 61.90, 14.59.

[0089] Example 2: (E)-2-cyano-3-(5-(2-fluorophenyl)-l-(pyridin-2-ylmethyl)-lH-pyrrol-3- yl)acrylic acid ethyl ester (Compound I-1)

[0090] Step 1:

[0091] In a 100 mL round bottom flask, Int. 11-a (5.0 g, 26.4 mmol) was dissolved in 100 mL of ethanol, then L-proline (1.22 g, 10.56 mmol) and ethyl cyanoacetate (3.89 g, 34.40 mmol) were added, and the reaction was stirred at room temperature for 12 h. A large amount of light yellow solid was precipitated. After the reaction was completed by TLC monitoring, 100 mL of ice water was added to the reaction solution, stirred for 0.5 h, then filtered, and the filter cake was washed with ice water for 3-5 times to obtain the pure product I-11 (7.22 g, 96.2%).

[0092] ESI-MS (m / z): 376.2 [M+H] +

[0093] 1 H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J = 3.9 Hz, 1H), 8.29 (s, 1H), 8.06 (d, J = 1.9 Hz, 1H), 7.68 (m, 1H), 7.46 (m, 1H), 7.38 - 7.17 (m, 4H), 7.04 (d, J = 1.9 Hz, 1H), 6.87 (dd, J = 7.8, 1.3 Hz, 1H), 5.27 (s, 2H), 4.27 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 163.56, 159.88, 156.17, 149.71, 149.54, 137.48, 135.14, 132.55, 131.64, 131.20, 125.12, 123.27, 121.70, 119.10, 118.60, 117.50, 116.32, 110.55, 94.62, 61.96, 53.16, 14.57.

[0094] Example 3: (E)-2-cyano-3-(5-(2-fluorophenyl)-l-(pyridin-2-ylmethyl)-lH-pyrrol-3- yl)acrylic acid (Compound I-2)

[0095] In a 100 mL round bottom flask, I-1 (0.45 g, 1.2 mmol) was dissolved in 8 mL of tetrahydrofuran, then excess lithium hydroxide monohydrate (0.50 g, 12.0 mmol) was added, and hydrolysis was carried out at room temperature for 2 h. After the reaction was completed by TLC monitoring, tetrahydrofuran was removed by distillation under reduced pressure, about 20 mL of ethyl acetate was added, stirred for 30 min, separated, the aqueous phase was adjusted to PH <1, a large amount of solid was precipitated, and the target compound I-2 (0.28 g, 67.2%) was obtained by filtration and drying.

[0096] ESI-MS (m / z): 348.2.

[0097] 1 H NMR (400 MHz, DMSO-d6) δ 8.44 (d, J = 3.9 Hz, 1H), 8.29 (s, 1H), 8.06 (d, J = 1.9 Hz, 1H), 7.68 (m, 1H), 7.46 (m, 1H), 7.38 - 7.17 (m, 4H), 7.04 (d, J = 1.9 Hz, 1H), 6.87 (dd, J = 7.8, 1.3 Hz, 1H), 5.27 (s, 2H), 4.27 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 164.95, 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.

[0098] Example 4: (E)-2-cyano-3-(5-(2-fluorophenyl)-l-(pyridin-3-ylmethyl)-lH-pyrrol-3- yl)acrylic acid ethyl ester (Compound I-3)

[0099] Compound I-3 was prepared according to the procedure for the synthesis of Reference Compound I-l.

[0100] ESI-MS (m / z): 376.2 [M+H] +

[0101] 1 H NMR (400 MHz, DMSO-d6) δ 8.43 (dd, J = 4.3, 2.2 Hz, 1H), 8.28 (s, 1H), 8.12 (dd, J = 2.2, 1.1 Hz, 1H), 8.08 (d, J = 1.9 Hz, 1H), 7.56 - 7.47 (m, 1H), 7.41 - 7.23 (m, 5H), 7.04 (d, J = 1.9 Hz, 1H), 5.23 (s, 2H), 4.27 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 163.49, 159.85, 149.41, 148.75, 135.23, 134.50, 132.75, 132.64, 131.91, 131.83, 131.01, 125.30, 124.07, 118.96, 118.37, 117.42, 116.41, 110.75, 94.92, 61.99, 49.17, 14.56.

[0102] Example 5: (E)-2-cyano-3-(5-(2-fluorophenyl)-l-(pyridin-3-ylmethyl)-lH-pyrrol-3- yl)acrylic acid (Compound I-4)

[0103] Compound I-4 was prepared according to the procedure for the synthesis of Reference Compound I-2, using I-3 as starting material.

[0104] ESI-MS (m / z): 348.2 [M+H] +

[0105] 1 H NMR (400 MHz, DMSO-d6) δ 13.38 (s, 1H), 8.43 (dd, J = 4.0, 2.5 Hz, 1H), 8.21 (s, 1H), 8.11 (t, J = 1.6 Hz, 1H), 8.03 (d, J = 2.0 Hz, 1H), 7.50 (m, 1H), 7.44 - 7.20 (m, 5H), 7.02 (d, J = 1.9 Hz, 1H), 5.23 (s, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 164.89, 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.

[0106] Example 6: (E)-2-cyano-3-(5-(2-fluorophenyl)-l-(pyridin-4-ylmethyl)-lH-pyrrol-3- yl)acrylic acid ethyl ester (Compound I-5)

[0107] Compound I-5 was prepared according to the procedure described for the synthesis of Reference Compound I-l.

[0108] ESI-MS (m / z): 376.2 [M+H] +

[0109] 1 H NMR (600 MHz, DMSO-d6) δ 8.47 - 8.40 (m, 2H), 8.30 (s, 1H), 8.07 (d, J = 1.9 Hz, 1H), 7.52 - 7.43 (m, 1H), 7.35 (td, J = 7.6, 1.8 Hz, 1H), 7.29 (ddd, J = 9.8, 8.4, 1.1 Hz, 1H), 7.23 (td, J = 7.5, 1.1 Hz, 1H), 7.07 (d, J = 1.8 Hz, 1H), 6.89 - 6.83 (m, 2H), 5.26 (s, 2H), 4.28 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H). 13CNMR (151 MHz, DMSO-d6) δ 163.48, 159.85, 150.27, 149.41, 146.30, 134.80, 132.59, 131.89, 131.84, 131.18, 125.28, 121.86, 118.83, 118.73, 118.48, 117.42, 116.41, 110.81, 95.16, 62.03, 50.41, 14.58.

[0110] Example 7: (E)-2-cyano-3-(5-(2-fluorophenyl)-l-(pyridin-4-ylmethyl)-lH-pyrrol-3- yl)acrylic acid (Compound I-6)

[0111] Compound I-6 was prepared according to the procedure described for the synthesis of Reference Compound I-2 using I-5 as starting material.

