Small molecule inhibitors of lactate dehydrogenase and methods of use thereof

Abstract

To provide novel LDH inhibitors with improved potency, selectivity and / or bioavailability for treatment of cancer.SOLUTION: Provided is a compound of formula (I), where Ar1, R1, U, V, W, X and p are as described herein. Also provided are methods of using a compound of formula (I), including a method of treating cancer, a method of treating a patient with cancer cells resistant to an anti-cancer agent, and a method of inhibiting lactate dehydrogenase A (LDHA) and / or lactate dehydrogenase B (LDHB) activity in a cell.SELECTED DRAWING: None

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application was filed on December 29, 2014, and is incorporated herein by reference in its entirety. This application claims priority to and benefit of issued U.S. Provisional Patent Application No. 62 / 097,226. [Background technology]

[0002] Factors that target enzymes involved in cancer cell metabolism preferentially target cancer tissue over normal tissue. This provides an attractive therapeutic route given the potential for targeting. Normal tissues have a low oxygen supply. Although cancer tissue typically uses glycolysis only when it is aerobic, regardless of the oxygen supply level, This characteristic is known as the Warburg effect (Vande r Heiden et al.,Science,2009,324(5930):1 Lactate dehydrogenase (LDH) is an enzyme that converts pyruvate to lactate. It is involved in the final step of the sugar cycle. It is involved in the splitting of pyruvate into the TCA (tricarboxylic acid) cycle. The decrease in ATP synthesis and the concomitant increase in lactate production are crucial for tumor growth and survival. There are two different subunits, LDH, LDHA and LDHB. Lactic acid also has the same active site and catalyzes the conversion of pyruvate to lactate. In this case, serum total lactate dehydrogenase (LDH5, a tetramer of LDHA subunits; involved in glycolysis) The levels of LDH (the main LDH isozyme involved) are often increased, and the LDHA gene is upregulated. Tumor cells can then metabolize lactate as an energy source. Injury to the mitochondrial membrane leads to stimulation of mitochondrial respiration as a compensatory mechanism. and reducing the ability of the drug to effectively metabolize glucose and reduce tumor cell proliferation and tumor growth. Therefore, compounds that inhibit LDH activity may advance anti-cancer treatments. It has a sexual nature.

[0003] LDHA inhibitors have been known for some time. For example, gossypol inhibits the synthesis of LDHA and lactic acid. Dehydrogenase B (LDHB) K i The NADH binding was 1.9 and 1.4 μM, respectively. It is a non-selective inhibitor of LDH that inhibits the binding of in.Invest.,2013,123(9):3685-3692). Billia rd et al. (Cancer and Metabolism, 2013, 1(19):1-1 7) is 3-((3-carbamoyl-7-(3,5-dimethylisoxazole-4-yl) Certain derivatives of (6-methoxyquinolin-4-yl)amino)benzoic acid are It is a potent inhibitor of H and is 10-80 times more selective for LDHA inhibition than for LDHB inhibition. However, the in vivo bioavailability of the inhibitor is insufficient. It was found that... [Prior art documents] [Non-patent literature]

[0004] [Non-Patent Document 1] Vander Heiden et al., Science, 2009, 324(5930):1029-1033 [Non-patent document 2] Doherty et al., J. Clin. Invest., 2013, 123(9):3685-3692 [Non-patent document 3] Billiard et al., Cancer and Metabolism, 2013, 1(19):1-17 Summary of the Invention [Problem to be solved by the invention]

[0005] In view of the above, the efficacy, selectivity, and / or bioavailability of There remains a need to provide new LDH inhibitors with improved efficacy. [Means for solving the problem]

[0006] The present invention relates to a compound of formula (I) [ka] (I) (In the formula, Ar 1 , R 1 , U, V, W, X and p are as described herein. The compounds defined by formula (I) are useful for treating lactate dehydrogenase A (LD HA) and / or lactate dehydrogenase B (LDHB) activity, which It has been found that LDHA produces compounds that are effective in treating cancer. and / or LDHB inhibitors are useful for treating fibrosis, including idiopathic pulmonary fibrosis. It has also been found that the compounds of formula (I) inhibit the activity of other dehydrogenases (e.g., GAPDH and selective for LDHA and / or LDHB compared to PHGDH; and / or The anticancer drug has desirable solubility, permeability, and / or pharmacokinetic profile (e.g., It is anticipated that these compounds will be desirable for treating cancer because they tend to have favorable ADME.

[0007] As such, the present disclosure provides a method of treating cancer in a patient, comprising administering to the patient an effective amount of a compound of formula (I) or a prodrug or pharmaceutically acceptable salt thereof The method further comprises:

[0008] In another embodiment, the present disclosure provides a method for treating fibrosis, including idiopathic pulmonary fibrosis, in a patient. The method comprises administering to a patient an effective amount of a compound of formula (I) or a prodrug or The method further comprises administering a pharmaceutically acceptable salt thereof.

[0009] Also provided is a method for treating a patient having cancer cells resistant to an anticancer drug, comprising administering to the patient: an effective amount of a compound of formula (I) or a prodrug or pharmaceutically acceptable salt thereof and an anti-inflammatory agent; and administering a cancer drug to the cancer patient, thereby administering the compound, its prodrug, or a pharmaceutically acceptable salt thereof. The above method is also provided, wherein the acceptable salt resensitizes cancer cells to anti-cancer drugs.

[0010] The present invention relates to a method for producing lactate dehydrogenase A (LDHA) and / or lactate dehydrogenase B (LDHA) in cells. 1. A method for inhibiting the activity of a compound of formula (I) or a prodrug or pharmaceutical The method further comprises administering to the cell a salt that is acceptable to the cell. DETAILED DESCRIPTION OF THE INVENTION

[0011] The present invention relates to a compound of formula (I) [ka] (I) (In the formula, Ar 1 contains 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and sulfur and optionally substituted heteroaryls containing at least one 5- or 6-membered monocyclic heteroaryl. It is a part of U is aryl, —C(O)aryl, Het, or —C(O)Het; each of which is optionally substituted, where Het is a group having at least two double bonds, and a heteroatom containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and sulfur. a monocyclic or bicyclic moiety containing cycloalkyl; R 1 is halo, -CO2R 4 , -C(O)NR 5 R 6 , -(C1-C8 hydrocarbyl ), —C(O)NHOH, —(C0-C4 hydrocarbyl)((independently of N, O and S) mono- or bicyclic heterocycle having 1 to 4 heteroatoms selected from the group consisting of -C(O)O-( C0-C4 hydrocarbyl) (1 to 4 heteroatoms independently selected from N, O and S Mono- or bicyclic heterocycles having the formula (III), -P(O)(OH)2, -SO2(OH), -B( OR 13 )(OR 14 ), -C(O)NHS(O)2Me and -SO2NR 5 R 6 From Germany R, excluding halo, is chosen independently. 1 each of which is substituted or unsubstituted; R 2 is hydroxyl, halo, -CN, -NO2, C1-C8 hydrocarbyl, -O( C1-C8 hydrocarbyl), -(C0-C4 hydrocarbyl)C3-C8 cycloalkyl -O(C0-C4 hydrocarbyl)C3-C8 cycloalkyl, -(C0-C4 hydro -O(C0-C4 hydrocarbyl)C3-C8 cycloalkenyl, -O(C0-C4 hydrocarbyl)C3-C 8 Cycloalkenyl, -O(C0-C4 hydrocarbyl)C6-C 12 Aryl, -(C C6-C0-C4 Hydrocarbyl 12 Aryl, -O(C0-C4 hydrocarbyl)( Mono- and bicyclic heterocycles containing 1 to 4 heteroatoms independently selected from N, O, and S ), -(C0-C4 hydrocarbyl) (containing 1 to 4 heteroatoms independently selected from N, O, and S) Mono- and bicyclic heterocycles with heteroatoms), -P(O)(OH), -B(OR 13 )( OR 14 ), -SO2(OH), -C(O)NHS(O)2Me and -SO2NR 5 R 6 R, independently selected from 1 each of which is substituted or unsubstituted; V is aryl, heteroaryl, or heterocycloalkyl, each of which However, -(R 2 ) n and wherein the heteroaryl or heterocycloalkyl The group is a 5 to 10 carbon atom group containing 1, 2 or 3 heteroatoms selected from nitrogen, oxygen and sulfur. or a six-membered monocyclic moiety; W is -(R 3 ) m or [ka] and; R 2 is hydroxyl, halo, -CN, -NO2, C1-C8 hydrocarbyl, -O( C1-C8 hydrocarbyl), -(C0-C4 hydrocarbyl)C3-C8 cycloalkyl -O(C0-C4 hydrocarbyl)C3-C8 cycloalkyl, -(C0-C4 hydro -O(C0-C4 hydrocarbyl)C3-C8 cycloalkenyl, -O(C0-C4 hydrocarbyl)C3-C 8 Cycloalkenyl, -O(C0-C4 hydrocarbyl)C6-C 12 Aryl, -(C C6-C0-C4 Hydrocarbyl 12 Aryl, -O(C0-C4 hydrocarbyl)( Mono- and bicyclic heterocycles containing 1 to 4 heteroatoms independently selected from N, O, and S ), -(C0-C4 hydrocarbyl) (containing 1 to 4 heteroatoms independently selected from N, O, and S) Mono- and bicyclic heterocycles containing heteroatoms), -C(O)R 4 , -CO2R 4 , -C(O) NR 5 R 6 , -NR 5 C(O)R 4 , -(CH2) q NR 5 (SO2)R 4 , -(CH2 ) q NR 5 C(O)R 4 , -(CH2) q NR 7 C(O)NR 5 R 6 , -(CH2) q N R 5 R 6 , -(CH2) q SO2NR 5 R 6 , -(CH2) q SO2R 4 Selected independently from C1-C8 hydrocarbyl, -O(C1-C8 hydrocarbyl), -(C0-C4 hydrocarbyl)C3-C8 cycloalkyl, -O(C0-C4 hydrocarbyl)C3- C8 cycloalkyl, -(C0-C4 hydrocarbyl)C3-C8 cycloalkenyl, - -O(C0-C4 hydrocarbyl)C3-C8 cycloalkenyl, -O(C0-C4 hydrocarbyl)C3-C8 cycloalkenyl, Calvil) C6~C 12 Aryl, -(C0-C4 hydrocarbyl)C6-C 12 Ally -O(C0-C4 hydrocarbyl) (1 to 4 independently selected from N, O and S) Mono- and bicyclic heterocycles containing heteroatoms), -(C0-C4 hydrocarbyl)(N, O and S) each of mono- and bicyclic heterocycles having 1 to 4 heteroatoms independently selected from each may be substituted or unsubstituted; R 3 are hydroxyl, halo, -CN, -NO2, -SF5, C1 to C8 hydrocarbyl -O(C1-C8 hydrocarbyl), -(C0-C4 hydrocarbyl)C3-C8 silyl chloroalkyl, -O(C0-C4 hydrocarbyl)C3-C8 cycloalkyl, -(C0 -C4 hydrocarbyl) C3-C8 cycloalkenyl, -O(C0-C4 hydrocarbyl )C3-C8 cycloalkenyl, -O(C0-C4 hydrocarbyl)C6-C 12 Ally -(C0-C4 hydrocarbyl)C6-C 12 Aryl, -O(C0-C4 Hydrocarbon cyclohexyl) (mono- and dicyclohexyl) having 1 to 4 heteroatoms independently selected from N, O and S -(C0-C4 hydrocarbyl)(one independently selected from N, O, and S) Mono- and bicyclic heterocycles containing up to 4 heteroatoms), -C(O)R 4 , -CO2R 4 , -C(O)NR 5 R 6 , -NR 5 C(O)R 4 , -(CH2) q NR 5 (SO2)R 4 , -(CH2) q NR 5 C(O)R 4 , -(CH2) q NR 7 C(O)NR 5 R 6 , -(C H2) q NR 5 R 6 , -(CH2) q SO2NR 5 R 6 , -(CH2)q SO2R 4 from independently selected from C1-C8 hydrocarbyl, -O(C1-C8 hydrocarbyl), -( -O(C0-C4 hydrocarbyl)C3-C8 cycloalkyl, -O(C0-C4 hydrocarbyl -(C0-C4 hydrocarbyl)C3-C8 cycloalkyl, -(C0-C4 hydrocarbyl)C3-C8 cycloalkyl alkenyl, -O(C0-C4 hydrocarbyl) C3-C8 cycloalkenyl, -O(C0- C4 Hydrocarbyl) C6~C 12 Aryl, -(C0-C4 hydrocarbyl)C6-C 12 aryl, —O(C0-C4 hydrocarbyl)(independently selected from N, O, and S Mono- and bicyclic heterocycles containing 1 to 4 heteroatoms), -(C0-C4 hydrocarbyl ) (mono- and bicyclic heterocyclic rings having 1 to 4 heteroatoms independently selected from N, O, and S) each of the heterocycles) is substituted or unsubstituted; or When W is phenyl, two R 3 The moieties and the phenyl groups to which they are attached are At least one additional R 3 forming an optionally substituted naphthyl group at the site; Each R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are the same or different, and each C1-C8 alkyl, C2-C8 alkenyl, C3-C6 cycloalkyl, C6-C 12 is aryl, heteroaryl, or heterocycloalkyl; Each R 13 and R 14 are the same or different, and each is hydrogen, C1-C8 alkyl, , C2-C8 alkenyl, C3-C6 cycloalkyl, C6-C 12It is an aryl, So, R 13 and R 14 are optionally joined together to form a ring; X is a bond, -CR 8 R 9 -, -NR 5 -, -CR 8 NR 5 -, -NR 5 CR 8 -,- NR 5 C(O), -O-, -SO-, -SO2-, or -S-; m, n, and q are the same or different and each is 0 or an integer from 1 to 5; p is 0, 1 or 2, however, Ar 1 is quinolinyl, then U is not pyrimidinyl; Ar 1 -indolyl when U is 2-(1H-indol-1-yl)thiazolyl X at position 3 of the indolyl group is not a bond or -CH2-, or W at position 3 of the indolyl group is not a fluoro group. or R at the 3-position of the indolyl group 3 but not benzyl; Ar 1 -pyrazolyl when U is 2-(1H-pyrazol-1-yl)thiazolyl W at the 3-position of the group is not 4-trifluoromethylphenyl or 4-nitrophenyl or X at position 4 of the pyrazolyl group is not a bond) or a prodrug or pharmaceutically acceptable salt thereof.

[0012] In an embodiment, Ar 1 are indolyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3 ,2-c]pyridinyl, pyrazolo[3,4-b]pyridinyl, quinolinyl, indazolyl , imidazolyl, oxazolyl, thiazolyl, furanyl, thiofuranyl, pyrrolyl, pyranyl azolyl, pyridinyl, pyrazinyl, or pyrimidinyl, each of which is optionally It is substituted with Ar. 1 When substituted, 1 to 3 identical or different substituents ( Suitable substituents include, for example, C1 to C6. C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C6 cycloalkynyl C3-C6 cycloalkyl alkyl, hydroxyl, C1-C8 alkoxy, C3- C6 cycloalkyloxy, C1-C8 haloalkoxy, C1-C8 haloalkyl, halo , -CN, cyanoalkyl, -NO2, -CO2R 4 , -C(O)NR 5 R 6 , -NR 5 (SO2)R 4 , -NR 5 C(O)R 4 , -NR 7 C(O)NR 5 R 6 , -NR 5 R 6 , -SO2NR 5 R 6 , -SO2R 4 , aryl, heteroaryl, and / or heterocyclohexyl Examples include chloroalkyl.

[0013] In certain compounds, Ar 1 is a pyrazolyl, indolyl, or pyrrolo[2, 3-b]pyridinyl, each of which is optionally substituted. For example, Ar 1 is a substituent, for example, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl C3-C6 cycloalkyl, C3-C6 cycloalkylalkyl, hydroxyl, C 1-C8 alkoxy, C3-C6 cycloalkyloxy, C1-C8 haloalkoxy, C 1-C8 haloalkyl, halo, -CN, cyanoalkyl, -NO2, -CO2R 4 , -C (O)NR 5 R 6 , -NR 5 (SO2)R 4 , -NR 5 C(O)R 4 , -NR 7 C(O) NR 5 R 6 , -NR 5 R 6 , -SO2NR 5 R 6 , -SO2R 4 , aryl, aryl a substituted with alkyl, heteroaryl, heteroarylalkyl, or heterocycloalkyl The pyrazolyl may be a C1-C8 alkyl or indolyl. , cyclopropyl, -CH2-cyclopropyl, -CH=CH2, -C≡C-cyclopropyl Pyr, -OH, -CO2H, C1-C8 alkoxy, CF3, Cl, F, I, -CN, - CH2CN, NH2, -C(O)NH2, -NH-pyridinyl, -CH2-tetrazolyl , phenyl, benzyl, or -SO2Me.

[0014] In any of the above embodiments, U is phenyl, —C(O)phenyl, indolyl , imidazolyl, oxazolyl, thiazolyl, furanyl, thiofuranyl, pyrrolyl, pyranyl Zolyl, pyridinyl, pyrazinyl, pyrimidinyl, or 6-oxo-1,6-dihydro pyridazin-3-yl, each of which is optionally substituted.

[0015] In other embodiments, U is Het or —C(O)Het, and Het is

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[0016] In an embodiment, U is [ka] [ka] [ka] [ka] [ka] or [ka] each of which is optionally substituted, and each point of attachment is Ar 1 or R 1 Noi It could be either one.

[0017] When U is substituted, there may be one or two substituents which may be the same or different. Examples of the substituent include C1 to C8 alkyl, C2 to C8 alkenyl, C2 to C8 alkyl, Nyl, C3-C6 cycloalkyl, C3-C6 cycloalkylalkyl, hydroxyl, C1 to C8 alkoxy, C3 to C6 cycloalkyloxy, C1 to C8 haloalkoxy, C1-C8 haloalkyl, halo, -CN, cyanoalkyl, -NO2, CO2R 4 , C( O)NR 5 R 6 , N.R.5 (SO2)R 4 , N.R. 5 C(O)R 4 , N.R. 7 C(O)NR 5 R 6 , -NR 5 R 6 , -SO2NR 5 R 6 , -SO 2 R 4 , aryl, arylalkyl, It includes heteroaryl and / or heterocycloalkyl.

[0018] In certain embodiments of compounds of Formula (I), Ar 1 pyrazolyl, indolyl or pyrrolo[2,3-b]pyridinyl, each of which is optionally substituted. And U is [ka] [ka] [ka] [ka] [ka] or [ka] and each of which is optionally substituted. In this embodiment, the following formula ( I): [ka] (In the formula, X 2 is -NR 5 -, -O-, or -S-; p is 0; 1 or 2 ;R 1 is halo, -CO2R 4 , -C(O)NR 5 R 6 , -CH2OH, -CHCF3O H, -C(CF3)2OH, -C(O)NHOH-C(O)OCR 5 R 6 OC(O)OR 4 , -C(O)O-2,3-dihydro-1H-indenyl, -C(O)O-(5-methyl -2-oxo-1,3-dioxol-4-yl)methyl, 1,3,4-oxadiazo isoxazol-2(3H)-one, isoxazol-3(2H)-one, -P(O)(OH)2, -B(OR 13 )(OR 14 ), -SO2(OH), -SO2NR 5 R 6 , or tetra The core structure of zolyl can be formed.

[0019] In any of the above embodiments, R 1 -CO2H or -CO2(C1-C8 alkyl) C1-C8 alkyl may be substituted or unsubstituted, or its prodrug or a pharmaceutically acceptable salt thereof.

[0020] In any of the above embodiments, V is selected from the group consisting of phenyl, piperazinyl, pyrrolinyl, pyrazinyl, and pyrazinyl. nyl, piperidyl, tetrahydrofuranyl, tetrahydrothiophenyl, morpholinyl, pyridinyl, pyridazinyl, pyrimidyl, or pyrazinyl, each of which is -( R 2 ) n In some embodiments, V is substituted with -(R 2 ) n is replaced by It is phenyl.

[0021] In any of the above embodiments, R 2 is -SO2NR 5 R 6 and;R 5 and R 6 are the same or different and each is H or C1-C8 alkyl (e.g., methyl, Ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, or tert -butyl). In some embodiments, R 2 is -SO2NH2.

[0022] In any of the above embodiments, n is 1, such that V is monosubstituted. .

[0023] In any of the above embodiments, W is [ka] is.

[0024] In any of the above embodiments, R 3 are independently halo, C1-C8 haloalkyl , C1-C8 haloalkoxy, substituted or unsubstituted C1-C4 alkyl, or substituted or unsubstituted C1-C4 alkyl. or unsubstituted phenyl.

[0025] In any of the above embodiments, m is 1 or 2.

[0026] In any of the above embodiments, X is -CR 8 R 9 - (e.g., -CH2-), - -O-, or -NH-, where R 8 and R 9 are the same or different, and each is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C3-C6 cycloalkyl, or or aryl.

[0027] In some embodiments, the compound of formula (I) has the formula (Ia): [ka] (Ia) (In the formula, Y 1 , Y 2 , Y 3 , Y 4 , and Y 5 are each independently CH or N; R 1 is halo, -C(O)R 4 , -CH2OH, -C(O)NHCN, -C(O)NH SO2H, -C(S)R 4 , -CO2R 4 , -C(O)NR 5 R 6 , -(C1~C8 Hydro -C(O)NHOH, -C(O)OCR 5 R 6 OC(O)OR 4 , -(C C0-C4 hydrocarbyl) ((1 to 4 heteroatoms independently selected from N, O and S) mono- or bicyclic heterocycle having the formula (C(O)O-(C0-C4 hydrocarbyl)(N mono- or bicyclic heterocycles having 1 to 4 heteroatoms independently selected from O and S; ), -P(O)(OH)2, -B(OR 13 )(OR 14 ), -SO2(OH), -C( O)NHS(O)2Me and -SO2NR 5 R 6 R, independently selected from 1 of each may be substituted or unsubstituted; R 2 is hydroxyl, halo, -CN, -NO2, C1-C8 hydrocarbyl, -O( C1-C8 hydrocarbyl), -(C0-C4 hydrocarbyl)C3-C8 cycloalkyl -O(C0-C4 hydrocarbyl)C3-C8 cycloalkyl, -(C0-C4 hydro -O(C0-C4 hydrocarbyl)C3-C8 cycloalkenyl, -O(C0-C4 hydrocarbyl)C3-C 8 Cycloalkenyl, -O(C0-C4 hydrocarbyl)C6-C 12 Aryl, -(C C6-C0-C4 Hydrocarbyl 12 Aryl, -O(C0-C4 hydrocarbyl)( Mono- and bicyclic heterocycles containing 1 to 4 heteroatoms independently selected from N, O, and S ), -(C0-C4 hydrocarbyl) (containing 1 to 4 heteroatoms independently selected from N, O, and S) Mono- and bicyclic heterocycles containing heteroatoms), -C(O)R 4 , -CO2R 4 , -C(O) NR 5 R 6 , -NR 5 C(O)R 4 , -(CH2) q NR 5 (SO2)R 4 , -(CH2 ) q NR 5 C(O)R 4 , -(CH2) q NR 7 C(O)NR 5 R 6 , -(CH2) q N R 5 R 6 , -(CH2) q SO2NR 5 R 6 , -(CH2) q SO2R 4 Selected independently from C1-C8 hydrocarbyl, -O(C1-C8 hydrocarbyl), -(C0-C4 hydrocarbyl)C3-C8 cycloalkyl, -O(C0-C4 hydrocarbyl)C3- C8 cycloalkyl, -(C0-C4 hydrocarbyl)C3-C8 cycloalkenyl, - -O(C0-C4 hydrocarbyl)C3-C8 cycloalkenyl, -O(C0-C4 hydrocarbyl)C3-C8 cycloalkenyl, Calvil) C6~C 12 Aryl, -(C0-C4 hydrocarbyl)C6-C 12 Ally -O(C0-C4 hydrocarbyl) (1 to 4 independently selected from N, O and S) Mono- and bicyclic heterocycles containing heteroatoms), -(C0-C4 hydrocarbyl)(N, O and S) each of mono- and bicyclic heterocycles having 1 to 4 heteroatoms independently selected from each may be substituted or unsubstituted; R 3 are hydroxyl, halo, -CN, -NO2, -SF5, C1 to C8 hydrocarbyl -O(C1-C8 hydrocarbyl), -(C0-C4 hydrocarbyl)C3-C8 silyl chloroalkyl, -O(C0-C4 hydrocarbyl)C3-C8 cycloalkyl, -(C0 -C4 hydrocarbyl) C3-C8 cycloalkenyl, -O(C0-C4 hydrocarbyl )C3-C8 cycloalkenyl, -O(C0-C4 hydrocarbyl)C6-C 12 Ally -(C0-C4 hydrocarbyl)C6-C 12 Aryl, -O(C0-C4 Hydrocarbon cyclohexyl) (mono- and dicyclohexyl) having 1 to 4 heteroatoms independently selected from N, O and S -(C0-C4 hydrocarbyl)(one independently selected from N, O, and S) Mono- and bicyclic heterocycles containing up to 4 heteroatoms), -C(O)R 4 , -CO2R 4 , -C(O)NR 5 R 6 , -NR 5 C(O)R 4 , -(CH2) q NR 5 (SO2)R 4 , -(CH2)q NR 5 C(O)R 4 , -(CH2) q NR 7 C(O)NR 5 R 6 , -(C H2) q NR 5 R 6 , -(CH2) q SO2NR 5 R 6 , -(CH2) q SO2R 4 from independently selected from C1-C8 hydrocarbyl, -O(C1-C8 hydrocarbyl), -( -O(C0-C4 hydrocarbyl)C3-C8 cycloalkyl, -O(C0-C4 hydrocarbyl -(C0-C4 hydrocarbyl)C3-C8 cycloalkyl, -(C0-C4 hydrocarbyl)C3-C8 cycloalkyl alkenyl, -O(C0-C4 hydrocarbyl) C3-C8 cycloalkenyl, -O(C0- C4 Hydrocarbyl) C6~C 12 Aryl, -(C0-C4 hydrocarbyl)C6-C 12 aryl, —O(C0-C4 hydrocarbyl)(independently selected from N, O, and S Mono- and bicyclic heterocycles containing 1 to 4 heteroatoms), -(C0-C4 hydrocarbyl ) (mono- and bicyclic heterocyclic rings having 1 to 4 heteroatoms independently selected from N, O, and S) each of the heterocycles) is substituted or unsubstituted; or The Two R's 3 The moieties and the phenyl groups to which they are attached may be naphthyl groups, or in the case forming heterocyclic analogs thereof substituted by Each R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are the same or different, and each C1-C8 alkyl, C2-C8 alkenyl, C3-C6 cycloalkyl, aryl , heteroaryl, or heterocycloalkyl; R 10 is hydrogen, halo, -CN, -NO2, -CO2R 4 , -C(O)NR 5 R 6 ,- NR 5 (SO2)R 4 , -NR 5 C(O)R 4 , -NR 7 C(O)NR 5 R 6 , -NR 5 R 6 , -SO2NR 5 R 6 , -SO2R 4 , C1-C8 hydrocarbyl, -O(C1-C -(C0-C4 hydrocarbyl)C3-C8 cycloalkyl, -O (C0-C4 hydrocarbyl)C3-C8 cycloalkyl, -(C0-C4 hydrocarbyl -O(C0-C4 hydrocarbyl)C3-C8 cycloalkenyl, -O(C0-C4 hydrocarbyl)C3-C8 cycloalkenyl, Alkenyl, -O(C0-C4 hydrocarbyl)C6-C 12 Aryl, -(C0-C4 Hydrocarbyl) C6~C 12 Aryl, -O(C0-C4 hydrocarbyl) (N, O and and S), mono- and bicyclic heterocycles having 1 to 4 heteroatoms independently selected from C0-C4 hydrocarbyl) (1 to 4 heteroatoms independently selected from N, O and S and R excluding hydrogen, halo, -CN, and -NO 1 0 each of which is substituted or unsubstituted; Each R 13 and R 14are the same or different, and each is hydrogen, C1-C8 alkyl, , C2-C8 alkenyl, C3-C6 cycloalkyl, C6-C 12 It is an aryl, So, R 13 and R 14 are optionally joined together to form a ring; X 1 is a bond, -CR 8 R 9 -, -NR 5 -, -CR 8 NR 5 -, -NR 5 CR 8 -, -NR 5 C(O)-, -O-, or -S-; X 2 is -NR 5 -, -O-, -CO-, -SO2-, or -S-; m, n, and q are the same or different and each is 0 or an integer from 1 to 5; p is 1 or 2) .

[0028] In an embodiment of formula (Ia), R 1 is halo, -CO2R 4 , -CONH2, -C(O)NHOH, -P(O)(OH )2, -B(OR 13 )(OR 14 ), -SO2(OH), -SO2NR 5 R 6 , -(C 1-C8 alkylene)OH, C1-C4 alkyl, C1-C4 alkoxy, C1-C2 ha -C(O)O-heteroaryl, ... independently selected from hydrogen, halo, -P(O)(OH)2, -CONH2, and -S R excluding O2(OH) 1 each of which is substituted or unsubstituted; Each R 4 , R 5 , and R 6 are the same or different, and each is hydrogen, C1 to C8 alkyl alkyl, C2-C8 alkenyl, C3-C6 cycloalkyl, C6-C 12 Aril, Haitai aryl, or heterocycloalkyl, and R excluding H 4 , R 5 , and R 6 Each of is substituted or unsubstituted; R 2 are hydroxyl, halo, -CN, -NO2, C1-C8 alkyl, C2-C8 alkyl Alkenyl, C3-C6 cycloalkyl, C1-C8 alkoxy, -O-C3-C6 cyclo Alkyl, C6-C 12 Aryl, -O-C6~C 12 Aryloxy, -(CH2) q Aryl, -(CH2) q Heteroaryl, -(CH2) q Heterocycloalkyl, -C (O)R 4 , -CO2R 4 , -C(O)NR 5 R 6 , -NR 5 C(O)R 4 , -(CH2 ) q NR 5 (SO2)R 4 , -(CH2) q NR 5 C(O)R 4 , -(CH2) q NR 7 C(O)NR 5 R 6 , -(CH2) q NR 5 R 6 , -(CH2) q SO2NR 5 R 6 , and Bi-(CH2) qSO2R 4 independently selected from hydrogen, hydroxyl, halo, -CN, -R excluding NO2 and SF5 2 each of which is substituted or unsubstituted; R 3 are hydroxyl, halo, -CN, -NO2, SF5, C1-C8 alkyl, C2 ~C8 alkenyl, C2~C8 alkynyl, C3~C6 alkenynyl, C1~C8 alkoxy oxy, -(CH2) q C3-C8 cycloalkyl, -O(CH2) q C3~C8 cycloa Rukill, -(CH2) q C3-C8 cycloalkenyl, -(C2-C4 alkynyl)(C 3-C6 cycloalkenyl), -(CH2) q C6~C 12 Aryl, -O(CH2) q C6~C 12 Aryl, -(CH2) q Heteroaryl, -O(CH2) q Heteroary -(C2-C4 alkenyl)heteroaryl, -(C2-C4 alkynyl)heteroaryl Reel, -(CH2) q Heterocycloalkenyl, -O(CH2) q (Heterocycloal -(C2-C4 alkenyl)heterocycloalkenyl, -(C2-C4 alkynyl) heterocycloalkenyl, -(CH2) q Heterocycloalkyl, -O(CH2) q Heterocycloalkyl, -(C2-C4 alkenyl)heterocycloalkyl, and -(C 2-C4 alkynyl)heterocycloalkyl; R excluding halo, -CN, -NO2, and SF5 3 each of which is substituted or unsubstituted; R 10is hydrogen, -CN, hydroxyl, halo, C1-C8 alkyl, C2-C8 alkoxy alkynyl, C2-C8 alkynyl, C1-C6 alkoxy, -(C0-C2 alkyl)NR 5 R 6 , -(C0-C2 alkyl)C3-C6 cycloalkyl, -C≡C(C3-C6 cycloalkyl Chloroalkyl)-(C0-C2 alkyl)C6-C 12 Aryl, -(C0-C2 alkyl) -(C0-C2 alkyl)heteroaryl, or -(C0-C2 alkyl)heteroaryl; R excluding hydrogen, hydroxyl, and halo 10 each of which is substituted or unsubstituted; Each R 13 and R 14 are the same or different, and each is hydrogen, C1-C8 alkyl, , C2-C8 alkenyl, C3-C6 cycloalkyl, C6-C 12 It is an aryl, So, R 13 and R 14 are sometimes bonded to each other to form a ring.

[0029] In another embodiment of Formula (Ia), R 1 is halo, hydroxyl, -CONH2, C1-C4 alkyl, C1-C4 alkoxy Kishi, -CO2R 4 , -CH2OH, -CHCF3OH, -C(CF3)2OH, -C( O)NHOH, -P(O)(OH)2, -B(OR 13 )(OR 14 ), -SO2(OH ), -SO2NR 5 R 6 , -C(O)O-2,3-dihydro-1H-indenyl, -C( O) O-(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl, 1,3 ,4-oxadiazol-2(3H)-one, isoxazol-3(2H)-one, and and tetrazolyl, R excluding hydrogen and halo; 1 Each of and; R 2 is halo and -(CH2) q SO2NR 5 R 6 are independently selected from R 2 One of the , -(CH2) q SO2NR 5 R 6 and; R 3 are hydroxyl, halo, -CN, -NO2, SF5, C1-C8 alkyl, C2 ~C8 alkenyl, C2~C8 alkynyl, C3~C6 alkenynyl, C1~C8 alkoxy Kishi, -(CH2) q C3-C8 cycloalkyl, -O(CH2) q C3~C6 cycloalkoxy Le, -(CH2) q C3-C6 cycloalkenyl, -(C2-C4 alkynyl)(C3- C6 cycloalkenyl), -(CH2) q C6~C 12 Phenyl, -O(CH2) q C6~C 12 phenyl, -(CH2) q Heteroaryl, -O(CH2) q Heteroaryl, -(C2-C4 alkyl -(C2-C4 alkynyl)heteroaryl, and -(C2-C4 alkynyl)heteroaryl (wherein Heteroaryl groups include oxazolyl, thienyl, thiazolyl, furanyl, pyrazolyl, and and an imidazolyl group; -(CH2) q Heterocycloalkenyl, -O(CH2) q (Heterocycloalkenyl , -(C2-C4 alkenyl)heterocycloalkenyl, -(C2-C4 alkynyl)heterocycloalkenyl Heterocycloalkenyl (wherein heterocycloalkenyl is dihydropyranyl, dihydropyranyl, dihydrothiopyranyl, dihydropyridinyl, and dihydropyridinyl; -(CH2) q Heterocycloalkyl, -O(CH2) q Heterocycloalkyl, -( -(C2-C4 alkenyl)heterocycloalkyl, -(C2-C4 alkynyl)heterocyclo heterocycloalkyl (wherein heterocycloalkyl is tetrahydropyranyl, tetrahydrofuran, is independently selected from the group consisting of aryl, piperazinyl, piperidinyl, and pyrrolidinyl; R excluding hydrogen, hydroxyl, halo, -CN, -NO2, and SF5 3 Each of or unsubstituted; Each R 4 , R 5 , and R 6 are the same or different, and each is H or C1-C8 alkyl. alkyl, wherein C1-C8 alkyl is substituted or unsubstituted; R 10 is hydrogen, -OH, halo, -CH2OH, -CN, -CH2CN, -NH2, C 1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkoxy, C1-C2 haloal alkyl, C1-C2 haloalkoxy, -(C0-C3 alkyl)-cyclopropyl, -(C (0-C3 alkyl)-cyclobutyl, -C≡C-cyclopropyl, -C≡C-cyclobutyl -phenyl, benzyl, or -CH2-tetrazolyl; cyclopropyl, -(C (1-C3 alkyl)-cyclopropyl, -CH=CH2, -C≡C-cyclopropyl, each of phenyl, or benzyl is substituted or unsubstituted; Each R 13 and R 14 are the same or different, and each is hydrogen, C1-C8 alkyl, , C2-C8 alkenyl, C3-C6 cycloalkyl, C6-C 12 It is an aryl, So, R 13 and R 14 are sometimes bonded to each other to form a ring.

[0030] In yet another embodiment of Formula (Ia), R 1 is hydroxyl, halo, -CO2H, -SO2NH2, C1-C4 alkyl, C 1-C4 alkoxy, C1-C2 haloalkyl optionally substituted with halo, C1- independently selected from C2 haloalkoxy, and -CO2(C1-C6 alkyl); R 2 is selected from F and -SO2NH2, where R 2 One of them is -SO2NH2 can be; R 3 is the following: (a) Halogens, hydroxyl, SF5; (b) C1-C6 hydrocarbyl (wherein any alkyl group in the hydrocarbyl chain wherein the olefin (CH2) group is optionally replaced by NH, O, or S); (c) -C0-C2 hydrocarbyl(phenyl), -C0-C2 hydrocarbyl(furan) Phenyl), -C0-C2 hydrocarbyl (thiophenyl), -C0-C2 hydrocarbyl (oxazolyl), -C0-C2 hydrocarbyl (thiazolyl), -C0-C2 hydroca -C0-C2 hydrocarbyl (C3-C6 cycloalkenyl) alkyl), -C0-C2 hydrocarbyl (C3-C6 cycloalkyl), -C0-C2 hydroxy -C0-C2 hydrocarbyl (C3-C6 cycloalkanyl), -C0-C2 hydrocarbyl (C3-C6 Cycloalkenyl), -C0-C2 hydrocarbyl (tetrahydropyrenyl), -C0- C2 hydrocarbyl (imidazolyl), -C0-C2 hydrocarbyl (thiophenyl) ( wherein any alkylene (CH2) group in the C0-C2 hydrocarbyl chain is optionally and each independently selected from: Each of (b) is unsubstituted or is selected from the group consisting of halogen, hydroxyl, cyano, amino, and the like. one independently selected from C1-C2 haloalkyl, and C1-C2 haloalkoxy; and is substituted with the following substituents: Each of (c) is unsubstituted or is selected from the group consisting of halogen, hydroxyl, cyano, amino, and the like. C1-C4 alkyl, C1-C6 cycloalkyl, mono- or di-C1-C4 alkyl alkylamino, C1-C4 alkoxy, C1-C2 haloalkyl, and C1-C2 haloa substituted with one or more substituents independently selected from alkoxy;

[0031] In some embodiments, the compound of formula (I) has the formula (Ib): [ka] (Ib) (In the formula, R 1 is halo, -CO2R 4 , -C(O)NR 5 R 6 , -(C1-C8 hydrocarbyl ), -C(O)NHOH, -C(O)OCR 5 R 6 OC(O)OR 4 , -P(O)(OH )2, -B(OR 13 )(OR 14 ), -SO2(OH), -C(O)NHS(O)2M e and -SO2NR 5 R 6 R, independently selected from 1 Each of the is a substitution; R 2 is hydroxyl, halo, -CN, -NO2, C1-C8 hydrocarbyl, -O( C1-C8 hydrocarbyl), -(C0-C4 hydrocarbyl)C3-C8 cycloalkyl -O(C0-C4 hydrocarbyl)C3-C8 cycloalkyl, -(C0-C4 hydro -O(C0-C4 hydrocarbyl)C3-C8 cycloalkenyl, -O(C0-C4 hydrocarbyl)C3-C 8 Cycloalkenyl, -O(C0-C4 hydrocarbyl)C6-C 12 Aryl, -(C C6-C0-C4 Hydrocarbyl 12 Aryl, -O(C0-C4 hydrocarbyl)( Mono- and bicyclic heterocycles containing 1 to 4 heteroatoms independently selected from N, O, and S ), -(C0-C4 hydrocarbyl) (containing 1 to 4 heteroatoms independently selected from N, O, and S) Mono- and bicyclic heterocycles containing heteroatoms), -C(O)R 4 , -CO2R 4 , -C(O) NR 5 R 6 , -NR 5 C(O)R 4 , -(CH2) q NR 5 (SO2)R 4 , -(CH2 ) q NR 5 C(O)R 4 , -(CH2) q NR 7 C(O)NR 5 R 6 , -(CH2) q N R 5 R 6 , -(CH2) q SO2NR 5 R 6 , -(CH2) q SO2R 4 , -(CH2) q Aryl, -(CH2)q Heteroaryl, or -(CH2) q Heterocycloalkane independently selected from C1-C8 hydrocarbyl, -O(C1-C8 hydrocarbyl) , -(C0-C4 hydrocarbyl)C3-C8 cycloalkyl, -O(C0-C4 hydro -(C0-C4 hydrocarbyl)C3-C8 cycloalkyl, -(C0-C4 hydrocarbyl)C3-C8 cyclo -O(C0-C4 hydrocarbyl)C3-C8 cycloalkenyl, -O( C0-C4 Hydrocarbyl)C6-C 12 Aryl, -(C0-C4 hydrocarbyl)C 6~C 12 aryl, —O(C0-C4 hydrocarbyl) (independently selected from N, O and S) Mono- and bicyclic heterocycles containing 1 to 4 heteroatoms, -(C0-C4 hydrocarbyl groups) cyclohexyl) (mono- and dicyclohexyl) having 1 to 4 heteroatoms independently selected from N, O and S each of the heterocyclic rings) is substituted or unsubstituted; R 3 are hydroxyl, halo, -CN, -NO2, -SF5, C1 to C8 hydrocarbyl -O(C1-C8 hydrocarbyl), -(C0-C4 hydrocarbyl)C3-C8 silyl chloroalkyl, -O(C0-C4 hydrocarbyl)C3-C8 cycloalkyl, -(C0 -C4 hydrocarbyl) C3-C8 cycloalkenyl, -O(C0-C4 hydrocarbyl )C3-C8 cycloalkenyl, -O(C0-C4 hydrocarbyl)C6-C 12 Ally -(C0-C4 hydrocarbyl)C6-C 12 Aryl, -O(C0-C4 Hydrocarbon cyclohexyl) (mono- and dicyclohexyl) having 1 to 4 heteroatoms independently selected from N, O and S -(C0-C4 hydrocarbyl)(one independently selected from N, O, and S) Mono- and bicyclic heterocycles containing up to 4 heteroatoms), -C(O)R 4 , -CO2R 4 , -C(O)NR 5 R 6 , -NR 5 C(O)R 4 , -(CH2) q NR 5 (SO2)R 4 , -(CH2) q NR 5 C(O)R 4 , -(CH2) q NR 7 C(O)NR 5 R 6 , -(C H2) q NR 5 R 6 , -(CH2) q SO2NR 5 R 6 , -(CH2) q SO2R 4 from independently selected from C1-C8 hydrocarbyl, -O(C1-C8 hydrocarbyl), -( -O(C0-C4 hydrocarbyl)C3-C8 cycloalkyl, -O(C0-C4 hydrocarbyl -(C0-C4 hydrocarbyl)C3-C8 cycloalkyl, -(C0-C4 hydrocarbyl)C3-C8 cycloalkyl alkenyl, -O(C0-C4 hydrocarbyl) C3-C8 cycloalkenyl, -O(C0- C4 Hydrocarbyl) C6~C 12 Aryl, -(C0-C4 hydrocarbyl)C6-C 12 aryl, —O(C0-C4 hydrocarbyl)(independently selected from N, O, and S Mono- and bicyclic heterocycles containing 1 to 4 heteroatoms), -(C0-C4 hydrocarbyl ) (mono- and bicyclic heterocyclic rings having 1 to 4 heteroatoms independently selected from N, O, and S) each of the heterocycles) is substituted or unsubstituted; or Each R 4 , R5 , R 6 , R 7 , R 8 , and R 9 are the same or different, and each C1-C8 alkyl, C2-C8 alkenyl, C3-C6 cycloalkyl, aryl , heteroaryl, or heterocycloalkyl, and C1-C8 alkyl, C2-C 8 alkenyl, C3-C6 cycloalkyl, aryl, heteroaryl, or heterocycloalkyl each chloroalkyl is substituted or unsubstituted; R 10 is hydrogen, halo, -CN, -NO2, -CO2R 4 , -C(O)NR 5 R 6 ,- NR 5 (SO2)R 4 , -NR 5 C(O)R 4 , -NR 7 C(O)NR 5 R 6 , -NR 5 R 6 , -SO2NR 5 R 6 , -SO2R 4 , C1-C8 hydrocarbyl, -O(C1-C -(C0-C4 hydrocarbyl)C3-C8 cycloalkyl, -O (C0-C4 hydrocarbyl)C3-C8 cycloalkyl, -(C0-C4 hydrocarbyl -O(C0-C4 hydrocarbyl)C3-C8 cycloalkenyl, -O(C0-C4 hydrocarbyl)C3-C8 cycloalkenyl, Alkenyl, -O(C0-C4 hydrocarbyl)C6-C 12 Aryl, -(C0-C4 Hydrocarbyl) C6~C 12 Aryl, -O(C0-C4 hydrocarbyl) (N, O and and S), mono- and bicyclic heterocycles having 1 to 4 heteroatoms independently selected from C0-C4 hydrocarbyl) (1 to 4 heteroatoms independently selected from N, O and S and R excluding hydrogen, halo, -CN, and -NO 1 0 each of which is substituted or unsubstituted; Each R 13 and R 14 are the same or different, and each is hydrogen, C1-C8 alkyl, , C2-C8 alkenyl, C3-C6 cycloalkyl, C6-C 12 It is an aryl, So, R 13 and R 14 are optionally joined together to form a ring; X 1 is a bond, -CR 8 R 9 -, -NR 5 -, -CR 8 NR 5 -, -NR 5 CR 8 -, -NR 5 C(O)-, -O-, -CO-, -SO2-, or -S-; X 2 is -NR 5 -, -O-, -SO-, or -SO2-, or -S-; X 3 is CH or N; m, n, and q are the same or different and each is 0 or an integer from 1 to 5; p is 1 or 2) .