[0112] ESI-MS (m / z): 348.2 [M+H] +

[0113] 1 H NMR (400 MHz, DMSO-d6) δ 8.43 (d, J = 6.1 Hz, 2H), 8.23 (s, 1H), 8.02 (d, J = 1.9 Hz, 1H), 7.46 (m, 1H), 7.38 - 7.18 (m, 3H), 7.05 (s, 1H), 6.86 (d, J = 6.1 Hz, 2H), 5.25 (s, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 164.86, 159.83, 150.23, 148.70, 146.43, 134.05, 132.58, 131.82, 131.74, 130.94, 125.25, 121.81, 118.95, 118.80, 118.47, 117.90, 116.38, 110.76, 96.69, 50.34.

[0114] Example 8: (E)-3-(l-benzyl-5-(2-fluorophenyl)-lH-pyrrol-3-yl)-2-cyanoacrylic acid ethyl ester (Compound I-7)

[0115] Compound I-7 was prepared according to the procedure described for the synthesis of Reference Compound I-1.

[0116] ESI-MS (m / z): 375.2 [M+H] +

[0117] 1H NMR (400 MHz, DMSO-d6) δ 8.26 (s, 1H), 8.02 (d, J = 1.9 Hz, 1H), 7.54 - 7.44 (m, 1H), 7.40 - 7.27 (m, 2H), 7.27 - 7.18 (m, 4H), 7.02 (d, J = 1.9 Hz, 1H), 6.90 (dd, J = 7.5, 2.0 Hz, 2H), 5.16 (s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 1.27 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 163.54, 159.87, 149.48, 137.19, 134.58, 132.60, 131.77, 131.68, 131.18, 129.02, 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.

[0118] Example 9: (E)-3-(l-benzyl-5-(2-fluorophenyl)-lH-pyrrol-3-yl)-2-cyanacrylic acid (Compound I-8)

[0119] Compound I-8 was prepared from I-7 according to the procedure for the synthesis of Reference Compound I-2.

[0120] ESI-MS (m / z): 347.2 [M+H] +

[0121] 1 H NMR (400 MHz, DMSO-d6) δ 13.26 (s, 1H), 8.21 (s, 1H), 7.98 (d, J = 2.0 Hz, 1H), 7.49 (m, 1H), 7.39 - 7.28 (m, 2H), 7.28 - 7.17 (m, 4H), 7.02 (d, J = 1.9 Hz, 1H), 6.94 - 6.84 (m, 2H), 5.16 (s, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 164.93, 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.

[0122] Example 10: (E)-2-cyano-3-(5-(2-fluorophenyl)-l-(naphthalen-2-ylmethyl)-lH- pyrrol-3-yl)acrylic acid ethyl ester (Compound I-9)

[0123] Compound I-9 was prepared according to the procedure described for the synthesis of Reference Compound I-l.

[0124] ESI-MS (m / z): 425.2 [M+H] +

[0125] 1 H NMR (600 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.07 (d, J = 1.9 Hz, 1H), 7.86 (dd, J = 6.1, 3.4 Hz, 1H), 7.82 (d, J = 8.5 Hz, 1H), 7.76 (dd, J = 6.1, 3.4 Hz, 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, 1.8 Hz, 1H), 7.07 (d, J = 2.0 Hz, 1H), 5.33 (s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 1.28 (t, J = 7.1 Hz, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 163.56, 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, 126.70, 126.30, 125.39, 125.26, 119.17, 118.38, 117.52, 116.41, 110.54, 94.69, 61.97, 51.66, 14.58.

[0126] Example 11: (E)-2-cyano-3-(5-(2-fluorophenyl)-l-(naphthalen-2-ylmethyl)-lH-pyrrol-3- yl)acrylic acid (Compound I-10)

[0127] Compound I-10 was prepared according to the procedure described for the synthesis of Reference Compound I-2, using I-9 as starting material.

[0128] ESI-MS (m / z): 397.2 [M+H] +

[0129] 1H NMR (400 MHz, DMSO-d6) δ 12.84 (s, 1H), 8.23 (s, 1H), 8.03 (d, J = 1.9 Hz, 1H), 7.89 - 7.72 (m, 3H), 7.49 (m, 3H), 7.42 - 7.36 (m, 2H), 7.31 (m, 1H), 7.23 (td, J = 7.5, 1.2 Hz, 1H), 7.10 (dd, J = 8.5, 1.8 Hz, 1H), 7.05 (d, J = 1.9 Hz, 1H), 5.33 (s, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 172.47, 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.

[0130] Example 12: (E)-2-cyano-3-(5-(2-fluorophenyl)-lH-pyrrol-3-yl)acrylic acid (Compound I-12)

[0131] Compound I-12 was prepared from I-11 following the procedure for the synthesis of Reference Compound I-2.

[0132] ESI-MS (m / z): 257.1 [M+H] +

[0133] 1 H NMR (400 MHz, DMSO-d6) δ 12.40 (s, 1H), 8.26 (s, 1H), 7.91 (s, 1H), 7.77 (m, 1H), 7.42 (q, J = 2.3 Hz, 1H), 7.39 - 7.25 (m, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 165.08, 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.

[0134] Example 13: (E)-2-cyano-3-(l-(2-fluorobenzyl)-5-(2-fluorophenyl)-lH-pyrrol-3- yl)acrylic acid ethyl ester (Compound I-13)

[0135] Compound 1-13 was prepared according to the procedure described for the synthesis of reference compound 1-1.

[0136] ESI-MS (m / z): 393.2 [M+H] +

[0137] 1 H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 8.02 (d, J = 1.9 Hz, 1H), 7.50 (m, 1H), 7.42 - 7.21 (m, 4H), 7.15 - 7.04 (m, 2H), 7.02 (d, J = 1.9 Hz, 1H), 6.86 (m, 1.7 Hz, 1H), 5.22 (s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 1.28 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 163.51, 160.12, 159.92, 149.48, 134.53, 132.56, 131.79, 131.13, 130.65, 129.89, 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.

[0138] Example 14: (E)-2-cyano-3-(1-(2-fluorobenzyl)-5-(2-fluorophenyl)-1H-pyrrol-3- yl)acrylic acid (Compound 1-14)

[0139] Compound 1-14 was prepared according to the procedure described for the synthesis of reference compound 1-2, using 1-13 as starting material.

[0140] ESI-MS (m / z): 365.2 [M+H] +

[0141] 1 H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 8.02 (d, J = 1.9 Hz, 1H), 7.50 (m, 1H), 7.42 - 7.21 (m, 4H), 7.15 - 7.04 (m, 2H), 7.02 (d, J = 1.9 Hz, 1H), 6.86 (m, 1.7 Hz, 1H), 5.22 (s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 1.28 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 164.94, 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.

[0142] Example 15: (E)-2-cyano-3-(1-(3-fluorobenzyl)-5-(2-fluorophenyl)-1H-pyrrol-3- yl)acrylic acid ethyl ester (Compound I-15)

[0143] Compound I-15 was prepared according to the procedure for the synthesis of Reference Compound I-1.

[0144] ESI-MS (m / z): 393.2 [M+H] +

[0145] 1 H NMR (600 MHz, DMSO-d6) δ 8.28 (s, 1H), 8.05 (d, J = 1.9 Hz, 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 = 7.1 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H). 13 C NMR (151 MHz, DMSO-d6) δ 163.51, 162.54, 159.89, 149.46, 140.04, 134.65, 132.62, 131.82, 131.09, 125.27, 123.34, 118.99, 118.35, 117.45, 116.40, 114.97, 114.20, 110.66, 94.89, 62.00, 50.92, 14.58.

[0146] Example 16: (E)-2-cyano-3-(1-(3-fluorobenzyl)-5-(2-fluorophenyl)-1H-pyrrol-3- yl)acrylic acid (Compound I-16)

[0147] Compound I-16 was prepared according to the procedure for the synthesis of Reference Compound I-2, using I-15 as starting material.

[0148] ESI-MS (m / z): 365.2 [M+H] +

[0149] 1 H NMR (400 MHz, DMSO-d6) δ 13.34 (s, 1H), 8.22 (s, 1H), 8.00 (d, J = 1.9 Hz, 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 (101 MHz, DMSO-d6) δ 164.89, 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.

[0150] Example 17: (E)-2-cyano-3-(1-(4-fluorobenzyl)-5-(2-fluorophenyl)-1H-pyrrol-3- yl)acrylic acid ethyl ester (Compound 1-17)

[0151] Compound 1-17 was prepared according to the procedure for the synthesis of Reference Compound 1-1.

[0152] ESI-MS (m / z): 393.2 [M+H] +

[0153] 1 H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1H), 8.02 (d, J = 1.9 Hz, 1H), 7.50 (m, 1H), 7.40 - 7.18 (m, 3H), 7.12 - 7.04 (m, 2H), 7.02 (d, J = 1.9 Hz, 1H), 6.99 - 6.89 (m, 2H), 5.15 (s, 2H), 4.27 (q, J = 7.1 Hz, 2H), 1.28 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 163.52, 161.97, 159.87, 149.45, 134.49, 133.34, 132.61, 131.78, 131.07, 129.57, 125.24, 119.08, 118.28, 117.45, 116.37, 115.84, 110.63, 94.72, 61.97, 50.80, 14.56.

[0154] Example 18: (E)-2-cyano-3-(1-(4-fluorobenzyl)-5-(2-fluorophenyl)-1H-pyrrol-3- yl)acrylic acid (Compound 1-18)

[0155] Compound 1-18 was prepared from 1-17 according to the procedure described for the synthesis of Reference Compound 1-2.

[0156] ESI-MS (m / z): 365.2 [M+H] +

[0157] 1 H NMR (400 MHz, DMSO-d6) δ 8.03 (s, 1H), 7.82 (d, J = 1.9 Hz, 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 (101 MHz, DMSO-d6) δ 165.21, 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.

[0158] Example 19: (E)-ethyl 2-cyano-3-(5-(2-fluorophenyl)-1-(2-(trifluoromethyl)benzyl)-1H- pyrrol-3-yl)acrylate (Compound 1-19)

[0159] Compound 1-19 was prepared according to the procedure described for the synthesis of Reference Compound 1-1.

[0160] ESI-MS (m / z): 443.2 [M+H] +

[0161] 1 H NMR (600 MHz, DMSO-d6) δ 8.31 (s, 1H), 8.03 (d, J = 2.0 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.60 (d, J = 7.7 Hz, 1H), 7.51 - 7.39 (m, 2H), 7.32 - 7.24 (m, 2H), 7.17 (t, J = 7.5 Hz, 1H), 7.10 (d, J = 1.9 Hz, 1H), 6.74 (d, J = 7.8 Hz, 1H), 5.40 (s, 2H), 4.28 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H). 13C NMR (151 MHz, DMSO-d6) δ 163.47, 159.86, 149.45, 135.40, 135.07, 133.57, 132.57, 131.86, 131.27, 128.74, 128.30, 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.

[0162] Example 20: (E)-2-cyano-3-(5-(2-fluorophenyl)-l-(2-(trifluoromethyl)benzyl)-lH- pyrrol-3-yl)acrylic acid (Compound I-20)

[0163] Compound I-20 was prepared according to the procedure described for the synthesis of Reference Compound I-2 using I-19 as the starting material.

[0164] ESI-MS (m / z): 415.2 [M+H] +

[0165] 1 H NMR (400 MHz, DMSO-d6) δ 13.01 (s, 1H), 8.25 (s, 1H), 8.00 (d, J = 1.9 Hz, 1H), 7.71 - 7.57 (m, 2H), 7.52 - 7.38 (m, 2H), 7.34 - 7.21 (m, 2H), 7.17 (td, J = 7.5, 1.1 Hz, 1H), 7.09 (d, J = 1.8 Hz, 1H), 6.72 (d, J = 7.8 Hz, 1H), 5.40 (s, 2H). 13 C NMR (101 MHz, DMSO-d6) δ 164.84, 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.

[0166] Example 21: (E)-2-cyano-3-(5-(2-fluorophenyl)-l-(3-(trifluoromethyl)benzyl)-lH-pyrrol-3- yl)acrylic acid ethyl ester (Compound I-21)

[0167] Compound I-21 was prepared according to the procedure described for the synthesis of Reference Compound I-1.

[0168] ESI-MS (m / z): 443.2 [M+H] +

[0169] 1 H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 8.09 (d, J = 1.9 Hz, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.49 (m, 2H), 7.34 (td, J = 7.6, 1.9 Hz, 1H), 7.32 - 7.15 (m, 4H), 7.04 (d, J = 1.9 Hz, 1H), 5.30 (s, 2H), 4.27 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 163.48, 159.88, 149.42, 138.54, 134.58, 132.59, 131.82, 131.52, 130.97, 130.16, 129.59, 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.

[0170] Example 22: (E)-2-cyano-3-(5-(2-fluorophenyl)-l-(3-(trifluoromethyl)benzyl)-lH- pyrrol-3-yl)acrylic acid (Compound I-22)

[0171] Compound I-22 was prepared according to the procedure described for the synthesis of Reference Compound I-2 using I-21 as the starting material.