[0032] In some embodiments, the compound of formula (I) has the formula (Ic): [ka] (I C) (In the ceremony R 1 is halo, -CO2R 4, -C(O)NR 5 R 6 , -(C1-C8 hydrocarbyl ), -C(O)NHOH, -P(O)(OH)2, -B(OR 13 )(OR 14 ), -S O2(OH), -C(O)NHS(O)2Me and -SO2NR 5 R 6 independently selected from R excluding halo 1 each of which is substituted or unsubstituted; R 2 is hydroxyl, halo, -CN, -NO2, C1-C8 hydrocarbyl, -O( C1-C8 hydrocarbyl), -(C0-C4 hydrocarbyl)C3-C8 cycloalkyl -O(C0-C4 hydrocarbyl)C3-C8 cycloalkyl, -(C0-C4 hydro -O(C0-C4 hydrocarbyl)C3-C8 cycloalkenyl, -O(C0-C4 hydrocarbyl)C3-C 8 Cycloalkenyl, -O(C0-C4 hydrocarbyl)C6-C 12 Aryl, -(C C6-C0-C4 Hydrocarbyl 12 Aryl, -O(C0-C4 hydrocarbyl)( Mono- and bicyclic heterocycles containing 1 to 4 heteroatoms independently selected from N, O, and S ), -(C0-C4 hydrocarbyl) (containing 1 to 4 heteroatoms independently selected from N, O, and S) Mono- and bicyclic heterocycles containing heteroatoms), -C(O)R 4 , -CO2R 4 , -C(O) NR 5 R 6 , -NR 5 C(O)R 4 , -(CH2) q NR 5 (SO2)R 4 , -(CH2 ) q NR 5 C(O)R 4 , -(CH2)q NR 7 C(O)NR 5 R 6 , -(CH2) q N R 5 R 6 , -(CH2) q SO2NR 5 R 6 , -(CH2) q SO2R 4 Selected independently from C1-C8 hydrocarbyl, -O(C1-C8 hydrocarbyl), -(C0-C4 hydrocarbyl)C3-C8 cycloalkyl, -O(C0-C4 hydrocarbyl)C3- C8 cycloalkyl, -(C0-C4 hydrocarbyl)C3-C8 cycloalkenyl, - -O(C0-C4 hydrocarbyl)C3-C8 cycloalkenyl, -O(C0-C4 hydrocarbyl)C3-C8 cycloalkenyl, Calvil) C6~C 12 Aryl, -(C0-C4 hydrocarbyl)C6-C 12 Ally -O(C0-C4 hydrocarbyl) (1 to 4 independently selected from N, O and S) Mono- and bicyclic heterocycles containing heteroatoms), -(C0-C4 hydrocarbyl)(N, O and S) each of mono- and bicyclic heterocycles having 1 to 4 heteroatoms independently selected from each may be substituted or unsubstituted; R 3 are hydroxyl, halo, -CN, -NO2, -SF5, C1 to C8 hydrocarbyl -O(C1-C8 hydrocarbyl), -(C0-C4 hydrocarbyl)C3-C8 silyl chloroalkyl, -O(C0-C4 hydrocarbyl)C3-C8 cycloalkyl, -(C0 -C4 hydrocarbyl) C3-C8 cycloalkenyl, -O(C0-C4 hydrocarbyl )C3-C8 cycloalkenyl, -O(C0-C4 hydrocarbyl)C6-C 12 Ally -(C0-C4 hydrocarbyl)C6-C 12 Aryl, -O(C0-C4 Hydrocarbon cyclohexyl) (mono- and dicyclohexyl) having 1 to 4 heteroatoms independently selected from N, O and S -(C0-C4 hydrocarbyl)(one independently selected from N, O, and S) Mono- and bicyclic heterocycles containing up to 4 heteroatoms), -C(O)R 4 , -CO2R 4 , -C(O)NR 5 R 6 , -NR 5 C(O)R 4 , -(CH2) q NR 5 (SO2)R 4 , -(CH2) q NR 5 C(O)R 4 , -(CH2) q NR 7 C(O)NR 5 R 6 , -(C H2) q NR 5 R 6 , -(CH2) q SO2NR 5 R 6 , -(CH2) q SO2R 4 from independently selected from C1-C8 hydrocarbyl, -O(C1-C8 hydrocarbyl), -( -O(C0-C4 hydrocarbyl)C3-C8 cycloalkyl, -O(C0-C4 hydrocarbyl -(C0-C4 hydrocarbyl)C3-C8 cycloalkyl, -(C0-C4 hydrocarbyl)C3-C8 cycloalkyl alkenyl, -O(C0-C4 hydrocarbyl) C3-C8 cycloalkenyl, -O(C0- C4 Hydrocarbyl) C6~C 12 Aryl, -(C0-C4 hydrocarbyl)C6-C 12 aryl, —O(C0-C4 hydrocarbyl)(independently selected from N, O, and S Mono- and bicyclic heterocycles containing 1 to 4 heteroatoms), -(C0-C4 hydrocarbyl ) (mono- and bicyclic heterocyclic rings having 1 to 4 heteroatoms independently selected from N, O, and S) each of the heterocyclic rings is substituted or unsubstituted; Each R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are the same or different, and each C1-C8 alkyl, C2-C8 alkenyl, C3-C6 cycloalkyl, aryl , heteroaryl, or heterocycloalkyl; R 10 is hydrogen, halo, -CN, -NO2, -CO2R 4 , -C(O)NR 5 R 6 ,- NR 5 (SO2)R 4 , -NR 5 C(O)R 4 , -NR 7 C(O)NR 5 R 6 , -NR 5 R 6 , -SO2NR 5 R 6 , -SO2R 4 , C1-C8 hydrocarbyl, -O(C1-C -(C0-C4 hydrocarbyl)C3-C8 cycloalkyl, -O (C0-C4 hydrocarbyl)C3-C8 cycloalkyl, -(C0-C4 hydrocarbyl -O(C0-C4 hydrocarbyl)C3-C8 cycloalkenyl, -O(C0-C4 hydrocarbyl)C3-C8 cycloalkenyl, Alkenyl, -O(C0-C4 hydrocarbyl)C6-C 12 Aryl, -(C0-C4 Hydrocarbyl) C6~C 12 Aryl, -O(C0-C4 hydrocarbyl) (N, O and and S), mono- and bicyclic heterocycles having 1 to 4 heteroatoms independently selected from C0-C4 hydrocarbyl) (1 to 4 heteroatoms independently selected from N, O and S and R excluding hydrogen, halo, -CN, and -NO 1 0 each of which is substituted or unsubstituted; Each R 13 and R 14 are the same or different, and each is hydrogen, C1-C8 alkyl, , C2-C8 alkenyl, C3-C6 cycloalkyl, C6-C 12 It is an aryl, So, R 13 and R 14 are optionally joined together to form a ring; Ring Cy is a substituted or unsubstituted C3-C6 cycloalkyl; X 1 is a bond, -CR 8 R 9 -, -NR 5 -, -CR 8 NR 5 -, -NR 5 CR 8 -, -NR 5 C(O)-, -O-, -CO-, -SO-, -SO2-, or -S-; X 2 is -NR 5 -, -O-, -SO2-, or -S-; m, n, and q are the same or different and each is 0 or an integer from 1 to 5; p is 1 or 2) .

[0033] In some embodiments, the compound of formula (I) has the formula (Id): [ka] (Id) (In the ceremony R 1 is halo, -CO2R 4 , -C(O)NR 5 R 6 , -(C1-C8 hydrocarbyl ), —C(O)NHOH, —(C0-C4 hydrocarbyl)((independently of N, O and S) mono- or bicyclic heterocycle having 1 to 4 heteroatoms selected from the group consisting of -C(O)O-( C0-C4 hydrocarbyl) (1 to 4 heteroatoms independently selected from N, O and S mono- or bicyclic heterocycles having the formula (III), -P(O)(OH), -B(OR 13 )(OR 1 4 ), -SO2(OH), -SO2NR 5 R 6 R, independently selected from 1 Each each may be substituted or unsubstituted; R 3 are hydroxyl, halo, -CN, -NO2, -SF5, C1 to C8 hydrocarbyl -O(C1-C8 hydrocarbyl), -(C0-C4 hydrocarbyl)C3-C8 silyl chloroalkyl, -O(C0-C4 hydrocarbyl)C3-C8 cycloalkyl, -(C0 -C4 hydrocarbyl) C3-C8 cycloalkenyl, -O(C0-C4 hydrocarbyl )C3-C8 cycloalkenyl, -O(C0-C4 hydrocarbyl)C6-C 12 Ally -(C0-C4 hydrocarbyl)C6-C 12 Aryl, -O(C0-C4 Hydrocarbon cyclohexyl) (mono- and dicyclohexyl) having 1 to 4 heteroatoms independently selected from N, O and S -(C0-C4 hydrocarbyl)(one independently selected from N, O, and S) Mono- and bicyclic heterocycles containing up to 4 heteroatoms), -C(O)R 4 , -CO2R 4 , -C(O)NR 5 R 6 , -NR 5 C(O)R 4 , -(CH2) q NR 5 (SO2)R 4 , -(CH2) q NR 5 C(O)R 4 , -(CH2) q NR 7 C(O)NR 5 R 6 , -(C H2) q NR 5 R 6 , -(CH2) q SO2NR 5 R 6 , -(CH2) q SO2R 4 from independently selected from C1-C8 hydrocarbyl, -O(C1-C8 hydrocarbyl), -( -O(C0-C4 hydrocarbyl)C3-C8 cycloalkyl, -O(C0-C4 hydrocarbyl -(C0-C4 hydrocarbyl)C3-C8 cycloalkyl, -(C0-C4 hydrocarbyl)C3-C8 cycloalkyl alkenyl, -O(C0-C4 hydrocarbyl) C3-C8 cycloalkenyl, -O(C0- C4 Hydrocarbyl) C6~C 12 Aryl, -(C0-C4 hydrocarbyl)C6-C 12 aryl, —O(C0-C4 hydrocarbyl)(independently selected from N, O, and S Mono- and bicyclic heterocycles containing 1 to 4 heteroatoms), -(C0-C4 hydrocarbyl ) (mono- and bicyclic heterocyclic rings having 1 to 4 heteroatoms independently selected from N, O, and S) each of the heterocycles) is substituted or unsubstituted; or The Two R's 3 The moieties and the phenyl groups to which they are attached may be naphthyl groups, or in the case forming heterocyclic analogs thereof substituted by Each R 4 , R 5 , R 6 , and R 7 are the same or different, and each is hydrogen, C1 to C 8 alkyl, C2-C8 alkenyl, C3-C6 cycloalkyl, C6-C 12 Aryl , C1~C 12 Heteroaryl, or C1-C 12 Heterocycloalkyl, C1 ~C8 alkyl, C2~C8 alkenyl, C3~C6 cycloalkyl, C6~C 12 Ants C1~C 12 Heteroaryl, or C1-C 12 Each heterocycloalkyl is , substituted or unsubstituted; R 10 is hydrogen, halo, -CN, -NO2, -CO2R 4 , -C(O)NR 5 R 6 ,- NR 5 (SO2)R 4 , -NR 5 C(O)R 4 , -NR 7 C(O)NR 5 R 6 , -NR 5 R 6 , -SO2NR 5 R 6 , -SO2R 4 , C1-C8 hydrocarbyl, -O(C1-C -(C0-C4 hydrocarbyl)C3-C8 cycloalkyl, -O (C0-C4 hydrocarbyl)C3-C8 cycloalkyl, -(C0-C4 hydrocarbyl -O(C0-C4 hydrocarbyl)C3-C8 cycloalkenyl, -O(C0-C4 hydrocarbyl)C3-C8 cycloalkenyl, Alkenyl, -O(C0-C4 hydrocarbyl)C6-C 12 Aryl, -(C0-C4 Hydrocarbyl) C6~C 12 Aryl, -O(C0-C4 hydrocarbyl) (N, O and and S), mono- and bicyclic heterocycles having 1 to 4 heteroatoms independently selected from C0-C4 hydrocarbyl) (1 to 4 heteroatoms independently selected from N, O and S and R excluding hydrogen, halo, -CN, and -NO 1 0 each of which is substituted or unsubstituted; Each R 13 and R 14 are the same or different, and each is hydrogen, C1-C8 alkyl, , C2-C8 alkenyl, C3-C6 cycloalkyl, C6-C 12 It is an aryl, So, R 13 and R 14 are optionally joined together to form a ring; X 2 is -NR 5 -, -O-, -SO-, -SO2-, or -S-; m and q are the same or different and each is 0 or an integer from 1 to 5; p is 1 or 2) .

[0034] In any of the above embodiments of formulas (Ia)-(Ic), R 10 is hydrogen, C1 to C 8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C6 cycloalkyl , C3-C6 cycloalkyl alkyl, aryl, aryl alkyl, hydroxyl, Hydroxyalkyl, halo, C1-C8 haloalkyl, -CN, cyanoalkyl, -NR 5 R 6 or heteroarylalkyl. In embodiments, R 10is hydrogen, C1 to C 8Alkyl, -CH=CH2, cyclopropyl, -C≡C-cyclopropyl, -OH, - CH2OH, -CF3, -CF2CF3, -Cl, -F, -I, -CN, -CH2CN, -NH2, phenyl, benzyl, or -CH2-tetrazolyl.

[0035] In any of the above embodiments of formulas (Ia)-(Ic), R 1 is -CO2H, and is a substituted or unsubstituted -CO2(C1-C8 alkyl), or a prodrug thereof or a pharmaceutically acceptable salt thereof. In an aspect of this embodiment, p is 1.

[0036] In any of the above embodiments of formulas (Ia)-(Ic), R 2 is -SO2NR 5 R 6 and;R 5 and R 6 are the same or different and each is hydrogen or a substituted or It is an unsubstituted C1-C8 alkyl.

[0037] In any of the above embodiments of formulas (Ia)-(Ic), n is 1.

[0038] In any of the above embodiments of formulas (Ia)-(Ic), R 3 is hydrogen, halo, substituted or unsubstituted C1-C8 haloalkyl, substituted or unsubstituted C1-C8 haloalkane alkoxy, or substituted or unsubstituted aryl.

[0039] In any of the above embodiments of formulas (Ia)-(Id), m is 1 or 2.

[0040] In any of the above embodiments of formulas (Ia)-(Ic), X 1 -CR8 R 9 -( For example, —CH—, —O—, or —NH—, where R 8 and R 9 is the same or different, each of which is hydrogen, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C1-C8 alkyl, or unsubstituted C2-C8 alkenyl, substituted or unsubstituted C3-C6 cycloalkyl or substituted or unsubstituted aryl.

[0041] In any of the above embodiments of formulas (Ia)-(Id), X 2 is -S-.

[0042] In any of the above embodiments of compounds of formula (Ib), X 3 is -CH-.

[0043] In embodiments, the compound of formula (Ia) has the formula (Ia-1): [ka] (Ia-1) (In the formula, R a -R 4 , -OR 4 , or -NR 5 R 6 and each of these is a substitution or is non-substituted; R b and R c are the same or different and each is H or substituted or unsubstituted C1-C8 alkyl; Each R 2 are the same or different and are hydroxyl, C1-C8 alkyl, C2-C8 Alkenyl, C3-C6 cycloalkyl, C1-C8 alkoxy, C3-C6 cycloalkenyl Aryloxy, aryloxy, halo, C1-C8 haloalkoxy, C1-C8 haloalkoxy haloaryl, haloaryloxy, -CN, -NO2, -C(O)R 4 , -CO2 R 4 , -C(O)NR 5 R 6 , -NR 5 C(O)R 4 , -(CH2) q NR 5 (SO2) R 4 , -(CH2) q NR 5 C(O)R 4 , -(CH2) q NR 7 C(O)NR 5 R 6 , -(CH2) q NR 5 R 6 , -(CH2) q SO2NR 5 R 6 , -(CH2) q SO2R 4 , -(CH2) q Aryl, -(CH2) q Heteroaryl, and -(CH2) q Haitai R is independently selected from hydroxyl and halo; 2 Each of the or unsubstituted; R 3 is hydroxyl, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl Quinyl, C3-C6 cycloalkyl, -(C1-C4 hydrocarbyl)C3-C6 cyclo Alkyl, C1-C8 alkoxy, -(C0-C4 alkoxy)C3-C6 cycloalkoxy -(C0-C4 alkoxy)aryl, halo, C1-C8 haloalkoxy, C1-C 8 Haloalkyl, haloaryl, haloaryloxy, -CN, -NO2, -C(O)R 4 , -CO2R 4 , -C(O)NR5 R 6 , -NR 5 C(O)R 4 , -(CH2) q NR 5 (SO2)R 4 , -(CH2) q NR 5 C(O)R 4 , -(CH2) q NR 7 C(O) NR 5 R 6 , -(CH2) q NR 5 R 6 , -(CH2) q SO2NR 5 R 6 , -(CH2 ) q SO2R 4 , -(C0-C4 hydrocarbyl)aryl, -(C0-C4 hydrocarbyl)aryl -(C0-C4 alkoxy)heteroaryl, -(C0-C4 alkoxy)heteroaryl, -(C0-C4 hydrocarbyl)heterocycloalkyl, and -(C0-C4 hydrocarbyl)heterocycloalkyl R is independently selected from alkyl and hydroxyl, excluding hydroxyl and halo. 3 Each of is exchangeable; or The Two R's 3 The moieties, and the phenyl groups to which they are attached, are optionally substituted. forming a naphthyl group; Each R 4 , R 5 , R 6 , and R 7 are the same or different, and each is hydrogen, C1 to C 8 alkyl, or C3 to C6 cycloalkyl, and C1 to C8 alkyl and C3 to C Each of the 6 cycloalkyls is substituted or unsubstituted; R 10 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl , C3-C6 cycloalkyl, C3-C6 cycloalkylalkyl, hydroxyl, hydroxyl oxyalkyl, C1-C8 alkoxy, halo, C1-C8 haloalkyl, -CN, -C O2R 4 , -NR 5 R 6 , aryl, arylalkyl, heteroarylalkyl, or Ha-SO2R 4 and R is excluding hydrogen, hydroxyl, and halo. 10 but substituted or unsubstituted and; X 1 is a bond, -CR 8 R 9 -, -NR 5 -, -O-, -S(O)-, or -S(O )2-, or -S-; n is an integer from 0 to 4; m and q are the same or different and each is 0 or an integer from 1 to 5. The compound may be a compound, a prodrug or a pharmaceutically acceptable salt.

[0044] In an embodiment of the compound of formula (Ia-1), R a is hydroxyl or -O(C1 -C8 alkyl); R b and R c is H;R 2 is hydrogen; R 3 Ha, ha aryl, or haloaryl (e.g., halo or phenyl); or The Two R's 3 The moieties, and the phenyl groups to which they are attached, may be optionally substituted naphthalene groups. R 10 is hydrogen, C1-C8 alkyl, cyclopropyl, -C H2-cyclopropyl, -CH2CH2cyclopropyl, cyclobutyl, -CH2-cyclo -butyl, -CH=CH2, -C≡C-cyclopropyl, phenyl, benzyl, -I, - CF3, -NH2, or -CN; X 1 is -CH2- or -NH-; m is 0, 1 or 2.

[0045] In embodiments, the present disclosure includes compounds and salts of formula (Ia-1): During the ceremony, R a is R 4 , -OR 4 , or -NR 5 R 6 and; R 2 are halo, hydroxyl, -CN, -NO2, amino, -C(O)R 4 , -CO2 R 4 , -C(O)NR 5 R 6 , -NR 5 C(O)R 4 , C1-C2 alkyl, C1-C2 independently selected from alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy; are one or more substituents that are Each R 4 , R 5 , and R 6 are the same or different, and each is hydrogen or C1-C2 is alkyl; R 10 is hydrogen, hydroxyl, halo, -CN, C1-C4 alkyl, hydroxyl C 1-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyl, (C3-C6 cyclo alkyl) C0-C2 alkyl, C1-C2 haloalkyl, C1-C2 haloalkoxy, -CO2R 4 , -NR 5 R 6 , or -SO2R 4 is.

[0046] In embodiments, the present disclosure also includes compounds and salts of formula (Ia-1): During the ceremony, R 3 One of them is C2-C6 alkynyl, -(C0-C2 alkyl)C3-C6 cycloalkenyl alkyl, -(C2-C4 alkenyl)C3-C6 cycloalkyl, -(C2-C4 alkyl -(C0-C2 alkoxy)C3-C6 cycloalkyl dihydropyranyl, -(C0-C4 alkoxy)phenyl, -(C0-C4 alkyl )phenyl, -(C2-C4 alkenyl)phenyl, -(C2-C4 alkynyl)phenyl -(C0-C4 alkoxy)heteroaryl, -(C0-C4 alkyl)heteroaryl -(C2-C4 alkenyl)heteroaryl, and -(C2-C4 alkynyl)heteroaryl and heteroaryl, wherein heteroaryl is selected from thienyl, furanyl, thiazolyl, each of the one or more substituents is selected from hydroxyl, pyrazolyl, and imidazolyl; Halo, -CN, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkynyl, C 1-C4 alkoxy, (C3-C6 cycloalkyl)C0-C2 alkyl, C1-C2 halides and C1-C2 haloalkoxy; zero or more R 3 but, Hydroxyl, halo, -CN, C1-C4 alkyl, C1-C4 alkoxy, C1-C2 It is selected from haloalkyl, and C1-C2 haloalkoxy.

[0047] In embodiments, the compound of formula (Ia-1) has formula (Ia-2): [ka] (Ia-2) (In the formula, Y=-CH=CH-, O, S, NH; R a -R 4 , -OR4 , or -NR 5 R 6 and R 4 , R 5 , and R 6 Each of is substituted or unsubstituted; Each R 2 are the same or different, and each is hydrogen, hydroxyl, C1-C8 alkyl, C2-C8 alkenyl, C3-C6 cycloalkyl, C3-C6 cycloalkylalkenyl alkyl, C1-C8 alkoxy, C3-C6 cycloalkyloxy, aryloxy, halo , C1-C8 haloalkoxy, C1-C8 haloalkyl, haloaryl, haloaryl Oxygen, -CN, -NO2, -C(O)R 4 , -CO2R 4 , -C(O)NR 5 R 6 , -N R 5 C(O)R 4 , -(CH2) q NR 5 (SO2)R 4 , -(CH2) q NR 5 C(O )R 4 , -(CH2) q NR 7 C(O)NR 5 R 6 , -(CH2) q NR 5 R 6 , -(C H2) q SO2NR 5 R 6 , -(CH2) q SO2R 4 , -(CH2) q Aryl, -( CH2) q Heteroaryl, or -(CH2) q heterocycloalkyl, hydrogen, R excluding hydroxyl and halo 2 each of which is substituted or unsubstituted; Each R 11 and R 12 is hydroxyl, halo, -CN, NO2, C1-C8 alkyl, C2-C8 alkenyl, C1-C8 alkoxy, C1-C2 haloalkoxy, C1-C2 halo alkyl, -C(O)R 4 , -CO2R 4 , -C(O)NR 5 R 6 , -NR 5 C(O) R 4 , -(CH2) q NR 5 (SO2)R 4 , -(CH2) q NR 5 C(O)R 4 , -( CH2) q NR 7 C(O)NR 5 R 6 , -(CH2) q NR 5 R 6 , -(CH2) q SO 2NR 5 R 6 , and -(CH2) q SO2R 4 independently selected from hydroxyl, halo, R other than -CN and NO2 11 and R 12 each of which is substituted or unsubstituted; Each R 4 , R 5 , R 6 , and R 7 are the same or different, and each is hydrogen, C1 to C 8 alkyl, or C3 to C6 cycloalkyl, and C1 to C8 alkyl and C3 to C Each of the 6 cycloalkyls is substituted or unsubstituted; R 10 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl , C3-C6 cycloalkyl, C3-C6 cycloalkylalkyl, hydroxyl, hydroxyl alkoxyalkyl, C1-C8 alkoxy, halo, C1-C8 haloalkyl, aryl, Aryl alkyl, heteroaryl alkyl, -CN, -CO2R 4 , -NR 5 R 6 ,Also Ha-SO2R 4 and R excluding hydrogen and halo 10 each of which is substituted or unsubstituted; m and q are the same or different; m' is 0 or an integer from 1 to 4), It is a useful salt.

[0048] In embodiments, the compound of formula (Ia-1) has formula (Ia-3): [ka] (In the ceremony R a -R 4 , -OR 4 , or -NR 5 R 6 and R 4 , R 5 , and R 6 Each of is substituted or unsubstituted; Each R 2 are the same or different, and each is hydrogen, hydroxyl, C1-C8 alkyl, C2-C8 alkenyl, C3-C6 cycloalkyl, C3-C6 cycloalkylalkenyl alkyl, C1-C8 alkoxy, C3-C6 cycloalkyloxy, aryloxy, halo , C1-C8 haloalkoxy, C1-C8 haloalkyl, haloaryl, haloaryl Oxygen, -CN, -NO2, -C(O)R 4 , -CO2R 4 , -C(O)NR 5 R 6 , -N R 5 C(O)R 4 , -(CH2) q NR 5 (SO2)R 4 , -(CH2) q NR 5 C(O )R 4 , -(CH2) q NR 7 C(O)NR 5 R 6 , -(CH2) q NR 5 R 6 , -(C H2) q SO2NR 5 R 6 , -(CH2) q SO2R 4 , -(CH2) q Aryl, -( CH2) q Heteroaryl, or -(CH2) q heterocycloalkyl, hydrogen, R excluding hydroxyl and halo 2 each of which is substituted or unsubstituted; R 3 is hydroxyl, C1-C8 alkyl, C2-C8 alkenyl, C3-C6 cyclo C3-C6 cycloalkylalkyl, C1-C8 alkoxy, C3-C6 cycloalkyl Chloroalkyloxy, aryloxy, halo, C1-C8 haloalkoxy, C1-C8 halo haloalkyl, haloaryl, haloaryloxy, -CN, -NO2, -C(O)R 4 , -CO2R 4 , -C(O)NR 5 R 6 , -NR 5 C(O)R 4 , -(CH2) q NR 5 ( SO2)R 4 , -(CH2) q NR 5 C(O)R 4, -(CH2) q NR 7 C(O)NR 5 R 6 , -(CH2) q NR 5 R 6 , -(CH2) q SO2NR 5 R 6 , -(CH2) q SO2R 4 , -(CH2) q Aryl, -(CH2) q Heteroaryl, or -(CH 2) q R is heterocycloalkyl, excluding hydroxyl and halo 3 Each of or unsubstituted; Each R 4 , R 5 , R 6 , and R 7 are the same or different, and each is hydrogen, C1 to C 8 alkyl, or C3 to C6 cycloalkyl, and C1 to C8 alkyl and C3 to C Each of the 6 cycloalkyls is substituted or unsubstituted; R 4 represents hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkylalkyl, hydroxyl, hydro alkoxyalkyl, C1-C8 alkoxy, halo, C1-C8 haloalkyl, aryl, aryl Aryl alkyl, heteroaryl alkyl, -CN, -CO2R 4 , -NR 5 R 6 ,or -SO2R 4 and; q is the same or different; m' is 0 or an integer from 1 to 4 R 10 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl , C3-C6 cycloalkyl, C3-C6 cycloalkylalkyl, hydroxyl, hydroxyl alkoxyalkyl, C1-C8 alkoxy, halo, C1-C8 haloalkyl, aryl, Aryl alkyl, heteroaryl alkyl, -CN, -CO2R 4 , -NR 5 R 6 ,Also Ha-SO2R 4 and R excluding hydrogen and halo 10 each of which is substituted or unsubstituted; R d represents hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkylalkyl, hydroxyl, hydro alkoxyalkyl, C1-C8 alkoxy, halo, C1-C8 haloalkyl, aryl, aryl Heteroaryl alkyl, heteroaryl, heteroaryl alkyl, -CN, -CO2R 4 , -N R 5 R 6 , or -SO2R 4 and R other than hydrogen and -CN. 11 Each of these may and n is 0, 1 or 2. The compound, prodrug or pharmaceutically acceptable salt of the formula (III) is substituted with 2 or 3. In certain embodiments, R d is phenyl, thienyl, thiazolyl, furanyl, oxazolyl, pyrazolyl, oxadiazolyl, or imidazolyl, Each is substituted or unsubstituted. In certain embodiments, R d phenyl, thienyl thiazolyl, furanyl, oxazolyl, pyrazolyl, oxadiazolyl, or imino and azolyl, each of which is unsubstituted or substituted with hydroxyl, cyano, aryl, benzoyl ... amino, C1-C2 alkyl, C1-C2 alkoxy, mono- or di-C1-C2 alkyl and C1-C2 haloalkoxy, independently selected from C1-C2 haloalkyl, C1-C2 haloalkyl, and C1-C2 haloalkoxy. In certain embodiments, R d Is, It is thienyl substituted with thienyl. In certain embodiments, the present disclosure includes compounds and salts of formula (Ia-3), wherein , R a is hydrogen, hydroxyl, amino, C1-C2 alkyl, C1-C2 alkoxy, and mono- or di-C1-C2 alkylamino-; Each R 2 are the same or different and can be hydrogen, halo, hydroxyl, -CN, -NO2, Amino, -C(O)R 4 , -CO2R 4 , -C(O)NR 5 R 6 , -NR 5 C(O)R 4 , C1-C2 alkyl, C1-C2 alkoxy, C1-C2 haloalkyl, and C1-C 2 independently selected from haloalkoxy; Each R 3 are hydroxyl, halo, -CN, NO2, C1-C2 alkyl, C1-C2 alkyl independently selected from alkoxy, C1-C2 haloalkoxy, and C1-C2 haloalkyl; ; Each R 4 , R 5 , R 6 , and R 7 are the same or different and each is hydrogen or C1 ~C2 alkyl; m' is 0 or an integer from 1 to 4; R 10 is hydrogen, hydroxyl, halo, -CN, C1-C4 alkyl, hydroxyl C 1-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyl, (C3-C6 cyclo alkyl) C0-C2 alkyl, C1-C2 haloalkyl, C1-C2 haloalkoxy, -CO2R 4 , -NR 5 R 6 , or -SO2R 4 is. In this embodiment, R d can be thienyl substituted with methyl.

[0049] In an embodiment of the compound of formula (Ia-2), R a is a hydroxyl or substituted or is unsubstituted -O(C1-C8 alkyl); R 2 is hydrogen, substituted or unsubstituted C 1-C8 alkyl, substituted or unsubstituted C1-C8 alkoxy, or halo; R 11 and R 12 are each a substituted or unsubstituted C1-C8 alkyl (e.g., C 1- 4 alkyl (e.g., methyl, ethyl, propyl, or butyl), substituted or unsubstituted C1-C8 alkoxy, or halo (e.g., -F, -I, -Cl, or -Br); Independently selected; 10 is hydrogen, substituted or unsubstituted C1-C8 alkyl, cyclo Propyl, -CH2-cyclopropyl, cyclobutyl, -CH2-cyclobutyl, -CH =CH2, -C≡C-cyclopropyl, -C≡C-cyclobutyl, phenyl, benzyl, -I, -CF3, -NH2, or -CN; m is 0, 1, or 2; and m' is , 0.

[0050] The present disclosure also provides a compound of formula (Ia-4): [ka] (Ia-4) The present invention also includes compounds or salts of the formula:

[0051] In formula (Ia-4), R a -R 4 , -OR 4 , or -NR 5 R 6 and R 4 , R 5 , and R 6 Each of is substituted or unsubstituted; Each R 2 are the same or different and are hydrogen, hydroxyl, C1-C8 alkyl, C2 ~C8 alkenyl, C3~C6 cycloalkyl, C3~C6 cycloalkylalkyl, C 1-C8 alkoxy, C3-C6 cycloalkyloxy, aryloxy, halo, C1- C8 haloalkoxy, C1-C8 haloalkyl, haloaryl, haloaryloxy, - CN, -NO2, -C(O)R 4 , -CO2R 4 , -C(O)NR 5 R 6 , -NR 5 C( O)R 4 , -(CH2) q NR 5 (SO2)R 4 , -(CH2) q NR 5 C(O)R 4 , -(CH2) q NR 7 C(O)NR 5 R 6 , -(CH2) q NR 5 R 6 , -(CH2) q SO2NR 5 R 6 , -(CH2) q SO2R 4 , -(CH2) q Aryl, -(CH2) q Heteroaryl, or -(CH2)q Heterocycloalkyl is hydrogen, hydroxy R excluding sill and halo 2 each of which is substituted or unsubstituted; R 3 is C2-C6 alkynyl, -(C0-C2 alkyl)C3-C6 cycloalkyl , -(C2-C4 alkenyl) C3-C6 cycloalkyl, -(C2-C4 alkynyl) C3-C6 cycloalkyl, -(C0-C2 alkoxy)C3-C6 cycloalkyl, di Hydropyranyl, -(C0-C4 alkoxy)phenyl, -(C0-C4 alkyl)phenyl -nyl, -(C2-C4 alkenyl)phenyl, -(C2-C4 alkynyl)phenyl, - (C0-C4 alkoxy)heteroaryl, -(C0-C4 alkyl)heteroaryl, -(C2-C4 alkenyl)heteroaryl and -(C2-C4 alkynyl)heteroaryl wherein heteroaryl is independently selected from N, O, and S. , 5- or 6-membered heteroaryl having 2, 3, or 4 heteroatoms, So, each R 3 is unsubstituted or is selected from the group consisting of hydroxyl, halo, -CN, C1-C4 alkyl, C 2-C4 alkenyl, C1-C4 alkynyl, C1-C4 alkoxy, (C3-C6 cyclo C0-C2 alkyl, C1-C2 haloalkyl, and C1-C2 haloalkane substituted with one or more substituents selected from: Each R 11 is hydroxyl, halo, -CN, NO2, C1-C8 alkyl, C2-C8 Alkenyl C1-C8 alkoxy, C1-C2 haloalkoxy, C1-C2 haloalkyl , -C(O)R 4 , -CO2R 4 , -C(O)NR 5 R 6 , -NR 5C(O)R 4 , -( CH2) q NR 5 (SO2)R 4 , -(CH2) q NR 5 C(O)R 4 , -(CH2) q NR 7 C(O)NR 5 R 6 , -(CH2) q NR 5 R 6 , -(CH2) q SO2NR 5 R 6 , and -(CH2) q SO2R 4 independently selected from hydroxyl, halo, -CN , R other than NO2 11 and R 12 each of which is substituted or unsubstituted; Each R 4 , R 5 , R 6 , and R 7 are the same or different, and each is hydrogen, C1 to C 8 alkyl, or C3 to C6 cycloalkyl, and C1 to C8 alkyl and C3 to C Each of the 6 cycloalkyls is substituted or unsubstituted; R 10 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl , C3-C6 cycloalkyl, C3-C6 cycloalkylalkyl, hydroxyl, hydroxyl alkoxyalkyl, C1-C8 alkoxy, halo, C1-C8 haloalkyl, aryl, Aryl alkyl, -CN, -CO2R 4 , -NR 5 R 6 , or -SO2R 4 and water R excluding elements and halos 10 each of which is substituted or unsubstituted; m is 0 or 1, 2, 3, 4, or 5; m' is 0 or an integer of 1 to 4.

[0052] In embodiments, the present disclosure includes a compound or salt of formula (Ia-4), wherein: R a is hydrogen, hydroxyl, amino, C1-C2 alkyl, C1-C2 alkoxy, and mono- or di-C1-C2 alkylamino-; Each R 2 are the same or different and can be hydrogen, halo, hydroxyl, -CN, -NO2, Amino, -C(O)R 4 , -CO2R 4 , -C(O)NR 5 R 6 , -NR 5 C(O)R 4 , C1-C2 alkyl, C1-C2 alkoxy, C1-C2 haloalkyl, and C1-C 2 independently selected from haloalkoxy; R 3 is C2-C6 alkynyl, -(C0-C2 alkyl)C3-C6 cycloalkyl , -(C2-C4 alkenyl) C3-C6 cycloalkyl, -(C2-C4 alkynyl) C3-C6 cycloalkyl, -(C0-C2 alkoxy)C3-C6 cycloalkyl, di Hydropyranyl, -(C0-C4 alkoxy)phenyl, -(C0-C4 alkyl)phenyl -nyl, -(C2-C4 alkenyl)phenyl, -(C2-C4 alkynyl)phenyl, - (C0-C4 alkoxy)heteroaryl, -(C0-C4 alkyl)heteroaryl, -(C2-C4 alkenyl)heteroaryl and -(C2-C4 alkynyl)heteroaryl wherein heteroaryl is selected from thienyl, furanyl, thiazolyl, pyridine, and each of the one or more substituents is selected from hydroxyl, halo, -CN, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkynyl, C1-C 4 alkoxy, (C3-C6 cycloalkyl) C0-C2 alkyl, C1-C2 haloal selected from alkyl, and C1-C2 haloalkoxy; Each R 11 is hydroxyl, halo, -CN, C1-C4 alkyl, C1-C4 alkoxy independently selected from aryl, C1-C2 haloalkyl, and C1-C2 haloalkoxy; Each R 4 , R 5 , and R 6 are the same or different, and each is hydrogen or C1-C2 is alkyl; m' is 0 or an integer from 1 to 4; R 10 is hydrogen, hydroxyl, halo, -CN, C1-C4 alkyl, hydroxyl C 1-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyl, (C3-C6 cyclo alkyl) C0-C2 alkyl, C1-C2 haloalkyl, C1-C2 haloalkoxy, -CO2R 4 , -NR 5 R 6 , or -SO2R 4 is.