[0172] ESI-MS (m / z): 415.2 [M+H] +

[0173] 1 H NMR (400 MHz, DMSO-d6) δ 8.28 (s, 1H), 8.09 (d, J = 1.9 Hz, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.49 (m, 2H), 7.34 (td, J = 7.6, 1.9 Hz, 1H), 7.32 - 7.15 (m, 4H), 7.04 (d, J = 1.9 Hz, 1H), 5.30 (s, 2H), 4.27 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 164.87, 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.

[0174] Example 23: (E)-2-cyano-3-(5-(2-fluorophenyl)-l-(4-(trifluoromethyl)benzyl)-lH- pyrrol-3-yl)acrylic acid ethyl ester (Compound I-23)

[0175] Compound I-23 was prepared according to the procedure described for the synthesis of Reference Compound I-l.

[0176] ESI-MS (m / z): 443.2 [M+H] +

[0177] 1 H NMR (400 MHz, DMSO-d6) δ 8.29 (s, 1H), 8.06 (d, J = 1.9 Hz, 1H), 7.63 (d, J = 8.1 Hz, 2H), 7.49 (m, 1H), 7.36 (m, 1H), 7.33 - 7.19 (m, 2H), 7.11 (d, J = 8.0 Hz, 2H), 7.05 (d, J = 1.9 Hz, 1H), 5.30 (s, 2H), 4.27 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 163.47, 159.86, 149.40, 142.03, 134.66, 132.59, 131.85, 131.18, 128.65, 127.95, 125.90, 125.26, 123.17, 118.89, 118.46, 117.41, 116.37, 110.70, 95.01, 62.00, 50.95, 14.55.

[0178] Example 24: (E)-2-cyano-3-(5-(2-fluorophenyl)-l-(4-(trifluoromethyl)benzyl)-lH- pyrrol-3-yl)acrylic acid (Compound I-24)

[0179] Compound I-24 was prepared according to the procedure described for the synthesis of Reference Compound I-2, using I-23 as starting material.

[0180] ESI-MS (m / z): 415.2 [M+H]+

[0181] 1 H NMR (400 MHz, DMSO-d6) δ 13.35 (s, 1H), 8.22 (s, 1H), 8.01 (d, J = 1.9 Hz, 1H), 7.63 (d, J = 8.1 Hz, 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 (101 MHz, DMSO-d6) δ 164.86, 159.86, 148.85, 142.15, 134.02, 132.59, 131.79, 130.99, 128.61, 127.88, 125.90, 125.25, 118.98, 118.44, 117.84, 116.37, 110.68, 96.31, 50.91, 25.09.

[0182] Example 25: (E)-2-cyano-3-(5-(2-fluorophenyl)-l-(pyridin-3-ylsulfonyl)-lH-pyrrol-3- yl)acrylic acid ethyl ester (Compound I-25)

[0183] Step 1:

[0184] Into a 50 mL round bottom flask was added I-11 (1.0 g, 3.52 mmol), DMAP (21.5 mg, 0.18 mmol), dissolved in 5 mL ACN, then added DIPEA (454.6 mg, 3.52 mmol), stirred for 10 min, then added pyridine-3-sulfonyl chloride (937.7 mg, 5.28 mmol) in ACN (1 mL), heated the reaction at 40 °C oil bath for about 5 hours, TLC monitored the completion of the reaction, removed the acetonitrile under reduced pressure, extracted with dichloromethane / water three times, took the organic phase to remove under reduced pressure to get the crude product, and then purified by column chromatography to get the pure product I-25 (0.93 g, 62.1%).

[0185] ESI-MS (m / z): 426.1 [M+H] +

[0186] 1H NMR (400 MHz, DMSO-d6) δ 8.93 (dd, J = 4.9, 1.6 Hz, 1H), 8.64 (d, J = 1.9 Hz, 1H), 8.59 (dd, J = 2.6, 0.7 Hz, 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 = 1.9 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 162.39, 160.66 156.10, 147.79, 147.63, 135.77, 133.82, 133.48, 133.12, 132.98, 130.24, 125.29, 124.54, 120.99, 117.48, 116.34, 115.85, 114.57, 100.96, 62.60, 14.45.

[0187] Example 26: (E)-3-(l-((6-chloropyridin-3-yl)sulfonyl)-5-(2-fluorophenyl)-lH-pyrrol-3-yl)-2- cyanoacrylic acid ethyl ester (Compound I-26)

[0188] Compound I-26 was prepared according to the procedure described for the synthesis of Reference Compound I-25.

[0189] ESI-MS (m / z): 460.1 [M+H] +

[0190] 1 H NMR (400 MHz, DMSO-d6) δ 8.63 (d, J = 1.9 Hz, 1H), 8.46 (d, J = 2.6 Hz, 1H), 8.36 (s, 1H), 8.00 (dd, J = 8.6, 2.7 Hz, 1H), 7.81 (d, J = 8.6 Hz, 1H), 7.60 (m, 1H), 7.34 - 7.21 (m, 3H), 7.06 (d, J = 1.9 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 162.37, 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.

[0191] Example 27: (E)-2-cyano-3-(5-(2-fluorophenyl)-l-((2-methoxypyridin-3-yl)sulfonyl)-lH- pyrrol-3-yl)acrylic acid ethyl ester (Compound I-27)

[0192] Compound I-27 was prepared according to the procedure described for the synthesis of Reference Compound I-25.

[0193] ESI-MS (m / z): 456.2 [M+H] +

[0194] 1 H NMR (400 MHz, DMSO-d6) δ 8.62 (d, J = 1.9 Hz, 1H), 8.53 (dd, J = 4.9, 1.8 Hz, 1H), 8.47 (s, 1H), 7.56 (dd, J = 7.8, 1.9 Hz, 1H), 7.53 - 7.44 (m, 1H), 7.22 - 6.97 (m, 5H), 4.31 (q, J = 7.1 Hz, 2H), 3.89 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 162.59, 160.45, 159.56, 154.99, 148.32, 140.72, 134.30, 133.62, 132.68, 129.44, 124.32, 119.33, 117.77, 117.41, 116.63, 115.66, 114.01, 100.07, 62.50, 55.37, 55.10, 14.49.

[0195] Example 28: (E)-3-(l-((5-bromopyridin-3-yl)sulfonyl)-5-(2-fluorophenyl)-lH-pyrrol-3-yl)-2- cyanoacrylic acid ethyl ester (Compound I-28)

[0196] Compound I-28 was prepared according to the procedure described for the synthesis of Reference Compound I-25.

[0197] ESI-MS (m / z): 504.1 [M+H] +

[0198] 1 H NMR (400 MHz, DMSO-d6) δ 9.11 (d, J = 2.1 Hz, 1H), 8.62 (dd, J = 12.5, 2.0 Hz, 2H), 8.36 (s, 1H), 8.11 (t, J = 2.1 Hz, 1H), 7.61 (m, 1H), 7.33 - 7.17 (m, 3H), 7.07 (d, J = 1.9 Hz, 1H), 4.31 (q, J = 7.1 Hz, 2H), 1.30 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 162.38, 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.

[0199] Example 29: (E)-3-(l-((2-chloropyridin-3-yl)sulfonyl)-5-(2-fluorophenyl)-lH-pyrrol-3-yl)-2- cyanoacrylic acid ethyl ester (Compound I-29)

[0200] Compound I-29 was prepared according to the procedure described for the synthesis of Reference Compound I-25.

[0201] ESI-MS (m / z): 460.1 [M+H] +

[0202] 1 H NMR (400 MHz, DMSO-d6) δ 8.80 - 8.66 (m, 2H), 8.45 (s, 1H), 7.72 (dd, J = 8.0, 1.8 Hz, 1H), 7.49 (td, J = 8.4, 4.0 Hz, 2H), 7.16 (dd, J = 5.2, 2.9 Hz, 2H), 7.12 - 7.03 (m, 2H), 4.31 (q, J = 7.1 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 162.44, 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.

[0203] Example 30: (E)-2-cyano-3-(5-(2-fluorophenyl)-l-(phenylsulfonyl)-lH-pyrrol-3- yl)acrylic acid ethyl ester (Compound I-30)

[0204] Compound I-30 was prepared according to the procedure described for the synthesis of Compound I-25.

[0205] ESI-MS (m / z): 425.1 [M+H] +

[0206] 1 H NMR (400 MHz, DMSO-d6) δ 8.80 - 8.66 (m, 2H), 8.45 (s, 1H), 7.72 (dd, J = 8.0, 1.8 Hz, 1H), 7.49 (td, J = 8.4, 4.0 Hz, 2H), 7.16 (dd, J = 5.2, 2.9 Hz, 2H), 7.12 - 7.03 (m, 2H), 4.31 (q, J = 7.1 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 162.44, 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.

[0207] Example 31: (E)-2-cyano-3-(l-((4-ethoxyphenyl)sulfonyl)-5-(2-fluorophenyl)-lH-pyrrol-3- yl)acrylic acid ethyl ester (Compound I-31)

[0208] Compound I-31 was prepared according to the procedure described for the synthesis of Compound I-25.

[0209] ESI-MS (m / z): 469.2 [M+H] +

[0210] 1 H NMR (400 MHz, DMSO-d6) δ 8.80 - 8.66 (m, 2H), 8.45 (s, 1H), 7.72 (dd, J = 8.0, 1.8 Hz, 1H), 7.49 (td, J = 8.4, 4.0 Hz, 2H), 7.16 (dd, J = 5.2, 2.9 Hz, 2H), 7.12 - 7.03 (m, 2H), 4.31 (q, J = 7.1 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H). 13C NMR (101 MHz, DMSO-d6) δ 162.44, 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.

[0211] Example 32: (E)-3-(l-((4-butoxyphenyl)sulfonyl)-5-(2-fluorophenyl)-lH-pyrrol-3-yl)-2- cyanoacrylic acid ethyl ester (Compound 1-32)

[0212] Compound 1-32 was prepared according to the procedure described for the synthesis of Reference Compound 1-25.

[0213] ESI-MS (m / z): 497.2 [M+H] +

[0214] 1 H NMR (400 MHz, DMSO-d6) δ 8.57 (d, J = 1.9 Hz, 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, 1.8 Hz, 1H), 7.10 - 7.03 (m, 2H), 6.99 (d, J = 1.9 Hz, 1H), 4.29 (q, J = 7.1 Hz, 2H), 4.07 (t, J = 6.5 Hz, 2H), 1.70 (m, 2H), 1.48 - 1.36 (m, 2H), 1.29 (t, J = 7.1 Hz, 3H), 0.93 (t, J = 7.4 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 164.30, 162.52, 160.78, 147.97, 133.46, 133.06, 132.69, 132.61, 130.18, 127.72, 124.33, 120.39, 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.

[0215] Example 33: (E)-2-cyano-3-(l-((4-ethylphenyl)sulfonyl)-5-(2-fluorophenyl)-lH-pyrrol-3- yl)acrylic acid ethyl ester (Compound 1-33)

[0216] Reference compound I-25 was prepared according to the procedure described for the synthesis of compound I-33.

[0217] ESI-MS (m / z): 453.2 [M+H] +

[0218] 1 H NMR (400 MHz, DMSO-d6) δ 8.60 (d, J = 1.9 Hz, 1H), 8.37 (s, 1H), 7.57 (m, 1H), 7.42 (s, 4H), 7.24 (t, J = 8.9 Hz, 2H), 7.15 (td, J = 7.5, 1.8 Hz, 1H), 7.01 (d, J = 1.8 Hz, 1H), 4.30 (q, J = 7.1 Hz, 2H), 2.69 (q, J = 7.6 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H), 1.17 (t, J = 7.6 Hz, 3H). 13 C NMR (101 MHz, DMSO-d6) δ 162.48, 160.76, 152.76, 147.88, 134.24, 133.40, 133.13, 132.67, 130.31, 129.71, 127.74, 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.

[0219] Example 34: (E)-3-(1-benzoyl-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-2-cyanoacrylic acid ethyl ester (compound I-34)

[0220] First step: synthesis of intermediate Int. I-34

[0221] Step 1:

[0222] In a 50 ml round bottom flask was added Int. I-11-a (1.0 g, 5.3 mmol), DMAP (32.4 mg, 0.3 mmol), triethylamine (0.64 g, 6.4 mmol), dissolved in 20 mL of dichloromethane, protected by nitrogen, added Int. I-34-a (0.89 g, 6.3 mmol) at 0°C, stirred at room temperature overnight, extracted with dichloromethane / water three times, dried the organic phase and distilled under reduced pressure to obtain the crude product, which was purified by column chromatography to obtain pure Int. I-34 (0.8 g, 51.5%).

[0223] ESI-MS (m / z): 294.1 [M+H] +

[0224] Step 2: Synthesis of compound I-34

[0225] Step 1:

[0226] Into a 50 mL round bottom flask was placed Int. I-34 (0.7 g, 2.4 mmol), dissolved in 20 mL of ethanol, followed by the addition of L-proline (0.35 g, 3.12 mmol) and ethyl cyanoacetate (0.35 g, 3.12 mmol). The reaction was stirred at room temperature for 6 h, during which time a large amount of light yellow solid precipitated. After the reaction was complete as monitored by TLC, 20 mL of ice water was added to the reaction, and the mixture was stirred for 0.5 h and then filtered. The filter cake was washed with ice water 3-5 times to give pure I-1 (0.83 g, 89.1%).