[0053] In certain embodiments, the present disclosure includes a compound or salt of formula (Ia-4): Inside, R a is hydrogen, hydroxyl, C1-C2 alkyl, or C1-C2 alkoxy. the law of nature; Each R 2 are the same or different and are hydrogen, halo, hydroxyl, C1-C2 alkyl , C1-C2 alkoxy, C1-C2 haloalkyl, and C1-C2 haloalkoxy Independently selected; R 3is C2-C6 alkynyl, -(C0-C2 alkyl)C3-C6 cycloalkyl , -(C2-C4 alkenyl) C3-C6 cycloalkyl, -(C2-C4 alkynyl) C3-C6 cycloalkyl, -(C0-C2 alkoxy)C3-C6 cycloalkyl, di Hydropyranyl, -(C0-C4 alkoxy)phenyl, -(C0-C4 alkyl)phenyl -nyl, -(C2-C4 alkenyl)phenyl, -(C2-C4 alkynyl)phenyl, - (C0-C4 alkoxy)heteroaryl, -(C0-C4 alkyl)heteroaryl, -(C2-C4 alkenyl)heteroaryl and -(C2-C4 alkynyl)heteroaryl wherein heteroaryl is selected from thienyl, furanyl, thiazolyl, pyridine, and each of the one or more substituents is selected from hydroxyl, halo, -CN, C1-C4 alkyl, C2-C4 alkenyl, C1-C4 alkynyl, C1-C 4 alkoxy, (C3-C6 cycloalkyl) C0-C2 alkyl, C1-C2 haloal selected from alkyl, and C1-C2 haloalkoxy; Each R 11 is hydroxyl, halo, -CN, C1-C4 alkyl, C1-C4 alkoxy independently selected from aryl, C1-C2 haloalkyl, and C1-C2 haloalkoxy; m' is 0 or an integer from 1 to 4; R 10 is hydrogen, hydroxyl, halo, -CN, C1-C4 alkyl, hydroxyl C 1-C4 alkyl, C1-C4 alkoxy, C2-C4 alkenyl, (C3-C6 cyclo alkyl) C0-C2 alkyl, C1-C2 haloalkyl, or C1-C2 haloalkane It's Kishi.

[0054] The present disclosure further includes compounds and salts of formula (Ia-4), wherein: R a is hydroxyl; Each R 2 are independently selected from hydrogen and halogen.

[0055] In any of the embodiments of formulae (Ia-1 to Ia-4), the group [ka] is R a is hydroxyl, NHCN, or NHSO2H, -NHSO2 alkyl, C H2SO2 may be a group that is phenyl, -NHOH, or -NHO alkyl; HA-C(O)R a -CH2OH, -P(O)(OH)2, -P(O)(OH) alkyl It may be a group replaced by -SO2OH or -SO2OH.

[0056] In some embodiments, the compound of formula (Ib) has the formula (Ib-1): [ka] (Ib-1) (In the ceremony R a -R 4 , -OR 4 , or -NR 5 R 6 and R 4 , R 5 , and R 6 Each of is substituted or unsubstituted; R b and R c are the same or different and each is H or substituted or unsubstituted C1-C8 alkyl; Each R 2 are the same or different, and each is hydrogen, hydroxyl, C1-C8 alkyl, C2-C8 alkenyl, C3-C6 cycloalkyl, C1-C8 alkoxy, C3- C6 cycloalkyloxy, aryloxy, halo, C1-C8 haloalkoxy, C1- C8 haloalkyl, haloaryl, haloaryloxy, -CN, -NO2, -C(O) R 4 , -CO2R 4 , -C(O)NR 5 R 6 , -NR 5 C(O)R 4 , -(CH2) q N R 5 (SO2)R 4 , -(CH2) q NR 5 C(O)R 4 , -(CH2) q NR 7 C(O )NR 5 R 6 , -(CH2) q NR 5 R 6 , -(CH2) q SO2NR 5 R 6 , -(CH 2) q SO2R 4 , -(CH2) q Aryl, -(CH2) q heteroaryl, or - (CH2) q Heterocycloalkyl is hydrogen, hydroxyl, halo, -CN, and - R excluding NO2 2 each of which is substituted or unsubstituted; R 3 is halo, -C(O)R4, C2-C8 alkynyl, haloaryl, -(CH2) q Aryl, -(CH2) q Heteroaryl, or -(CH2) q Heterocycloalkane R 3 each of which is substituted or unsubstituted; Each R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 are the same or different, and each C1-C8 alkyl, C2-C8 alkenyl, C3-C6 cycloalkyl, aryl , heteroaryl, or heterocycloalkyl, and C1-C8 alkyl, C2-C 8 alkenyl, C3-C6 cycloalkyl, aryl, heteroaryl, or heterocycloalkyl each chloroalkyl is substituted or unsubstituted; R 10 is hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl , C3-C6 cycloalkyl, C3-C6 cycloalkylalkyl, hydroxyl, hydroxyl C1-C8 alkoxyalkyl, C1-C8 haloalkyl, halo, aryl, Aryl alkyl, heteroaryl alkyl, -CN, -CO2R 4 , -NR 5 R 6 ,Also Ha-SO2R 4 and R is excluding hydrogen, hydroxyl, halo, and -CN. 10 Each of the substituted or unsubstituted; X 1 is a bond, -CR 8 R 9 -, -NR 5 -, -O-, -SO-, or -SO2-, or -S- and R 5 , R 8 , and R 9 each of which is substituted or unsubstituted; X 3 is CH or N; m and q are the same or different and each is 0 or an integer from 1 to 5. The compound may be a compound, a prodrug or a pharmaceutically acceptable salt.

[0057] In an embodiment of the compound of formula (Ib-1), R a is a hydroxyl or substituted or is unsubstituted -O(C1-C8 alkyl); R b and R c are each hydrogen; R 2 is hydrogen; R 3 is halo, substituted or unsubstituted -C(O)morpholinyl, or or substituted or unsubstituted 2-fluorophenyl; R 10 is hydrogen, substituted or Unsubstituted C1-C8 alkyl, substituted or unsubstituted -CH=CH2, substituted or unsubstituted substituted or unsubstituted -C≡C-cyclopropyl, substituted or unsubstituted -C≡C-cyclopropyl, substituted or unsubstituted -C≡C-cyclopropyl, Substituted cyclobutyl, substituted or unsubstituted -C≡C-cyclobutyl, -OH, -CH2 OH, -CF3, -CF2CF3, -Cl, -F, -I, -CN, -CH2CN, -NH 2. Substituted or unsubstituted phenyl, substituted or unsubstituted benzyl, or substituted or is unsubstituted -CH2-tetrazolyl; X 1 is -CH2- or -NH-; m is 0, 1 or 2.

[0058] Compounds of formula (I), including compounds of formula (Ia), (Ib), (Ic) and (Id), Representative examples are listed in Table 6 below. Prodrugs and pharmaceutically acceptable salts of the exemplified compounds are listed below. Acceptable salts are also included in this disclosure.

[0059] [term] The terms "a," "an," "the," and "at lea "at least one" and in the context of describing the present invention (especially The use of similar referents (in the context of the claims below) is not intended to be construed as limiting the scope of the invention as defined elsewhere in this specification. Unless otherwise indicated or clearly contradicted by context, both the singular and the plural The phrase "at least one" followed by a list of one or more items should be interpreted as encompassing all possible approaches. Use of "at least one of A and B (at least one of A and B))") is a compound of formula (I) unless otherwise indicated herein. Unless otherwise clearly contradicted by the context, one item selected from the list may be used. means any item (A or B) or any combination of two or more of the listed items (A and B) The terms "comprising," "having" and " ), "including," and "containing" , unless otherwise stated, open-ended terms (i.e., "including The values ​​in this specification should be interpreted as meaning "including but not limited to." The description of a range of is intended to include each separate value within that range, unless otherwise indicated herein. are merely intended to serve as a shorthand way of individually referencing each separate value. The values ​​are incorporated herein as if individually set forth herein. All methods described herein are intended to be illustrative and not restrictive. The steps may be performed in any suitable order unless otherwise clearly contradicted by context. The term "for example" refers to any and all examples or examples provided herein. etc.) are merely intended to better clarify the invention and are not intended to be limiting unless otherwise claimed. Unless otherwise specified, no term in this specification should be construed as limiting the scope of the present invention. Nothing in this application should be construed as indicating any non-claimed element as essential to the practice of the invention. It won't be.

[0060] The term "substituted" as used herein means to substitute the indicated element. Any one or more hydrogen atoms in the molecule or group may be replaced by a choice from the group shown. This means that the valence of the atom shown does not exceed the normal valence of the atom shown. When a group is oxo (i.e., =O), two hydrogens on the atom are replaced When an oxo group substitutes a heteroatom moiety, the resulting molecule may exhibit tautomeric forms. For example, pyridyl substituted with oxo at the 2- or 4-position. The group may be referred to as pyridine or hydroxypyridine. Combinations of variables may be used where such combinations produce stable compounds or useful synthetic intermediates. Stable compounds or stable structures can be obtained by isolation from the reaction mixture. and suggest compounds that are potent enough to survive subsequent formulation into effective therapeutic agents. Unless otherwise specified, substituents are named on the core structure. For example, Aminoalkyl means that the point of attachment of this substituent to the core structure is the alkyl portion; It is understood that alkylamino means that the point of attachment is to the nitrogen of the amino group. sea ​​bream.

[0061] Suitable groups that may be present in the "substituted" or "optionally substituted" positions Examples include, but are not limited to, halogen; cyano; —OH; nitro; 1 to about 8 carbon atoms; or alkyl groups having 1 to about 6 carbon atoms (cycloalkyl and (cycloalkyl) alkyl group); one or more unsaturated linkages and 2 to about 8 or 2 to about 6 carbon atoms alkenyl and alkynyl groups, including groups having one or more oxygen linkages and 1 to about 8, or an alkoxy group having 1 to about 6 carbon atoms; an aryloxy, such as phenoxy one or more thioether linkages and 1 to about 8 carbon atoms or 1 to about 6 carbon atoms For example, "substituted" or Suitable groups that may be present at the "optionally substituted" position include hydroxyl, halogen, Examples of the alkyl groups include aryl, cyano, alkyl groups, and alkoxy groups.

[0062] In any of the above embodiments, the term "alkyl" refers to an alkyl group having, for example, about 1 to about 8 carbon atoms. Atoms, for example, straight or branched alkyl substituents containing from about 1 to about 6 carbon atoms. Examples of alkyl groups are methyl, ethyl, n-propyl, isopropyl, n- Butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl , n-hexyl, etc. This definition also includes "alkyl" as used herein, for example, C3 to C6 6 Cycloalkyl, alkyl, hydroxyalkyl, haloalkyl (e.g., monohaloal alkyl, dihaloalkyl, and trihaloalkyl), cyanoalkyl, aminoalkyl, Where does it occur as part of a group in alkylamino, dialkylamino, arylalkyl, etc. Alkyl may be substituted or unsubstituted as described herein. It can be unsubstituted. When alkyl is an alkylene chain (e.g., -(CH) n -) in the case However, the alkyl group may be substituted or unsubstituted. An example of a substituted alkylene chain is -CF 2-cyclopropyl is an example.

[0063] In any of the above embodiments, the term "alkenyl" as used herein For example, about 2 to about 8 carbon atoms (branched alkenyl is about 3 to about 8 carbon atoms). A branched alkenyl group has about 3 to about 6 carbon atoms. According to an embodiment, the alkenyl group is a linear alkenyl group containing 1 to 3 carbon atoms. The alkenyl group is a C2-C4 alkenyl group. Examples of alkenyl groups include ethenyl, aryl, and the like. 2-propenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1-hexenyl, etc. As used herein, alkenyl is As listed, they may be substituted or unsubstituted.

[0064] In any of the above embodiments, the term "alkynyl" as used herein When the hydroxyl group is a hydroxyl group, it has at least one carbon-carbon triple bond and, for example, from about 2 to about 8 carbon atoms. (branched alkynyl is about 4 to about 12 carbon atoms), for example, about 2 to about 6 carbon atoms (branched alkynyl can be from about 4 to about 8 carbon atoms), for example, from about 2 to about 4 alkynyl groups containing 1 to 3 carbon atoms. Examples of such groups include protons, vinyl, propargyl, n-butynyl, pentynyl, isopentynyl, hexynyl, octynyl Alkynyl is an alkynyl group that can be substituted as described herein. or may be unsubstituted.

[0065] In any of the above embodiments, the term "cycloalkyl" as used herein When the ring structure is formed, for example, a ring structure containing 3 to 6 carbon atoms or 5 to 6 carbon atoms is Examples of such moieties are cyclopropyl, cyclobutyl, cyclopropyl ... Cycloalkyl includes, as defined herein, cyclopentyl, cyclohexyl, and the like. It can be substituted or unsubstituted, as described above, for example, as a substituted cycloalkyl. , halo- or haloalkyl-substituted cyclopropyl, for example, 2-fluorocyclopropyl 2,2-difluorocyclopropyl, 1-(trifluoromethyl)cyclopropyl, and 2-(trifluoromethyl)cyclopropyl.

[0066] In any of the above embodiments, the term "hydrocarbyl" refers to the substituent shown in the structure. It refers to an aliphatic group having the specified number of carbon atoms and appropriate valence in view of the number of substituents. Carbyl groups contain at least carbon and hydrogen and may be formed by single, double, or triple carbon-carbon bonds. In certain embodiments, the hydrocarbyl group may contain N, O, , S, Si, P, or one or more (e.g., 1 to 8) selected from the group consisting of The hydrocarbyl group may be unsubstituted or is substituted with one or more substituents up to the valence allowed by the hydrocarbyl group. For example, the hydrocarbyl group may be hydroxyl, cyano, amino, halogen, o containing 1 to 3 heteroatoms selected from xo, cycloalkyl, N, O, and S 5-7 membered heterocycloalkyl, 1-5 heteroatoms selected from N, O, and S and phenyl, optionally substituted with 5- or 6-membered heteroaryl selected from stomach.

[0067] In any of the above embodiments, the term "hydroxy" refers to the group --OH.

[0068] In any of the above embodiments, the terms "alkoxy" and "cycloalkyloxy" are linear or branched alkyl and cycloalkyl groups attached to divalent oxygen, respectively. Alkyl and cycloalkyl groups include those described herein. The term "aryloxy" refers to an aryl group attached to a divalent oxygen. The aryl group is the same as described herein.

[0069] In any of the above embodiments, the term "halo" refers to fluorine, chlorine, bromine, and iodine. refers to a halogen selected from:

[0070] In any of the above embodiments, the term "aryl" refers to one, two, or three aromatic monocyclic, bicyclic, or tricyclic carbocyclic ring systems having rings, such as phenyl, naphthyl, The term "aryl" is used in the art to refer to anthracenyl, anthracenyl, or biphenyl. As commonly understood, it refers to an unsubstituted or substituted aromatic carbocyclic moiety, including monocyclic and and polycyclic aromatics, such as phenyl, biphenyl, naphthyl, anthracenyl, pyrenyl The aryl moiety may be, for example, an alkyl group having 6 to 30 carbon atoms, an alkyl group having 6 to 18 carbon atoms, or the like. They generally contain 1 to 14 carbon atoms, or 6 to 10 carbon atoms. The molecule is planar and contains 4n+2 π electrons (n=1, 2 or 3). This definition also includes "aryl." is, for example, haloaryl (e.g., monohaloaryl, dihaloaryl, and trihaloaryl). This also applies wherever it occurs as part of a radical in aryl, arylalkyl, etc. The aryl can be substituted or unsubstituted as described herein.

[0071] In any of the above embodiments, the term "heteroaryl" refers to a heteroaryl group having at least one heteroatom in at least one of the rings. Aromatic 5- or 6-membered monocyclic ring with at least one heteroatom (O, S, or N) It refers to a cyclic group, a 9- or 10-membered bicyclic group, and an 11- to 14-membered tricyclic group. Each ring of the heteroaryl group has 1 or 2 oxygen or sulfur atoms and / or It may contain 1 to 4 nitrogen atoms, provided that the total number of heteroatoms in each ring is The number of rings shall not exceed four, and each ring shall have at least one carbon atom. The fused rings completing the cyclic group may contain only carbon atoms and may be saturated, partially unsaturated, or The nitrogen and sulfur atoms may optionally be oxidized, and the nitrogen atoms may be unsaturated or unsaturated. The heteroaryl group may be optionally quaternized. Heteroaryl groups that are bicyclic or tricyclic must contain at least one fully aromatic ring, but may contain other fused ring(s) The heteroaryl group may be any of the aryls in any of the rings. Attachment may be at any available nitrogen or carbon atom. Illustrative examples of heteroaryl groups are: Pyridinyl, pyridazinyl, pyrimidyl, pyrazinyl, benzimidazolyl, triazinyl imidazolyl, (1,2,3)- and (1,2,4)-triazolyl, pyrazinyl, Tetrazolyl, furyl, pyrrolyl, thienyl, isothiazolyl, thiazolyl, isoxa Heteroaryl is any of the heteroaryls described herein. As mentioned above, it can be substituted or unsubstituted.

[0072] The term "Het" refers to a ring structure having at least two double bonds, 3 to 7 carbon atoms, and nitrogen. , sulfur, and / or oxygen. In an embodiment, "heterocycloalkyl" refers to a monocyclic or bicyclic ring system. "Het" is a 5-, 6-, or 7-membered monocyclic ring selected from nitrogen, oxygen, and sulfur. In some instances, "Het" refers to a group containing 1, 2, or 3 heteroatoms. As described herein, it is heteroaryl.

[0073] The term "heterocycloalkyl" refers to a heterocycloalkyl group having 3 to 7 ring members of carbon atoms and nitrogen, sulfur, and and / or a stable, saturated, or partially unsaturated monocyclic ring containing other atoms selected from oxygen. In embodiments, heterocycloalkyl refers to 5, bicyclic, and spirocyclic ring systems. a 6- or 7-membered monocyclic ring having 1, 2, or 3 atoms selected from nitrogen, oxygen, and sulfur; Heterocycloalkyl contains one or more heteroatoms. The bond to the parent structure can be through any heteroatom of the heterocycloalkyl. Examples of such heterocycloalkyl rings are isoxazolyl, thiazolinyl, imidazolidinyl, and the like. piperazinyl, homopiperazinyl, pyrrolyl, pyrrolinyl, pyrazolyl, pyranyl, piperidyl, oxazolyl, and morpholinyl. Heterocycloalkyl is defined herein as As described herein, the amino acid may be substituted or unsubstituted.

[0074] In any of the above embodiments, the alkyl, alkoxy, and alkylamino groups are It can be linear or branched.

[0075] In other embodiments, any substituent that is not hydrogen (e.g., C1-C8 alkyl, C2-C 8 alkenyl, C2-C8 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloa alkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl Heterocycloalkyl, heterocycloalkyl, or heterocycloalkylalkyl) is optionally substituted The substituted site may be at any suitable position (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, at least one substituent (e.g., at the 1, 2, 3, 4, 5, or 6 position, etc.) , 4, 5, 6, etc.) The aryl group may have a substituent such as halo, amino, When substituted by alkyl, OH, alkoxy, etc., the aromatic ring hydrogens are This means that any of the available hydrogens, e.g., 2, 3, 4, It may occur at the 5, and / or 6 positions, where the 1 position is an aryl group in the compounds of the present invention. Suitable substituents include, for example, halo, alkyl, alkenyl, and alkyl groups. Alkynyl, hydroxy, nitro, cyano, amino, alkylamino, alkoxy, aryl alkoxy, aralkoxy, carboxyl, carboxyalkyl, carboxyalkyloxy aryl, heteroaryl, and heteroaryl groups. and cycloalkyl, each of which is described herein. In some cases, the substituents may include at least one alkyl, halo, and / or halo. alkyl (eg, 1 or 2).

[0076] In any of the above embodiments, when a range of the number of atoms in a structure is given, At any time (e.g., C1~12 , C 1~8 , C 1~6 , or C 1~4 Alkyl, cyclo alkyl, etc.), any subrange or individual number of carbon atoms within the ranges shown. It is specifically contemplated that such may be used. is used with respect to any chemical group (e.g., alkyl, cycloalkyl, etc.) 1 to 8 carbon atoms (e.g., C1 to C8), 1 to 6 carbon atoms (e.g., C1 to C6 ), 1 to 4 carbon atoms (e.g., C1 to C4), 1 to 3 carbon atoms (e.g., C1 to A reference to a range of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 3 , 4, 5, 6, 7, and / or 8 carbon atoms, and optionally any thereof Subranges (e.g., 1-2 carbon atoms, 1-3 carbon atoms, 1-4 carbon atoms, etc.) can be added as needed. carbon atoms, 1-5 carbon atoms, 1-6 carbon atoms, 1-7 carbon atoms, 1-8 carbon atoms carbon atoms, 2-3 carbon atoms, 2-4 carbon atoms, 2-5 carbon atoms, 2-6 carbon atoms carbon atoms, 2-7 carbon atoms, 2-8 carbon atoms, 3-4 carbon atoms, 3-5 carbon atoms carbon atoms, 3-6 carbon atoms, 3-7 carbon atoms, 3-8 carbon atoms, 4-5 carbon atoms This also includes 4-6 carbon atoms, 4-7 carbon atoms, 4-8 carbon atoms, etc. This includes and specifically describes:

[0077] The subscripts "m" and "n" refer to substituents, e.g., R 2 or R 3 It represents the number of where each substituent, e.g., R 2 or R 3 may be the same or different. The subscripts m and n may be the same or different and each represents 0 or 1 to 5. It is one of the integers (i.e., 1, 2, 3, 4, or 5). m or n is 0 When the corresponding substituent, i.e., R 2 or R 3 is not present in compounds of formula (I). The subscripts "o" and "q" represent the number of methylene repeat units. is either 0 or an integer between 1 and 5 (i.e., 1, 2, 3, 4, or 5) When o or q is 0, the respective moiety does not contain any methylene repeat units. do not.

[0078] In any of the embodiments described herein, the compounds of the invention may be prodrugs. Prodrugs may also be provided as drugs, for example, in the form of an ester or amide. until it is converted in the body through normal metabolic processes, such as hydrolysis to the active drug. Drug derivatives or drugs that are typically inactive or less active than fully active A prodrug is a precursor compound. A prodrug may be selected and used in place of a parent drug; This may be, for example, in its prodrug form, which is less toxic and / or has a similar effect to the parent drug. This is because they may have better absorption, distribution, metabolism, and excretion (ADME) properties than Prodrugs also allow drugs to selectively interact with cells or processes that are not their intended targets. This approach may be used to improve the way drugs are used, particularly in severely impaired patients. may be prone to unwanted and undesirable side effects, particularly adverse effects in cancer treatments It may be particularly useful for preventing or reducing

[0079] The term "prodrug" refers to a derivative of a compound, which derivative is capable of reacting with a warm-blooded animal, e.g., a human For example, when administered to a subject, the compound is converted into a compound (drug). Enzymatic and / or chemical hydrolytic cleavage of the compound releases the proven drug form and The site or site fragment remains non-toxic or is metabolized to a non-toxic metabolic site. For example, a carboxylic acid group can be substituted with, for example, a methyl or ethyl group. The ester can be esterified with an alkyl group to produce an ester. When provided, the ester is reacted enzymatically or non-enzymatically, reductively, oxidatively, or It is hydrolytically cleaved to reveal an anionic group, which subsequently decomposes to reveal an activated compound. A moiety (e.g., acyloxymethyl ester) that is cleaved to reveal an intermediate compound that gives rise to the product. It can be esterified with

[0080] Prodrugs include compounds of formula (Ia), (Ib), (Ic) or (Id) Preferably, the compound of formula (I) is isolated and purified in situ or by addition of the purified compound. For example, a hydroxy group can be prepared by reacting it separately with a suitable derivatizing agent. It can be converted to an ester via treatment with a carboxylic acid in the presence of a catalyst. Examples of co-prodrug moieties include substituted or unsubstituted, branched or unbranched alkyl groups. alkyl ester moieties, e.g., ethyl ester, alkenyl ester, di-alkylamino Alkyl esters, for example, dimethylaminoethyl esters, acylaminoalkyl esters esters, acyloxyalkyl esters (e.g., pivaloyloxymethyl esters), aryl esters, e.g., phenyl esters; aryl-alkyl esters, e.g., methyl benzyl esters optionally substituted with aryl, halo, or methoxy substituents. esters, aryl and aryl-alkyl esters, amides, alkylamides, di-alkyl amides, and hydroxyamides.

[0081] Knowing the disclosure herein, it is possible to use compounds of the present invention in the form of prodrugs. and that such prodrugs can be prepared using reagents and synthetic transformations well known to those skilled in the art. It will be appreciated that the effectiveness of a particular prodrug may be determined by one or more methods well known to those skilled in the art. Using the above analytical methods (e.g., pharmacokinetics, bioassays, in vivo efficacy studies, etc.) It can be requested.

[0082] More particularly, compounds of the formula (Ia), (Ib), (Ic) or (Id) Prodrugs of compounds of formula (I) may be prepared using conventional chemical procedures. The hydroxyl substituents in the compounds of formula (I) are -CO-alkyl, -CO2 alkyl -CONH-alkyl, -CO-alkenyl, -CO2-alkenyl, -CONH- Alkenyl, -CO-aryl, -CO2-aryl, -CONH-aryl, -CO- substituted with heterocycle, -CO2-heterocycle, -CONH-heterocycle, or -PO3H2 Specific examples of the modifying group for hydroxyl include acetyl, propionyl, isobutyl, and the like. thylyl, pivaloyl, palmitoyl, benzoyl, 4-methylbenzoyl, dimethylcalcium Examples include bamoyl, dimethylaminomethylcarbonyl, sulfo, alanyl, and fumaryl groups. can be done.

[0083] The amino group can be -CO-alkyl, -CO2-alkyl, -CO-alkenyl, -CO2 -Alkenyl, -CO2-aryl, -CO-aryl, -CO-heterocycle, -CO2-heterocycle The alkyl, alkenyl, aryl, and and the heterocyclic moiety may be halogen, alkyl, hydroxyl, alkoxy, carboxy, amino , by amino acid residues, -PO3H2, -SO3H, -OPO3H2, and -OSO3H Specific examples of the amino modifying group include tert-butyl. methyloxy, docosanoyl, pivaloylmethyloxy, alanyl, hexylcarbamoyl, pentyl propylcarbamoyl, 3-methylthio-1-(acetylamino)propylcarbonyl, 1- sulfo-1-(3-ethoxy-4-hydroxyphenyl)methyl, (5-methyl-2-oxo so-1,3-dioxol-4-yl)methyl, (5-methyl-2-oxo-1,3-di oxol-4-yl)methoxycarbonyl, tetrahydrofuranyl, and pyrrolidinyl Chill is one example.

[0084] Suitable modifying groups for carboxyl include, for example, methyl, ethyl, propyl, isopropyl butyl, isobutyl, tert-butyl, pivaloyloxymethyl, carboxymethyl dimethylaminomethyl, 1-(acetyloxy)ethyl, 1-(ethoxycarbonyl oxy)ethyl, 1-(isopropyloxycarbonyloxy)ethyl, 1-(cyclohexyloxy)ethyl (5-methyl-2-oxo-2 ... (so-1,3-dioxol-4-yl)methyl, benzyl, phenyl, o-tolyl, mol Examples include phthalidyl, N,N-diethylcarbamoylmethyl, and phthalidyl.

[0085] In any of the above embodiments, the phrase "salt" or "pharmaceutically acceptable salt" refers to a salt that is a pharmaceutically acceptable salt, as conventionally understood. Non-toxic salts synthesized from parent compounds containing basic or acidic moieties by chemical methods Generally, such salts are intended to include the free acid or base forms of these compounds. in water, or in an organic solvent, or in a mixture of the two, with a stoichiometric amount of the appropriate It can be prepared by reacting with a base or an acid, for example, an inorganic acid (e.g., hydrochloric acid, sulfuric, phosphoric, or hydrobromic acids), organic acids (e.g., oxalic, malonic, citric , fumaric acid, lactic acid, malic acid, succinic acid, tartaric acid, acetic acid, trifluoroacetic acid, gluconic acid , ascorbic acid, methylsulfonic acid, or benzylsulfonic acid), inorganic bases (e.g. For example, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, (e.g., ammonium hydroxide), organic bases (e.g., methylamine, diethylamine, triethylamine, ethylamine, triethanolamine, ethylenediamine, tris(hydroxymethyl)methyl amino acids (e.g., methylamine, guanidine, choline, or cinchonine) or amino acids (e.g., In general, non-aqueous media such as Typically ether, ethyl acetate, ethanol, isopropanol, or acetonitrile A list of suitable salts can be found in Remington's Pharmaceuticals Sciences,18th ed.,Mack Publishing Compa. New York, Easton, PA, 1990, p. 1445 and Journal of Pha See, for example, Pharmaceutical Science, 66, 2-19 (1977). For example, these include alkali metals (e.g., sodium or potassium), alkaline earth metals, It may be a salt of a metal (eg, calcium) or an ammonium salt.

[0086] The methods described herein also include the preparation of a compound of formula (I) or a prodrug thereof. or a pharmaceutically acceptable salt thereof in the form of a pharmaceutical composition. The product comprises at least one compound of formula (I) or a prodrug or pharmaceutically acceptable salt thereof. The pharmaceutical compositions described herein include pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers. Suitable excipients, such as vehicles, adjuvants, carriers or diluents, are readily apparent to those skilled in the art. Pharmaceutically acceptable carriers are well known and readily available to the public. Typically, pharmaceutically acceptable carriers are used in combination with active chemically inert to reactive compounds and have no adverse side effects or toxicity under the conditions of use. It does not exist.

[0087] The pharmaceutical compositions may be administered orally, sublingually, transdermally, subcutaneously, topically, by absorption through epithelial or mucosal linings, Intravenous, nasal, intraarterial, intramuscular, intratumoral, peritumoral, intraperitoneal, intrathecal, colonic, intravaginal, or In some embodiments, the pharmaceutical composition can be administered orally or in an aerosol formulation. It is administered intravenously.

[0088] According to any of the embodiments, a compound of formula (I) or a prodrug or pharmaceutical thereof The physiologically acceptable salts may be orally administered to a subject in need thereof. Formulations Suitable for Oral Administration (a) For example, dissolved in a diluent, such as water, saline, or orange juice an effective amount of the compound, and an additive, such as cyclodextrin (e.g., α-, β- , or γ-cyclodextrin, hydroxypropyl cyclodextrin) or poly (b) as a liquid containing ethylene glycol (e.g., PEG 400); (b) as a solid or granule capsules, sachets, tablets, lozenges, and toro, each containing a predetermined amount of the active ingredient. (c) powders; (d) suspensions in suitable liquids; and (e) suitable emulsions and Liquid formulations can consist of diluents such as water and alcohol, e.g. , ethanol, benzyl alcohol, and polyethylene alcohol, May contain, with or without added surfactants, suspending agents, or emulsifying agents. Capsule dosage forms may contain, for example, surfactants, lubricants, and inert fillers, such as lactose. A typical hard granulated sugar containing corn starch, sucrose, calcium phosphate, and corn starch. Tablet forms may be of the lactose, sucrose, or soft shell gelatin type. starch, mannitol, corn starch, potato starch, alginic acid, microcrystalline Cellulose, Acacia, Gelatin, Guar Gum, Colloidal Silicon Dioxide, Crosscamera Sodium stearate, talc, magnesium stearate, calcium stearate, stearyl Zinc phosphate, stearic acid, as well as other excipients, colorants, diluents, buffers, disintegrants, It may contain one or more of a wetting agent, a preservative, a flavoring agent, and a pharmacologically compatible carrier. Lozenge dosage forms contain active ingredients, usually sucrose, and acacia or tragacanth. It may also contain an inert base such as gelatin and glycerin, or sucrose. Pastilles containing the active ingredient in rose and acacia, and capsules containing the active ingredient and such carriers. emulsions, gels, and the like are known in the art.

[0089] Suitable formulations for parenteral administration include aqueous and non-aqueous sterile isotonic injection solutions, which may be , antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient. and aqueous and The compound of formula (I) or a salt thereof may be, for example, Pharmaceutically acceptable surfactants, such as soaps or detergents, suspending agents, such as pectic cellulose, carbomer, methylcellulose, hydroxypropyl methylcellulose, or carboxymethylcellulose, or emulsifiers and other pharmaceutical adjuvants added or In pharmaceutical carriers, physiologically acceptable diluents such as water, saline, saline, aqueous dextrose and related sugar solutions, alcohols, e.g., ethanol, isopropanol, or hexadecyl alcohol, glycols such as propylene glycol, glycol or polyethylene glycol, glycerol ketal, e.g., 2,2-diglycerol Methyl-1,3-dioxolane-4-methanol, ethers, e.g., poly(ethylene glycol) Recall) 400, oils, fatty acids, fatty acid esters or glycerides, or acetylated It may be administered in a sterile liquid or mixture of liquids, including fatty acid glycerides.

[0090] Oils that can be used in parenteral formulations include petroleum, animal, vegetable, or synthetic oils. Specific examples of oils include peanut, soybean, sesame, cottonseed, corn, olive, Suitable fatty acids for use in parenteral formulations include oleic acid, petrolatum, and mineral oils. stearic acid, and isostearic acid. Isopropyl phosphate is an example of a suitable fatty acid ester. Soaps include fatty alkali metal, ammonium, and triethanolamine salts; Suitable detergents include (a) cationic detergents, such as dimethyldialkylammonium alkylpyridinium halides, and alkylpyridinium halides, etc.; (b) anionic detergents, e.g. , alkyl, aryl, and olefin sulfonates, alkyl, olefin, ethers , and monoglyceride sulfates, and sulfosuccinates, etc.; (c) nonionic surfactants, such as fatty amine oxides, fatty acid alkanolamides, and polyoxyethylene ethylene-polypropylene copolymers, (d) amphoteric detergents, e.g., alkyl-β-amines propionates, and 2-alkyl-imidazoline quaternary ammonium salts, and (3) Mixtures of these.

[0091] Parenteral formulations typically contain from about 0.5 to about 25% by weight of the inhibitor in solution. Suitable preservatives and buffering agents may be used in such formulations. To minimize or eliminate the presence of hydroxybenzoates, such compositions should have a hydrophilic-lipophilic ratio of about 12 to about 17. The composition may contain one or more nonionic surfactants having a high HLB. The amount of surfactant in the formulation is in the range of about 5 to about 15% by weight. polyethylene sorbitan fatty acid esters, for example, sorbitan monooleate; and ethylene glycol formed by the condensation of propylene oxide with propylene glycol. Parenteral formulations include single or multiple doses of ethylene oxide and hydrophobic bases. may be provided in multi-dose sealed containers, such as ampoules and vials, and may be used immediately prior to administration. to a sterile liquid carrier, e.g., freeze-dried (lyophilized), which requires only the addition of water for injection. Extemporaneous injection solutions and suspensions may be prepared in the form of sterile powders, granules, or suspensions of the kind previously described. and tablets.

[0092] The inhibitor may be made into an injectable formulation. The requirements for an effective pharmaceutical carrier for an injectable composition are: , well known to those skilled in the art. Pharmaceutics and Pharmacy Pr actice,JBLippincott Co.,Philadelphia,P a., Banker and Chalmers, eds., pages 238-25 0(1982), and ASHP Handbook on Injectable Dr. ugs, Toissel, 4th ed., pages 622-630 (1986) Please refer to.

[0093] Topically applied compositions are generally available in the form of liquids (e.g., mouthwashes), creams, pastes, etc. It is available in the form of lotion and gel. For topical administration, it is administered to the oral cavity, oral epithelium, palate, and gingiva. In some embodiments, the composition is applied to the oral mucosa, including the nasal mucosa. The composition contains at least one active ingredient and a suitable vehicle or carrier. It may also contain other ingredients, such as anti-irritants. The carrier may be liquid, solid, or semi-solid. In embodiments, the composition is an aqueous solution, such as a mouthwash. The composition may be a dispersion, emulsion, gel, lotion, or mixture of various ingredients. In one embodiment, the primary vehicle is water, or substantially The liquid vehicle is a biocompatible solvent that is neutral or made substantially neutral. Other materials, such as buffers, alcohol, glycerin, and mineral oil, are known in the art. Included with various known emulsifiers or dispersants to achieve the desired pH, consistency, and viscosity The composition can be produced as a solid, for example, a powder or granules. The solid is applied directly or dissolved in water or a biocompatible solvent prior to use to substantially neutralize the solid. forming a solution that is neutral or substantially neutral and that can be applied to the target site. In an embodiment of the present invention, the vehicle for topical application to the skin is water, a buffer solution, or the like. buffer solutions, various alcohols, glycols such as glycerin, lipid materials such as Contains fatty acids, mineral oil, phosphoglycerides, collagen, gelatin and silicone-based materials. This can be done.

[0094] The compound of formula (I) or a prodrug or a pharmaceutically acceptable salt thereof may be used alone or in combination. or other suitable components, and made into an aerosol formulation to be administered via inhalation. These aerosol formulations can be formulated using pressurized acceptable propellants, such as dichlorodifluoromethane. These can be introduced into the gases, for example, by nebulizers or It may also be formulated as a medicament for non-pressurized preparation in an atomizer.

[0095] In accordance with the present invention, the dose administered to mammals, particularly humans and other mammals, is The dose should be sufficient to affect the desired response in a mammal. Age, condition or disease state, predisposition to disease, genetic defect(s), and physical It will be recognized that the size of the dose will be determined by various factors, including the weight of the The route, timing, and frequency of administration of the particular inhibitor and the desired effect will determine the appropriate treatment. The presence, nature, and extent of any adverse side effects may also be determined by the presence, nature, and extent of any adverse side effects. It will be appreciated by those skilled in the art that conditions may require long-term treatment, including multiple administrations. It is recognized.

[0096] The method of the present invention comprises administering an effective amount of a compound of formula (I) or a prodrug or pharmaceutically acceptable salt thereof An "effective amount" includes administering an acceptable salt thereof. cytotoxicity (e.g., inhibition of growth, inhibition of survival of cancer cells, reduction of proliferation, tumor reduction in size and / or mass of tumors (e.g., solid tumors), or the progression of certain cancer-related Treat, cure, prevent, delay the onset of, or arrest other related medical condition(s) It means an amount sufficient to promote at least one aspect of remission. The meaningful benefits are measured at any suitable level (10, 20, 30, 40, 50, 60, In some embodiments, the chromatic aberration may be up to 70, 80, 90% or more. wherein one or more symptoms of cancer are treated with a compound of formula (Ia), (Ib), (Ic) or (Id) or a prodrug or pharmaceutically acceptable salt thereof. to at least some extent by preventing, reducing, ceasing, or eliminating the to effectively treat cancer.

[0097] An effective amount is determined based on the biological effect desired in the individual, the condition being treated, and / or the formula ( A compound of formula Ia), (Ib), (Ic) or (Id), or a prodrug or The specific characteristics of the compound of formula (I), including pharmaceutically acceptable salts thereof, as well as the individual characteristics of the compound of formula (I), In this respect, the suitable dose of the compound of formula (I) or its prodrug may be varied. The compound or a pharmaceutically acceptable salt thereof is administered to a patient (e.g., The various general considerations to be considered when determining an "effective amount" are well known to those skilled in the art. and known from, for example, Gilman, each of which is incorporated herein by reference. et al., eds., Goodman And Gilman's: The Pha rmacological Bases of Therapeutics,8th e d., Pergamon Press, 1990; and Remington's Pha rmaceutical Sciences,17th Ed.,Mack Publi shing Co., Easton, Pa., 1990. Formula (Ia): A compound of formula (I), including compounds (Ib), (Ic) or (Id), or a promoter thereof The dose of the prodrug or pharmaceutically acceptable salt is preferably determined based on the mammal's body weight (mg / kg) from about 0.1 mg to about 400 mg / kg (e.g., about 0 .75mg / kg, approx. 5mg / kg, approx. 30mg / kg, approx. 75mg / kg, approx. 100m In another embodiment, the dose comprises about 100 mg / kg, about 200 mg / kg, or about 300 mg / kg. In the present invention, a compound of formula (I), including a compound of formula (Ia), (Ib), (Ic) or (Id), The dosage ranges from about 0.5 mg / kg to about 300 mg / kg (e.g., about 0.75 mg / kg , about 5 mg / kg, about 50 mg / kg, about 100 mg / kg, or about 200 mg / kg g), about 10 mg / kg to about 200 mg / kg (e.g., about 25 mg / kg, about 75 mg / kg, or about 150 mg / kg), or about 50 mg / kg to about 100 mg / kg (e.g., about 60 mg / kg, about 70 mg / kg, or about 90 mg / kg).

[0098] In an embodiment, the compound of formula (I) inhibits LDHA and / or LDHB. In some embodiments, the compounds of formula (I) may inhibit other dehydrogenases (e.g., GAPDH and PHGDH). ) is selective for LDHA and / or LDHB over one or more At least twice as many (e.g., less) dehydrogenases as LDHA and / or LDHB compared to other dehydrogenases at least 5 times, at least 10 times, at least 20 times, at least 50 times, or less It can be more selective (up to 100-fold).

[0099] High levels of LDHA are associated with many types of cancer that are predominantly glycolytic and / or hypoxic. Although LDHB is a marker for some cancers (e.g., lung adenocarcinoma, prostate For example, McCleland et al., Clin Cancer Res,2013;19(4):773-784 and Leibl ich et al.,Oncogene,2006;25(20):2953-296 0. Thus, in some embodiments of the present invention, LDHB is selectively and providing compounds capable of inhibiting LDHA or both LDHA. In an embodiment, the compound of formula (I) selectively inhibits LDHB. In such an embodiment, the compound has selectivity for LDHA. may or may not have such that the inhibition is greater for LDHA than for LDHB. more selective, or the inhibition of LDHA is approximately equal to the inhibition of LDHB, or The inhibition is more selective for LDHB compared to LDHA.