[0227] ESI-MS (m / z): 389.1 [M+H] +

[0228] 1 H NMR (500 MHz, Chloroform-d) δ 8.06 (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, 1.5 Hz, 1H), 6.40 (t, J = 1.9 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H). 13 C NMR (125 MHz, Chloroform-d) δ 167.56, 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.

[0229] Example 35: (E)-3-(1-benzoyl-5-(2-fluorophenyl)-1H-pyrrol-3-yl)-2-cyanacrylic acid (Compound I-35)

[0230] Compound I-35 was prepared according to the procedure for Reference Compound I-2 using I-34 as the starting material.

[0231] ESI-MS (m / z): 361.1 [M+H] +

[0232] 1 H NMR (500 MHz, Chloroform-d) δ 8.06 (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, 1.4 Hz, 1H), 6.40 (t, J = 1.9 Hz, 1H). 13 C NMR (125 MHz, Chloroform-d) δ 167.56, 163.77, 161.14, 159.15, 135.21, 134.17, 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, 115.60, 107.03.

[0233] Example 36: (E)-3-(5-(2-bromophenyl)-l-(pyridin-2-ylmethyl)-lH-pyrrol-3-yl)-2- cyanoacrylic acid ethyl ester (Compound I-36)

[0234] Compound I-36 was prepared according to the procedure for the synthesis of Reference Compound I-l.

[0235] ESI-MS (m / z): 436.1 [M+H] +

[0236] 1 H NMR (500 MHz, Chloroform-d) δ 8.06 (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, 1.4 Hz, 1H), 6.40 (t, J = 1.9 Hz, 1H). 13C NMR (125 MHz, Chloroform-d) δ 163.77, 156.20, 149.92, 137.32, 135.20, 134.19, 134.17, 133.25, 131.01, 129.90, 128.87, 126.43, 125.15, 122.93, 122.30, 122.22, 115.60, 109.87, 107.03, 53.57.

[0237] Example 37: (E)-3-(5-(2-bromophenyl)-l-(pyridin-2-ylmethyl)-lH-pyrrol-3-yl)-2- cyanoacrylic acid (Compound I-37)

[0238] Compound I-37 was prepared according to the procedure described for the synthesis of Reference Compound I-2 using I-36 as the starting material.

[0239] ESI-MS (m / z): 408.1 [M+H] +

[0240] 1 H NMR (500 MHz, Chloroform-d) δ 8.39 (dd, J = 4.1, 1.6 Hz, 1H), 7.97 (s, 1H), 7.64 (dd, J = 7.8, 1.4 Hz, 1H), 7.53 (ddd, J = 7.3, 6.5, 1.6 Hz, 1H), 7.48 - 7.40 (m, 2H), 7.36 (ddd, J = 7.5, 6.6, 1.3 Hz, 1H), 7.27 - 7.21 (m, 1H), 7.09 (dq, J = 6.6, 1.1 Hz, 1H), 6.30 - 6.26 (m, 1H), 6.10 (d, J = 1.7 Hz, 1H), 5.82 (s, 1H), 5.82 (d, J = 1.9 Hz, 1H). 13 C NMR (125 MHz, Chloroform-d) δ 163.77, 156.20, 149.92, 137.32, 135.20, 134.19, 134.17, 133.25, 131.01, 129.90, 128.87, 126.43, 125.15, 122.93, 122.30, 122.22, 115.60, 109.87, 107.03, 53.57.

[0241] Example 38: (E)-2-cyano-3-(5-(3-fluorophenyl)-l-(pyridin-2-ylmethyl)-lH-pyrrol-3- yl)acrylic acid ethyl ester (Compound I-38)

[0242] Compound 1-38 was prepared according to the procedure for the synthesis of Reference Compound 1-1.

[0243] ESI-MS (m / z): 376.1 [M+H] +

[0244] 1 H NMR (500 MHz, Chloroform-d) δ 8.39 (dd, J = 4.2, 1.6 Hz, 1H), 8.00 (s, 1H), 7.86 (m, 1H), 7.56 - 7.45 (m, 2H), 7.28 - 7.21 (m, 2H), 7.17 (m, 1H), 7.09 (m, 1H), 6.28 (m, 1H), 6.10 (d, J = 1.7 Hz, 1H), 5.82 (t, J = 0.9 Hz, 2H), 4.33 (q, J = 7.1 Hz, 2H), 1.29 (t, J = 7.1 Hz, 3H). 13 C NMR (125 MHz, Chloroform-d) δ 164.59, 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.

[0245] Example 39: (E)-2-cyano-3-(5-(3-fluorophenyl)-l-(pyridin-2-ylmethyl)-lH-pyrrol-3- yl)acrylic acid (Compound 1-39)

[0246] Compound 1-39 was prepared according to the procedure for the synthesis of Reference Compound 1-2, using 1-38 as the starting material.

[0247] ESI-MS (m / z): 348.1 [M+H] +

[0248] 1H NMR (500 MHz, Chloroform-d) δ 8.39 (dd, J = 4.1, 1.7 Hz, 1H), 7.97 (s, 1H), 7.86 (m, 1H), 7.56 - 7.45 (m, 2H), 7.28 - 7.21 (m, 2H), 7.17 (m, 1H), 7.09 (m, 1H), 6.30 - 6.26 (m, 1H), 6.10 (d, J = 1.6 Hz, 1H), 5.82 (s, 1H), 5.82 (d, J = 1.9 Hz, 1H). 13 C NMR (125 MHz, Chloroform-d) δ 164.03, 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.

[0249] Example 1: Compound in vitro lactic acid release experiment

[0250] 1) Instruments and reagents

[0251] The experimental apparatus and main experimental reagents for the in vitro lactic acid release experiment are as follows (see Table 2):

[0252] Table 2

[0253] The main experimental reagents for the in vitro lactic acid release experiment are as follows (see Table 3):

[0254] Table 3

[0255] 2) Experimental operation

[0256] First step: MCF-10A cell passage

[0257] (1) Aspirate the original culture solution;

[0258] (2) Add about 2 mL of PBS, gently shake the culture bottle to rinse the cells, and discard the aspirated PBS;

[0259] (3) Add about 1 mL of trypsin, gently shake the culture bottle to infiltrate all the cells;

[0260] Note: MCF-10A cells are difficult to digest, so extend the digestion time, and digest until the cells shrink and round, then tap the side of the flask, and the cells will fall off, then stop the digestion; usually 10-15 min.

[0261] (4) Put into the incubator to digest, and stop when the cells in the middle of the cell mass are obviously rounded and have gaps under the microscope; do not tap the flask during the whole process;

[0262] (5) Add 3 mL of serum-containing medium to stop the digestion, blow the cells to make them detach, and repeatedly blow them in the liquid to make them into a single-cell suspension as much as possible;

[0263] (6) Collect the cell suspension and centrifuge at 1200 rpm / min for 3 minutes, aspirate the supernatant and discard it;

[0264] (7) Add fresh medium, mix the cells by blowing a few times, and inoculate them into a new culture flask according to the proportion, add medium, and culture with a loose cap or a breathable cap.