[0100] Inhibition of LDHA and / or LDHB has been recognized in the art as a viable treatment for cancer. For example, Billiard et al. (Cancer and See Metabolism, 2013, 1(19):1-17. , a compound of formula (Ia), (Ib), (Ic) or (Id) or a prodrug thereof Certain invention compounds of formula (I), including pharmaceutically acceptable salts thereof, may be used in the presence of These compounds can be administered to patients suffering from cancer to treat the cancer. Although we do not wish to be influenced by this, inhibition of LDH stimulates mitochondrial respiration and increases cell proliferation and The anti-cancer activity is believed to be due to the assays described herein. Activity may be measured by any suitable method, including by ELISA. Generally, activity is measured by any method that quantifies glycolysis. as a function of lactate production, %ECAR (extracellular acidification rate), and / or mitochondrial It is measured as %OCR (oxygen consumption rate), which is a measure of respiration.

[0101] The type of cancer is not particularly limited, but in certain embodiments, the cancer is a normal tumor of the same type. It is characterized as hypoxic and / or highly glycolytic compared to tissues. "Sexual" cells, as used herein, are considered to be normal or healthy. A temporary or permanent lower partial pressure of oxygen (pO2) than typical for cells in tissues The present invention relates to one or more cells that are exposed to hypoxic conditions. Hypoxic cells include, for example, cells in solid tumors. In tumors, cells with reduced or no access to the vasculature can be identified. This can be done.

[0102] Examples of cancers treatable by the methods of the invention include cancers of the head and neck, eye, skin, mouth, throat, and esophagus. , chest, bones, lungs, colon, sigmoid colon, rectum, stomach, prostate, breasts, ovaries, kidneys, liver, pancreas, brain More particularly, cancers include solid tumors, cancers of the liver, intestine, heart, or adrenal gland. sarcoma, carcinoma, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma , Lymphangiosarcoma, Lymphangioendothelial sarcoma, Periostoma, Mesothelioma, Ewing's tumor, Smooth muscle Sarcoma, rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma Carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary gland carcinoma cystadenocarcinoma, bone marrow carcinoma, bronchial carcinoma, renal cell carcinoma, liver cancer, bile duct carcinoma, Choriomas, seminoma, embryonal carcinoma, Wilms' tumor, cervical cancer, testicular tumor, lung carcinoma, small Cell lung carcinoma, bladder carcinoma, epithelial carcinoma, glioma, astrocytoma, medulloblastoma, craniopharynx tumor, ependymoma, Kaposi's sarcoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, myeloma Meningioma, melanoma, neuroblastoma, retinoblastoma, blood-bone tumors, acute lymphoblastic leukemia, Acute lymphoblastic B-cell leukemia, acute lymphoblastic T-cell leukemia, acute myeloblastic leukemia Blood diseases: acute promyelocytic leukemia, acute monoblastic leukemia, acute erythroleukemia, acute megakaryoblastic leukemia acute myelomonocytic leukemia, acute nonlymphocytic leukemia, acute undifferentiated leukemia, chronic myeloid leukemia Examples of leukemia include lymphoma, chronic lymphocytic leukemia, hairy cell leukemia, and multiple myeloma. , Harrison's Principles of Internal Medicine ine,Eugene Braunwald et al.,eds.,pp.491 762 (15th ed. 2001). In some embodiments, the cancer is According to an embodiment, the cancer is leukemia, melanoma, liver cancer, pancreatic cancer, Selected from lung cancer, colon cancer, brain cancer, ovarian cancer, breast cancer, prostate cancer, and kidney cancer In another embodiment, the cancer is liver cancer, pancreatic cancer, non-small cell lung cancer, or breast cancer. , or kidney cancer.

[0103] The present invention provides a method for treating a patient having cancer cells resistant to an anti-cancer drug, comprising: an effective amount of a compound of formula (I), including a compound of formula (Ia), (Ib), (Ic) or (Id); or a prodrug or a pharmaceutically acceptable salt thereof, and an anticancer drug. providing a compound, a prodrug or a pharmaceutically acceptable salt thereof. The present invention provides a method for resensitizing cancer cells to anticancer drugs. According to an embodiment, the cancer cells are leukemia cells. , melanoma, liver cancer, pancreatic cancer, lung cancer, colon cancer, brain tumor, ovarian cancer, breast cancer, prostate cancer In another embodiment, the cancer cells are selected from liver cancer, adenocarcinoma, and renal cancer. Pancreatic cancer, non-small cell lung cancer, breast cancer, or kidney cancer.

[0104] In certain embodiments of this method, a compound of formula (Ia), (Ib), (Ic) or (Id) is Id) or a prodrug or pharmaceutically acceptable salt thereof of a compound of formula (I), The tolerable salts are administered concurrently with anti-cancer drugs (e.g., chemotherapy) and / or radiation therapy. In embodiments, the methods include administering one or more therapeutic regimens (e.g., chemotherapy or radiation) to a subject. an amount of a compound, prodrug, or The term "co-administered" or "co-administration" refers to simultaneous or sequential administration of A compound may be administered prior to, simultaneously with, or following the administration of another compound.

[0105] One or more than one anti-cancer agent may be administered, for example, two, three, or more. In this regard, the present invention provides a compound comprising a pharmaceutically acceptable carrier and a compound of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij ... a compound of formula (I), including a compound of formula (I) or (Id), or a prodrug thereof, or a pharmaceutically acceptable salt thereof with at least one anti-cancer agent (e.g., a chemotherapeutic agent). The present invention relates to pharmaceutical compositions comprising the combination.

[0106] Examples of anticancer drugs include platinum compounds (e.g., cisplatin, carboplatin, oxaliplatin, platin), alkylating agents (e.g., cyclophosphamide, ifosfamide, chloramphenicol, Bucil, nitrogen mustard, thiotepa, melphalan, busulfan, procarbazine, treptozocin, temozolomide, dacarbazine, bendamustine), antitumor antibiotics (e.g. For example, daunorubicin, doxorubicin, idarubicin, epirubicin, mitoxantro bleomycin, mitomycin C, plicamycin, dactinomycin), taxanes anti-cancer drugs (e.g., paclitaxel and docetaxel), antimetabolites (e.g., 5-fluorouracil, Uracil, cytarabine, pemetrexed, thioguanine, floxuridine, capecitabine and methotrexate), nucleoside analogues (e.g., fludarabine, clofaxine, rabine, cladribine, pentostatin, nelarabine), topoisomerase inhibitors (e.g. topotecan and irinotecan), hypomethylating agents (e.g., azacitidine and decitabine), proteasome inhibitors (e.g., bortezomib), epipodophyllotoxins (e.g., etoposide and teniposide), DNA synthesis inhibitors (e.g., hydroxyurea), Vincine alkaloids (e.g., vincristine, vindesine, vinorelbine, and vinbrain) tyrosine kinase inhibitors (e.g., imatinib, dasatinib, nilotinib, solanacearum), rafenib, sunitinib), monoclonal antibodies (e.g., rituximab, cetuximab , panitumumab, tositumomab, trastuzumab, alemtuzumab, gemtuzumab ozoga mycin, bevacizumab), nitrosoureas (e.g., carmustine, fotemustine, and lomustine), enzymes (e.g., L-asparaginase), biological agents (e.g., interleukin-1, feron and interleukin), hexamethylmelamine, mitotane, angiogenesis inhibitors ( thalidomide, lenalidomide), steroids (e.g., prednisone, dexamethasone, steroids, steroids, and prednisolone), hormones (e.g., tamoxifen, raloxifene) , leuprolide, bicalutamide, granisetron, flutamide), aromatase inhibitors ( e.g., letrozole and anastrozole), arsenic trioxide, tretinoin, nonselective cysteine Chlorooxygenase inhibitors (e.g., nonsteroidal anti-inflammatory drugs, salicylates, aspirin) piroxicam, ibuprofen, indomethacin, naprosyn, diclofenac, Lumetin, ketoprofen, nabumetone, oxaprozin), selective cyclooxygenase COX-2 inhibitors, or any combination thereof.

[0107] As used herein, the term "patient" refers to a subject that is typically a mammal. For example, a subject may be The patient may be any patient with a disease requiring chemotherapy and / or radiation therapy. Mammals include, but are not limited to, rodents, e.g., mice, and lagomorphs, e.g., rats. In some embodiments, mammals include felines (cats) and canines ( the order Carnivora, including the subfamily Bovinae (cattle) and the family Suidae (pigs); In some embodiments, the mammal is from the order Equidae, including the family Equidae (horses). of the orders Acanthidae, Ceboids, or Simoidea (monkeys), or of the suborder Anthropoidea (humans and ape-like creatures) In an embodiment of the invention, the patient is a human.

[0108] The present invention relates to a method for producing lactate dehydrogenase A (LDHA) and / or lactate dehydrogenase B (LDHA) in cells. A method for inhibiting (LDHB) activity, comprising: Id) or a prodrug or pharmaceutically acceptable salt thereof of a compound of formula (I), Tolerable salts are administered to cells, thereby inhibiting the activity of LDHA and / or LDHB. The present invention is further directed to the above method, which comprises administering LDHA and LDHB activity to a subject. There are many methods known in the art for measuring enzyme inhibition, including by the assay described in Typically, LDHA and LDHB activity is measured by any known method. Inhibition of activity resulted in decreased lactate accumulation and / or increased pyruvate compared to control samples. This is therefore proven.

[0109] The following examples are provided for further illustration and should not be construed as limiting in any way. It won't be. [Example]

[0110] Example 1 This example is used in characterizing the compounds of formula (I) in accordance with an embodiment of the present invention. The main biochemical assays for human LDHA are described below.

[0111] Test compounds were prepared using Greiner Bio-One (Monroe, NC) 1536-U. The wells were placed in a black, no-hole assay plate. Cl, pH 7.4, 100 micromolar (μM) EDTA and 0.01% TWEEN -20(trademark) ) (final concentration) was used as the assay buffer. 2 nanomolar (nM) human LDHA (Meridian Life Sciences) in Seibu buffer The substrate reagent was Acetyle, Inc., Memphis, TN) (final concentration). 0.06 mM NADH and 0.2 mM sodium pyruvate (final) in assay buffer The resazurin / diaphorase coupling reagent was 0.01% in assay buffer. 0.037 mM resazurin and 0.133 milligrams per milliliter (mg / mL) dihydrochloride aphorase (final concentration). The order of steps, the amount and type of reagents, and each step The time required for the uptake is listed in Table 1. Inhibition of LDHA activity was measured by fluorescence emission. did.

[0112] [Table 1]

[0113] <Example 2> This example is used in characterizing the compounds of formula (I) in accordance with an embodiment of the present invention. A human LDHB counterscreening biochemical assay is described.

[0114] Test compounds were prepared using Greiner Bio-One (Monroe, NC) 1536-U. The wells were placed in a black, non-hole assay plate. 4, 100 μM EDTA and 0.01% TWEEN-20™ (final concentrations) The LDHB reagent was used as the assay buffer. HB (Meridian Life Science, Inc., Memphis, TN) ) (final concentration). The substrate reagent was 0.13 mM NADH and Sodium pyruvate (final concentration) was 0.16 mM. Resazurin / diaphorase The coupling reagent was 0.037 mM resazurin and 0.133 mM thiazolinone in assay buffer. The final concentration of diaphorase was 100 mg / mL. The time required for each step is also listed in Table 2. Inhibition of LDHB activity was evaluated by measuring the fluorescence emission. was measured by.

[0115] [Table 2]

[0116] Example 3 This example is used in characterizing the compounds of formula (I) in accordance with an embodiment of the present invention. A human PHGDH counterscreening biochemical assay is described.

[0117] Test compounds were prepared using Greiner Bio-One (Monroe, NC) 1536-U. The wells were placed in a black, no-hole assay plate. MgCl2, 0.05% BSA, and 0.01% TWEEN-20™ (maximum The final concentration of the substrate reagent was 10 μM in the assay buffer. EDTA, 0.625 mM glutamate, 500 nM human PSAT1, 500 nM Human PSPH, 0.05 mM 3-phosphoglycerate, 0.1 mM resazurin, and The final concentration of diaphorase was 0.1 mg / mL. 0.15mM NAD in buffer + and 10 nM human PHGDH (final concentration). The order of steps, the amount and type of reagents, and the time required for each step are listed in Table 3. Inhibition of PHGDH activity was measured by fluorescence emission.

[0118] [Table 3]

[0119] Example 4 This example is used in characterizing the compounds of formula (I) in accordance with an embodiment of the present invention. This paper describes a human GAPDH counterscreening biochemical assay.

[0120] Test compounds were prepared using Greiner Bio-One (Monroe, NC) 1536-U. The wells were placed in a black, no-hole assay plate. 0.4, 10 μM EDTA, 1.27 mM KH2PO4, 0.875 mM MgCl2 , 0.0875% BSA, 0.01 mM DTT, and 0.01% TWEEN-20 (trademark) (final concentration) was used as the assay buffer. The substrate reagent was , 0.48 mM 3-phosphate glyceraldehyde, 0.06 mM resazurin, and 0. The final concentration of diaphorase was 21 mg / mL. The GAPDH reagent was prepared in assay buffer. 0.007mM NAD in the preparation + and 2.5 nM human GAPDH (final concentration). The order of steps, the amount and type of reagents, and the time required for each step are shown in Table 4. The inhibition of GAPDH activity was measured by fluorescence emission.

[0121] [Table 4]

[0122] <Example 5> This example illustrates the quality control used to characterize compounds of formula (I) in accordance with embodiments of the present invention. We describe a cell-based metabolite assay by mass spectrometry (MS).

[0123] The order of steps, the amount and type of reagents, and the time required for each step are shown in Table 5. Write it down.

[0124] [Table 5]

[0125] Example 6 This example illustrates the ratios used to characterize compounds of formula (I) in accordance with embodiments of the present invention. A cell-based metabolite assay with colorimetric / fluorimetric detection is described.

[0126] The cell-based HT lactate assay is a compact Biovision lactate colorimetric / fluorimetric assay Assay kit (Cat. No. K607-100). The assay is The assay is approximately 3.5 hours long and is performed in a lab format. For each cell line, lactate production was measured to achieve an optimal number equivalent to approximately 90% of the standard curve range. Optimization of cell number per well was performed with the following cell lines: The samples were: MiaPaCa2-500 cells / well, SNU398-500 cells / well / well, and P493-500 cells / well. The order of steps, amount and type of reagents, etc. The time required for each step is also shown in Table 6.

[0127] [Table 6]

[0128] Example 7 This example illustrates the use of 2-bromothiazole-4-carboxylic acid te in an embodiment of the present invention. The preparation of rt-butyl 1 is described. Scheme 1 [ka]

[0129] tert-Butyl 2,2,2-trichloroacetimidate (17.20 ml, 96 mm ol, 2 equivalents) to 2-bromothiazole-4-carboxylic acid (10 g, 48.1 mmol , 1 equivalent) in dichloromethane (DCM) (100 mL) and tetrahydrofuran (THF ) (50 mL) was added to the stirred suspension, followed by BF3·OEt2 (0.938 ml, 7. The mixture was stirred at room temperature for 16 hours, concentrated, and saturated. The mixture was slowly quenched with saturated bicarbonate solution and extracted with ethyl acetate. After washing with carbonate and brine and drying, the crude product was purified by 5-30% acetic acid in hexane. Biotage (Charlotte, NH) eluted with ethyl acetate over 12 column volumes. C) Purification by flash system. The product fractions were concentrated and purified by 2-bromothiazole. tert-Butyl 4-carboxylate 1 was obtained as a white solid (10.4 g, 82%).

[0130] Example 8 This example illustrates the use of 2-hydrazinylthiazole-4-carvone in an embodiment of the present invention. The preparation of tert-butyl acetate 2 is described. See Scheme 1.

[0131] tert-Butyl 2-bromothiazole-4-carboxylate 1 (10.9%) from Example 1 6g, 41.5mmol, 1eq) and hydrazine hydrate (13ml, 415mmol, A solution of 10 equivalents of ethanol in 80 mL of EtOH was refluxed for 2 hours. After the reaction was completed, the solvent was removed. Ice water was added and the precipitate that formed was collected by filtration, washed with cold water and dried under air. The crude product (tert-butyl 2-hydrazinylthiazole-4-carboxylate 2) was obtained by It was of sufficient purity to be used in the following reaction.

[0132] Example 9 This example illustrates the use of 2-hydrazinylthiazole-4-carvone in an embodiment of the present invention. The preparation of ethyl acetate 3 is described. See Scheme 1.

[0133] Ethyl bromopyruvate (15.71 ml, 113 mmol) was dissolved in 2-acetylhydrazine Add 15g of benzophenone carbothioamide (113mmol) to a suspension in 200mL of ethanol. The mixture was stirred at room temperature for 30 minutes until the solution became clear, and then refluxed for 1.5 hours. The solution was concentrated and stirred with 20 mL of MeOH and 300 mL of ether. The precipitate was collected by filtration, washed with ether, and dried to give a yellow solid (2-hydrazinium Ethyl thiazole-4-carboxylate 3) was obtained as the HBr salt.

[0134] Example 10 This example illustrates one synthesis of substituted benzoylacetonitrile 4 according to an embodiment of the present invention. The general procedure will be explained. Scheme 2 [ka]

[0135] Acetonitrile (ACN) (5.33 ml, 102 mmol, 2 equiv.) was added to a In the solution, 1 molar lithium diisopropylamide (LDA) (102 ml, 102 mmol) The reaction mixture was stirred for 30 minutes and then cooled to 40 mL of THF (40 mL). Then, a solution of the acid chloride (51.0 mmol, 1 equiv.) in 20 mL of THF was added over 15 min. The reaction was allowed to reach room temperature over 4 hours and then quenched with 1M (molar) HCl. The product was extracted with ethyl acetate, and the organic layer was then washed with water and brine, and The crude product was purified by elution with 5-75% ethyl acetate in hexane over 12 column volumes. The product was purified on a Biotage (Charlotte, NC) flash system eluting with The substituted benzoylacetonitrile 4 was obtained as a yellow solid.

[0136] Example 11 This example illustrates the use of 4-(2-cyano-3-oxo-3-aryl)-2-phenylpropanol in an embodiment of the present invention. A general procedure for the synthesis of (propyl)benzenesulfonamide 5 is described below. See Scheme 2. I want to be done that.

[0137] 2,6-dimethyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid diethyl ester Hantzsch ester (12.21 g, 48.2 mmol, 1.4 equiv.) and L-propanol Cholesterol (0.793 g, 6.89 mmol, 20 mol%) was added to 3-oxo-3-phenylenediamine. Di-propanenitrile 4 (34.4 mmol, 1 equiv.) and 4-formylbenzenesulfonyl Dissolve benzophenone (7.02 g, 37.9 mmol, 1.1 equiv.) in ethanol (150 mL). The mixture was stirred at 60°C for 30 minutes. The mixture was then cooled and silica gel was added. Mix with, concentrate, and then wash with 20-100% ethyl acetate in hexane for over 6 column volumes. Biotage (Charlotte) with 100% ethyl acetate over 8 column volumes Purification was performed using a flash system to obtain 4-(2-cyano-3-oxo-3-aryl)- (Dimethylpropyl)benzenesulfonamide 5 was obtained as a white solid.

[0138] Example 12 This example illustrates the use of 2-(5-amino-3-aryl-4-(4 -sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxamide A general procedure for the synthesis of sylate 6 is described. See Scheme 2.

[0139] 2-Hydrazinylthiazole-4-carboxylate ethyl hydrobromide (3, 1.5g, 5 0.59 mmol, 1 equiv.), 4-(2-cyano-3-oxo-3-arylpropyl)benzyl A mixture of benzenesulfonamide (5.59 mmol, 1 equiv.) and tosylic acid (2.128 g, 11. 19 mmol, 2 equiv.) in ethanol (15 mL) was microwaved for 15 min. The precipitate that formed was collected by filtration and washed with cold ethanol to give the pure product. 2-(5-amino-3-aryl-4-(4-sulfamoylbenzyl)-1H-pyridin Ethyl thiazole-1-yl-4-carboxylate 6) was obtained as a yellow solid.

[0140] Example 13 This example illustrates the use of 2-(5-iodo-3-aryl-4-(4 -Sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carvone A general procedure for the synthesis of ethyl acetate 7 is described. See Scheme 2.

[0141] Tosylic acid (5.37 g, 28.2 mmol, 3.5 equiv.) was added to 2-(5-amino-3- Aryl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazo Ethyl 4-aminobenzoate 6 (8.07 mmol, 1 equiv.) was suspended in ACN (100 mL). The suspension was added and stirred for 10 minutes. During this time, the solution became clear and then NaNO2 (1.113 g, 16.13 mmol, 2 equiv.) and KI (4.02 g, 24.20 mm ol, 3 equiv.) dropwise at room temperature over a period of 10-15 min. The reaction mixture was stirred at room temperature overnight. After the reaction was completed, the excess solvent was removed under reduced pressure. The crude product was extracted with ethyl acetate, and the organic layer was then washed with saturated sodium thiosulfate solution, water, The crude product was extracted with 1-15% acetone or hexachloromethane. High-speed column elution with 1 to 100% ethyl acetate in ethanol over 20 column volumes. Purification was performed using a Biotage (Charlotte, NC) flash system. , to obtain the pure product.

[0142] Example 14 This example illustrates the use of 2-(5-iodo-3-aryl-4-(4 -Sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carvone A general procedure for the trifluoromethylation of ethyl acid 7 is described. Scheme 3 [ka]

[0143] 2-(5-iodo-3-aryl-4-(4-sulfamoylbenzyl)-1H-pyra Ethyl (1-isothiazole-4-yl) thiazolecarboxylate 7 (0.4 g, 0.673 mmol) l) 7 and 1,10-phenanthroline)(trifluoromethyl)copper(I)8 (0.31 6 g, 1.009 mmol, 1.5 eq) was degassed with argon and then DMF (2 mL) was added and stirred for 1 hour at 55° C. The reaction mixture was diluted with ethyl acetate The organic layer was dried over MgSO4, concentrated, and evaporated. Biotag elutes over 12 column volumes with 20-100% ethyl acetate in xanthan gum Purified on a (Charlotte, NC) flash system and purified with 2-(5-trifluoromethyl-2- ... Methyl-3-aryl-4-(4-sulfamoylbenzyl)-1H-pyrazole-1- Ethyl)thiazole-4-carboxylate 9 was obtained as a white solid.

[0144] Example 15 This example illustrates the use of 2-(5-iodo-3-aryl-4-(4 -Sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carvone A general procedure for the Suzuki coupling of ethyl acetate 7 is described. See Scheme 3. stomach.

[0145] In a sealed microwave vial, add 2 molar Na2CO3 (0.17 mL, 0. 336 mmol, 2 equivalents) to 2-(5-iodo-3-aryl-4-(4-sulfamoyl)- Ethylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate 7( 0.168 mmol, 1 eq), SILIACAT™ DPP-Pd (0.1 g), A mixture of boronic acids (0.336 mmol, 2 equiv.) in dimethyl ether (DME) ( 2 mL) and then heated in a microwave at 130° C. for 30 minutes. The residue was taken up in DMF (2 mL). , stirred with silica-bound DMT, and then filtered through a thiol resin cartridge. Finally, the compound was purified by preparative HPLC to remove any leached palladium. The pure coupled product 10 was obtained.

[0146] Example 16 This example illustrates the use of 2-(5-iodo-3-aryl-4-(4 -Sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carvone A general procedure for the Sonogashira coupling of ethyl acetate (7) is described. See Scheme 3. I want to be illuminated.

[0147] 2-(5-iodo-3-aryl-4-(4-sulfamoylbenzyl)-1H-pyra Ethyl (1-thiazole-1-yl)thiazole-4-carboxylate 7 (0.202 mmol, 1 equiv.) ), bis(triphenylphosphine)palladium(II) chloride (0.014 g, 0.02 0 mmol, 10 mol%), and CuI (3.84 mg, 0.020 mmol, 10 m A mixture of 1% by volume of THF (1 mL) was added to the flask under nitrogen atmosphere with triethylamine (TEA ) (0.169 ml, 1.211 mmol, 6 equiv.), followed by alkyne (0.404 m mol, 2 equivalents) was added. The vial was sealed and stirred at 80°C for 4 hours. The product was extracted with ethyl acetate and the organic layer was washed with 1 molar HCl and brine. Biotage (Charlotte, NC) eluting with 20-100% ethyl acetate Purify on a flash system or by preparative HPLC to obtain the pure coupling product 10 obtained.

[0148] Example 17 This example illustrates the use of 2-(5-iodo-3-aryl-4-(4 -Sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carvone A general procedure for the cyanation of ethyl acid 7 is described. See Scheme 3.

[0149] 2-(5-iodo-3-aryl-4-(4-sulfamoylbenzyl)-1H-pyra Ethyl (1-thiazole-1-yl)thiazole-4-carboxylate 7 (0.168 mmol, 1 equiv.) ) and CuCN (0.023 g, 0.252 mmol, 1.5 equiv.). Dimethyl sulfoxide (DMSO) (0.5 ml) was heated in a microwave at 160°C for 0.5 hours. The product was extracted with ethyl acetate, and the organic layer was washed with saturated bicarbonate solution, water, and brine. The crude product was washed with 30-100% ethyl acetate in hexane for 15 columns. Purification was performed using a Biotage (Charlotte, NC) flash system with elution at over 1000 vol. The pure product 10 was obtained.

[0150] Example 18 This example demonstrates the hydrolysis of ethyl and methyl esters 10 in accordance with an embodiment of the present invention. A general procedure for this is described in Scheme 3.

[0151] 1.5 M LiOH solution in water was added to 2-(3-aryl-4-(4-sulfamoylbenzene) Ethyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate 10(0.25 2 mmol, 1 equiv.) in THF / MeOH (3 mL / 1.5 mL) at room temperature. After stirring for 0.5 to 1 hour, the solvent was evaporated under reduced pressure and the residue was dissolved in DMSO. Finally, compound 11 was purified by preparative HPLC.

[0152] Example 19 This example illustrates the use of 2-(5-(cyanomethyl)-3-aryl)-2-(5-cyanomethyl)-3-aryl-2-methylpropanol in an embodiment of the present invention. -4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4 A general procedure for the preparation of ethyl-carboxylate 12a is described (Scheme 4, step a). Scheme 4 [ka]

[0153] DMSO (2.5 mL) was dissolved in 0.147 g of KF (2.52 mmol, 3 equiv.). 9 mL of aqueous solution, followed by 2-(5-iodo-3-aryl-4-(4-sulfonyl)-2-(4-isopropyl ... ethyl amoylbenzyl-1H-pyrazol-1-yl-thiazole-4-carboxylate 7 (0.841 mmol, 1 equiv.), PdCl2(dppf)-CH2Cl2 adduct (0 0.137g, 0.168mmol, 20mol%), and 4-(4,4,5,5-tetramethyl-2-( ... Methyl-1,3,2-dioxaborolan-2-yl)isoxazole (0.246 g, The mixture was bubbled with argon for 2 minutes. The vial was then sealed and heated to 130°C in a preheated heating block. After stirring for 3 h, another 0.9 mL portion of water was added and the mixture was further heated at 130 °C. The mixture was stirred for 21 hours. After the reaction was completed, a silica-bound metal scavenger was added and the mixture was stirred for 30 minutes. The reaction mixture was diluted with ethyl acetate and filtered through a silica plug. The filtrate was diluted with water, saturated chloride solution The crude product was purified by 20-100% ethyl acetate in hexanes. Biotage (Charlotte, NC) flash system with elution by ethanol. Purify and obtain the pure product 2-(5-(cyanomethyl)-3-aryl-4-(4-sulfamoyl) Ethyl (1H-benzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate 12a was obtained as a white solid.

[0154] Example 20 This example illustrates the use of 2-(5-(cyanomethyl)-3-aryl)-2-(5-cyanomethyl)-3-aryl-2-methylpropanol in an embodiment of the present invention. -4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4 - The general procedure for carboxylic acid 12b is described. See Scheme 4, step c. stomach.

[0155] 2-(5-(cyanomethyl)-3-phenyl-4-(4-sulfamoylbenzyl)- Ethyl 1H-pyrazol-1-yl)thiazole-4-carboxylate 12a (0.049m mol) and hydroxytrimethylstannane (0.018 g, 0.099 mmol, 2 A mixture of 100 equivalents of 100% ethanol in dichloroethane (DCE) was stirred at 80°C for 24 hours. The residue was taken up in DMSO and passed through a sulfonic acid cartridge. The crude product 2-(5-(cyanomethyl)-3- Aryl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazo The 4-carboxylic acid 12b was purified by HPLC.

[0156] <Example 21> This example illustrates a general procedure for the synthesis of tetrazole 13a in accordance with an embodiment of the present invention. See Scheme 4, step b.

[0157] 2-(5-(cyanomethyl)-3-aryl-4-(4-sulfamoylbenzyl)- Ethyl 1H-pyrazol-1-yl)thiazole-4-carboxylate 12a (0.414 m mol, 1 equiv.), NH4Cl (0.066 g, 1.241 mmol, 3 equiv.), and N aN3 (0.081 g, 1.241 mmol, 3 equiv.) in DMF (2 ml) The mixture was heated in a microwave at 125°C for 2 hours. The product was purified by reversed-phase flash system. , to give the pure product 13a.

[0158] <Example 22> This example illustrates a general procedure for the synthesis of tetrazole derivative 13c in accordance with an embodiment of the present invention. See Scheme 4, step e.

[0159] 2-(5-((1H-tetrazol-5-yl)methyl)-3-aryl-4-(4- Sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid A solution of ethyl 13a (0.091 mmol, 1 equiv.) in THF (3 ml) was cooled and The reaction mixture was added to iAlH4 (0.363 ml, 0.363 mmol, 4 equiv.). The mixture was stirred at room temperature for 1 hour, then quenched with water. The residue was suspended in a DCM / MeOH mixture. The crude product 13c obtained after evaporation of the solvent was purified by preparative H It was purified by PLC.

[0160] Example 23 This example illustrates the N,N-bis(3,4-dimethoxybenzyl) The preparation of 4-nitrobenzenesulfonamide 14 is described in Scheme 5, first step. Please refer to the following. Scheme 5 [ka]

[0161] 4-Nitrobenzene-1-sulfonyl chloride (1.746 g, 7.88 mmol, 1 equiv. ) to bis(3,4-dimethoxybenzyl)amine (2.5 g, 7.88 mmol, 1 equiv. ) and Hunig's base (2.75 ml, 15.75 mmol, 2 equiv.) in DCM (15 The reaction mixture was stirred at room temperature for 1 hour. After evaporation of the solvent, The crude product was purified by Biota elution with 25-100% ethyl acetate in hexane. Purification was performed using a GE (Charlotte, NC) flash system and N,N-bis(3,4 (-dimethoxybenzyl)-4-nitrobenzenesulfonamide 14 was obtained as a yellow solid Yield (2.85g, 72%).

[0162] Example 24 This example illustrates the use of 4-amino-N,N-bis(3,4-dimethacrylate) in an embodiment of the present invention. The preparation of (hydroxybenzyl)benzenesulfonamide 15 is described in Scheme 5, second step. Please refer to the following.

[0163] A 10 mL solution of ammonium chloride (0.8 g, 14.92 mmol) and iron powder ( 1.389 g, 24.87 mmol) to N,N-bis(3,4-dimethoxybenzyl)- Ethyl 4-nitrobenzenesulfonamide 14 (2.5 g, 4.97 mmol, 1 equiv.) The reaction mixture was stirred at 85° C. overnight. The mixture was diluted with methanol and filtered through a pad of CELITE™. The filtrate was concentrated. The mixture was neutralized with bicarbonate and extracted with DCM. The DCM layer was washed with bicarbonate and brine. The crude product was purified by eluting with 1-15% MeOH (ammoniated) in DCM. Purified by a 4-amino-N,N-bis(2-amino-N,N-biphenyl)-2-hydroxybenzoate (Charlotte, NC) flash system. (3,4-dimethoxybenzyl)benzenesulfonamide 15 was obtained as a white solid. Yield (2.2g, 94%).

[0164] Example 25 This example illustrates the N,N-bis(3,4-dimethoxybenzyl) )-4-((3-aryl-1H-pyrazol-4-yl)amino)-benzenesulfone The general preparation of amide 16 is described. See Scheme 5, step 3.

[0165] In a microwave (MW) vial, 4-bromo-3-aryl-1H-pyrazole (1. 569 mmol, 1 equivalent), 4-amino-N,N-bis(3,4-dimethoxybenzyl) Benzenesulfonamide 15 (1.038 g, 2.197 mmol, 1.4 equiv), t- Butylbretphos (CAS number 1160861-53-9) (Stem Chemical als, Newburyport, MA, Catalog No. 15-1164) (0.038 g , 0.078 mmol, 5 mol%) and t-butyl phosphate paradoxacycle (CA S No. 1148148-01-9) (Stem Chemicals, Newbury, Ort, MA, Catalog No. 46-0325) (0.067 g, 0.078 mmol, 5 The mixture was purged with argon and then added THF (4 ml), followed by lithium Lithium hexamethyldisilazide (LHMDS) (2.62 ml, 3.92 mmol, 2.5 equivalents) The mixture was stirred in a preheated block at 80° C. for 14 hours. The reaction mixture was poured into acidified water (1 molar HCl) and extracted with ethyl acetate. Wash with water and brine. The crude product N,N-bis(3,4-dimethoxybenzyl)- 4-((3-aryl-1H-pyrazol-4-yl)amino)-benzenesulfonamido The compound 16 was purified by Biotage™ chromatography (C ) eluting with 30-100% ethyl acetate in hexane. Purification was performed using a (Harlotte, NC) flash system.

[0166] Example 26 This example illustrates the 2-(4-((4-(N,N-bis(3,4 -dimethoxybenzyl)sulfamoyl)phenyl)amino)-3-aryl-1H- General preparation of tert-butyl pyrazol-1-yl)thiazole-4-carboxylate 17 See Scheme 5, step 4.

[0167] N,N-bis(3,4-dimethoxybenzyl)-4-((3-aryl-1H-pyrazoline) (4-(4-yl)amino)benzenesulfonamide 16 (0.732 mmol, 1 equiv.) , K2CO3 (0.202 g, 1.464 mmol), and 2-bromothiazole-4- Mixture of tert-butyl carboxylate (0.213 g, 0.805 mmol, 1.1 equiv.) The reaction mixture was stirred at 125°C for 12 hours in DMSO (1.5 mL). The solution was diluted with ethanol and filtered through a pad of CELITE™. The crude product 2-(4-((4-(N,N-bis(3,4-dimeth- yl (Oxybenzyl)sulfamoyl)phenyl)-amino)-3-aryl-1H-pyrazo tert-Butyl (1-phenyl)thiazole-4-carboxylate 17 was dissolved in hexane for 40 min. Biotage (Charlotte, NC) filters eluted with 100% ethyl acetate. It was purified using the Rush system.

[0168] Example 27 This example illustrates the use of (N,N-bis(3,4-dimethoxybenzyl)phenyl)-2-methylpropanol in an embodiment of the present invention. A general procedure for the deprotection of the (ethyl) and t-butyl groups and the synthesis of compound 18 is described. See Scheme 5, step 5.

[0169] 2-(4-((4-(N,N-bis(3,4-dimethoxybenzyl)sulfamoyl) -phenyl)amino)-3-aryl-1H-pyrazol-1-yl)thiazole-4- tert-Butyl carboxylate (0.251 mmol) 17 in DCM (1.5 mL) A mixture of trifluoroacetic acid (TFA) (1.5 mL) was heated in a microwave oven at normal absorption for 10 min. The mixture was heated at 0°C for 15 min. The solvent was removed by forced air and the crude product 18 was dissolved in DMSO. The product was dissolved and then purified using preparative HPLC.

[0170] Example 28 This example illustrates the use of 2-(3-phenyl-4-(4-sulfamoyl)phenyl)- ... Synthesis of (1H-(1H-ylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid 19 Explain. Scheme 6 [ka]

[0171] Step 1: 2-(4-bromo-3-phenyl-1H-pyrazol-1-yl)thiazo Synthesis of ethyl 4-aminobenzoate In a microwave tube, add ethyl 2-bromothiazole-4-carboxylate (1058 mg , 4.48 mmol), 3-bromo-4-phenyl-1H-pyrrole (995 mg, 4. 48 mmol), and K2CO3 (929 mg, 6.72 mmol). The flask was sealed and DMSO (4 ml) was added. The mixture was heated at 120° C. for 4 hours. Pour into vigorously stirred H2O (100 mL), filter the solid and triturate with H2O. The solid was redissolved in EtOAc and filtered. Some of the undissolved material was removed by filtration. The filtrate was concentrated and triturated with approximately 3% EtOAc / hexanes. 2-(4-Bromo-3-phenyl-1H-pyrazol-1-yl)thiazole-4-carboxamide Ethyl benzoate (1329 mg, 3.51 mmol, 78% yield) was obtained.

[0172] Step 2: 2-(3-phenyl-4-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)-1H-pyrazol-1-yl)thiazol-4-yl Synthesis of ethyl benzoate In a microwave tube, 2-(4-bromo-3-phenyl-1H-pyrazole-1-yl) Ethyl thiazole-4-carboxylate (378 mg, 1 mmol), 4,4,4',4 ',5,5,5',5'-Octamethyl-2,2'-bi(1,3,2-dioxaborolane) )(330mg, 1.300mmol), PdCl2(dppf)(73.2mg, 0. 100 mmol), and potassium acetate (294 mg, 3.00 mmol). The tube was sealed, evacuated and refilled with N2 (2-3 times). Water (4 ml) was added and the mixture was stirred at 95°C (preheated) overnight. The mixture was diluted with EtOAc. The extract was diluted and filtered through CELITE™, eluting with EtOAc. The product was purified by silica gel chromatography using 10-25% EtOAc / hexane as the eluent. The product was purified by chromatography to give the product, which was triturated with a small amount of hexane, It is then dried and 2-(3-phenyl-4-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)thiazol-4- Ethyl carboxylate (540 mg, 0.762 mmol, 76% yield) was obtained as a solid. The product contained about 40% of the reduced (deBr) product, which could be purified without further purification. This was then used in the next step.

[0173] Step 3: 2-(3-phenyl-4-(4-sulfamoylbenzyl)-1H-pyra Synthesis of ethyl thiazole-1-yl-4-carboxylate In a microwave tube, 2-(3-phenyl-4-(4,4,5,5-tetramethyl- 1,3,2-Dioxaborolan-2-yl)-1H-pyrazol-1-yl)thiazole Ethyl 4-carboxylate (70.9 mg, 0.1 mmol), 4-(bromomethyl)benzoate zenesulfonamide (25.01 mg, 0.100 mmol), and Pd(Ph3P)4 (11.56 mg, 10.00 μmol) was added. The tube was sealed and air was removed. Refill with N2 (2-3 times). Toluene (0.75 ml, ratio: 2.500) / EtOH (0.3 ml, ratio: 1.000) mixture was added, followed by 2N NaCO 3(水性 ) (0.3 mL, 0.6 mmol, 6 equiv.) was added. The mixture was heated at 80 °C (preheated). The mixture was stirred for 2 hours. The organic layer was separated, and the aqueous layer was extracted with EtOAc (2 mL x 3). The organic layer was dried (Na2SO4) and filtered. After removal of the solvent, the product was obtained as eluent. Purification was performed by silica gel chromatography using 30-60% EtOAc / hexane. 2-(3-phenyl-4-(4-sulfamoylbenzyl)-1H-pyrazole- 1-yl)thiazole-4-carboxylate ethyl (29 mg, 0.062 mmol, 61. 9% yield) as a white solid.

[0174] Step 4: 2-(3-phenyl-4-(4-sulfamoylbenzyl)-1H-pyra Synthesis of (1-thiazole-1-yl)thiazole-4-carboxylic acid (19) 2-(3-phenyl-4-(4-sulfamoylbenzyl)-1H-pyrazole-1- Ethyl)thiazole-4-carboxylate (26 mg, 0.055 mmol) in THF( 1ml) solution with LiOH (水性) (1.5N in HO, 0.4 mL, 0.6 mmol) The mixture was stirred at room temperature for 2 hours. Then, 1N HCl was added. (水性) (about 0.6~ 0.65 mL) was added until the pH of the aqueous layer was about 4. Then, hexane (5 mL) The resulting solid was filtered and triturated with H2O (1 ml x 2) and hexane (2 ml x 2). Refrigerate, dry, and 2-(3-phenyl-4-(4-sulfamoylbenzyl)- 1H-pyrazol-1-yl)thiazole-4-carboxylic acid 19 (21 mg, 0.048 The compound was obtained (2 mmol, 86% yield).

[0175] The compound was sufficiently pure to be directly loaded onto the system (19 mg). 1 H NMR(4 00MHz,DMSO-d6)δ13.18(s,1H),8.21(s,2H),7. 80-7.71(m,2H),7.72-7.63(m,2H),7.52-7.37( m,5H),7.28(s,2H),4.15(s,2H);MS(M+H) + =441 .

[0176] Example 29 This example illustrates the use of 2-(3-([1,1'-biphenyl]-3 -yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazo The synthesis of 20 is described. Scheme 7 [ka]

[0177] Step 1: Synthesis of 3-([1,1'-biphenyl]-3-yl)-1H-pyrazole In a two-neck flask, 3-(3-bromophenyl)-1H-pyrazole (1115 mg, 5 mmol), phenylboronic acid (914 mg, 7.50 mmol), PdCl2 (dp pf) (366 mg, 0.500 mmol), and K2CO3 (2073 mg, 15.0 The air was removed and refilled with N2 (2-3 times). Then, 1,4 - a mixture of dioxane (12 ml, ratio: 2.000) and water (6 ml, ratio: 1.000) The mixture was stirred at 95°C (preheated) for 5 hours. The organic layer was separated and the aqueous layer was diluted with EtOAc ( The combined organic layer was dried (Na2SO4) and filtered. After removal, the product was purified by elution with 30-40-50% EtOAc / hexane. Purification by silica gel chromatography gave 3-([1,1'-biphenyl]-3-isopropyl) (I)-1H-pyrazole (1050 mg, 4.77 mmol, 95% yield) was obtained.

[0178] Step 2: 3-([1,1'-biphenyl]-3-yl)-4-bromo-1H-pyra Synthesis of zoles 3-([1,1'-biphenyl]-3-yl)-1H-pyrazole (1050 mg, 4 A solution of NBS (891 mg, 5.01 mmol) in DMF (7.5 ml) ) was added. The mixture was stirred at room temperature for 1 hour. The mixture was diluted with EtOAc / H2O / saturated N The organic layer was poured into a CO (aq) (50 mL / 30 mL / 20 mL). 50 mL), dried (Na2SO4) and filtered. After removal of the solvent, the product The eluate was analyzed by silica gel chromatography using 20-30% EtOAc / hexane as the eluent. Purified by chromatography and purified by 3-([1,1'-biphenyl]-3-yl)-4-bromo-1 H-pyrazole (1200 mg, 4.01 mmol, 84% yield) was obtained.

[0179] Step 3: 2-(3-([1,1'-biphenyl]-3-yl)-4-bromo-1H Synthesis of ethyl (pyrazol-1-yl)thiazole-4-carboxylate In a microwave tube, add ethyl 2-bromothiazole-4-carboxylate (472 mg, 2mmol), 3-([1,1'-biphenyl]-3-yl)-4-bromo-1H-pyro ol (596 mg, 2.000 mmol), and K2CO3 (415 mg, 3.00 mmol) The tube was sealed and DMSO (4 ml) was added. The mixture was heated to 130°C. The mixture was poured into H2O (100 mL) and the solid was filtered and washed with H2O. The solid was dissolved in EtOAc and filtered. The undissolved material was removed by filtration. The resulting hydrolysis acid was (21, about 110 mg containing a small amount of impurities). The filtrate was concentrated to give about 5% Trituration with EtOAc / hexane gave 420 mg of pure product. The solution was concentrated. The extract from the original aqueous layer was combined and then eluted with 20-30% EtOAc / hexane as the eluent. Purification by silica gel chromatography using hexane yielded another 210 mg. A total of 630 mg of 2-(3-([1,1'-biphenyl]-3-yl)-4- Bromo-1H-pyrazol-1-yl)thiazole-4-carboxylate ethyl (630mg , 1.387 mmol, 69.3% yield).

[0180] Step 4: 2-(3-([1,1'-biphenyl]-3-yl)-4-(4,4,5 ,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole- Synthesis of ethyl 1-ylthiazole-4-carboxylate In a microwave tube, 2-(3-([1,1'-biphenyl]-3-yl)-4-bromo- 454 mg of ethyl bromo-1H-pyrazol-1-yl)thiazole-4-carboxylate ( 1mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-biphenyl (1,3,2-dioxaborolane) (381 mg, 1.500 mmol), PdCl2 ( dppf) (73.2 mg, 0.100 mmol), and potassium acetate (294 mg, 3 The tube was sealed, evacuated, and refilled with N2 (2- Then, 1,4-dioxane (4 ml) was added and the mixture was stirred at 95°C (preheated) overnight. The mixture was diluted with EtOAc and filtered through CELITE™. After removal of the solvent, the product was purified by elution with 10-25% EtOAc / hexane as the eluent. The product was purified by silica gel chromatography using ethyl acetate to give the product, which was then hexane, and then dried to give 2-(3-([1,1'-biphenyl [4,4,5,5-tetramethyl-1,3,2-dioxaborola Ethyl (4-benzoyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate The product was obtained as a solid (50 mg, 0.494 mmol, 49.4% yield). It contained 5% of the reduced (deBr) product.

[0181] Step 5: 2-(3-([1,1'-biphenyl]-3-yl)-4-(4-sulfuryl)- ethyl amoylbenzyl-1H-pyrazol-1-yl-thiazole-4-carboxylate Synthesis of In a microwave tube, 2-(3-([1,1'-biphenyl]-3-yl)-4-( 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyridin Ethyl (thiazol-1-yl)thiazole-4-carboxylate (91 mg, 0.1 mmol) , 4-(bromomethyl)benzenesulfonamide (25.01 mg, 0.100 mmol ), and Pd(Ph3P)4 (11.56 mg, 10.00 μmol). The tube was sealed, evacuated and refilled with N2 (2-3 times). Toluene (0.75 ml, A mixture of 0.3 ml of ethanol (ratio: 2.500) / EtOH (ratio: 1.000) was then added, followed by , 2N NaCO 3(水性) (0.3 mL, 0.6 mmol, 6 equiv.) was added. The mixture was stirred at 80°C (preheated) for 2 hours. The organic layer was separated and the aqueous layer was diluted with EtOAc (2 ml The combined organic layers were dried (Na2SO4) and filtered. Removal of solvent The product was then purified by silica gel chromatography using 30-60% EtOAc / hexane as the eluent. Purification by chromatography gave 2-(3-([1,1'-biphenyl]-3-yl) -4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4 Ethyl carboxylate 20 (35 mg, 0.064 mmol, 64.3% yield) was obtained as a white solid. The reduction product from either the reaction and / or the previous step (approximately 30 mg) was obtained as a compound. ) was collected and hydrolyzed to give 22 (see Example 31, Scheme 7A). ) was obtained.

[0182] Step 6: 2-(3-([1,1'-biphenyl]-3-yl)-4-(4-sulfuryl)- amoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid (20 ) synthesis 2-(3-([1,1'-biphenyl]-3-yl)-4-(4-sulfamoylphenyl)benzyl ethyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate (35 mg, A solution of 0.064 mmol) in THF (1 ml) was treated with LiOH (aqueous) (1.5 N in H2O, 0.4 mL, 0.6 mmol) was added. The mixture was stirred at room temperature for 2 hours. N HCl (aqueous) (approximately 0.6-0.65 mL) was added to adjust the pH of the aqueous layer to approximately 4. Next, hexane (5 mL) was added, and the resulting solid was filtered and washed with H2O (1 mL x 2), then Triturate with hexane (2 mL × 2) and dry. Phenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazole-1 (-yl)thiazole-4-carboxylic acid 20 (28 mg, 0.054 mmol, 84% yield) rate).

[0183] The compound was sufficiently pure to be directly loaded onto the system (24 mg). 1 H NMR(4 00MHz,DMSO-d6)δ13.20(s,1H),8.29(s,1H),8. 24(s,1H),7.81(d,J=1.8Hz,1H),7.80-7.74(m, 2H),7.74-7.67(m,2H),7.57(d,J=7.6Hz,3H),7 .50-7.42(m,4H),7.37(dd,J=8.4,6.3Hz,1H),7 .30(s,2H), 4.21(s,2H); MS(M+H) + =517.

[0184] Example 30 This example illustrates the use of 2-(3-([1,1'-biphenyl]-3 -yl)-4-bromo-1H-pyrazol-1-yl)thiazole-4-carboxylic acid,T The synthesis of FA21 is described.

[0185] The by-product from Step 3 in Example 28 was repurified by reverse phase chromatography. 2-(3-([1,1'-biphenyl]-3-yl)-4-bromo-1H-pyrazole- 1-yl)thiazole-4-carboxylic acid, TFA21, was obtained. 1 H NMR (400MH z,DMSO-d6)δ13.25(s,1H),8.93(s,1H),8.28(s ,1H),8.12(d,J=1.8Hz,1H),7.85(dd,J=7.7,1. 5Hz,1H),7.79(dd,J=7.9,1.5Hz,1H),7.72(dd, J=7.5,1.7Hz,2H),7.63(t,J=7.8Hz,1H),7.50( t,J=7.6Hz,2H),7.40(t,J=7.4Hz,1H);MS(M+H) + =427

[0186] Example 31 This example illustrates the use of 2-(3-([1,1'-biphenyl]-3 (1H-pyrazol-1-yl)thiazole-4-carboxylic acid, TFA22 The synthesis is illustrated in Scheme 7A. Scheme 7A [ka]

[0187] 2-(3-([1,1'-biphenyl]-3-yl)-1H-pyrazol-1-yl) Ethyl thiazole-4-carboxylate (30 mg, 0.080 mmol) in THF (1 ml ) solution with LiOH (水性) (1.5N in HO, 0.4 mL, 0.6 mmol) was added. The mixture was stirred at room temperature for 2 hours. Then, 1N HCl (水性) (about 0.6~0.6 The pH of the aqueous layer was adjusted to about 4. Then, hexane (5 mL) was added, and the resulting The solid was filtered and triturated with H2O (1 mL x 2) and then hexane (2 mL x 2). The product still contained a small amount of impurity, which was dissolved in DMF and dried. , filtered and purified to obtain 2-(3-([1,1'-biphenyl]-3-yl )-1H-pyrazol-1-yl)thiazole-4-carboxylic acid, TFA22 (0.8m g, 1.734 μmol, 2.170% yield). MS (M+H) + =348.

[0188] Example 32 This example illustrates the 2-(3-(3,4-difluorophenyl) -1H-pyrrolo[2,3-b]pyridin-1-yl)thiazole-4-carboxylic acid, TF The synthesis of A23 is described. Scheme 8 [ka]

[0189] Step 1: 3-(3,4-difluorophenyl)-1H-pyrrolo[2,3-b]pyrrolidine Synthesis of Gin In a two-neck flask, 3-bromo-1H-pyrrolo[2,3-b]pyridine (788 mg, 4mmol), (3,4-difluorophenyl)boronic acid (758mg, 4.80mmol l), PdCl2(dppf) (146 mg, 0.200 mmol), and K2CO3 ( The air was removed and refilled with N2 (2 3 times). Then, 1,4-dioxane (12 ml, ratio: 2.000) and water (6 ml, ratio: A mixture of 1:1.000 was added and stirred at 95°C (preheated) for 3 hours. The organic layer was separated. The aqueous layer was extracted with EtOAc (5 mL × 2). The combined organic layers were dried (NaSO 4) and filtered. After removal of the solvent, the product was purified by elution with 30-40% EtOAc / hexanes. The product was purified by silica gel chromatography using hexane to obtain 3-(3,4-difluoromethyl-2-methyl-2-propanol). (260 mg, 1.129 mmol)-1H-pyrrolo[2,3-b]pyridine , 28.2% yield).

[0190] Step 2: 2-(3-(3,4-difluorophenyl)-1H-pyrrolo[2,3-b Synthesis of tert-butyl ]pyridin-1-yl)thiazole-4-carboxylate In a microwave tube, 3-(3,4-difluorophenyl)-1H-pyrrolo[2,3 -b]pyridine (50.6 mg, 0.220 mmol), 2-bromothiazole-4-carboxylate tert-Butyl carboxylate (52.8 mg, 0.2 mmol), (1S,2S)-N 1 , N 2 -dimethylcyclohexane-1,2-diamine (5.69 mg, 0.040 mmol) ), CuI (3.81 mg, 0.020 mmol), and K3PO4 (127 mg, 0. The air was evacuated and refilled with N2 (3 times). C. After cooling to room temperature, the mixture was diluted with Et The mixture was diluted with OAc (3 mL), filtered through Celite, and eluted with EtOAc. The mixture was concentrated and purified by silica gel chromatography using 10–30% EtOAc / hexane as the eluent. The product was purified by column chromatography to give 2-(3-(3,4-difluorophenyl)-1H -pyrrolo[2,3-b]pyridin-1-yl)thiazole-4-carboxylic acid tert-butyl The resulting material was purified by HPLC (75 mg, 0.181 mmol, 91% yield). It contained Br starting material and was used for deprotection and purification in the next step.

[0191] Step 3: 2-(3-(3,4-difluorophenyl)-1H-pyrrolo[2,3-b Synthesis of ]pyridin-1-yl)thiazole-4-carboxylic acid, TFA (23) 2-(3-(3,4-difluorophenyl)-1H-pyrrolo[2,3-b]pyridine- tert-Butyl (1-yl)thiazole-4-carboxylate (75 mg, 0.181 mmol) l) in 1,4-dioxane (1 mL) with HCl (4 M in dioxane, 1 mL, 4 mm ol) was added. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated and the crude product was extracted with DMF. The resulting solution was filtered and purified to give 2-(3-(3,4-difluorophenyl) (yl)-1H-pyrrolo[2,3-b]pyridin-1-yl)thiazole-4-carboxylic acid, TFA23 (1.6 mg, 3.39 μmol, 1.871% yield) was obtained. MS (M+ H) + =358.

[0192] Example 33 This example illustrates the use of 2-(5-hydroxy-3-phenyl-4- (4-Sulfamoylphenoxy)-1H-pyrazol-1-yl)thiazol-4-yl The synthesis of carboxylic acid, TFA24, is described. Scheme 9 [ka]

[0193] Step 1: 3-oxo-3-phenyl-2-(4-sulfamoylphenoxy)propanol Synthesis of ethyl pionate Sodium 4-sulfamoylphenolate (195 mg, 1 mmol) and 2-bromo Ethyl mo-3-oxo-3-phenylpropionate (298 mg, 1.100 mmol) To the mixture was added EtOH (1 ml). The mixture was stirred at room temperature for 30 minutes. Concentrate and chromatograph on silica gel using 30-50% EtOAc / hexane as eluent. Purified by chromatography and purified by 3-oxo-3-phenyl-2-(4-sulfamoylphenyl) (hydroxy)ethyl propionate (66 mg, 0.182 mmol, 18.16% yield) Got it.

[0194] Step 2: 2-(5-hydroxy-3-phenyl-4-(4-sulfamoylphenoxy) (1H-pyrazol-1-yl)thiazole-4-carboxylic acid, TFA (24) Synthesis obtained In a microwave tube, 3-oxo-3-phenyl-2-(4-sulfamoylphenoxy) Ethyl 2-hydroxypropionate (66 mg, 0.182 mmol), 2-hydrazinylthiazolidinol Ethyl 4-isothiazolinone carboxylate (34.0 mg, 0.182 mmol), and p-TsOH (34.5 mg, 0.182 mmol) was placed in the flask, and EtOH (2 ml) was added. The container was sealed and heated at 150°C for 20 minutes. The solvent was removed by blowing off air, and then In THF (1 mL) and 1.5 N LiOH (水性) (1 mL, 1.5 mmol) was added The mixture was stirred at room temperature for 1 hour. Then, 1N HCl was added. (水性) (about 1.5~1 0.55 mL) was added (pH of the aqueous layer is about 3), and the aqueous layer was washed with EtOAc (3 mL x 4). The combined organic layers were dried (Na2SO4), filtered and concentrated. The crude product was Dissolved in MF and purified to give 2-(5-hydroxy-3-phenyl-4-(4-sulfamoyl)- (1H-pyrazol-1-yl)thiazole-4-carboxylic acid, TFA 24 (20.8 mg, 0.036 mmol, 20.00% yield) was obtained. MS (M+H ) + =459

[0195] Example 34 This example illustrates the 2-(3-(3,4-difluorophenyl) -1H-pyrazolo[3,4-b]pyridin-1-yl)thiazole-4-carboxylic acid 25 The synthesis of Scheme 10 [ka]

[0196] Step 1: 2-(3-iodo-1H-pyrazolo[3,4-b]pyridin-1-yl) Synthesis of ethyl thiazole-4-carboxylate In a microwave tube, add ethyl 2-bromothiazole-4-carboxylate (472 mg, 2 mmol), 3-iodo-1H-pyrazolo[3,4-b]pyridine (515 mg, 2. 100 mmol), and K2CO3 (304 mg, 2.200 mmol). The vessel was sealed and DMSO (2 ml) was added. The mixture was heated at 140°C for 2 hours. The mixture was poured into EtOAc / H2O (30 mL / 30 mL). The organic layer was dried (Na After removal of the solvent, the product was purified by elution with 30-50-80% E. Purification by silica gel chromatography using tOAc / hexane gave 2-(3- Iodo-1H-pyrazolo[3,4-b]pyridin-1-yl)thiazole-4-carvone Ethyl acetate (328 mg, 0.820 mmol, 41.0% yield) was obtained.

[0197] Step 2: 2-(3-(3,4-difluorophenyl)-1H-pyrazolo[3,4- Synthesis of ethyl b)pyridin-1-yl)thiazole-4-carboxylate In a two-neck flask, add 2-(3-iodo-1H-pyrazolo[3,4-b]pyridine-1- Ethyl)thiazole-4-carboxylate (40.0 mg, 0.1 mmol), (3,4 -difluorophenyl)boronic acid (31.6 mg, 0.200 mmol), PdCl2( dppf) (7.32 mg, 10.00 μmol), and K2CO3 (69.1 mg, 0 The air was removed and refilled with N2 (2-3 times). 1,4-dioxane (1 mL, ratio: 2.000) and water (0.5 ml, ratio: 1.000) The mixture was added and stirred at 95°C (preheated) for 3 hours. The organic layer was separated, and the aqueous layer was diluted with Et The combined organic layer was dried (Na2SO4) and filtered. After removal of the solvent, the product was purified using 40-70% EtOAc / hexane as the eluent. The compound was purified by silica gel chromatography to give 2-(3-(3,4-difluorophenyl) (I)-1H-pyrazolo[3,4-b]pyridin-1-yl)thiazole-4-carboxylic acid Ethyl (11 mg, 0.028 mmol, 28.5% yield) was obtained.

[0198] Step 3: 2-(3-(3,4-difluorophenyl)-1H-pyrazolo[3,4- Synthesis of b]pyridin-1-yl)thiazole-4-carboxylic acid (25) 2-(3-(3,4-difluorophenyl)-1H-pyrazolo[3,4-b]pyridine T of ethyl (1-yl)thiazole-4-carboxylate (10 mg, 0.026 mmol) A solution of LiOH (aqueous) (1.5 N in HO, 0.4 mL, 0.6 mmol) in HF (1 mL) l) was added. The mixture was stirred at room temperature for 2 hours. Then, 1N HCl (aq) (ca. 0.1 mL) was added. The pH of the aqueous layer was adjusted to approximately 4. Then, hexane (5 mL) was added. The resulting solid was filtered, triturated with hexane (2 mL x 2), and dried. , 2-(3-(3,4-difluorophenyl)-1H-pyrazolo[3,4-b]pyridine (1-yl)thiazole-4-carboxylic acid 25 (6 mg, 0.017 mmol, 64.7 % yield). 1 H NMR(400MHz,DMSO-d6)δ13.16(s, 1H),8.88-8.78(m,2H),8.33(s,1H),8.15(ddd, J=11.7,7.7,2.2Hz,1H),8.05-7.97(m,1H),7.6 8(dt,J=10.8,8.5Hz,1H),7.60(dd,J=8.1,4.6H z, 1H); MS (M+H) + =359.

[0199] Example 35 This example illustrates the 2-(3-(4-sulfamoylbenzyl) -1H-pyrrolo[2,3-b]pyridin-1-yl)thiazole-4-carboxylic acid 26 Synthesis will be explained. Scheme 11 [ka]

[0200] Step 1: 2-(3-bromo-1H-pyrrolo[2,3-b]pyridin-1-yl)thio Synthesis of ethyl azole-4-carboxylate In a microwave tube, add ethyl 2-bromothiazole-4-carboxylate (944 mg, 4mmol), 3-bromo-1H-pyrrolo[2,3-b]pyridine (867mg, 4.4 0 mmol), and K2CO3 (663 mg, 4.80 mmol). The mixture was sealed and DMSO (7.5 ml) was added. The mixture was heated at 150° C. for 3 hours. The organics were poured into EtOAc / H2O (30 mL / 30 mL). The organics were dried (Na2 SO4) and filtered. After removal of the solvent, the product was purified by elution with 10-20% EtOAc. Purification by silica gel chromatography (twice) using hexane gave 2-(3- Bromo-1H-pyrrolo[2,3-b]pyridin-1-yl)thiazole-4-carboxylic acid Ethyl (587 mg, 1.667 mmol, 41.7% yield) was obtained.

[0201] Step 2: 2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaboro) lan-2-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl)thiazol-4- Synthesis of ethyl carboxylate In a microwave tube, 2-(3-bromo-1H-pyrrolo[2,3-b]pyridine-1 -yl)thiazole-4-carboxylate ethyl (352 mg, 1 mmol), 4,4,4' ,4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaboro) Ran) (330 mg, 1.300 mmol), PdCl2(dppf) (73.2 mg, 0.100 mmol) and AcOK (294 mg, 3.00 mmol). The tube was sealed, evacuated and refilled with N2 (2-3 times). Water (3 ml) was added and the mixture was stirred at 95°C (preheated) overnight. The mixture was diluted with EtOAc. The extract was diluted and filtered through CELITE™, eluting with EtOAc. The product was purified by silica gel chromatography using 10-25% EtOAc / hexane as the eluent. The product was purified by chromatography to give the product, which was triturated with a small amount of hexane, 2-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl )-1H-pyrrolo[2,3-b]pyridin-1-yl)thiazole-4-carboxylic acid ethyl ester The resulting product was purified by HPLC to give 1,3-dimethyl-2,4-trimethyl- ...

[0202] Step 3: 2-(3-(4-sulfamoylbenzyl)-1H-pyrrolo[2,3-b Synthesis of ethyl thiazole-4-carboxylate In a microwave tube, 2-(3-(4,4,5,5-tetramethyl-1,3,2-di Oxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl)thiazo Ethyl 4-bromomethylpropional (39.9 mg, 0.1 mmol), 4-(bromomethyl) Benzenesulfonamide (25.01 mg, 0.100 mmol), and Pd(PhP ) 4 (11.56 mg, 10.00 μmol) was added. The tube was sealed and air was removed. The mixture was then refilled with N2 (2-3 times). Toluene (0.75 ml, ratio: 2.500) / Et A mixture of 2N Na2CO3 ( aq) (0.3 mL, 0.6 mmol, 6 equiv.) was added. The mixture was heated to 80°C (preheated The mixture was stirred at rt for 2 hours. The organic layer was separated, and the aqueous layer was extracted with EtOAc (2 mL x 3). The combined organic layers were dried (Na2SO4) and filtered. After removal of the solvent, the product was extracted with eluent. by silica gel chromatography using 30-80% EtOAc / hexanes. The compound was purified by 2-(3-(4-sulfamoylbenzyl)-1H-pyrrolo[2,3-b]piperidinyl)- Ethyl lysin-1-yl)thiazole-4-carboxylate (28 mg, 0.063 mmol) , 63.3% yield) as a white solid.

[0203] Step 4: 2-(3-(4-sulfamoylbenzyl)-1H-pyrrolo[2,3-b Synthesis of ]pyridin-1-yl)thiazole-4-carboxylic acid (26) 2-(3-(4-sulfamoylbenzyl)-1H-pyrrolo[2,3-b]pyridine- 1-yl)thiazole-4-carboxylate ethyl (28 mg, 0.063 mmol) F (1 ml) solution in LiOH (水性) (1.5N in H2O, 0.4mL, 0.6mmol ) was added. The mixture was stirred at room temperature for 2 hours. Then, 1N HCl (水性) (about 0. The pH of the aqueous layer was adjusted to about 4. Then, hexane (5 mL) was added. The resulting solid was filtered and diluted with H2O (1 ml x 2) and then hexane (2 mL x 2). Triturated with, dried, and purified by 2-(3-(4-sulfamoylbenzyl)-1H-pyrrolidine dihydrate. (2,3-b)pyridin-1-yl)thiazole-4-carboxylic acid 26 (21 mg, 0 The product was obtained in an amount of 0.051 mmol, 80% yield. 1 H NMR (400 MHz, DMSO-d 6)δ13.04(s,1H),8.46(dd,J=4.8,1.5Hz,1H),8 .19(s,1H),8.09(dd,J=7.8,1.5Hz,1H),8.07(s ,1H),7.80-7.72(m,2H),7.58(d,J=8.2Hz,2H), 7.32(dd,J=7.9,4.8Hz,1H),7.27(s,2H),4.23( s,2H); MS(M+H) + =415.

[0204] Example 36 This example illustrates the use of 2-(4-(methylsulfonyl)benzoates in accordance with an embodiment of the present invention. (3-phenyl-1H-pyrazol-1-yl)thiazole-4-carboxylic acid 27 The synthesis of Scheme 12 [ka]

[0205] Step 1: 2-(4-(4-(methylsulfonyl)benzyl)-3-phenyl-1H Synthesis of ethyl (pyrazol-1-yl)thiazole-4-carboxylate In a microwave tube, 2-(3-phenyl-4-(4,4,5,5-tetramethyl- 1,3,2-Dioxaborolan-2-yl)-1H-pyrazol-1-yl)thiazole Ethyl 4-carboxylate (70.9 mg, 0.1 mmol), 1-(bromomethyl)-4 -(methylsulfonyl)benzene (24.91 mg, 0.100 mmol), and Pd( Ph3P4 (11.56 mg, 10.00 μmol) was added. The tube was sealed and evacuated. The gas was evacuated and refilled with N2 (2-3 times). Toluene (0.75 ml, ratio: 2.500 ) / EtOH (0.3 ml, ratio: 1.000) mixture was added, followed by 2N Na CO 3(水性) (0.3 mL, 0.6 mmol, 6 equiv.) was added. The mixture was heated to 80°C ( The mixture was stirred for 2 hours at room temperature (preheated). The organic layer was separated, and the aqueous layer was extracted with EtOAc (2 mL × 3). The combined organic layers were dried (Na2SO4) and filtered. After removal of the solvent, the product was obtained as follows: Silica gel chromatography using 25-50% EtOAc / hexane as the eluent Purified by HPLC and purified by 2-(4-(4-(methylsulfonyl)benzyl)-3-phenyl- Ethyl 1H-pyrazol-1-yl)thiazole-4-carboxylate (35 mg, 0.07 5 mmol, 74.9% yield) as a white solid.

[0206] Step 2: 2-(4-(4-(methylsulfonyl)benzyl)-3-phenyl-1H Synthesis of (pyrazol-1-yl)thiazole-4-carboxylic acid (27) 2-(4-(4-(methylsulfonyl)benzyl)-3-phenyl-1H-pyrazole T-1-yl)ethyl thiazole-4-carboxylate (35 mg, 0.075 mmol) LiOH in HF (1 ml) solution (水性) (1.5N in H2O, 0.4mL, 0.6mmo l) was added. The mixture was stirred at room temperature for 2 hours. Then, 1N HCl (水性) (about 0 The pH of the aqueous layer was adjusted to approximately 4. Then, hexane (5 mL) was added. The resulting solid was filtered and washed with HO (1 ml × 2) and then hexane (2 mL × 2 ), dried, and 2-(4-(4-(methylsulfonyl)benzyl)-3 -phenyl-1H-pyrazol-1-yl)thiazole-4-carboxylic acid 27 (30 mg , 0.068 mmol, 91% yield). 1 H NMR (400 MHz, DMSO -d6)δ13.17(s,1H),8.34(s,1H),8.23(d,J=1.7 Hz,1H),7.86-7.79(m,2H),7.70-7.62(m,2H),7 .53-7.37(m,5H),4.19(s,2H),3.17(s,3H);MS( M+H) + =440.

[0207] Example 37 This example illustrates the use of 2-(3-phenyl-4-(4-(trifluoromethyl)phenyl)-2-(3-phenyl- ... (benzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid, The synthesis of TFA28 is described. Scheme 13 [ka]

[0208] Step 1: 2-(3-phenyl-4-(4-(trifluoromethyl)benzyl)-1 Synthesis of ethyl (H-pyrazol-1-yl)thiazole-4-carboxylate In a microwave tube, 2-(3-phenyl-4-(4,4,5,5-tetramethyl- 1,3,2-Dioxaborolan-2-yl)-1H-pyrazol-1-yl)thiazole Ethyl 4-carboxylate (70.9 mg, 0.1 mmol), 1-(bromomethyl)-4 -(trifluoromethyl)benzene (23.90 mg, 0.100 mmol), and Pd (Ph3P)4 (11.56 mg, 10.00 μmol) was added. The tube was sealed. The air was evacuated and refilled with N2 (2-3 times). Toluene (0.75 ml, ratio: 2.50 A mixture of 2N NaCl (0.3 ml, ratio: 1.000) was added, followed by 2N NaCl. 2CO 3(水性) (0.3 mL, 0.6 mmol, 6 equiv.) was added. The mixture was heated to 80°C. The mixture was stirred at RT (preheated) for 2 hours. The organic layer was separated, and the aqueous layer was extracted with EtOAc (2 mL × 3). The combined organic layers were dried (Na2SO4) and filtered. After removal of the solvent, the product was Silica gel chromatography using 10-25% EtOAc / hexane as the eluent Purified by filtration and purified by 2-(3-phenyl-4-(4-(trifluoromethyl)benzyl )-1H-pyrazol-1-yl)thiazole-4-carboxylate ethyl (58 mg, 0. This material was mixed with the reduction product to give a white solid (0.70 mmol, 69.7% yield). The resulting mixture was combined and used directly for hydrolysis and purified in the next step.

[0209] Step 2: 2-(3-phenyl-4-(4-(trifluoromethyl)benzyl)-1 Synthesis of H-pyrazol-1-yl)thiazole-4-carboxylic acid, TFA (28) 2-(3-phenyl-4-(4-(trifluoromethyl)benzyl)-1H-pyrazoline Ethyl (1-yl)thiazole-4-carboxylate (58 mg, 0.070 mmol) THF (1 ml) solution 水性) (1.5N in H2O, 0.4mL, 0.6mm ol) was added. The mixture was stirred at room temperature for 2 hours. Then, 1N HCl (水性) (about 0.6-0.65 mL) was added to adjust the pH of the aqueous layer to about 4. The mixture was then concentrated. The residue was dissolved in DMF, filtered and purified to give 2-(3-phenyl-4 -(4-(trifluoromethyl)benzyl)-1H-pyrazol-1-yl)thiazole -4-carboxylic acid, TFA28 (13 mg, 0.024 mmol, 34.3% yield) Got it. 1 H NMR(400MHz,DMSO-d6)δ13.17(s,1H),8. 33(s,1H),8.23(s,1H),7.69-7.59(m,4H),7.50 -7.36(m,5H),4.18(s,2H);MS(M+H) + =430.

[0210] Example 38 This example illustrates the use of 2-(3-([1,1'-biphenyl]-3 -yl)-1H-pyrrolo[2,3-b]pyridin-1-yl)thiazole-4-carvone The synthesis of the acid, TFA29, is described. Scheme 14 [ka]

[0211] Step 1: 2-(3-([1,1'-biphenyl]-3-yl)-1H-pyrrolo[2 Synthesis of ethyl 3-b-pyridin-1-yl)thiazole-4-carboxylate In a two-neck flask, add 2-(3-bromo-1H-pyrrolo[2,3-b]pyridine-1-yl) ethyl thiazole-4-carboxylate (35.2 mg, 0.1 mmol), [1,1' -biphenyl]-3-ylboronic acid (39.6 mg, 0.200 mmol), PdCl2 (dppf) (7.32 mg, 10.00 μmol), and K2CO3 (69.1 mg, The air was removed and refilled with N2 (2-3 times). , 1,4-dioxane (1 mL, ratio: 2.000) and water (0.5 mL, ratio: 1.000 The mixture was added with 100 ml of ethanol and stirred at 95°C (preheated) for 3 hours. The organic layer was separated and the aqueous layer was The mixture was extracted with tOAc (5 mL x 3). The combined organic layers were dried (Na2SO4) and filtered. After removal of the solvent, the product was purified using 40-70% EtOAc / hexane as the eluent. The product was purified by silica gel chromatography to give 2-(3-([1,1'-biphenyl ]-3-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl)thiazole-4-carboxylate Ethyl carboxylate (30 mg, 0.053 mmol, 52.9% yield) was obtained. The product contained some impurities and was used in the next step without further purification. Ta.

[0212] Step 2: 2-(3-([1,1'-biphenyl]-3-yl)-1H-pyrrolo[2 Synthesis of [3-b]pyridin-1-yl)thiazole-4-carboxylic acid, TFA (29) 2-(3-([1,1'-biphenyl]-3-yl)-1H-pyrrolo[2,3-b]pi Ethyl lysin-1-yl)thiazole-4-carboxylate (30 mg, 0.071 mmol ) in THF (1 ml) with LiOH (水性) (1.5N in H2O, 0.4mL, 0.6 (mmol) was added. The mixture was stirred at room temperature for 3 hours. Then, 1N HCl (水性) ( Approximately 0.6 to 0.65 mL of HCl was added to adjust the pH of the aqueous layer to approximately 4. The mixture was concentrated to remove the remaining The product was dissolved in DMF, filtered, and purified to give 2-(3-([1,1'-biphenyl]-2-methyl-2-propanol). [phenyl]-3-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl)thiazole -4-carboxylic acid, TFA29 (2.1 mg, 4.11 μmol, 5.82% yield) Got it. 1 H NMR(400MHz,DMSO-d6)δ13.08(s,1H),8. 68(s,1H),8.57(d,J=4.7Hz,1H),8.55-8.50(m, 1H),8.28(s,1H),8.07(d,J=2.0Hz,1H),7.83(m ,3H),7.68(d,J=7.7Hz,1H),7.61(t,J=7.6Hz,1 H),7.54-7.44(m,3H),7.43-7.35(m,1H);MS(M+ H) + =398.

[0213] Example 39 This example illustrates the 2-(5-(morpholine-4-carbonyl) -3-(4-sulfamoylbenzyl)-1H-indol-1-yl)thiazole-4 -The synthesis of carboxylic acid 30 is described. Scheme 15 [ka]

[0214] Step 1: (3-Bromo-1H-indol-5-yl)(morpholino)methanone synthesis 3-Bromo-1H-indole-5-carboxylic acid (960 mg, 4 mmol) and HA To a mixture of TU (2281 mg, 6.00 mmol), DMF (5 ml) was added, followed by morpholine. Phosphorus (697 mg, 8.00 mmol) and Hunig's base (1.048 ml, 6.0 0 mmol) was added. The mixture was stirred at room temperature for 1.5 hours. The mixture was diluted with EtOAc / H The organic layer was dried (Na2SO4) and filtered. After removal of the solvent, the product was purified using 50-100% EtOAc / hexane as the eluent. The product was purified by silica gel chromatography to give (3-bromo-1H-indole-5 -yl)(morpholino)methanone (1204 mg, 3.89 mmol, 97% yield) Got it.

[0215] Step 2: 2-(3-bromo-5-(morpholine-4-carbonyl)-1H-indo Synthesis of ethyl (1-yl)thiazole-4-carboxylate In a microwave tube, add ethyl 2-bromothiazole-4-carboxylate (425 mg, 1.800mmol), (3-bromo-1H-indol-5-yl)(morpholino)methyl Tanone (464 mg, 1.5 mmol), and K2CO3 (415 mg, 3.00 mmol) The tube was sealed and DMSO (3 ml) was added. The mixture was heated at 125°C. The mixture was poured into vigorously stirred H2O (100 mL) and the solid was filtered. The solid was triturated with H2O and dried. Hexane (30 mL) was added to the solid and mixed. The product was sonicated and filtered. The solid was dried and 2-(3-bromo-5-(morpholine-4 -carbonyl)-1H-indol-1-yl)thiazole-4-carboxylate ethyl (4 The compound was obtained as follows: 85 mg, 1.045 mmol, 69.6% yield.

[0216] Step 3: 2-(5-(morpholine-4-carbonyl)-3-(4,4,5,5-tetramethyl)-2-(5- ... tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-1-yl ) Synthesis of ethyl thiazole-4-carboxylate In a microwave tube, 2-(3-bromo-5-(morpholine-4-carbonyl)-1 Ethyl H-indol-1-ylthiazole-4-carboxylate (464 mg, 1 mmol) l), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3 ,2-dioxaborolane) (381 mg, 1.500 mmol), PdCl2 (dppf ) (73.2 mg, 0.100 mmol), and potassium acetate (294 mg, 3.00 m The tube was sealed, evacuated, and refilled with N2 (2-3 times). Then 1,4-dioxane (3 ml) was added and stirred at 95° C. (preheated) overnight. The mixture was diluted with EtOAc and filtered through CELITE™, eluting with EtOAc. After removal of the solvent, the product was purified by elution with 40-100% EtOAc / hexane. The product was purified by silica gel chromatography using a small amount of hexane. Triturate with HCl to obtain 2-(5-(morpholine-4-carbonyl)-3-(4,4 ,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole Ethyl (1-yl)thiazole-4-carboxylate (360 mg, 0.669 mmol, The resulting material (66.9% yield) was obtained as a solid. This material contained very small amounts of the reduced (deBr) product. , which contained approximately 5% and was used without further purification.

[0217] Step 4: 2-(5-(morpholine-4-carbonyl)-3-(4-sulfamoyl) Synthesis of ethyl benzyl-1H-indol-1-yl-thiazole-4-carboxylate In a microwave tube, 2-(5-(morpholine-4-carbonyl)-3-(4,4, 5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole -1-yl)thiazole-4-carboxylate ethyl (77 mg, 0.15 mmol), 4- (Bromomethyl)benzenesulfonamide (49.9 mg, 0.200 mmol), and Pd(Ph3P)4 (17.33 mg, 0.015 mmol) was added. The tube was sealed. The mixture was then evacuated and refilled with N2 (2-3 times). Toluene (0.75 ml, ratio: 2. A mixture of 2N NaCl (0.500) / EtOH (0.3 ml, ratio: 1.000) was added, followed by 2N NaCl. NaCO 3(水性) (0.3 mL, 0.6 mmol, 4 equiv.) was added. The mixture was mixed with 8 The mixture was stirred at 0°C (preheated) for 2 hours. The organic layer was separated, and the aqueous layer was diluted with EtOAc (2 mL x 3). The combined organic layers were dried (Na2SO4) and filtered. After removal of the solvent, the product The material was purified by silica gel chromatography using 90-100% EtOAc / hexane as the eluent. The product was purified by HPLC and purified to give 2-(5-(morpholine-4-carbonyl)-3-(4-sulfonyl)- (1H-indol-1-yl)thiazole-4-carboxylic acid ester The ethyl acetate (70 mg, 0.126 mmol, 84% yield) was obtained as a white solid.

[0218] Step 5: 2-(5-(morpholine-4-carbonyl)-3-(4-sulfamoyl) Synthesis of (benzyl)-1H-indol-1-yl)thiazole-4-carboxylic acid (30) 2-(5-(morpholine-4-carbonyl)-3-(4-sulfamoylbenzyl)- Ethyl 1H-indol-1-yl)thiazole-4-carboxylate (65 mg, 0.11 7 mmol) in THF (1 ml) (水性) (1.5N in H2O, 0.4m L, 0.6 mmol) was added. The mixture was stirred at room temperature for 2 hours. Then, 1N HCl l (水性) (approximately 0.6 to 0.65 mL) was added to adjust the pH of the aqueous layer to approximately 4. Xanthan Gum (5 mL) was added, and the resulting solid was filtered and washed with H2O (1 mL x 2) and then hexane. The solid was collected and triturated with 10% CHCl. 2 / hexane (15 mL) was added, the mixture was sonicated and filtered. The solid was dried and 2-(5-(morpholine-4-carbonyl)-3-(4-sulfamoylbenzyl)-1 H-indol-1-yl)thiazole-4-carboxylic acid 30 (19 mg, 0.036 m mol, 30.8% yield). 1 H NMR (400 MHz, DMSO-d6) δ 13.20(s,1H),8.40(d,J=8.5Hz,1H),8.20(s,1H ),7.95(s,1H),7.73(d,J=8.0Hz,2H),7.61(s,1 H),7.55(d,J=8.0Hz,2H),7.43(d,J=8.6Hz,1H) ,7.25(s,2H),4.21(s,2H),3.76-3.34(m,8H);M S(M+H) + =527.

[0219] <Example 40> This example illustrates the use of 2-(5-fluoro-3-(4-sulfamoyl)methylpropional in an embodiment of the present invention. Synthesis of (1H-indol-1-yl)benzyl-1H-indol-1-yl-thiazole-4-carboxylic acid 31 Explain. Scheme 16 [ka]

[0220] Step 1: Synthesis of 3-bromo-5-fluoro-1H-indole 5-Fluoro-1H-indole (1351 mg, 10 mmol) in CHCl at 0 °C 3 (10 ml) and pyridine (1.779 ml, 22.00 mmol) To a solution of 2,5-dichloro-1,5-dichloro-2 ... The mixture was concentrated to remove most of the solvent. The residue was dissolved in EtOAc (50 ml L), and the organic layer was dissolved in 0.5N HCl (水性) (50 mL), H2O (50 mL) , 2N NaCO 3(水性) (50 mL), washed with HO (50 mL), dried (N a2SO4), filtered. The product was confirmed by LCMS, dried, and purified by 3-bromo-5 -Fluoro-1H-indole (1945 mg, 9.09 mmol, 91% yield) was obtained. This material was used in the next step without further purification.