[0265] Step 2: Determine the maximum lactic acid release rate concentration of UK-5099

[0266] (1) Use the positive drug UK-5099 to treat cells and detect the amount of LA release. Set different concentrations: 0, 2.5, 5, 10, 20, 50, 100 μM.

[0267] (2) Culture MCF-10A cells, and collect the cells after digestion. Inoculate 1 × 10 6 cells / dish in a 6 cm culture dish, and incubate overnight for 12 h. Add different concentrations of UK-5099, with 2 replicates for each concentration, and incubate for 36 h.

[0268] (3) Take out the cells to be tested, add 0.8 mL of extraction solution I, and lyse at room temperature for 30 min. Centrifuge at 12000 g at 4°C for 10 min, take 0.8 mL of supernatant, add 0.15 mL of extraction solution II, centrifuge at 12000 g at 4°C for 10 min, and take the supernatant for testing.

[0269] (4) Sample addition table (see Table 4):

[0270] Table 4

[0271] (5) Calculate the LA content (mM / 10 6 cell) = (A 测定 -A 空白 ) / (A 标准 -A 空白 ) × C 标准

[0272] C 标准 = concentration of standard, 3 mM

[0273] The data obtained were processed to calculate the concentration of the positive drug UK-5099 at the maximum release rate of lactic acid as 10 μM.

[0274] Step 3: Detection of lactic acid (LA) content

[0275] (1) The concentration of the positive drug UK-5099 at the maximum release rate of lactic acid was used as 10 μM.

[0276] (2) MCF-10A cells were cultured, and after the cells were fully grown, the cells were collected by digestion and inoculated in 6 cm culture dishes at a concentration of 1 x 10 6 cells / dish, and after overnight culture for 12 h, 10 μM of different compounds were added to culture the cells for 36 h.

[0277] (3) The cells to be detected were taken out, 0.8 mL of extraction solution I was added, and the cells were lysed at room temperature for 30 min. After centrifugation at 12000 g at 4°C for 10 min, 0.8 mL of supernatant was taken, 0.15 mL of extraction solution II was added, and after centrifugation at 12000 g at 4°C for 10 min, the supernatant was taken for detection.

[0278] (4) Sample addition table (see Table 5):

[0279] Table 5

[0280] (5) Calculation of the relative expression amount of LA in the cells after the addition of the compounds: the absorbance of the DMSO group was taken as a unit, and the ratio of each group to the DMSO group was calculated.

[0281] 3) Results of the lactic acid release promoting experiment of the compounds (see Table 6)

[0282] Table 6

[0283] The experimental results shown in the above Table 6 show that there is no obvious structure-activity relationship between the structure of the compounds and the lactic acid release promoting effect. In the tests of the present application, some compounds of the present application, 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 lactic acid release promoting effect compared with the positive control (UK-5099).

[0284] Example 2: Hair growth experiment of C57BL / 6J mice

[0285] 1) Experimental conditions

[0286] (1) Experimental animals

[0287] Species: C57BL / 6J mice, grade: SPF, body weight: 18 g for male mice (purchased from Shanghai Slac Laboratory Animal Co., Ltd.);

[0288] (2) Environmental adaptation

[0289] Environmental adaptation for 7 days before the test;

[0290] (3) Feeding conditions

[0291] Feeding density: 10 / cage, cage space displacement frequency: 1 time / week;

[0292] (4) Feeding environmental conditions

[0293] Feeding environmental conditions: GB 14925-2010 of the People's Republic of China;

[0294] (5) Feed

[0295] Feeding method: free intake;

[0296] Routine nutritional ingredient indicators: crude protein, crude fat, crude fiber, crude ash, moisture, calcium, and phosphorus.

[0297] (6) Drinking water

[0298] Type: experimental animal drinking water (sterilized by autoclaving tap water);

[0299] Water supply method: drinking bottle, free intake;

[0300] 2) Experimental method

[0301] (1) Administration route: skin smearing; administration volume: 20 μM 300 μL; dose: distilled water, anhydrous ethanol, and polyethylene 400 (5:3:2).

[0302] (2) Test period: administration once a day, and observation for 16 days after administration.

[0303] (3) Observation index:

[0304] General performance:

[0305] The skin and hair growth of mice were observed daily, and the time for the skin of each mouse in the depilation area to change from pink to gray and then to be fully covered with hair was recorded, photographed, and scored.

[0306] The scoring standard is as follows (see Table 7):

[0307] Table 7

[0308] Systemic necropsy:

[0309] After termination of dosing for 16 days, the animals were bled out under 3% sodium pentobarbital anesthesia and examined for hair growth.

[0310] 3) The experimental results are as follows (see Table 8):

[0311] Table 8

[0312] The experimental results shown in Table 8 above show that the compounds of the present application all show better or equivalent hair growth promoting effects compared with the positive control (UK-5099), and the compounds are all superior to the marketed drug minoxidil.

[0313] Example 3: Effect of compounds on hERG potassium channel

[0314] The hERG potassium ion channel inhibition test was used to preliminarily investigate the potential in-vitro cardiotoxic side effects of some of the compounds of the present application. The experimental operation is as follows:

[0315] 1) Cell preparation

[0316] CHO-hERG cells (Millipore PrecisION TM hERG-CHO Recombinant Cell Line, Cat# CYL3038) were cultured in 175 cm 2 flasks, and when the cell density grew to 60-80%, the culture solution was removed, washed once with 7 mL of PBS, and then 3 mL of Detachin (Yagi Biological, A1110501) was added for digestion.

[0317] After complete digestion, 7 mL of culture solution was added for neutralization, and then centrifuged, the supernatant was aspirated, and 5 mL of culture solution was added for resuspension to ensure that the cell density was 2-5 x 10 6 / mL.

[0318] 2) Electrophysiological recording process

[0319] The single cell high impedance seal and whole cell configuration were automatically performed by the Qpatch instrument. After obtaining the whole cell recording configuration, the cell was clamped at -80 mV. A 5 s +20 mV depolarization stimulus was given, followed by a 50 ms -50 mV prepulse, repolarization to -50 mV for 5 s, and return to -80 mV. This voltage stimulus was applied every 15 s, and recording was performed for 2 min. After 2 min of extracellular recording, the drug administration process was started. The compound concentration was 0.1 uM, and each test concentration was given for 2 min. After all the concentrations were given, the positive control compound 10 uM UK-5099 was given. At least 3 cells (n≥3) were tested for each concentration.