[0221] Step 2: 2-(3-bromo-5-fluoro-1H-indol-1-yl)thiazo Synthesis of ethyl 4-aminobenzoate In a microwave tube, add ethyl 2-bromothiazole-4-carboxylate (708 mg, 3mmol), 3-bromo-5-fluoro-1H-indole (642mg, 3.00m mol) and K2CO3 (829 mg, 6.00 mmol). The tube was sealed. DMSO (4 ml) was added. The mixture was heated at 125°C for 5 hours. Pour into gently stirred H2O (100 mL), filter the solid, add H2O, then hexane. Triturate with ethanol and dry to obtain 2-(3-bromo-5-fluoro-1H-indole Ethyl (7-1-yl)thiazole-4-carboxylate (800 mg, 2.167 mmol, 7 The product was obtained in a yield of 2.2%.

[0222] Step 3: 2-(5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2 -dioxaborolan-2-yl)-1H-indol-1-yl)thiazol-4-yl Synthesis of ethyl benzoate In a microwave tube, 2-(3-bromo-5-fluoro-1H-indole-1-yl) Ethyl thiazole-4-carboxylate (554 mg, 1.5 mmol), 4,4,4' ,4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaboro) Ran) (571 mg, 2.250 mmol), PdCl2(dppf) (110 mg, 0 0.150 mmol), and potassium acetate (442 mg, 4.50 mmol). The tube was sealed, evacuated, and refilled with N2 (2-3 times). Xanthan Gum (4 ml) was added and the mixture was stirred at 95° C. (preheated) overnight. Diluted and filtered through CELITE™, eluting with EtOAc. After removal of the solvent, The product was purified by silica gel chromatography using 5-20% EtOAc / hexane as eluent. The product was purified by HPLC to give the product, which was triturated with a small amount of hexane to give , 2-(5-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxabo Ethyl (loran-2-yl)-1H-indol-1-yl)thiazole-4-carboxylate (730 mg, approximately 55% purity, 0.965 mmol, 64.3% yield) as a solid This material contained approximately 45% of the reduced (deBr) product.

[0223] Step 4: 2-(5-fluoro-3-(4-sulfamoylbenzyl)-1H-yne Synthesis of ethyl thiazole-1-yl-4-carboxylate In a microwave tube, 2-(5-fluoro-3-(4,4,5,5-tetramethyl- 1,3,2-Dioxaborolan-2-yl)-1H-indol-1-yl)thiazole Ethyl 4-carboxylate (114 mg, 0.15 mmol, approximately 55% purity), 4-(bromo- (bromomethyl)benzenesulfonamide (49.9 mg, 0.200 mmol), and Pd (Ph3P)4 (17.33 mg, 0.015 mmol) was added. The tube was sealed. The air was evacuated and refilled with N2 (2-3 times). Toluene (0.75 ml, ratio: 2.50 A mixture of 2N NaCl (0.3 ml, ratio: 1.000) was added, followed by 2N NaCl. 2CO 3(水性) (0.3 mL, 0.6 mmol, 4 equiv.) was added. The mixture was heated to 80° C. The mixture was stirred at RT (preheated) for 2 hours. The organic layer was separated, and the aqueous layer was extracted with EtOAc (2 mL × 3). The combined organic layers were dried (Na2SO4) and filtered. After removal of the solvent, the product was Silica gel chromatography using 20-50% EtOAc / hexane as the eluent Purified by filtration and purified as 2-(5-fluoro-3-(4-sulfamoylbenzyl)-1H Ethyl (-indol-1-yl)thiazole-4-carboxylate (47 mg, 0.102 m mol, 68.2% yield) as a white solid.

[0224] Step 5: 2-(5-fluoro-3-(4-sulfamoylbenzyl)-1H-yne Synthesis of (1-thiazole-4-yl)thiazole-4-carboxylic acid (31) 2-(5-fluoro-3-(4-sulfamoylbenzyl)-1H-indole-1- Ethyl)thiazole-4-carboxylate (47 mg, 0.102 mmol) in THF( 1ml) solution with LiOH (水性) (1.5N in HO, 0.4 mL, 0.6 mmol) The mixture was stirred at room temperature for 2 hours. Then, 1N HCl was added. (水性) (about 0.6~ The pH of the aqueous layer was adjusted to about 4. Then, hexane (5 mL) was added. The resulting solid was filtered and triturated with H2O (1 mL x 2) and then hexane (2 mL x 2). It is irritated, dried and purified by filtration to give 2-(5-fluoro-3-(4-sulfamoylbenzyl) -1H-indol-1-yl)thiazole-4-carboxylic acid 31 (37 mg, 0.08 6 mmol, 84% yield). 1 H NMR (400 MHz, DMSO-d6) δ 13.17(s,1H),8.40(dd,J=9.2,4.5Hz,1H),8.19 (d,J=1.0Hz,1H),7.93(s,1H),7.73(d,J=8.0Hz ,2H),7.56(d,J=8.0Hz,2H),7.37(dd,J=9.2,2. 6Hz,1H),7.27-7.18(m,3H),4.16(s,2H);MS(M+ H) + =432.

[0225] <Example 41> This example illustrates the use of 2-(5-(morpholinomethyl)-3-(4 -Sulfamoylbenzyl)-1H-indol-1-yl)thiazole-4-carvone The synthesis of acid 32 is described. Scheme 17 [ka]

[0226] Step 1: 4-((3-bromo-1H-indol-5-yl)methyl)morpholine Synthesis of (3-Bromo-1H-indol-5-yl)(morpholino)methanonitrile was added under N2 at 0 °C. A solution of 711 mg (2.3 mmol) in 5 ml of CH2Cl2 was added to the solution of DIBAL-H 636 mg, 11.50 mmol) (1 M in THF, 11.5 mL) was added. After the addition of AL-H, the mixture was allowed to warm to room temperature for 2 hours. Rochelle salt solution (水性) (15 mL) and pour the mixture slowly into The mixture was stirred for 30 minutes. The aqueous layer was extracted with CH2Cl2 (10 mL x 2). The combined organic layer was After removal of the solvent, the product was extracted with 50-100 ml of hexane as eluent. Purification by silica gel chromatography using 0% EtOAc / hexane gave 4 -((3-bromo-1H-indol-5-yl)methyl)morpholine (477 mg, 1 The product was obtained in a yield of 0.616 mmol (70.3%).

[0227] Step 2: 2-(3-bromo-5-(morpholinomethyl)-1H-indole-1- Synthesis of ethyl thiazole-4-carboxylate In a microwave tube, add ethyl 2-bromothiazole-4-carboxylate (443 mg, 1.875mmol), 4-((3-bromo-1H-indol-5-yl)methyl)molybdenum fluphorine (443 mg, 1.5 mmol), and K2CO3 (311 mg, 2.250 mmol). The tube was sealed and DMSO (2 ml) was added. The mixture was diluted to 125 The mixture was poured into EtOAc / H2O (50 mL / 50 mL). The aqueous layer was extracted with EtOAc (50 mL × 2). The combined organic layers were dried (NaSO 4) and filtered. After removal of the solvent, the product was purified by elution with 40-100% EtOAc / Purification by silica gel chromatography using hexane gave 2-(3-bromo-5 -(morpholinomethyl)-1H-indol-1-yl)thiazole-4-carboxylic acid ester The resulting product was ethyl (426 mg, 0.946 mmol, 63.1% yield).

[0228] Step 3: 2-(5-(morpholinomethyl)-3-(4,4,5,5-tetramethyl)- -1,3,2-dioxaborolan-2-yl)-1H-indol-1-yl)thiazo Synthesis of ethyl benzoyl-4-carboxylate In a microwave tube, 2-(3-bromo-5-(morpholinomethyl)-1H-indo Ethyl (1-yl)thiazole-4-carboxylate (426 mg, 0.946 mmol ), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3, 2-Dioxaborolane) (480 mg, 1.892 mmol), PdCl2(dppf) (69.2 mg, 0.095 mmol), and potassium acetate (371 mg, 3.78 mmol) The tube was sealed, evacuated, and refilled with N2 (2-3 times). Then, 1,4-dioxane (2 ml) was added, and the mixture was stirred at 95°C (preheated) for 5 hours. The mixture was diluted with EtOAc and filtered through Celite, eluting with EtOAc. After removal, the product was purified by silica gel chromatography using 50-100% EtOAc / hexane as eluent. The product was purified by column chromatography to give 2-(5-(morpholinomethyl)-3-(4, 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indo Ethyl (1-yl)thiazole-4-carboxylate was obtained as a solid.

[0229] Step 4: 2-(5-(morpholinomethyl)-3-(4-sulfamoylbenzyl) Synthesis of ethyl (1H-indol-1-yl)thiazole-4-carboxylate In a microwave tube, 2-(5-(morpholinomethyl)-3-(4,4,5,5-tetramethyl-2-methyl-4- ...2-methyl-4-methyl-2-methyl tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indol-1-yl ) Ethyl thiazole-4-carboxylate (99 mg, 0.2 mmol), 4-(bromomethyl (Pd) benzenesulfonamide (50.0 mg, 0.2 mmol), and Pd(PhP) 4 (23.11 mg, 0.020 mmol) was added. The tube was sealed and air was removed. The flask was refilled with N2 (2-3 times). Toluene (0.75 ml, ratio: 2.500) / EtO A mixture of HCl (0.3 ml, ratio: 1.000) was added, followed by 2N NaCO 3(水 性) (0.3 mL, 0.6 mmol, 6 equiv.) was added. The mixture was heated to 80 °C (preheated). The mixture was stirred at RT for 2 hours. The organic layer was separated, and the aqueous layer was extracted with EtOAc (2 mL x 3). The combined organic layer was dried (Na2SO4) and filtered. After removal of the solvent, the product was obtained as eluent. by silica gel chromatography using 60-100% EtOAc / hexane. and purified as 2-(5-(morpholinomethyl)-3-(4-sulfamoylbenzyl)-1 Ethyl H-indol-1-ylthiazole-4-carboxylate (37 mg, 0.068 The compound (2,2-dimethyl-3,4-dichloro-2 ...

[0230] Step 5: 2-(5-(morpholinomethyl)-3-(4-sulfamoylbenzyl) Synthesis of (1H-indol-1-yl)thiazole-4-carboxylic acid (32) 2-(5-(morpholinomethyl)-3-(4-sulfamoylbenzyl)-1H-yne Ethyl (1-thiazole-4-carboxylate) (37 mg, 0.068 mmol ) in THF (1 ml) (水性) (1.5N in H2O, 0.4mL, 0.6 The mixture was stirred at room temperature for 2 hours. Then, 1N HCl (水性) (approximately 0.6 mL) was added to adjust the pH of the aqueous layer to approximately 6. Then, hexane (5 mL) was added. The solid was filtered and triturated with H2O (1 mL x 2) and then hexane (2 mL x 2). The resulting mixture was filtered, dried, and 2-(5-(morpholinomethyl)-3-(4-sulfamoylbenzene) (1H-indol-1-yl)-1H-indol-1-yl)thiazole-4-carboxylic acid 32 (23 mg, 0. 0.45 mmol, 65.6% yield). MS (M+H) + =513.

[0231] <Example 42> This example illustrates the use of 2-(3-phenyl-4-(4-sulfamoyl)phenyl)- ... Synthesis of (1H-pyrazol-1-yl)thiazole-4-carboxylic acid 33 Explain the composition. Scheme 18 [ka]

[0232] Step 1: Synthesis of 4-(2-oxo-2-phenylethoxy)benzenesulfonamide Growth 4-Hydroxybenzenesulfonamide (520 mg, 3.00 mmol) and K2C Acetone (10 mL) was added to a mixture of O3 (551 mg, 3.99 mmol) and the mixture was heated at room temperature. The mixture was stirred at rt for 30 min. Then, 2-bromo-1-phenylethanone (597 mg, 3 mm 100 ml of acetone (5 mL) was added. The mixture was stirred at room temperature for 20 hours. 20 (15 mL) and hexane (20 mL) were added to the reaction mixture. The solid was filtered and The solid was washed with 20 (2 mL x 2) and then with 5% EtOAc / hexane (5 mL x 3). The body was dried and 4-(2-oxo-2-phenylethoxy)benzenesulfonamide (80 4 mg, 2.76 mmol, 92% yield) as a white solid.

[0233] Step 2: 4-((3-phenyl-1H-pyrazol-4-yl)oxy)benzene Synthesis of sulfonamides In a microwave tube, 4-(2-oxo-2-phenylethoxy)benzenesulfone amide (291 mg, 1 mmol) and 1,1-dimethoxy-N,N-dimethylmethanamide The tube was sealed and heated to 90°C. The mixture was concentrated by blowing air through it, and the residue was concentrated in vacuo for several minutes. After drying for 1 hour, 4-((1-(dimethylamino)-3-oxo-3-phenylpropion-1 -en-2-yl)oxy)benzenesulfonamide (any isomer or aldehyde The crude intermediate was added to EtOH (4 mL) and N2H4 monohydrate ( MW=50, d=1.032, 0.145 mL, 3 mmol) was added. The mixture was sealed. The mixture was then heated at 60°C for 4 hours. After cooling to room temperature, the solvent was removed by blowing air over the mixture. The residue was then purified by silica gel chromatography using 40-80% EtOAc / hexanes as the eluent. Purification by chromatography gave 4-((3-phenyl-1H-pyrazol-4-yl )oxy)benzenesulfonamide (85 mg, 0.270 mmol, 27.0% yield ) (2 steps). This material contained some impurities and required further purification. It was used in the next step without further purification.

[0234] Step 3: 2-(3-phenyl-4-(4-sulfamoylphenoxy)-1H-pyridinyl)- Synthesis of ethyl thiazole-1-yl-4-carboxylate In a microwave tube, add ethyl 2-bromothiazole-4-carboxylate (70.0 mg , 0.296mmol), 4-((3-phenyl-1H-pyrazol-4-yl)oxy ) benzenesulfonamide (85 mg, 0.270 mmol), and potassium carbonate (55 The tube was sealed and DMSO (1.5 ml) was added. The mixture was heated at 120 °C for 3 h. The mixture was diluted with EtOAc / H2O (30 ml The aqueous layer was extracted with EtOAc (30 mL). The combined organic layer was The layer was dried (Na2SO4) and filtered. After removal of the solvent, the product was obtained by eluting with 30- Purification was performed by silica gel chromatography using 50-60% EtOAc / hexane. 2-(3-phenyl-4-(4-sulfamoylphenoxy)-1H-pyrazole Ethyl (2-1-yl)thiazole-4-carboxylate (35 mg, 0.074 mmol, 27 0.6% yield).

[0235] Step 4: 2-(3-phenyl-4-(4-sulfamoylphenoxy)-1H-pyridinyl)- Synthesis of (thiazol-1-yl)thiazole-4-carboxylic acid (33) 2-(3-phenyl-4-(4-sulfamoylphenoxy)-1H-pyrazole-1 -yl)thiazole-4-carboxylate ethyl (32 mg, 0.068 mmol) in THF (1 ml) solution of LiOH (水性) (1.5N in H2O, 0.4mL, 0.6mmol) The mixture was stirred at room temperature for 2 hours. Then, 1N HCl was added. (水性) (about 0.6 The pH of the aqueous layer was adjusted to about 4. Then, hexane (5 mL) was added. The resulting solid was filtered and washed with H2O (1 mL x 2) and then with hexane (2 mL x 2). Triturate, dry, and dissolve 2-(3-phenyl-4-(4-sulfamoylphenoxy) )-1H-pyrazol-1-yl)thiazole-4-carboxylic acid 33 (21 mg, 0.0 47 mmol, 69.8% yield).

[0236] <Example 43> This example illustrates the 2-(3-(4-sulfamoylbenzyl) -1H-pyrrolo[3,2-c]pyridin-1-yl)thiazole-4-carboxylic acid,NH Explain the synthesis of 334. Scheme 19 [ka]

[0237] Following a similar procedure as described above for 26, the title compound was obtained as 3-bromo-1H-pyrrolidone. The final product was prepared starting from 2[3,2-c]pyridine and purified by reversed-phase HPLC under basic conditions. C chromatography to give 2-(3-(4-sulfamoylbenzyl)-1 H-Pyrrolo[3,2-c]pyridin-1-yl)thiazole-4-carboxylic acid, NH33 4 (NH3 salt) was obtained. MS (M+H) + =415.

[0238] <Example 44> This example illustrates the 2-(3-(4-sulfamoylbenzyl) The synthesis of (1H-indazol-1-yl)thiazole-4-carboxylic acid (35) is described. do. Scheme 20 [ka]

[0239] Following a similar procedure as described above for 26, the title compound was converted to 3-bromoindazole. 2-(3-(4-sulfamoylbenzyl)-1H-indazole 3-(1-yl)thiazole-4-carboxylic acid 35 was obtained. 1 H NMR (400 MHz, D MSO-d6)δ13.15(s,1H),8.51(d,J=8.4Hz,1H),8 .18(s,1H),7.80(dd,J=8.0,1.0Hz,1H),7.77-7 .72(m,2H),7.67(ddd,J=8.3,7.0,1.1Hz,1H),7 .59-7.51(m,2H),7.35(ddd,J=8.1,7.0,0.9Hz, 1H),7.27(s,2H),4.49(s,2H);MS(M+H) + =415.

[0240] Example 45 This example illustrates the 2-(3-(4-sulfamoylbenzyl) -5-((tetrahydro-2H-pyran-4-yl)oxy)-1H-indole-1- The synthesis of (methyl)thiazole-4-carboxylic acid, NH336 is described. Scheme 21 [ka]

[0241] Step 1: 5-((tetrahydro-2H-pyran-4-yl)oxy)-1H-yne Doll Synthesis 1H-indol-5-ol (0.799 g, 6 mmol), tetrahydro-2H- Pyran-4-ol (0.919 g, 9.00 mmol) and PPh3 (2.361 g A mixture of diazene-1,2-dione (9.00 mmol) in THF (10 ml) was added under N2. -(E)-di-tert-butyl dicarboxylate (2.072 g, 9.00 mmol) A solution of HF (6 mL) was added. The mixture was then stirred at 50° C. for 3 hours. Dropyran-4-ol (3 mmol) was added, followed by PPh3 (3 mmol) and (E)-di-tert-butyl diazene-1,2-dicarboxylate (3mmol) in THF (5 mL) solution was added. The mixture was stirred at 50° C. for an additional 3 hours. The mixture was concentrated and The residue was purified by column chromatography using 20-40% EtOAc / hexane as eluent. Purification by silica gel chromatography gave 5-((tetrahydro-2H-pyran-4- (yl)oxy)-1H-indole (1.18 g, 5.43 mmol, 91% yield) Got it.

[0242] Step 2: 2-(3-(4-sulfamoylbenzyl)-5-((tetrahydro-2 (H-pyran-4-yl)oxy)-1H-indol-1-yl)thiazol-4-yl Synthesis of carboxylic acid, NH3(36) Following the same procedure as above for 31, the title compound was obtained as 5-((tetrahydro- Starting from 2H-pyran-4-yl)oxy)-1H-indole, the final product was purified by reverse-phase HPLC chromatography under basic conditions to give 2-(3-(4-sulfonyl)- (Sulfamoylbenzyl)-1H-pyrrolo[3,2-c]pyridin-1-yl)thiazole -4-carboxylic acid, NH336 (NH3 salt). MS (M+H) + =514.

[0243] <Example 46> This example illustrates the 2-(6-(morpholine-4-carbonyl) -3-(4-sulfamoylbenzyl)-1H-indol-1-yl)thiazole-4 -The synthesis of carboxylic acid, NH337 is described. Scheme 22 [ka]

[0244] Step 1: Synthesis of 3-bromo-1H-indole-6-carboxylic acid Methyl 3-bromo-1H-indole-6-carboxylate (1.270 g, 5 mmol) A solution of LiOH (aqueous) (1.5N in HO, 1 2 mL, 18 mmol) was added. The mixture was stirred at room temperature for 2 hours. Then, 1N H Cl(aq) was added to bring the pH of the aqueous layer to about 4. Hexane (30 mL) was then added. The resulting solid was filtered and triturated with H2O (3 mL x 2) and then hexane (5 mL x 2). It was immersed in 1,000 ml of 3-bromo-1H-indole-6-carboxylic acid (1.136 ml) and dried. g, 4.73 mmol, 95% yield).

[0245] Step 2: 2-(6-(morpholine-4-carbonyl)-3-(4-sulfamoyl) Benzyl)-1H-indol-1-yl)thiazole-4-carboxylic acid, NH337 synthesis Following a similar procedure as described above for 30, the title compound was obtained as 3-bromo-1H-yne The final product was prepared starting from dhol-6-carboxylic acid and purified by reversed-phase HPLC under basic conditions. Purification by chromatography gave 2-(6-(morpholine-4-carbonyl)-3- (4-Sulfamoylbenzyl)-1H-indol-1-yl)thiazol-4-carboxylate The carboxylic acid, NH337 (NH3 salt) was obtained. MS (M+H) + =527.

[0246] Example 47 This example illustrates the use of 1-(1H-benzo[d][1,2,3]trimethylsilyl)methylbenzoates in accordance with an embodiment of the present invention. The synthesis of riazol-1-yl-ketones is described. [ka]

[0247] 1H-benzo[d][1,2,3]triazole (4000mmol) in CH2Cl2 Thionyl chloride (SOCl2, 1000 mmol) was added to the solution and stirred at room temperature for 0.5 hours. Alkyl carboxylic acid (1000 mmol) was then added and the reaction mixture was stirred for 2 hours. Upon completion as detected by LCMS, the reaction mixture was filtered and the filter cake was The filtrate was slowly neutralized with bicarbonate solution and stirred for 30 min. The organic layer was washed with bicarbonate solution, then brine, and added with NaSO. The residue was washed with water, dried over 4°C, filtered, and concentrated. The residue was washed with an organic gradient (0–20% ethanol in hexanes) The first peak was collected and purified directly on silica using a 1000 vol sieve (over 10 CV with chilling). and dried to give an oil or solid.

[0248] <Example 48> This example illustrates the use of 4-(bromomethyl)benzenesulfonamide in an embodiment of the present invention. This explains the synthesis of . [ka]

[0249] Step 1: Synthesis of 4-methylbenzenesulfonamide derivatives 4-Methylbenzene-1-sulfonyl chloride (95 g, 455 mmol) in CH2Cl2 Ammonia was bubbled through the stirred solution for 45 minutes, and the reaction mixture was then filtered. The resulting off-white powder was collected and used for further purification or Used in next step without characterization; (M+H) + =190

[0250] Step 2: Synthesis of 4-(bromomethyl)benzenesulfonamide derivatives 4-Methyl-2 or 3-fluorobenzenesulfonamide (7.3 mmol), N- C of bromosuccinimide (NBS 9.5 mmol) and AIBN (0.73 mmol) A stirred solution of Cl4 (volume: 20 mL) was refluxed for 24 h. The solvent was evaporated and the residue was dissolved in ethyl acetate. The mixture was suspended in chilled water and filtered. The filtrate was washed with Na2S2O3, NaHCO3 and brine solutions. The mixture was dried over Na2SO4 and filtered. Silica gel was added and the solvent was removed under reduced pressure. The dried loaded product was purified by gradient elution (5-100% ethyl acetate in hexanes) Purified on silica using over 16 CV on a 120 g silica column. The product was used in the next step without further purification or characterization.

[0251] <Example 49> This example illustrates the use of 2-(5-(alkyl)-3-phenyl-4-methyl-2-methyl ... -(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazol-4-yl carboxylic acids and 2-(3-(alkyl)-5-phenyl-4-(4-sulfamoyl)benzene This example describes the synthesis of (1H-pyrazol-1-yl)thiazole-4-carboxylic acid. [ka]

[0252] Step 1: Synthesis of 1-phenyl-3-alkyl-1,3-diones 1-(1H-benzo[d][1,2,3]triazol-1-yl)-2-alkylketone ton (200 mmol) and magnesium bromide diethyl etherate (413 mmol) To a stirred solution of in CH2Cl2 was added the 1-phenylethanone derivative (165 mmol). Diisopropylethylamine (500 mmol) was added dropwise over several minutes, and the reaction mixture The mixture was stirred at room temperature for 2 hours. Upon completion as detected by LCMS, the reaction was diluted with 1.0 M H The mixture was slowly quenched with Cl and washed with 1.0 M HCl and brine. The residue was purified by gradient elution (0 to 100 ml of hexanes). The product was purified directly on silica using 30% ethyl acetate (over 20 CV). The resulting oil was used in the next step without further purification or characterization.

[0253] Step 2: 4-(2-benzoyl-3-oxo)-3-alkyl-benzenesulfone Synthesis of amides 1-phenyl-3-alkyl-1,3-dione (150 mmol) and cesium carbonate ( Cs2CO3 (226 mmol) was dissolved in DMSO (50 ml). The reaction mixture was stirred at room temperature. The mixture was stirred at rt for 10 min, at which point potassium iodide (KI, 150 mmol) and 4-(bromo- To the resulting mixture was added 165 mmol of bromomethyl-benzenesulfonamide. The mixture was stirred at room temperature for 1 hour. Upon completion as detected by LCMS, the reaction mixture was added to a large excess of The mixture was diluted with ethyl acetate and filtered through Celite. The filtrate was diluted with 1M HCl, saturated NH4Cl The residue was washed with water and brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Gradient elution (20-40% ethyl acetate in hexane over 16 CV) was used to It was purified by filtration.

[0254] Step 3: 2-(5-(alkyl)-3-phenyl)-4-(4-sulfamoyl)benzyl Ethyl (1H-pyrazol-1-yl)thiazole-4-carboxylate Method A - 4-(2-benzoyl-3-oxo)-3-alkyl-benzenesulfonamide HCl (6.7 mmol), ethyl 2-hydrazinylthiazole-4-carboxylate, 2HBr (7.3 mmol) and p-toluenesulfonic acid (pTsOH, 20 mmol) The amine solution was heated in a sealed vessel in a microwave at 160°C for 15 minutes. Upon completion of extraction, the reaction mixture was diluted with ethyl acetate and filtered through Celite. The solvent was removed under reduced pressure and the crude product was purified by gradient elution (0-100% ethyl acetate in hexanes). The mixture was purified directly on silica using a 1000 vol HPLC (>15 CV).

[0255] Method B - 4-(2-(benzoyl)-3-oxo-3-alkyl-benzenesulfonyl) amide (113 mmol), p-toluenesulfonic acid (pTsOH, 57 mmol), and A solution of pyrrolidine (57 mmol) in ethanol was stirred at 100°C for 1 hour, and then 2- Ethyl hydrazinylthiazole-4-carboxylate, 2HBr (136 mmol) was added. The resulting reaction mixture was refluxed overnight. Upon completion as detected by LCMS, the solvent was reduced. The residue was removed under reduced pressure and purified by gradient elution (20-40% ethyl acetate in hexanes). Purification was performed without workup directly on silica using 100 CV (>100 CV). After removing the solvent, the regioisomers were separated by gradient elution ( 50-100% acetonitrile modified with 0.1% TFA in water The second eluting peak was separated via a reversed-phase preparative column using toluene (>25 CV). The mixture was pooled and concentrated, and the resulting solid was stirred with a clear solution of NaHCO3. The precipitate was filtered. The resulting mixture was collected by filtration, washed with water, and then purified by high vacuum under air overnight and then under P2O5. Subsequent drying resulted in a colorless powder.

[0256] Step 4: 2-(5-(alkyl)-3-phenyl)-4-(4-sulfamoyl)benzyl Synthesis of (1H-pyrazol-1-yl)thiazole-4-carboxylic acid 2-(5-(alkyl)-3-phenyl)-4-(4-sulfamoylbenzyl)-1 Ethyl H-pyrazol-1-yl)thiazole-4-carboxylate (0.07mmol) To the THF / MeOH solution was added 1.5 M LiOH (0.27 mmol). The mixture was stirred at room temperature for 1 hour. Upon completion as detected by LCMS, the solvent was removed by forced air. The residue was taken up in DMSO and removed by gradient elution (in water modified with 0.1% TFA). via preparative reverse phase using 4-100% acetonitrile modified with 0.1% TFA The product fraction was directly frozen and lyophilized overnight to give an off-white A powder was obtained.

[0257] Example 50 This example illustrates the 2-(5-(cyclopropylmethyl)-4- (4-Sulfamoylbenzyl)-3-(meta-substituted-phenyl)-1H-pyrazole-1 The synthesis of (-yl)thiazole-4-carboxylic acid is described. [ka]

[0258] Step 1: 2-(5-(alkyl)-3-(3-(alk-1-yn-1-yl)phenyl)- ... (phenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazo Synthesis of ethyl 4-aminobenzoate 2-(3-(3-bromophenyl)-5-(alkyl)-4-(4-sulfamoylbenzyl) Ethyl (1H-pyrazol-1-yl)thiazole-4-carboxylate (0.16 1 mmol, using Method B in Step 3, Example 49, Steps 1-3 (prepared according to the procedure outlined in

[2002] ), tri(tert-butylphosphonium)tetrahydrofuran trifluoroborate (0.016 mmol), allylpalladium chloride dimer (0. A dioxane solution of DABCO (0.008 mmol) and DABCO (0.323 mmol) was Alkylethene was then added and the reaction mixture was allowed to bubble for 5 minutes at room temperature overnight. Upon completion as detected by LCMS, the reaction mixture was diluted with ethyl acetate and Palladium-trapped silica (DMT) was added. After stirring at room temperature for 2 hours, the slurry was The filtrate was concentrated and the residue was purified by gradient elution (20-40% in hexane). Purified on silica using 0% ethyl acetate over 20 CV).

[0259] Step 2: 2-(5-(alkyl)-3-(3-(alk-1-yn-1-yl)phenyl)- ... (phenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazo Synthesis of 4-amino-4-carboxylic acid The desired compound was synthesized according to the procedure outlined in Step 4 of Example 49, -(5-(alkyl)-3-(3-(alk-1-yn-1-yl)phenyl)-4-( 4-Sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carbo The carboxylic acid was obtained as an off-white solid.

[0260] <Example 51> This example illustrates the use of 4-((1-(4-oxo-3,4-dihydro- Rothieno[3,2-d]pyrimidin-7-yl)-3-phenyl-1H-pyrazole-4 The synthesis of (-yl)methyl)benzenesulfonamide 210 is described. Scheme 23 [ka]

[0261] Step 1: 7-Bromo-4-(tert-butoxy)thieno[3,2-d]pyrimidin Synthesis of phenanthrene At 0°C, 7-bromo-4-chlorothieno[3,2-d]pyrimidine (998 mg, 4 m A partial suspension of KOtBu (4.40 ml, 4.40 mmol) in THF (12 ml) was l) (1M solution in THF) was added. The mixture was stirred at 0°C for 1.5 hours. The mixture was 2O / NH4Cl (水性) (25 mL / 25 mL) and poured into EtOAc (50 mL × 2). The combined organic layers were dried (Na2SO4) and filtered. After removal of the solvent, The product was purified by silica gel chromatography using 5-10% EtOAc / hexane as the eluent. The product was purified by HPLC and 7-bromo-4-(tert-butoxy)thieno[3,2- d]pyrimidine (350 mg, 1.219 mmol, 30.5% yield).

[0262] Step 2: 4-((1-(4-(tert-butoxy)thieno[3,2-d]pyrimidine) (3-phenyl-1H-pyrazol-4-yl)methyl)-N,N-biphenyl- Synthesis of bis(4-methoxybenzyl)benzenesulfonamide In a microwave tube, N,N-bis(4-methoxybenzyl)-4-((3-phenyl) (1H-pyrazol-4-yl)methyl)benzenesulfonamide (138 mg, 0. 25mmol), 7-bromo-4-(tert-butoxy)thieno[3,2-d]pyrimidin (1S,2S)-N1,N2-dimethylsilyl Cyclohexane-1,2-diamine (7.11 mg, 0.050 mmol), CuI (4. 76 mg, 0.025 mmol), and potassium phosphate salt (159 mg, 0.750 mmol) The air was evacuated and refilled with N2 (3 times). Toluene (vol: 2 ml) was added and the mixture was stirred at 110° C. overnight. After cooling to room temperature, the mixture was The mixture was diluted with tOAc (3 mL), filtered through Celite, and eluted with EtOAc. The mixture was concentrated and purified by silica gel chromatography using 10-25% EtOAc / hexanes as the eluent. Purification by gel chromatography gave 4-((1-(4-(tert-butoxy)thio) Eno[3,2-d]pyrimidin-7-yl)-3-phenyl-1H-pyrazol-4-yl (methyl)-N,N-bis(4-methoxybenzyl)benzenesulfonamide (64m g, 0.084 mmol, 33.7% yield). MS (M+H) + =760.

[0263] Step 3: 4-((1-(4-oxo-3,4-dihydrothieno[3,2-d]pyridine) (1H-pyridin-7-yl)-3-phenyl-1H-pyrazol-4-yl)methyl)benzenes Synthesis of sulfonamide (210) 4-((1-(4-(tert-butoxy)thieno[3,2-d]pyrimidin-7-yl) -3-phenyl-1H-pyrazol-4-yl)methyl)-N,N-bis(4-methyl- 1,2-dihydroxybenzylbenzenesulfonamide (64 mg, 0.084 mmol) To the chloroethane (1 ml) solution was added TFA (1 ml, 12.98 mmol). The vessel was sealed and heated under microwave irradiation for 30 min at 100° C. The mixture was diluted with EtOAc / Pour into HO (30 mL / 30 mL) and add NaCO 3(水性) The pH of the aqueous layer is about 7. The organic layer, which had some suspension, was diluted with HO (20 mL × 3). ) and then concentrated to remove all solvent and traces of H2O. The product was purified in vacuo Dry for 10 minutes. The product was then washed with EtOAc (5 mL), and then with hexane (50 mL). mL) was added. The solid was filtered and washed with 5% EtOAc / hexane (3 mL x 3). , and then dried to give 4-((1-(4-oxo-3,4-dihydrothieno[3,2-d]pi (Irimidin-7-yl)-3-phenyl-1H-pyrazol-4-yl)methyl)benzene Sulfonamide 210 (36.5 mg, 0.079 mmol, 93% yield) was dissolved in HCl. The compound was obtained as a thiocyanate solid. 1 H NMR (400 MHz, DMSO-d6) δ 12.79 ( s,1H),8.71(s,1H),8.35(s,1H),8.27(s,1H),7 .74-7.68(m,2H),7.68-7.62(m,2H),7.45-7.39 (m,2H),7.39-7.34(m,3H),7.25(s,2H),4.16(s ,2H);MS(M+H) + =464.

[0264] <Example 52> This example illustrates the use of 4-((1-(4-aminothieno[3,2- d]pyrimidin-7-yl)-3-phenyl-1H-pyrazol-4-yl)methyl)benzyl The synthesis of benzenesulfonamide, TFA211, is described. Scheme 24 [ka]

[0265] Step 1: 7-Bromo-N-(tert-butyl)thieno[3,2-d]pyrimidine Synthesis of 4-amine At 80°C, 7-bromo-4-chlorothieno[3,2-d]pyrimidine (0.998 g, 4 mmol) in EtOH (6 ml), 0.585 g, 8.0 mmol) and then Hunig's base (0.699 ml, 4.0 mmol) mol) was added. The mixture was heated and stirred at 80 °C overnight. The mixture was diluted with CH2Cl2 The product was dissolved in EtOAc (50 mL) and concentrated to remove all solvent. The organic layer was washed with 20 (50 mL). The organic layer was dried (Na2SO4) and filtered. Removal of solvent The product was then purified by silica gel chromatography using 2–5–10% EtOAc / CH2Cl2 as the eluent. Purification by column chromatography yielded 7-bromo-N-(tert-butyl)thienoic acid. [3,2-d]pyrimidin-4-amine (1.09 g, 3.81 mmol, 95% yield) ) was obtained.

[0266] Step 2: 4-((1-(4-aminothieno[3,2-d]pyrimidin-7-yl) -3-phenyl-1H-pyrazol-4-yl)methyl)benzenesulfonamide, TF Synthesis of A(211) In a microwave tube, N,N-bis(4-methoxybenzyl)-4-((3-phenyl) (1H-pyrazol-4-yl)methyl)benzenesulfonamide (138 mg, 0. 25mmol), 7-bromo-N-(tert-butyl)thieno[3,2-d]pyrimidin N-4-amine (71.5 mg, 0.250 mmol), (1S,2S)-N1,N2- Dimethylcyclohexane-1,2-diamine (7.11 mg, 0.050 mmol), C uI (4.76 mg, 0.025 mmol), and potassium phosphate salt (159 mg, 0. The air was evacuated and refilled with N2 (3 times). Aqueous ether (2 ml) was added and the mixture was stirred at 110° C. overnight. After cooling to room temperature, the mixture The mixture was diluted with EtOAc (3 mL), filtered through Celite, and extracted with EtOAc. The solution was concentrated and the mixture was purified by silica gel chromatography using 10-25% EtOAc / hexane as eluent. The product was purified by column chromatography to give 4-((1-(4-(tert-butylamino) ) Thieno[3,2-d]pyrimidin-7-yl)-3-phenyl-1H-pyrazole-4 (-yl)methyl)-N,N-bis(4-methoxybenzyl)benzenesulfonamide The product contained some impurities and the protecting groups were removed directly. Dissolved in FA / dichloroethane (2 mL / 1 mL) and heated at 100°C for 1 hour under microwave irradiation. The mixture was then heated under microwave irradiation at 120°C for an additional 1.5 hours. The mixture was concentrated and purified to give 4-((1-(4-aminothieno[3,2-d]pyrimidinone). (1H-pyrazol-7-yl)-3-phenyl-1H-pyrazol-4-yl)methyl)benzenesulfonyl The amide, TFA211 (5.7 mg, 9.89 μmol, 3.95% yield) was obtained. . 1 H NMR(400MHz,DMSO-d6)δ8.92(d,J=4.9Hz,1 H),8.47(d,J=1.6Hz,1H),8.32(d,J=2.2Hz,1H) ,7.87(s,2H),7.69(m,4H),7.49-7.30(m,5H),7 0.26(s,2H), 4.17(s,2H); MS(M+H) + =463.

[0267] <Example 53> This example illustrates the use of 1-methyl-2-(3-phenyl-4-(4 -sulfamoylbenzyl)-1H-pyrazol-1-yl)-1H-imidazole-5 -The synthesis of the carboxylic acid, TFA212, is described. Scheme 25 [ka]

[0268] Step 1: 2-(4-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl) (I)benzyl)-3-phenyl-1H-pyrazol-1-yl)-1-methyl-1H-yl Synthesis of methyl midazole-5-carboxylate In a microwave tube, N,N-bis(4-methoxybenzyl)-4-((3-phenyl) (1H-pyrazol-4-yl)methyl)benzenesulfonamide (138 mg, 0. 25mmol), 2-bromo-1-methyl-1H-imidazole-5-carboxylic acid methyl ester (54.8 mg, 0.25 mmol), (1S,2S)-N1,N2-dimethylcyclohexane Xanthane-1,2-diamine (14.22 mg, 0.100 mmol), CuI (9.52 mg, 0.050 mmol), and potassium phosphate salt (159 mg, 0.750 mmol The air was evacuated and refilled with N2 (3 times). Toluene (2 ml) was then added. was added and the mixture was stirred at 110° C. overnight. After cooling to room temperature, the mixture was diluted with EtOAc ( The mixture was diluted with 3 mL of ethyl acetate, filtered through Celite, and eluted with EtOAc. The filtrate was concentrated and the mixture was The mixture was chromatographed on silica gel using 10-25% EtOAc / hexane as the eluent. The compound was purified by chromatography to give 2-(4-(4-(N,N-bis(4-methoxybenzyl)sulfonyl) (sulfamoyl)benzyl)-3-phenyl-1H-pyrazol-1-yl)-1-methyl -1H-imidazole-5-carboxylate methyl (57 mg, 0.082 mmol, 33. 0% yield). MS (M+H) + =692.

[0269] Step 2: 1-methyl-2-(3-phenyl-4-(4-sulfamoylbenzyl) -1H-pyrazol-1-yl)-1H-imidazole-5-carboxylic acid, TFA (21 Synthesis of 2) 2-(4-(4-(N,N-bis(4-methoxybenzyl)sulfamoyl)benzyl )-3-phenyl-1H-pyrazol-1-yl)-1-methyl-1H-imidazole- A solution of methyl 5-carboxylate (57 mg, 0.082 mmol) in THF (1 mL) was treated with Li OH (aq) (1.5 N, 0.4 mL, 0.6 mmol) was added. The mixture was stirred at room temperature for 2 Then, 1N HCl (aqueous) was slowly added until the pH of the aqueous layer reached about 4-5. The mixture was stirred for 1 hour at 20°C until no product was detected by UV in the organic layer. The combined organic layers were dried (Na2SO4) and filtered. After removal of the solvent, the product was dried in vacuo to give the crude acid intermediate. 1,2-dichloroethane / TFA (0.6 mL / 0.6 mL) in a microwave tube The tube was sealed and heated under microwave irradiation at 100°C for 20 minutes. The mixture was concentrated and the residue was dissolved in DMF, filtered and purified to give 1-methyl-2-(3-phenylpropanol). 4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)-1H-yl Midazole-5-carboxylic acid, TFA212 (2 mg, 3.63 μmol, 4.40% MS (M+H) + =438.

[0270] <Example 54> This example illustrates the use of 5-(3-phenyl-4-(4-sulfamoyl)methyl)-4-(4-sulfamoyl)methyl ... (1H-pyrazol-1-yl)benzyl-1H-thiophene-3-carboxylic acid, TFA2 The synthesis of 13 is explained. [ka]

[0271] Following the same procedure as above for 212, the title compound was obtained as N,N-bis(4- Methoxybenzyl)-4-((3-phenyl-1H-pyrazol-4-yl)methyl)benzyl Prepared starting from benzenesulfonamide and ethyl 5-bromothiophene-3-carboxylate The final product was purified by reverse phase HPLC chromatography. 5-(3-phenyl-4-(4-sulfamoylbenzyl)-1H-pyrazole-1 3-yl)thiophene-3-carboxylic acid, TFA213, was obtained. 1 H NMR (400MH z,DMSO-d6)δ12.88(s,1H),8.45(s,1H),7.96(d ,J=1.6Hz,1H),7.73-7.66(m,2H),7.63-7.55(m ,3H),7.44-7.32(m,5H),7.26(s,2H),4.08(s,2 H); MS(M+H) + =440.