[0320] 3) Compound preparation

[0321] The compound mother liquor was diluted with extracellular solution. 2 uL of the compound mother liquor was added to 998 uL of extracellular solution, and then 5-fold serial dilution was performed in extracellular solution containing 0.2% DMSO to obtain the final concentration required for testing. The experimental data were analyzed by XLFit software.

[0322] The experimental results are shown in Table 9:

[0323] Table 9

[0324] The experimental results shown in Table 9 above show that the hERG IC 50 values of the compounds of the present application are all greater than 10 uM, and the potential cardiotoxic side effects are small.

Claims

1. A compound of Formula (I) or a pharmaceutically acceptable salt thereof: wherein, n is 0 or 1; m is 1, 2, 3 or 4; X is -(C1-C4 alkylene)-, -C(=O)- or -S(=O)2-; R is independently hydrogen, halogen, cyano, Ci-C6alkyl, Ci-C6alkoxy, or substituted Ci-C6alkyl, Ci-C6alkoxy with one or more R 0-1 substituted Ci-C6alkyl, Ci-C6alkoxy, or substituted Ci-C6alkyl, Ci-C6alkoxy with one or more R 0-2 substituted Ci-C6alkyl, Ci-C6alkoxy, or substituted Ci-C6alkyl, Ci-C6alkoxy with one or more R substituents, which are the same or different; R 0-1 and R 0-2 independently C1-C6alkyl, halogen or amino; R 1 independently H, 5-10 membered heterocycloalkyl, 6-10 membered aryl, 6-10 membered aryl substituted with one or more R 1-1 independently H, 5-10 membered heterocycloalkyl, 6-10 membered aryl, 6-10 membered aryl substituted with one or more R 1-1 independently H, 5-10 membered heterocycloalkyl, 6-10 membered aryl, 6-10 membered aryl substituted with one or more R 1-1 independently H, 5-10 membered heterocycloalkyl, 6-10 membered aryl, 6-10 membered aryl substituted with one or more R R 1-1 independently C1-C6alkyl, C1-C6alkyl substituted with one or more halogen, C1-C6alkoxy, halogen, or amino; R 2 -COOR 2-1 ; R 2-1 is hydrogen, Ci-C6-alkyl or Ci-C6-alkyl substituted by one or more R 2-1-1 identical or different; or R3is phenyl, which is unsubstituted or substituted by one or more R R 2-1-1 independently C1-C6alkyl, halogen, or amino; R 3 is cyano.

2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having Formula (I), wherein which satisfies one or more of the following conditions: (1) the halogen is independently fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine or bromine; (2) the C1-C4 alkylene is independently methylene; (3) the C1-C6 alkoxy is independently methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy or t-butoxy, preferably ethoxy or n-butoxy; (4) the C1-C6 alkyl is independently methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl, preferably ethyl; (5) the 6-10 membered aryl is independently phenyl or naphthyl; and (6) the 5-10 membered heteroaryl groups are each independently a 5- or 6-membered heteroaryl group having 1 or 2 heteroatoms which are N; preferably pyridyl, e.g.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having Formula (I), wherein which satisfies one or more of the following conditions: (1) n is 0 or 1; (2) m is 1; (3) R is independently halogen or cyano, preferably halogen; (4) R 1 independently H, 6-10 membered aryl, 6-10 membered aryl substituted with one or more R 1-1 independently H, 6-10 membered aryl, 6-10 membered aryl substituted with one or more R 1-1 independently H, 6-10 membered aryl, 6-10 membered aryl substituted with one or more R (5) R 1-1 independently C1-C6alkyl, C1-C6alkyl substituted with one or more halogen, C1-C6alkoxy, or halogen; (6) R 2 -COOR 2-1 , R 2-1 is hydrogen or C1-C6alkyl; and (7) X is independently -(C1-C4 alkylene)- or -S(=O)2-.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having Formula (I), wherein which satisfies one or more of the following conditions: (1) X is -CH2-, -C(=O)- or -S(=O)2-, preferably -CH2- or -S(=O)2-; (2) m is 1, R is independently fluorine or bromine, preferably fluorine; (3) n is 0, R 1 is H; or, n is 1, R 1 is and (4) are independently 5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having Formula (I), wherein The compound as shown in formula (I) is a compound as shown in formula (I-A) or a compound as shown in formula (I-B): wherein R and R 1 The definition is as in claim 1.

6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, having Formula (I), wherein The compound as shown in formula (I) is any one of the following compounds:

7. A compound of formula (II) ###0002### (II) wherein m, R and R 2 are as defined in any one of claims 1 to 4.

8. A method for preparing a compound as shown in formula (I), characterized in that, which comprises Scheme 1 or Scheme 2: Scheme 1: (1) when R 2 is -COOR 2-1 ; R 2-1 is C1-C6 alkyl or C1-C6 alkyl substituted by one or more R 2-1-1 , the process for preparing the compound of formula (I) is prepared by the following steps: in a solvent, the compound of formula (II) is subjected to substitution reaction with the compound of formula (Int-I) to obtain the compound of formula (I): wherein n, m, R, R 1 , R 2 , R 3 and X are as defined in any one of claims 1 to 4; Y is halogen, preferably bromine; and / or, (2) when R 2 when R is a carboxyl group, the preparation method of the compound of formula (I) further comprises performing a hydrolysis reaction in addition to the above substitution reaction. or, Scheme 2: in a solvent, a compound as shown in formula (III) 2 -CH2-CN, to give the compound as shown in formula (I); wherein X, m, n, R, R 1 , R 2 and R 3 are as defined in any one of claims 1 to 4; Preferably, the method for preparing a compound as shown in Formula (I) satisfies one or more of the following conditions: (1) in the substitution reaction in Scheme 1, the solvent is an amide solvent, preferably DMF; (2) in the substitution reaction 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 in Scheme 2, the solvent is one or more of an alcohol solvent, an ester solvent and an ether solvent, for example the alcohol solvent can be ethanol, the ester solvent can be ethyl acetate and the ether solvent can be tetrahydrofuran; and (4) in the addition reaction in 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 by, The pharmaceutical composition comprises: (1) a compound as shown in Formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-6, and (2) a pharmaceutically acceptable excipient.

10. Use of a compound as shown in Formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1-6, or a pharmaceutical composition according to claim 9, in the preparation of an MPC inhibitor.

11. Use of a compound of Formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, or a pharmaceutical composition according to claim 9, for the manufacture of a medicament, wherein, The drug satisfies one or more of the following conditions: (1) the drug is used for treating or preventing an MPC-mediated disease or disorder; for example the MPC-mediated disease or disorder is alopecia, diabetes, a metabolic disease or inflammation; (2) the drug is used for promoting lactic acid release; and (3) the drug is used for treating alopecia.

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