[0272] Example 55 This example illustrates the 2-(5-(cyclopropylmethyl)-3- (4-fluoro-3-(1-methyl-1H-pyrazol-4-yl)phenyl)-4-( 2-Fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazo The synthesis of benzoyl-4-carboxylic acid, TFA214, is described. Scheme 26 [ka]

[0273] Step 1: 2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(1- Methyl-1H-pyrazol-4-yl)phenyl)-4-(2-fluoro-4-sulfa Ethyl (1H-pyrazol-1-yl)thiazole-4-carboxylate and and 2-(3-(cyclopropylmethyl)-5-(4-fluoro-3-(1-methyl-1H -pyrazol-4-yl)phenyl)-4-(2-fluoro-4-sulfamoylbenzene Synthesis of ethyl (1H-pyrazol-1-yl)thiazole-4-carboxylate. In a microwave tube, 2-(3-(3-bromo-4-fluorophenyl)-5-(cyclohexyl)phenyl)- (chloropropylmethyl)-4-(2-fluoro-4-sulfamoylbenzyl)-1H-pi Ethyl thiazole-1-yl)thiazole-4-carboxylate (63.8 mg, 0.1 mmol) l) (two positional isomers), 1-methyl-4-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)-1H-pyrazole (41.6 mg, 0.20 mm ol), PdCl2(dppf)-CH2Cl2 adduct (8.17 mg, 10.0 μmol 1), and K2CO3 (69.1 mg, 0.50 mmol). Air was removed and N 2 was recharged (repeated three times). Then, 1,4-dioxane (1.5 ml) / water (0 A mixture of 0.5 ml of ethanol was added. The mixture was stirred at 95°C (preheated) for 1.5 hours. After cooling to room temperature, the mixture was extracted with EtOAc (2 mL × 3). The combined organic layers were dried. After removal of the solvent, the product was extracted with 40-70% ethanol as eluent. Purification by silica gel chromatography using EtOAc / hexane gave 2-( 5-(cyclopropylmethyl)-3-(4-fluoro-3-(1-methyl-1H-pyrazoline) (2-fluoro-4-sulfamoylbenzyl)-1 Ethyl H-pyrazol-1-yl)thiazole-4-carboxylate (27 mg, 0.042 2-(3-(cyclopropylmethyl)-5-(4-(4-methyl-2-methyl-2-propanol)-2-yl)-2-(3-(cyclopropylmethyl)-5 ... Fluoro-3-(1-methyl-1H-pyrazol-4-yl)phenyl)-4-(2-fluoro- (4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazol-4- A total of 54 mg of ethyl carboxylate (27 mg, 0.042 mmol, 42.3% yield) Got it.

[0274] Step 2: 2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(1- Methyl-1H-pyrazol-4-yl)phenyl)-4-(2-fluoro-4-sulfa (1H-pyrazol-1-yl)thiazole-4-carboxylic acid, TFA Synthesis of (214) 2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(1-methyl-1H -pyrazol-4-yl)phenyl)-4-(2-fluoro-4-sulfamoylbenzene Ethyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate (27 mg, 0 0.042 mmol) and 2-(3-(cyclopropylmethyl)-5-(4-fluoro-3 -(1-methyl-1H-pyrazol-4-yl)phenyl)-4-(2-fluoro-4- Sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid Ethyl acetate (27 mg, 0.042 mmol) in THF (1 ml) / MeOH (0.3 ml) To the solution was added LiOH (aq) (1.5 N, 0.4 mL, 0.6 mmol). The mixture was stirred at 50°C for 2 hours. After cooling to room temperature, 1N HCl (水性) The pH of the aqueous layer is The mixture was concentrated, and the residue was dissolved in DMF and filtered. Filtration and purification gave 2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-( 1-Methyl-1H-pyrazol-4-yl)phenyl)-4-(2-fluoro-4-sulfonyl) Famoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid, T FA (0.9 mg, 1.242 μmol, 2.94% yield) 214 (powder weight: 0.9 mg, tR = 5.30 min, final QC) and 2-(3-(cyclopropylmethyl)-5-( 4-Fluoro-3-(1-methyl-1H-pyrazol-4-yl)phenyl)-4-(2 -Fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole -4-carboxylic acid, TFA (not collected) (for 214). 1 H NMR (40 0MHz,DMSO-d6)δ13.15(s,1H),8.29(s,1H),8.0 1(d,J=2.1Hz,1H),7.78-7.72(m,2H),7.52(dd, J=9.6,1.8Hz,1H),7.46(dd,J=8.0,1.8Hz,1H), 7.40(s,2H),7.34(ddd,J=8.5,5.0,2.2Hz,1H), 7.26(dd,J=11.0,8.5Hz,1H),7.12(t,J=7.8Hz, 1H),4.10(s,2H),3.85(s,3H),3.15(d,J=7.0Hz ,2H),1.14-1.01(m,1H),0.37-0.14(m,4H);MS( M+H) + =611.

[0275] Example 56 This example illustrates the 2-(5-(cyclopropylmethyl)-3- (3-(3,5-dimethylisoxazol-4-yl)-4-fluorophenyl)-4 -(2-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thia 2-(3-(cyclopropylmethyl)-5-(2-methyl-2-isopropyl)-4-carboxylic acid, TFA215 and 2-(3-(cyclopropylmethyl)-5-(2-isopropyl)-4-carboxylic acid) (3-(3,5-dimethylisoxazol-4-yl)-4-fluorophenyl)-4 -(2-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thia The synthesis of thiazoline-4-carboxylic acid, TFA216, is described. [ka]

[0276] The title compound was prepared following a similar procedure as described above for 212, and the final product was obtained as Purification by reverse phase HPLC chromatography gave 2-(5-(cyclopropylmethyl) -3-(3-(3,5-dimethylisoxazol-4-yl)-4-fluorophenyl )-4-(2-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl ) thiazole-4-carboxylic acid, TFA215 and 2-(3-(cyclopropylmethyl) -5-(3-(3,5-dimethylisoxazol-4-yl)-4-fluorophenyl )-4-(2-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl ) Thiazole-4-carboxylic acid, TFA216 was obtained. MS (M+H) + =626.

[0277] Example 57 This example illustrates the use of 2-(5-(cyclopropylmethyl)-3-methyl-2 ... -(4-fluoro-3-(1-methyl-1H-pyrazol-4-yl)phenyl)-4- (3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazo 2-(3-(cyclopropylmethyl)-5-((cyclopropylmethyl)-4-carboxylic acid, TFA217, and 4-Fluoro-3-(1-methyl-1H-pyrazol-4-yl)phenyl)-4-(3 -Fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole The synthesis of TFA218, a 4-carboxylic acid, is described. [ka]

[0278] The title compound was prepared following a similar procedure as described above for 212, and the final product was obtained as Purification by reverse phase HPLC chromatography gave 2-(5-(cyclopropylmethyl) -3-(4-fluoro-3-(1-methyl-1H-pyrazol-4-yl)phenyl)- 4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thio Azole-4-carboxylic acid, TFA217 and 2-(3-(cyclopropylmethyl)-5 -(4-fluoro-3-(1-methyl-1H-pyrazol-4-yl)phenyl)-4- (3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazo The resulting carboxylic acid was TFA218. MS (M+H) + =611.

[0279] <Example 58> This example illustrates the use of 2-(5-(cyclopropylmethyl)-3-methyl-2 ... -(3-(3,5-dimethylisoxazol-4-yl)-4-fluorophenyl)- 4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thio Azole-4-carboxylic acid, TFA219 and 2-(3-(cyclopropylmethyl)-5 -(3-(3,5-dimethylisoxazol-4-yl)-4-fluorophenyl)- 4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thio The synthesis of azole-4-carboxylic acid, TFA220, is described. [ka]

[0280] The title compound was prepared following a similar procedure as described above for 212, and the final product was obtained as Purification by reverse phase HPLC chromatography gave 2-(5-(cyclopropylmethyl) -3-(3-(3,5-dimethylisoxazol-4-yl)-4-fluorophenyl )-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl ) thiazole-4-carboxylic acid, TFA219 and 2-(3-(cyclopropylmethyl) -5-(3-(3,5-dimethylisoxazol-4-yl)-4-fluorophenyl )-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl ) Thiazole-4-carboxylic acid, TFA220 was obtained. MS (M+H) + =626.

[0281] Example 59 This example illustrates the use of 2-(5-(cyclopropylmethyl)-3-methyl-2 ... -(4-fluoro-3-(4-methylthiophen-2-yl)phenyl)-4-(2-fluoro (4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4 -carboxylic acid, TFA221 and 2-(3-(cyclopropylmethyl)-5-(4-fluoromethyl)- 2-fluoro-3-(4-methylthiophen-2-yl)phenyl)-4-(2-fluoro-4- Sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid Here, the synthesis of TFA222 is described. [ka]

[0282] The title compound was prepared following a similar procedure as described above for 212, and the final product was obtained as Purification by reverse phase HPLC chromatography gave 2-(5-(cyclopropylmethyl) -3-(4-fluoro-3-(4-methylthiophen-2-yl)phenyl)-4-(2 -Fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole -4-carboxylic acid, TFA221 and 2-(3-(cyclopropylmethyl)-5-(4- Fluoro-3-(4-methylthiophen-2-yl)phenyl)-4-(2-fluoro- 4-Sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carbo The carboxylic acid, TFA222, was obtained. MS (M+H) + =627.

[0283] Example 60 This example illustrates the use of 2-(5-(cyclopropylmethyl)-3-methyl-2 ... -(4-fluoro-3-(4-methylthiophen-2-yl)phenyl)-4-(3-fluoro- (4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4 -carboxylic acid, TFA223 and 2-(3-(cyclopropylmethyl)-5-(4-fluoromethyl)- 3-fluoro-3-(4-methylthiophen-2-yl)phenyl)-4-(3-fluoro-4- Sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid ,The synthesis of TFA224 is described. [ka]

[0284] The title compound was prepared following a similar procedure as described above for 212, and the final product was obtained as Purification by reverse phase HPLC chromatography gave 2-(5-(cyclopropylmethyl) -3-(4-fluoro-3-(4-methylthiophen-2-yl)phenyl)-4-(3 -Fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole -4-carboxylic acid, TFA223 and 2-(3-(cyclopropylmethyl)-5-(4- Fluoro-3-(4-methylthiophen-2-yl)phenyl)-4-(3-fluoro- 4-Sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carbo The carboxylic acid, TFA224, was obtained. MS (M+H) + =627.

[0285] <Example 61> This example illustrates the use of 2-(5-(cyclopropylmethyl)-3-methyl-2 ... -(4-fluoro-3-(5-methylthiophen-2-yl)phenyl)-4-(2-fluoro (4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4 -carboxylic acid, TFA225 and 2-(3-(cyclopropylmethyl)-5-(4-fluoromethyl)- 4-(2-fluoro-3-(5-methylthiophen-2-yl)phenyl)-4-(2-fluoro-4- Sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid ,The synthesis of TFA226 is described. [ka]

[0286] The title compound was prepared following a similar procedure as described above for 212, and the final product was obtained as Purification by reverse phase HPLC chromatography gave 2-(5-(cyclopropylmethyl) -3-(4-fluoro-3-(5-methylthiophen-2-yl)phenyl)-4-(2 -Fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole -4-carboxylic acid, TFA225 and 2-(3-(cyclopropylmethyl)-5-(4- Fluoro-3-(5-methylthiophen-2-yl)phenyl)-4-(2-fluoro- 4-Sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carbo The carboxylic acid, TFA226, was obtained. MS (M+H) + =627.

[0287] <Example 62> This example illustrates the use of 2-(5-(cyclopropylmethyl)-3-methyl-2 ... -(4-fluoro-3-(5-methylthiophen-2-yl)phenyl)-4-(3-fluoro- (4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4 -carboxylic acid, TFA227 and 2-(3-(cyclopropylmethyl)-5-(4-fluoromethyl)- 4-(3-fluoro-3-(5-methylthiophen-2-yl)phenyl)-4-(3-fluoro-4- Sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid Here, the synthesis of TFA228 is described. [ka]

[0288] The title compound was prepared following a similar procedure as described above for 212, and the final product was obtained as Purification by reverse phase HPLC chromatography gave 2-(5-(cyclopropylmethyl) -3-(4-fluoro-3-(5-methylthiophen-2-yl)phenyl)-4-(3 -Fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole -4-carboxylic acid, TFA227 and 2-(3-(cyclopropylmethyl)-5-(4- Fluoro-3-(5-methylthiophen-2-yl)phenyl)-4-(3-fluoro- 4-Sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carbo The carboxylic acid, TFA228, was obtained. MS (M+H) + =627; (227, HCl salt). 1 H NMR(400MHz,DMSO-d6)δ13.13(s,1H),8.29( s,1H),7.67(t,J=7.9Hz,1H),7.62(dd,J=7.6,2 .2Hz,1H),7.58(s,2H),7.50(ddd,J=8.5,4.8,2 .2Hz,1H),7.34(dd,J=11.3,8.6Hz,1H),7.19(d d,J=11.3,1.6Hz,1H),7.13(dd,J=3.6,0.9Hz,1 H),7.06(dd,J=8.1,1.6Hz,1H),6.81(dt,J=3.6 ,1.1Hz,1H),4.14(s,2H),3.15(d,J=6.9Hz,2H) ,2.44(d,J=1.1Hz,3H),1.19-1.03(m,1H),0.39 -0.28(m,2H),0.24-0.14(m,2H).

[0289] <Example 63> This example illustrates the 2-(5-(cyclopropylmethyl)-3- (4-fluoro-3-(5-methylthiophen-2-yl)phenyl)-4-(3-fluoro (4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazol-4- The synthesis of ethyl carboxylate 229 is described. [ka]

[0290] In a microwave tube, 2-(3-(3-bromo-4-fluorophenyl)-5-(cyclohexyl)phenyl)- (chloropropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pi Ethyl (thiazol-1-yl)thiazole-4-carboxylate (287 mg, 0.45 mmol) l) (two positional isomers), PdCl2(dppf)-CH2Cl2 adduct (55.1 m g, 0.068 mmol), and K2CO3 (466 mg, 3.38 mmol) were added. The air was removed and refilled with N2 (repeated three times). Then, 4,4,5,5-tetrachloroethane was added. Methyl-2-(5-methylthiophen-2-yl)-1,3,2-dioxaborolane(2 52 mg, 1.125 mmol) in 1,4-dioxane (4.5 ml) and water (1.5 ml l) solution was added. The mixture was stirred at 90°C (preheated) for 1.5 hours. Cooled to room temperature. After that, the mixture was extracted with EtOAc (5 mL × 3). The combined organic layer was dried (Na 2SO4), and filtered. After removal of the solvent, the product was purified by elution with 25-35% EtOAc. Purification by silica gel chromatography using hexane gave the desired product. The product has a light brown color and can be recrystallized from a CH2Cl2 / hexane system. The product was dissolved in CH2Cl2 (5 mL) and then hexane (approximately 10 mL) was added. The solvent is then slowly removed by air blowing until the solvent volume is about 1 / 4, and then Hexane (15 mL) was added. The solid was filtered and dissolved in hexane (3 mL x 3). The resulting mixture was saturate, dried, and then 2-(5-(cyclopropylmethyl)-3-(4-fluoromethyl)- 4-(3-fluoro-3-(5-methylthiophen-2-yl)phenyl)- (1H-pyrazol-1-yl)thiazole-4-carboxylic acid ester Chill 229 (276 mg, 0.422 mmol, 94% yield) was obtained as an off-white solid. The result was 241mg + 35mg, a total of 276mg (two produced). 1 H NMR (400 MHz, chloroform-d) δ 7.96 (s, 1H), 7.81 (t, J = 7.8 Hz, 1H),7.55(dd,J=7.4,2.2Hz,1H),7.37(ddd,J=8 .5,4.7,2.2Hz,1H),7.15-7.04(m,3H),7.00(dd ,J=11.1,1.6Hz,1H),6.73(dt,J=3.7,1.0Hz,1H ),4.93(s,2H),4.40(q,J=7.1Hz,2H),4.07(s,2 H),3.21(d,J=6.8Hz,2H),2.49(d,J=1.1Hz,3H) ,1.41(t,J=7.1Hz,3H),1.19-1.06(m,1H),0.49 -0.38(m,2H),0.28(dt,J=6.1,4.7Hz,2H);MS(M +H) + =655.

[0291] <Example 64> This example illustrates the 2-(5-(cyclopropylmethyl)-3- (4-fluoro-3-(5-methylfuran-2-yl)phenyl)-4-(3-fluoro -4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carbohydrate The synthesis of carboxylic acid 230 is described. [ka]

[0292] Step 1: 2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(5- Methylfuran-2-yl)phenyl)-4-(3-fluoro-4-sulfamoylbenzene Synthesis of ethyl 1H-pyrazol-1-yl-thiazole-4-carboxylate In a microwave tube, 2-(3-(3-bromo-4-fluorophenyl)-5-(cyclohexyl)phenyl)- (chloropropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pi Ethyl (thiazol-1-yl)thiazole-4-carboxylate (31.9 mg, 0.05 mm ol) (two positional isomers), PdCl2(dppf)-CH2Cl2 adduct (8.17 mg, 10.0 μmol), and K2CO3 (51.8 mg, 0.375 mmol) were added. The air was removed and refilled with N2 (repeated three times). tetramethyl-2-(5-methylfuran-2-yl)-1,3,2-dioxaborolane(2 6.0 mg, 0.125 mmol) in 1,4-dioxane (1 ml) and water (0.5 ml A solution of ) was added. The mixture was stirred at 90°C (preheated) for 1.5 hours. Cooled to room temperature. After that, the mixture was extracted with EtOAc (3 mL × 3). The combined organic layer was dried (Na 2SO4), and filtered. After removal of the solvent, the product was purified by elution with 20-40% EtOAc. Purification was performed by silica gel chromatography using hexane to give 2-(5-(cyclohexyl)methylpropional. (4-fluoro-3-(5-methylfuran-2-yl)phenyl)-3-(4-fluoro-3-(5-methylfuran-2-yl)phenyl)- (3-fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl Ethyl thiazole-4-carboxylate (30 mg, 0.047 mmol, 94% yield) ) was obtained. MS (M+H) + =639.

[0293] Step 2: 2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(5- Methylfuran-2-yl)phenyl)-4-(3-fluoro-4-sulfamoylbenzene Synthesis of (1H-pyrazol-1-yl)thiazole-4-carboxylic acid (230) 2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-(5-methylfuran) -2-yl)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H- Ethyl pyrazol-1-ylthiazole-4-carboxylate (30 mg, 0.047 mm A solution of 1 ml of LiOH (aqueous) in THF (1 ml) / MeOH (0.3 ml) was , 0.4 mL, 0.6 mmol) was added. The mixture was stirred at 50°C for 1 hour. After cooling in 1N HCl (水性) was added until the pH of the aqueous layer reached about 3 to 4. The mixture was poured into EtOAc / H2O (5 mL / 5 mL). The aqueous layer was diluted with EtOAc (5 mL ×3). The combined organic layers were dried (Na2SO4) and filtered. After removal of the solvent The product was dissolved in CH2Cl2 (2 mL) and then hexane (40 mL) was added. The resulting solid was filtered, triturated with hexane (3 mL x 3), and then house-bake. Dry overnight at 50°C under vacuum to obtain 2-(5-(cyclopropylmethyl)-3-(4-fluoromethyl)- Oro-3-(5-methylfuran-2-yl)phenyl)-4-(3-fluoro-4-sulfonyl) Famoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid 23 0 (22 mg, 0.036 mmol, 77% yield). 1 H NMR (400MH z,DMSO-d6)δ13.10(s,1H),8.29(s,1H),7.76(d d,J=7.4,2.3Hz,1H),7.67(t,J=7.9Hz,1H),7.5 7(s,2H),7.54(ddd,J=8.6,4.8,2.3Hz,1H),7.3 3(dd,J=11.2,8.6Hz,1H),7.20(dd,J=11.3,1.6 Hz,1H),7.07(dd,J=8.1,1.6Hz,1H),6.70(t,J= 3.5Hz,1H),6.22(dt,J=3.1,1.0Hz,1H),4.15(s ,2H),3.15(d,J=6.9Hz,2H),2.27(s,3H),1.17- 1.06(m,1H),0.38-0.28(m,2H),0.24-0.14(m,2 H); MS(M+H) + =611.

[0294] Example 65 This example illustrates the 2-(5-(cyclopropylmethyl)-3- (4-fluoro-3-(5-methylthiazol-2-yl)phenyl)-4-(3-fluoro (4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazol-4- The synthesis of the carboxylic acid, TFA231, is described. [ka]

[0295] The title compound was prepared following a similar procedure as described above for 230 to give the final product. Purification by reverse phase HPLC chromatography gave 2-(5-(cyclopropylmethyl) -3-(4-fluoro-3-(5-methylthiazol-2-yl)phenyl)-4-(3 -Fluoro-4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole The 4-carboxylic acid, TFA231, was obtained. 1 H NMR (400 MHz, DMSO-d )δ13.13(s,1H),8.30(dd,J=7.2,2.3Hz,1H),8. 28(s,1H),7.70-7.59(m,3H),7.54(s,2H),7.43 (dd,J=11.1,8.7Hz,1H),7.16(dd,J=11.4,1.6H z,1H),7.05(dd,J=8.1,1.6Hz,1H),4.14(s,2H) ,3.19-3.14(m,2H),2.49(d,J=1.2Hz,3H),1.18 -1.05(m,1H),0.39-0.29(m,2H),0.24-0.15(m, 2H); MS(M+H) + =628.

[0296] <Example 66> This example illustrates the 2-(5-(cyclopropylmethyl)-3- (4-fluoro-3-(2-methylthiazol-5-yl)phenyl)-4-(3-fluoro (4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazol-4- The synthesis of carboxylic acid 232 is described. [ka]

[0297] The title compound was prepared following a similar procedure as described above for 230 to give 2-(5- (Cyclopropylmethyl)-3-(4-fluoro-3-(2-methylthiazol-5-yl)methyl)- (phenyl)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazo (Iron-1-yl)thiazole-4-carboxylic acid 232 was obtained. 1 H NMR (400 MHz) ,DMSO-d6)δ13.13(s,1H),8.27(s,1H),7.97(s, 1H),7.68(dd,J=7.4,2.0Hz,1H),7.64(d,J=7.9 Hz,1H),7.57(m,3H),7.39(dd,J=10.8,8.7Hz,1 H),7.17(d,J=11.3Hz,1H),7.05(d,J=8.3Hz,1H ),4.15(s,2H),3.16(d,J=6.9Hz,2H),2.66(s,3 H),1.18-1.01(m,1H),0.37-0.27(m,2H),0.21( d, J = 4.9 Hz, 2H); MS (M + H) + =628.

[0298] Example 67 This example illustrates the 2-(5-(cyclopropylmethyl)-3- (4-fluoro-3-(5-methylthiophen-2-yl)phenyl)-4-(2-fluoro (4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazol-4- The synthesis of carboxylic acid 233 is described. [ka]

[0299] The title compound was prepared following a similar procedure as described above for 230 to give 2-(5- (Cyclopropylmethyl)-3-(4-fluoro-3-(5-methylthiophene-2-yl) (phenyl)phenyl)-4-(2-fluoro-4-sulfamoylbenzyl)-1H-pyrazo (1-yl)thiazole-4-carboxylic acid 233 was obtained. 1 H NMR (400 MHz) ,DMSO-d6)δ13.09(s,1H),8.29(s,1H),7.63(dd ,J=7.5,2.2Hz,1H),7.56(dd,J=9.6,1.8Hz,1H) ,7.53-7.49(m,1H),7.49-7.44(m,1H),7.42(s, 2H),7.34(dd,J=11.3,8.6Hz,1H),7.19-7.11(m ,2H),6.81(dt,J=3.6,1.1Hz,1H),4.08(s,2H), 3.16(d,J=6.9Hz,2H),2.44(d,J=1.1Hz,3H),1. 17-1.02(m,1H),0.35-0.27(m,2H),0.22-0.14( m, 2H); MS (M+H) + =627.

[0300] <Example 68> This example illustrates the 2-(5-(cyclopropylmethyl)-3- (4-fluoro-3-(thiophen-2-yl)phenyl)-4-(3-fluoro-4- Sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid ,The synthesis of TFA234 is described. [ka]

[0301] The title compound was prepared following a similar procedure as described above for 230 to give the final product. Purification by reverse phase HPLC chromatography gave 2-(5-(cyclopropylmethyl) -3-(4-fluoro-3-(thiophen-2-yl)phenyl)-4-(3-fluoro -4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carbohydrate The carboxylic acid, TFA234, was obtained. MS (M+H) + =613.

[0302] Example 69 2-(5-hydroxy-3-(naphthalen-2-yl)-4-(4-sulfamoyl)benzyl (1H-pyrazol-1-yl)thiazole-4-carboxylic acid 451: [ka] [ka]

[0303] Step 1. Synthesis of ethyl 3-(naphthalen-1-yl)-3-oxopropionate. Lithium hexamethyldisiloxane (LHMDS) (1 M in hexane, 7.8 mL, 7 0.8 mmol) was dissolved in dry THF (5 mL) and cooled to -78°C. 60 μL, 7.8 mmol) was added dropwise and the reaction mixture was stirred at −78° C. for 30 minutes. 1-Naphthoyl (1 mL, 5.2 mmol) was dissolved in dry THF (5 mL) and heated at -78°C. To this solution was added dropwise the ethyl acetate / LHMDS solution and the reaction mixture was allowed to cool to ambient temperature. The reaction was quenched with ammonium chloride and ethyl acetate (50 The organic layer was separated and washed with water (50 mL), brine (50 mL), and dried over anhydrous The residue was dried over magnesium sulfate and purified by flash chromatography (Combi-f Purification was carried out by flash Rf, hexane ethyl acetate = 5% isocratic) to give 3-(naphthalene Ethyl phthalen-1-yl-3-oxopropionate (300 mg, 24%) was obtained.

[0304] Step 2. 3-(naphthalen-1-yl)-3-oxo-2-(4-sulfamoyl) Synthesis of ethyl (benzyl)propionate. Ethyl 3-(naphthalen-1-yl)-3-oxopropionate (300 mg, 1.2 4 mmol) in dry 1,4-dioxane (2 mL) and g, 1.74 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes, and 4-(bromo Methyl)benzenesulfonamide (372 mg, 1.48 mmol) was added to the reaction mixture. The mixture was stirred at room temperature overnight. The residue was purified by flash chromatography (Combi-fl Purify by hexane / methanol (0-60% gradient) and 3-(naphthalene) Ethyl 2-(4-sulfamoylbenzyl)propionate The obtained product was 380 mg (75%).

[0305] Step 3. 2-(5-hydroxy-3-(naphthalen-2-yl)-4-(4-sulfonyl)-2-hydroxy-3-(naphthalen-2-yl)-4-hydroxy-4-sulfonyl) Famoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid ethyl ester Synthesis of ru. 3-(Naphthalen-1-yl)-3-oxo-2-(4-sulfamoylbenzyl)propionate Ethyl propionate (260 mg, 0.63 mmol), 2-hydrazinylthiazole-4 -tert-Butyl carboxylate (137 mg, 0.63 mmol), p-toluenesulfonyl Add 120 mg (0.63 mmol) of carboxylic acid and 6 mL of ethanol to a microwave vial. The reaction mixture was diluted with ethyl acetate (50 mL) and irradiated at 110°C for 3 hours. Wash with saturated sodium bicarbonate (20 mL), brine (50 mL), and add anhydrous magnesium sulfate. The residue was purified by flash chromatography (Combi-flash Rf, D CM / methanol, 0-10% gradient) and purified to give 2-(5-hydroxy-3-(naphthalene)-2-methyl- phthalen-2-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazole-1- Ethyl)thiazole-4-carboxylate (210 mg, 60%) was obtained.

[0306] Step 4. 2-(5-hydroxy-3-(naphthalen-2-yl)-4-(4-sulfonyl)-2-hydroxy-3-(naphthalen-2-yl)-4-sulfonyl) Famoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid 45 1 2-(5-hydroxy-3-(naphthalen-2-yl)-4-(4-sulfamoyl)benzyl Ethyl (1H-pyrazol-1-yl)thiazole-4-carboxylate (50mg , 0.096 mmol) was dissolved in THF / MeOH (1 mL:1 mL) and LiOH (5 M, 500 μL) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with hydrochloric acid (1 The mixture was neutralized by the addition of 0.2M sodium hydroxide, diluted with ethyl acetate (15 mL) and washed with water (10 mL). The organic layer was purified by rotary evaporation and dried over anhydrous magnesium sulfate. The concentrate was dissolved in a mixture of DMSO and MEOH and purified by HPLC (Phenomenex G emini C18, 20% to 85% CH3CN with a gradient of H2O / CH3CN in 4 min , 0.1% TFA) to afford the title compound 451 (76%). 1 HN MR(d 6 -DMSO)δ8.19(s,1H),8.09(d,2H,J=1.6Hz ),8.00(d,1H,J=8Hz),7.86(d,1H,J=8Hz)7.63- 7.51(m,6H),7.12(d,1H,J=8Hz),3.69(s,2H);M S(ES)506.9(M+H) + LCMS RT=0.88 min.

[0307] Example 70 2-(3-(3,4-difluorophenyl)-5-hydroxy-4-(4-sulfamoyl) (Ilbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid 452 [ka]

[0308] The title compound was prepared using a procedure similar to that described for the preparation of 451 and purified by HPLC. Purified by C: 2-(3-(3,4-difluorophenyl)-5-hydroxy-4 -(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazol-4-yl Carboxylic acid 452. 1 H-NMR(d 6 -DMSO) δ 8.18 (s, 1H), 7.85 ( d,2H,J=8.4Hz),7.56(m,1H),7.45-7.41(m,4H) , 3.99(s,2H); MS(ES) 492.9(M+H) + LCMS RT=0.8 8 minutes.

[0309] <Example 71> 2-(5-hydroxy-3-(pyridin-3-yl)-4-(4-sulfamoylbenzene) (1H-pyrazol-1-yl)thiazole-4-carboxylic acid 453 [ka]

[0310] The title compound was prepared using a procedure similar to that described for the preparation of 451 and purified by HPLC. Purified by C: 2-(5-hydroxy-3-(pyridin-3-yl)-4-(4- Sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid 453. MS(ES)457.9(M+H)+LCMS RT=0.30 min.

[0311] <Example 72> 2-(3-(6-fluoronaphthalen-1-yl)-5-hydroxy-4-(4-sulfonyl) Famoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid 45 4 [ka]

[0312] The title compound was prepared using a procedure similar to that described for the preparation of 451 and purified by HPLC. Purified by C: 2-(3-(6-fluoronaphthalen-1-yl)-5-hydroxybenzoate 4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole 4-Carboxylic acid 454. 1 H-NMR(d 6 -DMSO) δ 8.20 (m, 2H), 7. 88(d,2H,J=8Hz),7.70-7.55(m,5H),7.32(m,1H ),7.12(d,1H,J=8Hz),3.69(s,2H);MS(ES)524. 9(M+H) + LCMS RT=0.94 min.

[0313] <Example 73> 2-(3-(3,4-difluorophenyl)-5-methoxy-4-(4-sulfamoyl) (1H-benzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid 455 [ka]

[0314] 2-(3-(3,4-difluorophenyl)-5-hydroxy-4-(4-sulfamoyl) (1H-pyrazol-1-yl)thiazole-4-carboxylic acid 452(2 0 mg, 0.038 mmol) was dissolved in anhydrous DMF (300 μL). methyl iodide (3 μL, 0.05 mmol) The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (5 mL). The organic layer was concentrated by rotary evaporation and HF (500 μL) and sodium hydroxide (5N, 200 μL) were added. The reaction mixture was neutralized with hydrochloric acid (0.1 M) and the residue was purified by HPLC (Phenomenex G emini C18, 20% to 95% CH3CN with a gradient of H2O / CH3CN in 4 min Purification by HCl (0.1% TFA) gave the title compound 455 (85%). 1 H- NMR(d 6 -DMSO)δ8.20(s,1H),7.81(d,2H,J=8Hz) ,7.54-7.50(m,2H),7.39-7.36(m,3H),3.69(s, 2H),3.49(s,3H);MS(ES)506.9(M+H) + LCMS RT= 0.89 minutes.

[0315] <Example 74> 2-(3-(3-isopropoxyphenyl)-4-(4-sulfamoylbenzyl)- 1H-Pyrazol-1-yl)thiazole-4-carboxylic acid 459 [ka] [ka]

[0316] Step 1. Synthesis of 3-(3-methoxyphenyl)-3-oxopropanal. 3-Methoxyphenylacetophenone (3 g, 0.17 mol) was dissolved in anhydrous THF (25 m L) and cooled to 0°C. Sodium hydride (930 mg, 0.23 mol) and Ethyl formate (4.3 mL, 0.53 mol) was added, and the reaction mixture was stirred at room temperature overnight. The mixture was quenched with sodium hydroxide (2N) and washed with diethyl ether. The mixture was acidified with 2N diethyl ether and extracted with diethyl ether (3 x 50 mL). The solution was dried over magnesium and concentrated on a rotary evaporator for use in subsequent reactions. 3-(3-methoxyphenyl)-3-oxopropanal (quantitative yield) of sufficient purity for rate).

[0317] Step 2. Synthesis of 3-(3-methoxyphenyl)-1H-pyrazole A stirred solution of 3-(3-methoxyphenyl)-3-oxopropanal in ethanol was Drazine (1 mL, 0.3 mmol) was added and the reaction mixture was refluxed for 3 hours. The mixture was concentrated to half of its original volume and diluted with water (50 mL) and sodium hydroxide (1 M, 100 mL). L) was added. The mixture was extracted with ethyl acetate (3 x 50 mL) and anhydrous magnesium sulfate The organic layer was filtered off and concentrated by rotary evaporation to give a yellow liquid (3 g, 92%). The product was sufficiently pure for further reactions.

[0318] Step 3. Synthesis of 4-bromo-3-(3-methoxyphenyl)-1H-pyrazole. 3-(3-Methoxyphenyl)-1H-pyrazole (3 g, 0.017 mol) was dissolved in anhydrous Dissolved in DMF (30 mL) and cooled to 0 °C. NBS (3.20 g, 0.018 mol ) was added in three portions and the reaction mixture was stirred at room temperature overnight. Pour into a mixture of saturated sodium bicarbonate and water (1:1, 300 mL), separate the organic layer, Wash with brine (2 x 100 mL) and dry over anhydrous magnesium sulfate. The solvent was removed by evaporation and then subjected to flash chromatography (Combi-flash Rf, hexane / ethyl acetate, 0-50% gradient) to give 4-bromo-3-( 3-Methoxyphenyl)-1H-pyrazole (3 g, 70%) was obtained.

[0319] Step 4. 2-(4-bromo-3-(3-methoxyphenyl)-1H-pyrazole- Synthesis of ethyl (1-yl)thiazole-4-carboxylate. 4-Bromo-3-(3-methoxyphenyl)-1H-pyrazole (3 g, 0.012 m ol) was dissolved in anhydrous DMSO (15 mL) and anhydrous potassium carbonate (2.46 g, 0.01 8 mol) and ethyl 2-bromothiazole-4-carboxylate (2.8 g, 0.012) The reaction mixture was heated at 120°C for 6 hours. After cooling, the reaction mixture was poured into water. The precipitate was filtered off and 2-(4-bromo-3-(3-methoxyphenyl)-1H-pyrazol-2-yl)- To obtain ethyl (1-thiazole-1-yl)thiazole-4-carboxylate (3.54 g, 73%).

[0320] Step 4A. Ethyl 2-(4-bromo-3-(3-hydroxyphenyl)-1H-pyridinyl)- Synthesis of (thiazol-1-yl)thiazole-4-carboxylic acid. 2-(4-bromo-3-(3-methoxyphenyl)-1H-pyrazol-1-yl)thio Ethyl azole-4-carboxylate (3 g, 0.008 mol) in anhydrous DCM (20 mL) Boron tribromide (1M in DCM, 9.5 mL, 0.0096 mol) was added dropwise. The reaction mixture was stirred at room temperature for 30 minutes. The precipitate was filtered off, washed with DCM and 2-(4-bromo-3-(3-hydroxyphenyl)-1H-pyrazol-1-yl)thio Azole-4-carboxylic acid (2 g, 60%) was obtained.

[0321] Step 4B. 2-(4-bromo-3-(3-isopropoxyphenyl)-1H-pyra Synthesis of isopropyl (1-thiazole-1-yl)thiazole-4-carboxylate. Ethyl 2-(4-bromo-3-(3-hydroxyphenyl)-1H-pyrazole-1- (yl)thiazole-4-carboxylic acid (500 mg, 0.1 mmol) was dissolved in anhydrous DMF. Potassium carbonate (2.1 g, 15 mmol) and isopropyl bromide (1.4 mL, 1 0 mmol) was added and the reaction was irradiated in a microwave reactor at 130 °C for 40 min. The reaction mixture was poured into water and extracted with ethyl acetate (3 x 40 mL). (2 x 50 mL) and dried over anhydrous magnesium sulfate. The solvent was removed by rotary evaporation. The eluate was removed by a filter and then subjected to flash chromatography (Combi-flash Rf, Hexanes / ethyl acetate, 0-20% gradient) to give 2-(4-bromo-3-( 3-Isopropoxyphenyl)-1H-pyrazol-1-yl)thiazole-4-carbo Isopropyl phosphate (520 mg, 84%) was obtained.

[0322] Step 5. 2-(3-(3-isopropoxyphenyl)-4-(4,4,5,5-tetramethylphenyl)-2 ... tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl ) Synthesis of isopropyl thiazole-4-carboxylate. 2-(4-bromo-3-(3-isopropoxyphenyl)-1H-pyrazol-1-yl Isopropyl thiazole-4-carboxylate (520 mg, 1.15 mmol) Dissolve potassium acetate (340 mg, 3.46 mmol), PdCl in THF (5 mL). 2(dppf) (0.9 mg, 0.0011 mmol) and bis(pinacolato)diborane (408 mg, 1.61 mmol) was added. The vial was purged with argon for 5 minutes. The reaction was heated at 100° C. for 2 hours. The reaction mixture was diluted with ethyl acetate and poured onto Celite. The solvent was removed by rotary evaporation and the residue was purified by flash chromatography. Chromatography (Combi-flash Rf, hexane / ethyl acetate, 0-40% gradient) ) and purified by 2-(3-(3-isopropoxyphenyl)-4-(4,4,5, 5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1 -yl)thiazole-4-carboxylate isopropyl and 2-(3-(3-isopropoxy) (phenyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid isopropyl A mixture was obtained.

[0323] Step 6. 2-(3-(3-isopropoxyphenyl)-4-(4-sulfamoyl) benzyl-1H-pyrazol-1-yl)thiazole-4-carboxylic acid isopropyl Synthesis. 2-(3-(3-isopropoxyphenyl)-4-(4,4,5,5-tetramethyl- 1,3,2-Dioxaborolan-2-yl)-1H-pyrazol-1-yl)thiazole -4-carboxylate isopropyl and 2-(3-(3-isopropoxyphenyl)-1H- (pyrazol-1-yl)thiazole-4-carboxylate (500 mg, 1 mmol) A mixture of potassium carbonate (414 mg, 3 mmol), Pd(PPh3)4 (1.2 mg , 0.001 mmol), and 4-(bromomethyl)benzenesulfonamide (27 5 mg, 1.1 mmol) was added to a microwave vial, followed by THF (8 mL) and Water (3 mL) was added. The vial was sealed and heated at 100° C. for 1 hour. The reaction mixture It was cooled, poured into water and extracted with ethyl acetate (3 x 20 mL). The organic layer was washed with brine (2 x 2 0 mL) and dried over anhydrous magnesium sulfate. The solvent was evaporated on a rotary evaporator. and then flash chromatography (Combi-flash Rf, hexane / ethyl acetate, 0-70% gradient) to give the title compound (150 mg, 27%) obtained.

[0324] Step 7. 2-(3-(3-isopropoxyphenyl)-4-(4-sulfamoyl) Synthesis of (benzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid 459 2-(3-(3-isopropoxyphenyl)-4-(4-sulfamoylbenzyl)- Isopropyl 1H-pyrazol-1-yl)thiazole-4-carboxylate (50 mg, 0 0.09 mmol) was dissolved in THF / MeOH (1 mL:1 mL) and LiOH (5 M, 5 00 μL) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with hydrochloric acid (1.2 M ), diluted with ethyl acetate (15 mL), washed with water (10 mL), The organic layer was dried over anhydrous magnesium sulfate and concentrated using a rotary evaporator. , dissolved in a mixture of DMSO and MEOH, and analyzed by HPLC (Phenomenex Gemi ni C18, 45%-85% CH3CN to H2O / CH3CN gradient in 7 min, 0. 1% TFA) to afford the title compound 459 (34 mg, 76%). 1 H -NMR(d 6 -DMSO)δ8.24(m,2H),7.78(d,2H,J=8Hz ),7.44(d,2H,J=8Hz),7.39-7.30(m,3H),7.22( d,1H,J=8Hz),7.09(d,1H,J=4Hz),6.99-6.96(m ,1H),4.51(m,1H),4.15(s,2H),1.27(d,6H,J=8 Hz); MS(ES) 499.0(M+H)+ LCMS RT=1.07 min.

[0325] Example 75 2-(3-(3-(cyclopentyloxy)phenyl)-4-(4-sulfamoylbenzyl) (1H-pyrazol-1-yl)thiazole-4-carboxylic acid 460 [ka]

[0326] The title compound was prepared using a procedure similar to that described for the preparation of 459, and purified by HPLC. Purified by C: 2-(3-(3-(cyclopentyloxy)phenyl)-4-(4 -Sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carvone Acid 460. 1 H-NMR(d 6 -DMSO) δ 8.55 (m, 2H), 8.25 (d, 2 H,J=4Hz),7.77(d,2H,J=4Hz),7.55-7.26(m,3H ),7.22(d,1H,J=8Hz),7.09(d,1H,J=8Hz),6.99 -6.96(m,1H),4.74(m,1H),4.15(s,2H),1.91-1 .82(m,2H),1.69-1.58(m,4H),1.23(m,2H);MS( ES)525.0(M+H) + LCMS RT=1.15 min.

[0327] <Example 76> 2-(4-(4-sulfamoylbenzyl)-3-(3-((tetrahydrofuran-3 -yl)methoxy)phenyl)-1H-pyrazol-1-yl)thiazole-4-carbo Phosphoric acid 461 [ka]

[0328] The title compound was prepared using a procedure similar to that described for the preparation of 459, and purified by HPLC. Purified by C: 2-(4-(4-sulfamoylbenzyl)-3-(3-((tetrahydrofuran)-2-yl)-4-methyl-2-propanol)-3-one (1H-pyrazol-1-yl)thiahydrofuran-3-yl)methoxy)phenyl) 4-diol-4-carboxylic acid 461. MS(ES) 540.7(M+H) + LCMS RT= 1.13 minutes.

[0329] <Example 77> 2-(3-(3-((3-methoxybenzyl)oxy)phenyl)-4-(4-sulfonyl) Amoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid 462 [ka]

[0330] The title compound was prepared using a procedure similar to that described for the preparation of 459, and purified by HPLC. Purified by C: 2-(3-(3-((3-methoxybenzyl)oxy)phenyl) -4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4 -Carboxylic acid 462. MS(ES) 576.9(M+H) + LCMS RT=1.02min .

[0331] Example 78 2-(4-(4-sulfamoylbenzyl)-3-(3-((tetrahydrofuran-2 -yl)methoxy)phenyl)-1H-pyrazol-1-yl)thiazole-4-carbo Phosphoric acid 463 [ka]

[0332] The title compound was prepared using a procedure similar to that described for the preparation of 459, and purified by HPLC. Purified by C: 2-(4-(4-sulfamoylbenzyl)-3-(3-((tetrahydrofuran)-2-yl)-4-methyl-2-propanol)-3-one (1H-pyrazol-1-yl)thiahydrofuran-2-yl)methoxy)phenyl) 4-diol-4-carboxylic acid 463. MS(ES) 540.9(M+H) + LCMS RT= 0.76 minutes.

[0333] Example 79 2-(3-(3-phenoxyphenyl)-4-(4-sulfamoylbenzyl)-1H -pyrazol-1-yl)thiazole-4-carboxylic acid 464 [ka]

[0334] The title compound was prepared using a procedure similar to that described for the preparation of 459, and purified by HPLC. Purified by C: 2-(3-(3-phenoxyphenyl)-4-(4-sulfamoyl) (1H-benzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid 464. MS (ES)532.9(M+H) + LCMS RT=0.98 min.

[0335] <Example 80> 2-(3-(3-(pyridin-3-ylmethoxy)phenyl)-4-(4-sulfamoyl) (Ilbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid, TFA4 65 [ka]

[0336] The title compound was prepared using a procedure similar to that described for the preparation of 459, and purified by HPLC. Purified by C: 2-(3-(3-(pyridin-3-ylmethoxy)phenyl)-4 -(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazol-4-yl Carboxylic acid, TFA465 MS(ES) 548.0(M+H) + LCMS RT=0.6 8 minutes.

[0337] <Example 81> 2-(3-(3-(pyridin-2-ylmethoxy)phenyl)-4-(4-sulfamoyl) (Ilbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid, TFA4 66 [ka]

[0338] The title compound was prepared using a procedure similar to that described for the preparation of 459, and purified by HPLC. Purified by C: 2-(3-(3-(pyridin-2-ylmethoxy)phenyl)-4 -(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazol-4-yl Carboxylic acid, TFA466. MS(ES) 547.9(M+H) + LCMS RT=0.6 8 minutes.

[0339] <Example 82> 2-(5-(naphthalen-2-yl)-4-(4-sulfamoylbenzyl)-1H- Pyrazol-1-yl)thiazole-4-carboxylic acid 474 [ka]

[0340] The title compound was prepared using a procedure similar to that described for the preparation of 459, and purified by HPLC. Purified by C: 2-(5-(naphthalen-2-yl)-4-(4-sulfamoyl) Benzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid 474 1 H- NMR(d 6 -DMSO)δ8.24(s,1H),8.13(s,1H),7.91- 8.03(m,4H),7.80(d,J=8.2Hz,2H),7.52-7.58( m,3H),7.32(s,2H),4.25(s,2H);MS(ES)491(M+ H) + LCMS RT 1.04 min.

[0341] <Example 83> 2-(5-(pyridin-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyridin (1-thiazol-1-yl)thiazole-4-carboxylic acid 475 [ka]

[0342] The title compound was prepared using a procedure similar to that described for the preparation of 459, and purified by HPLC. Purified by C: 2-(5-(pyridin-3-yl)-4-(4-sulfamoyl)benzyl)-4-(4-sulfamoyl)benzyl (1H-pyrazol-1-yl)thiazole-4-carboxylic acid 475 MS(E S)442(M+H) + LCMS RT 0.64 min.

[0343] <Example 84> 2-(3-(6-fluoro-4'-methyl-[1,1'-biphenyl]-3-yl)- 4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazol-4- Carboxylic Acid 476 [ka]

[0344] The title compound was prepared using a procedure similar to that described for the preparation of 459, and purified by HPLC. Purified by C: 2-(3-(6-fluoro-4'-methyl-[1,1'-biphenyl] [4-sulfamoylbenzyl]-1H-pyrazol-1-yl ) Thiazole-4-carboxylic acid 476. 1 H-NMR(d 6 -DMSO)δ8.27(d ,J=9.24Hz,2H),7.76-7.78(m,4H),7.29-7.46( m,8H),4.2(s,2H),2.35(s,3H);MS(ES)549(M+H ) + LCMS RT 1.27 min.

[0345] <Example 85> 2-(3-(6-fluoro-3'-methoxy-[1,1'-biphenyl]-3-yl) -4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4 -Carboxylic Acid 456 [ka] [ka]

[0346] 459, steps 1-2 were used to prepare 3-(3- Bromo-4-fluorophenyl)-1H-pyrazole was prepared.

[0347] Step 2A: 3-(3-bromo-4-fluorophenyl)-1H-pyrazole (10 0mg, 0.415mmol), 3-methoxyphenylboronic acid (95mg, 0.622 mmol), K2CO3 (678 mg, 4.977 mmol), and dioxane / H2O A 2:1 mixture (8.0 mL) of the following was combined in a microwave vial and then degassed: The reaction mixture was purged with argon (3x). Pd(dppf)Cl2 was added and the reaction mixture was stirred for 120 min. The reaction mixture was cooled to room temperature and NaOH (8 mL, 1 M) was added. The mixture was extracted with EtOAc (3×50 mL). The combined organic layers were then washed with brine. The crude product was extracted with HCl, dried over MgSO4, filtered, and concentrated by rotary evaporation. The eluate was analyzed by flash chromatography (Combi-flash Rf, dichloromethane / methan Purification was performed using ethanol (0-10% gradient) to obtain 3-[4-fluoro-3-(3-methoxyphenyl)-2-(4-methyl ... To obtain 419 mg (94%) of 1H-pyrazole, 419 mg of 1H-phenylphenyl was obtained. 1 H-NMR (CDCl3)δ7.69(1H,d,J=2.2Hz),7.71(1H,m),7. 63(1H,d,J=2.2Hz),7.37(1H,t,J=8.0Hz),7.21 -7.09(3H,m),6.78(1H,dd,J=8.2,2.3Hz),6.61 (1H,d,J=2.3Hz),3.84(3H,s). MS(M+H) + =270.1 .

[0348] Using procedures similar to those described in the preparation of 459, steps 3-7, the title compound was prepared and purified by HPLC: 2-(3-(6-fluoro-3'-methoxy-[ 1,1'-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-biphenyl (Thiazole-1-yl)thiazole-4-carboxylic acid 456 MS(ES) 565.0(M +H) + LCMS RT=1.08 min.

[0349] <Example 86> 2-(3-(3'-chloro-6-fluoro-[1,1'-biphenyl]-3-yl)- 4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazol-4- Carboxylic Acid 457 [ka]

[0350] The title compound was prepared using a procedure similar to that described for the preparation of 456, and purified by HPLC. Purified by C: 2-(3-(3'-chloro-6-fluoro-[1,1'-biphenyl] [4-sulfamoylbenzyl]-1H-pyrazol-1-yl ) Thiazole-4-carboxylic acid 457 MS (ES) 568.9 (M + H) + LCMS RT=1.16 minutes.

[0351] <Example 87> 2-(3-(3',6-difluoro-[1,1'-biphenyl]-3-yl)-4-( 4-Sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carbo Phosphoric acid 458 [ka]

[0352] The title compound was prepared using a procedure similar to that described for the preparation of 456, and purified by HPLC. Purified by C: 2-(3-(3',6-difluoro-[1,1'-biphenyl]- 3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thia 4-diol-4-carboxylic acid 458 MS(ES) 552.9(M+H) + LCMS RT= 1.12 minutes.

[0353] <Example 88> 2-(3-(4-methyl-3-(pyridin-3-yl)phenyl)-4-(4-sulfonyl)phenyl Amoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid 486 [ka]

[0354] 459, steps 1–6 were used to prepare 2-(3- (3-chloro-4-methylphenyl)-4-(4-sulfamoylbenzyl)-1H-pi (Thiazole-1-yl)thiazole-4-carboxylic acid was prepared.

[0355] Modification step 7: Add bis(tri-tert-butylphosphine) para to a flame-dried flask Sodium (5.1 mg, 10 mol%), cesium carbonate (1 mL, 1 M solution), pyridine- 3-ylboronic acid (25 mg, 0.2 mmol), 2-(3-(3-chloro-4-methyl) (phenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thia 4-diol-carboxylic acid (51 mg, 0.1 mmol) and THF (2 mL) were added. The reaction mixture was irradiated in a microwave at 120°C for 20 minutes, and the solvent was removed by rotary evaporation. The residue was filtered through a pad of Celite with MeOH and then The solvent was removed by rotary evaporation. The residue was purified by HPLC (Phenomenon). nex Gemini C18, 25% to 85% H2O / CH3CN from CH3CN The title compound 486 (32 mg, 6 0%). 1 H-NMR(MeOD)δ8.77(s,1H),8.72(s,1H ),8.40(s,1H),8.25(d,J=8.0Hz,1H),8.16(s,1 H),7.92(dd,J=7.6,5.6Hz,1H),7.81(d,J=8.4H z,2H),7.74(dd,J=7.6,1.6Hz,1H),7.47(d,J=8 .0Hz,2H),7.39(d,J=8.0Hz,2H),4.21(s,2H),2 0.34(s,3H); MS(ES) 532.7(M+H) + ,LCMS RT=0.82 Minutes.

[0356] <Example 89> 2-(3-(3'-amino-6-methyl-[1,1'-biphenyl]-3-yl)-4 -(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazol-4-yl Carboxylic Acid 487 [ka]

[0357] The title compound was prepared using a procedure similar to that described for the preparation of 486, and purified by HPLC. Purified by C: 2-(3-(3'-amino-6-methyl-[1,1'-biphenyl ]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl) Thiazole-4-carboxylic acid 487 1 H-NMR(MeOD) δ 8.37(s,1H) ,8.16(s,1H),7.81(d,J=8.4Hz,2H),7.63(dd,J =7.6,6.6Hz,1H),7.54(t,J=8.0Hz,1H),7.42(d ,J=1.6Hz,1H),7.40(s,2H),7.38(s,1H),7.27- 7.20(m,2H),7.15(s,1H),4.19(s,2H),2.30(s, 3H); MS(ES) 546.7(M+H) + ;LCMS RT=0.87 min.

[0358] <Example 90> 2-(3-(3'-ethyl-6-methyl-[1,1'-biphenyl]-3-yl)-4 -(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazol-4-yl Carboxylic Acid 488 [ka]

[0359] The title compound was prepared using a procedure similar to that described for the preparation of 486, and purified by HPLC. Purified by C: 2-(3-(3'-ethyl-6-methyl-[1,1'-biphenyl ]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl) Thiazole-4-carboxylic acid 488 1 H-NMR(MeOD) δ 8.34(s,1H) ,8.13(s,1H),7.83(d,J=8.4Hz,2H),7.59(dd,J =8.0,2.0Hz,1H),7.48(d,J=2.0Hz,1H),7.41(d ,J=8.0Hz,2H),7.35(d,J=8.0Hz,2H),7.23(d,J =8.0Hz,1H),7.15(s,1H),7.10(d,J=8.0Hz,1H) ,4.20(s,2H),2.73(q,J=8.0Hz,2H),2.29(s,3H ),1.30(t,J=8.0Hz,3H);MS(ES)559.4(M+H) + ;L CMS RT=1.28 minutes.

[0360] <Example 91> 2-(3-(3',5'-difluoro-6-methyl-[1,1'-biphenyl]-3- (4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazo 4-amino-4-carboxylic acid 489 [ka]

[0361] The title compound was prepared using a procedure similar to that described for the preparation of 486, and purified by HPLC. Purified by C: 2-(3-(3',5'-difluoro-6-methyl-[1,1'- Biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazole- 1-yl)thiazole-4-carboxylic acid 489; MS(ES) 569.6(M+H) + ; LCMS RT=1.24 min.

[0362] <Example 92> 2-(3-(4-methyl-3-(pyridin-4-yl)phenyl)-4-(4-sulfonyl) Amoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid 490 [ka]

[0363] The title compound was prepared using a procedure similar to that described for the preparation of 486, and purified by HPLC. Purified by C: 2-(3-(4-methyl-3-(pyridin-4-yl)phenyl) -4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4 -carboxylic acid 490; 1 H-NMR(MeOD)δ8.80(brs,2H),8.44 (s,1H),8.17(s,1H),7.85-7.76(m,5H),7.49(d ,J=6.0Hz,1H),7.41(d,J=2.0Hz,1H),7.40(s,1 H),7.38(s,1H),4.21(s,2H),2.39(s,3H);MS(E S)533.6(M+H) + ;LCMS RT=0.83 min.

[0364] <Example 93> 2-(3-(6-methyl-[1,1'-biphenyl]-3-yl)-4-(4-sulfonyl) Amoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid 491 [ka]

[0365] The title compound was prepared using a procedure similar to that described for the preparation of 486, and purified by HPLC. Purified by C: 2-(3-(6-methyl-[1,1'-biphenyl]-3-yl) -4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4 -Carboxylic Acid 491 1 H-NMR(MeOD)δ8.34(s,1H),8.14(s ,1H),7.89-7.82(m,2H),7.83(d,J=8.4Hz,2H), 7.60(dd,J=8.0,2.0Hz,1H),7.54(d,J=8.0Hz,2 H),7.49-7.35(m,4H),7.29(d,J=8.0Hz,2H),4. 20(s,2H),2.30(s,H);MS(ES)531.6(M+H) + ;LCM S RT=1.18 minutes.

[0366] <Example 94> 2-(3-(3',4'-difluoro-6-methyl-[1,1'-biphenyl]-3- (4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazo 4-amino-4-carboxylic acid 492 [ka]

[0367] The title compound was prepared using a procedure similar to that described for the preparation of 486, and purified by HPLC. Purified by C: 2-(3-(3',4'-difluoro-6-methyl-[1,1'- Biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazole- 1-yl)thiazole-4-carboxylic acid 492 MS(ES) 567.9(M+H) + ; LCMS RT=1.20 min.

[0368] <Example 95> 2-(3-(4'-fluoro-3',6-dimethyl-[1,1'-biphenyl]-3- (4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazo 4-amino-4-carboxylic acid 493 [ka]

[0369] The title compound was prepared using a procedure similar to that described for the preparation of 486, and purified by HPLC. Purified by C: 2-(3-(4'-fluoro-3',6-dimethyl-[1,1'- Biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazole- 1-yl)thiazole-4-carboxylic acid 493 MS(ES) 563.9(M+H) + ; LCMS RT=1.25 min.

[0370] <Example 96> 2-(3-(3'-fluoro-4'-methoxy-6-methyl-[1,1'-biphenyl] ]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl) Thiazole-4-carboxylic acid 494 [ka]

[0371] The title compound was prepared using a procedure similar to that described for the preparation of 486, and purified by HPLC. Purified by C: 2-(3-(3'-fluoro-4'-methoxy-6-methyl-[1 ,1'-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyra (1-isothiazol-1-yl)thiazole-4-carboxylic acid 494 MS(ES) 579.6 (M+ H) + ;LCMS RT=1.18 min.

[0372] <Example 97> 2-(4-(4-sulfamoylbenzyl)-3-(3',5',6-trimethyl-[ 1,1'-biphenyl]-3-yl)-1H-pyrazol-1-yl)thiazol-4- Carboxylic Acid 495 [ka]

[0373] The title compound was prepared using a procedure similar to that described for the preparation of 486, and purified by HPLC. Purified by C: 2-(4-(4-sulfamoylbenzyl)-3-(3',5', 6-trimethyl-[1,1'-biphenyl]-3-yl)-1H-pyrazol-1-yl ) Thiazole-4-carboxylic acid 495 MS (ES) 559.9 (M + H) + ;LCMS RT=1.29 minutes.

[0374] <Example 98> 2-(3-(3'-cyano-4',6-dimethyl-[1,1'-biphenyl]-3-yl) (4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole -4-carboxylic acid 496 [ka]

[0375] The title compound was prepared using a procedure similar to that described for the preparation of 486, and purified by HPLC. Purified by C: 2-(3-(3'-fluoro-6-methyl-[1,1'-biphenyl] [4-sulfamoylbenzyl]-1H-pyrazol-1-yl ) Thiazole-4-carboxylic acid 496 MS (ES) 549.6 (M + H) + ;LCMS RT=1.18 minutes.

[0376] Example 99 2-(3-(3'-fluoro-6-methyl-[1,1'-biphenyl]-3-yl)- 4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazol-4- Carboxylic Acid 497 [ka]

[0377] The title compound was prepared using a procedure similar to that described for the preparation of 486, and purified by HPLC. Purified by C: 2-(3-(3'-fluoro-6-methyl-[1,1'-biphenyl] [4-sulfamoylbenzyl]-1H-pyrazol-1-yl ) Thiazole-4-carboxylic acid 497 MS (ES) 549.6 (M + H) + ;LCMS RT=1.18 minutes.

[0378] Example 100 2-(3-(4'-fluoro-6-methyl-[1,1'-biphenyl]-3-yl)- 4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazol-4- Carboxylic acid 498 (compound VV) [ka]

[0379] The title compound was prepared using a procedure similar to that described for the preparation of 486, and purified by HPLC. Purified by C: 2-(3-(4'-fluoro-6-methyl-[1,1'-biphenyl] [4-sulfamoylbenzyl]-1H-pyrazol-1-yl ) Thiazole-4-carboxylic acid 498 MS (ES) 549.6 (M + H) + ;LCMS RT=1.16 minutes.

[0380] <Example 101> 2-(3-(3'-ethyl-6-fluoro-[1,1'-biphenyl]-3-yl)- 4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazol-4- Carboxylic Acid 513 [ka]

[0381] 459, steps 1–6 were used to prepare 2-(3- (3-chloro-4-fluorophenyl)-4-(4-sulfamoylbenzyl)-1H- Pyrazol-1-yl)thiazole-4-carboxylic acid was prepared.

[0382] Modification Step 7: 2-(3-(3-chloro-4-fluorophenyl)-4-(4-sulfonyl)-2 ... Famoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid (5 0 mg, 0.10 mmol) in dioxane / water (2.5 mL, 4:1) (phenyl)boronic acid (23 mg, 0.15 mmol), followed by Cs2CO3 (68 mg, 0.20 mmol), Pd2(dba)3 (10.0 mg, 0.01 mmol), and t -Bu3P (5 μL, 0.03 mmol) was added. The solution was capped and The reaction mixture was purged with ethanol. The reaction mixture was heated at 95°C for 24 hours. The reaction mixture was cooled and purified with HCl. The mixture was diluted with 10 mL of 1M HCl and extracted with ethyl acetate (3 x 15 mL). The combined organic layer was dried over MgSO4 and concentrated by rotary evaporation. The crude product was purified by HPLC (Phenomenex Gemini C18, 25% to 85% Purified by CH3CN to H2O / CH3CN gradient (4 min, 0.1% TFA) , 2-(3-(3'-ethyl-6-fluoro-[1,1'-biphenyl]-3-yl)- 4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazol-4- Carboxylic acid 513 (12 mg, 21%) was obtained. 1 H-NMR (MeOD) δ 8.37 ( s,1H),8.17(s,1H),7.86(d,J=8.24Hz,2H),7.7 7(d,J=6.4Hz,2H),7.44(d,J=8.2Hz,2H),7.33( t,J=9.62Hz,1H),7.16(d,J=7.79Hz,2H),7.03( m,1H),4.23(s,2H),3.63(q,J=7.1,14.2Hz,2H) ,1.20(t,J=7.1Hz,3H);MS(ES)562.9(M+H) + ;LC MS RT=1.24 min.

[0383] <Example 102> 2-(3-(3'-ethyl-6-fluoro-[1,1'-biphenyl]-3-yl)- 4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazol-4- Carboxylic Acid 514 [ka]

[0384] The title compound was prepared using a procedure similar to that described for the preparation of 513, and purified by HPLC. Purified by C: 2-(3-(3'-ethyl-6-fluoro-[1,1'-biphenyl] [4-sulfamoylbenzyl]-1H-pyrazol-1-yl ) Thiazole-4-carboxylic acid 514 1 H-NMR (MeOD) δ 8.36 (s, 1H ),8.16(s,1H),7.87(d,J=6.4Hz,2H),7.81(m,2 H),7.75(d,J=8.1Hz,2H),7.46(M,2H),7.34(m, 2H),4.24(s,2H);MS(ES)602.9(M+H) + ;LCMS RT =1.30 minutes.

[0385] <Example 103> 2-(3-(6-fluoro-[1,1'-biphenyl]-3-yl)-4-(4-sulfonyl) Famoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid 51 5 [ka]

[0386] The title compound was prepared using a procedure similar to that described for the preparation of 513, and purified by HPLC. Purified by C: 2-(3-(6-fluoro-[1,1'-biphenyl]-3-yl )-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-Carboxylic acid 515 MS(ES) 544.0(M+H) + LCMS RT=1.1 8 minutes.

[0387] <Example 104> 2-(3-(6-fluoro-3',4'-dimethyl-[1,1'-biphenyl]-3- (4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazo 4-carboxylic acid 516 [ka]

[0388] The title compound was prepared using a procedure similar to that described for the preparation of 513, and purified by HPLC. Purified by C: 2-(3-(6-fluoro-3',4'-dimethyl-[1,1'- Biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazole- 1-yl)thiazole-4-carboxylic acid 516 MS(ES) 562.9(M+H) + ; LCMS RT=1.23 min.

[0389] <Example 105> 2-(4-(4-sulfamoylbenzyl)-3-(3',4',6-trifluoro- [1,1'-biphenyl]-3-yl)-1H-pyrazol-1-yl)thiazole-4 -Carboxylic Acid 517 [ka]

[0390] The title compound was prepared using a procedure similar to that described for the preparation of 513, and purified by HPLC. Purified by C: 2-(4-(4-sulfamoylbenzyl)-3-(3',4', 6-trifluoro-[1,1'-biphenyl]-3-yl)-1H-pyrazol-1-yl (I)thiazole-4-carboxylic acid 517 MS(ES) 571.0(M+H) + ;LCM S RT=1.18 minutes.

[0391] <Example 106> 2-(3-(4',6-difluoro-3'-methoxy-[1,1'-biphenyl]-3 -yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazo 4-amino-4-carboxylic acid 518 [ka]

[0392] The title compound was prepared using a procedure similar to that described for the preparation of 513, and purified by HPLC. Purified by C: 2-(3-(4',6-difluoro-3'-methoxy-[1,1' -biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazole -1-yl)thiazole-4-carboxylic acid 518 MS(ES) 582.9(M+H) + ;LCMS RT=1.14 min.

[0393] <Example 107> 2-(3-(3'-methyl-[1,1'-biphenyl]-3-yl)-4-(4-sulfonyl) Famoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid 51 9 [ka]

[0394] The title compound was prepared using a procedure similar to that described for the preparation of 513, and purified by HPLC. Purified by C: 2-(3-(3'-methyl-[1,1'-biphenyl]-3-yl )-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-Carboxylic acid 519 MS(ES) 530.9(M+H) + ;LCMS RT=1.0 0 minutes.

[0395] <Example 108> 2-(3-(3',6-difluoro-4'-methyl-[1,1'-biphenyl]-3- (4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazo 4-carboxylic acid 520 [ka]

[0396] The title compound was prepared using a procedure similar to that described for the preparation of 513, and purified by HPLC. Purified by C: 2-(3-(3',6-difluoro-4'-methyl-[1,1'- Biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazole- 1-yl)thiazole-4-carboxylic acid 520 MS(ES) 566.9(M+H) + ; LCMS RT=1.22 min.

[0397] Example 109 2-(3-(3'-methoxy-[1,1'-biphenyl]-3-yl)-4-(4-sulfonyl) (Sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid 5 twenty one [ka]

[0398] The title compound was prepared using a procedure similar to that described for the preparation of 513, and purified by HPLC. Purified by C: 2-(3-(3'-methoxy-[1,1'-biphenyl]-3-yl) (4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole -4-carboxylic acid 521 MS(ES) 546.9(M+H) + ;LCMS RT=0. 89 minutes.

[0399] Example 110 2-(3-(3-(pyridin-3-yl)phenyl)-4-(4-sulfamoylphenyl)benzyl (1H-pyrazol-1-yl)thiazole-4-carboxylic acid 522 [ka]

[0400] The title compound was prepared using a procedure similar to that described for the preparation of 513, and purified by HPLC. Purified by C: 2-(3-(3-(pyridin-3-yl)phenyl)-4-(4- Sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid 522 MS(ES)517.9(M+H) + ;LCMS RT=0.82 min.

[0401] Example 111 2-(3-(3'-amino-[1,1'-biphenyl]-3-yl)-4-(4-sulfonyl) Famoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid 52 3 [ka]

[0402] The title compound was prepared using a procedure similar to that described for the preparation of 513, and purified by HPLC. Purified by C: 2-(3-(3'-amino-[1,1'-biphenyl]-3-yl )-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-Carboxylic acid 524 MS(ES) 532.0(M+H) + LCMS RT=0.7 0 minutes.

[0403] <Example 112> 2-(5-cyclopropyl-3-(4',6-difluoro-[1,1'-biphenyl] -3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thio Azole-4-carboxylic acid 482 [ka] [ka]

[0404] Step 1. 1-(3-chloro-4-fluorophenyl)-3-cyclopropylpropionate Synthesis of benzo-1,3-dione. 1-(3-chloro-4-fluorophenyl)ethan-1-one (1.5 g, 8.72 m mol, 1 equivalent) was dissolved in THF and cooled to -78°C. After 10 minutes of stirring, LHMDS (1M in hexane, 12.2 mL, 1.4 eq) was added dropwise over 20 minutes. The mixture was allowed to stir for 20 minutes, and then cyclopropanecarbonyl chloride (1.1 mL, 12.2 m mol, 1.4 equiv) was added dropwise. The reaction was allowed to stir for 3 hours, at which point it was allowed to come to room temperature. The reaction was quenched with 1M HCl and extracted with ethyl acetate. The aqueous layer was washed three times with ethyl acetate. The organic layer was washed with brine and dried over MgSO4. Chromatography (Combi-flash Rf, hexane / ethyl acetate, 0-2 0% gradient) to give 1-(3-chloro-4-fluorophenyl)-3-cyclohexane. Propylpropane-1,3-dione (1 g, 50%) was obtained. MS (ES) 241 (M+ H) + ;LCMS RT 1.357 min.

[0405] Step 2. 4-(2-(3-chloro-4-fluorobenzoyl)-3-cyclopropyl Synthesis of (3-oxopropyl)benzenesulfonamide 1-(3-chloro-4-fluorophenyl)-3-cyclopropylpropane-1,3- The dione (1 g, 4.16 mmol, 1 equiv.) was dissolved in DMSO (10 mL) and stirred. 4-(Bromomethyl)benzenesulfonamide (1.34 g, 5.4 mmol, 1.3 equiv.), Cs2CO3 (1.75 g, 5.4 mmol, 1.3 equiv.), and sodium iodide C. to 100° C. After stirring for 1 hour, ethanol (624 mg, 4.16 mmol, 1 equiv.) was added. The reaction was stirred at 50.degree. C. for 1 hour. After this time, the reaction mixture was poured into 1M HCl and extracted with ethyl acetate. The combined organic layers were washed with brine and dried over MgSO4. The reaction mixture was purified by flash chromatography (Combi-flash Rf, hexane / ethyl acetate). 4-(2-(3-chloro-4-fluorobenzophenone)-2-yl)- ... (zoyl)-3-cyclopropyl-3-oxopropyl)benzenesulfonamide (750 mg, 45%). MS: (ES) 410 (M+H) + ;LCMS RT 1.14 Minutes.

[0406] Step 3. 2-(3-(3-chloro-4-fluorophenyl)-5-cyclopropyl -4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4 -Synthesis of ethyl carboxylate. 4-(2-(3-chloro-4-fluorobenzoyl)-3-cyclopropyl-3-oxo (isopropyl)benzenesulfonamide (700 mg, 1.7 mmol, 1 equiv.) in 2-hydroxybenzoates. Ethyl thiazole-4-carboxylate (300 mg, 1.7 mmol, 1 equiv.) and p-toluenesulfonic acid (650 mg, 3.4 mmol, 2 equiv.) in a microwave oven. The reaction mixture was purged with argon gas and then diluted with ethanol (4 mL). The reaction was carried out in a microwave reactor at 100°C for 15 minutes. Chromatography (Combi-flash Rf, hexane / ethyl acetate = 0-8 0% gradient) to give 2-(3-(3-chloro-4-fluorophenyl)-5- Cyclopropyl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl Ethyl thiazole-4-carboxylate (300 mg) was obtained.

[0407] Step 4. 2-(5-cyclopropyl-3-(4',6-difluoro-[1,1'- Biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazole- 1-Il)thiazole-4-carboxylic acid 482 2-(3-(3-chloro-4-fluorophenyl)-5-cyclopropyl-4-(4- Sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid Ethyl (15 mg, 0.03 mmol) was dissolved in (4-fluorophenyl)boronic acid (8 mg, 0.06 mmol, 2 equivalents) and Pd(P(t-Bu)3)2 (5 mg) together with The reaction mixture was placed in a microwave vial and purged with vacuum and argon gas. Cs2CO3 (1M, 1 mL) and THF (2 mL) were added. The reaction was microwaved. The mixture was heated at 100°C for 15 minutes. LC / MS showed the conversion of the ester to the product with hydrolysis. After completion of the reaction, the solvent was removed by rotary evaporation and the reaction was analyzed by HPLC ( Phenomenex Gemini C18, 45%-85% H2 from CH3CN 0 / CH3CN gradient for 7 min, 0.1% TFA) to give the title compound 482 ( 5 mg) was obtained. 1 H-NMR(MeOD): δ8.27(s,1H)7.85(d,J =12Hz,2H),;7.57-7.63(m,1H),7.5(d,J=16Hz, 1H),7.29-7.42(m,4H),7.12-7.25(m,4H),4.25 (s,2H),2.32-2.41(m,1H),1.15(d,J=12Hz,2H) ,0.7(d,J=9Hz,2H);(ES)593(M+H) + LCMS RT=1. 28 minutes.

[0408] <Example 113> 2-(5-cyclopropyl-3-(6-fluoro-3'-methoxy-[1,1'-biphenyl] [phenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazole-1- (I)thiazole-4-carboxylic acid 483 [ka]

[0409] The title compound was prepared using a procedure similar to that described for the preparation of 482, and purified by HPLC. Purified by C: 2-(5-cyclopropyl-3-(6-fluoro-3'-methoxyphenyl)- ... -[1,1'-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H -pyrazol-1-yl)thiazole-4-carboxylic acid 483 1 H-NMR (CDCl 3)δ8.13(s,1H),7.85(d,J=8Hz,2H),7.55-7.59 (m,1H),7.35-7.39(m,2H),7.25-7.31(m,4H),7 .17(t,J=18.84Hz,1H),7.04(d,J=7.56Hz,1H), 6.91-6.94(dd,J=2,2Hz,1H), 6.73(s,1H),5.04 (s, broad, 2H), 4.17(s, 2H), 3.87(s, 3H), 2.23-2 .27(m,1H),1.12(d,J=7Hz,2H),0.73(d,J=5Hz, 2H), MS(ES) 605(M+H) + LCMS RT=1.25 min.

[0410] <Example 114> 2-(5-cyclopropyl-3-(6-fluoro-4'-methyl-[1,1'-biphenyl] [4-[4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl]-3-yl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl Thiazole-4-carboxylic acid 484 [ka]

[0411] The title compound was prepared using a procedure similar to that described for the preparation of 482, and purified by HPLC. Purified by C: 2-(5-cyclopropyl-3-(6-fluoro-4'-methyl- [1,1'-biphenyl]-3-yl)-4-(4-sulfamoylbenzyl)-1H- Pyrazol-1-yl)thiazole-4-carboxylic acid 484 1 H-NMR (CDCl )δ8.10(s,1H),7.82(d,J=8Hz,2H),7.5(dd,J1= 2;J2=2Hz,1H),7.41-7.45(m,1H),7.22-7.32(m ,7H),7.13(t,J=19Hz,1H),5.06(s,2H),4.14(s ,2H),2.40(s,3H),2.17-2.23(m,1H),1.07(d,J =8Hz,2H), 0.68(d,J=5.Hz,2H), MS(ES)589(M+H ) + LCMS RT=1.31 min.

[0412] Example 115 2-(5-(cyclopropylmethyl)-3-(3-(phenylamino)phenyl)-4 -(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazol-4-yl Carboxylic Acid 485 [ka]

[0413] 482, using a procedure similar to that described in the preparation of steps 1–3, 2-[3- (3-Bromophenyl)-5-(cyclopropylmethyl)-4-[(4-sulfamoyl (phenyl)methyl]-1H-pyrazol-1-yl]-1,3-thiazole-4-carbo Ethyl phosphate was prepared.

[0414] Modification Step 4: 2-[3-(3-bromophenyl)-5-(cyclopropylmethyl) -4-[(4-sulfamoylphenyl)methyl]-1H-pyrazol-1-yl]-1 , ethyl 3-thiazole-4-carboxylate (80 mg, 0.139 mmol), powdered K 3PO4 (56.6 mg, 0.267 mmol), aniline (18 μL, 0.199 mmol), ol), and dimethylacetamide (1.3 mL) were combined in a vial. The mixture was degassed and purged with argon after the addition of Pd(P(tBu)3)2 (x3). The vial was then sealed and the mixture was stirred at 100° C. for 16 hours. Upon completion, the reaction mixture Cool to room temperature, dilute with EtOAc (40 mL), add HO (2 × 10 mL), followed by salt. The organic layer was then dried over MgSO4, filtered, and evaporated. The reaction mixture was concentrated by a rotary evaporator. Purification by flash Rf, hexane / ethyl acetate, 0-80% gradient) yielded the title compound. Compound 485 (43 mg, 53%) was obtained. 1 H-NMR(CDCl3) δ 7.96(1 H,s),7.72(2H,d,J=8.3Hz),7.23-7.18(6H,m), 7.02-6.99(4H,m),6.88(1H,t,J=7.4Hz),4.02( 2H,s),3.10(2H,d,J=6.8Hz),1.01(1H,m),0.33 (2H,dd,J=13.8,5.8Hz),0.14(2H,dd,J=10.2,5 .0Hz); MS(ES) 585.7(M+H) + .

[0415] <Example 116> 2-(5-cyclopropyl-3-(4-methyl-3-(pyridin-3-yl)phenyl) )-4-(4-sulfamoyl-benzyl)-1H-pyrazol-1-yl)thiazole -4-carboxylic acid 499 [ka]

[0416] 482, steps 1–3 were used to prepare 2-(3- (3-chloro-4-methylphenyl)-5-cyclopropyl-4-(4-sulfamoyl) (Benzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylate was prepared. Ta.

[0417] Modification step 4: Add bis(tri-tert-butylphosphine) para to a flame-dried flask Sodium (5.1 mg, 10 mol%), cesium carbonate (1 mL, 1 M solution), pyridine- 3-ylboronic acid (22 mg, 0.2 mmol), 2-(3-(3-chloro-4-methyl) (phenyl)-5-cyclopropyl-4-(4-sulfamoylbenzyl)-1H-pyrazo (1-yl)thiazole-4-carboxylate ethyl (50 mg, 0.1 mmol), and The reaction mixture was microwaved at 120°C for 20 minutes, and the resulting solution was dissolved in water. The solvent was removed by rotary evaporation. The residue was purified by filtration through a Celite pad with MeOH. The residue was filtered through a condenser and the solvent was then removed by rotary evaporation. The resulting mixture was analyzed by HPLC (Phenomenex Gemini C18, 35% to 85% CH3 Purification was performed by HCl / CHCN gradient (from HCl / CHCN in 4 min, 0.1% TFA) and the title compound Compound 499 (15 mg, 30%) was obtained.1 H-NMR (MeOD) δ 8.86 (d, J=5.2Hz,1H),8.83(s,1H),8.45(d,J=8.4Hz,1H ),8.27(s,1H),8.13(dd,J=8.0,1.6Hz,1H),7.7 6(d,J=8.4Hz,2H),7.64(dd,J=8.0,1.6Hz,1H), 7.43(d,J=8.0Hz,1H),7.29(s,2H),7.27(s,1H. ),4.25(s,2H),2.42-2.34(m,1H),2.33(s,3H), 1.10(dt,J=8.4,4.6Hz,2H),0.69(dt,J=5.6,4. 6Hz, 2H); MS(ES) 572.9(M+H) + ;LCMS RT=0.87 min.

[0418] Example 117 2-(3-(3'-amino-6-methyl-[1,1'-biphenyl]-3-yl)-5 -Cyclopropyl-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl ) Thiazole-4-carboxylic acid 500 [ka]

[0419] The title compound was prepared using a procedure similar to that described for the preparation of 499, and purified by HPLC. Purified by C: 2-(3-(3'-amino-6-methyl-[1,1'-biphenyl ]-3-yl)-5-cyclopropyl-4-(4-sulfamoylbenzyl)-1H-pyridin (Thiazolidin-1-yl)thiazole-4-carboxylic acid 500: 1 H-NMR(MeOD)δ 8.26(s,1H),7.78(d,J=8.4Hz,2H),7.53(t,J=8 .0Hz,1H),7.49(dd,J=8.0,1.6Hz,1H),7.32(d, J=8.0Hz,1H),7.29(s,1H),7.27(s,3H),7.18(d ,J=8.0Hz,1H),7.13(s,1H),4.23(s,2H),2.41- 2.33(m,1H),2.27(s,3H),1.08(dt,J=8.4,6.4H z,2H),0.67(dt,J=5.6,4.6Hz,2H);MS(ES)586. 9(M+H) + ;LCMS RT=0.92 min.

[0420] <Example 118> 2-(3-(3-benzyloxy)phenyl)-5-cyclopropyl-4-(4-sulfonyl) (Sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid 5 01 [ka]

[0421] The title compound was prepared using a procedure similar to that described for the preparation of 482, and purified by HPLC. Purified by C: 2-(3-(3-(benzyloxy)phenyl)-5-cyclopropyl Pyr-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole -4-carboxylic acid 501: MS (ES) 549.6 (M+H) + ;LCMS RT=1. 16 minutes.

[0422] Example 119 2-(5-cyclopropyl-3-(3-phenoxyphenyl)-4-(4-sulfamoyl) (Ilbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid 502 [ka]

[0423] The title compound was prepared using a procedure similar to that described for the preparation of 482, and purified by HPLC. Purified by C: 2-(5-cyclopropyl-3-(3-phenoxyphenyl)-4 -(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazol-4-yl Carboxylic Acid 502: 1 H-NMR(MeOD)δ8.24(s,1H),7.76(d,J =8.4Hz,2H),7.40-7.31(m,4H),7.19(d,J=8.4H z,2H),7.13(t,J=8.4Hz,1H),7.07(s,1H),7.00 (dd,J=8.0,1.6Hz,1H),6.93(d,J=8.0Hz,2H),4 .15(s,2H),2.37-2.29(m,1H),1.03(dt,J=8.4, 6.4Hz,2H),0.62(dt,J=5.6,4.8Hz,2H);MS(ES) 573.6(M+H) + ;LCMS RT=0.94 min.

[0424] Example 120 2-(3-(3-(cyclopentyloxy)-4-methylphenyl)-5-(cyclopentyloxy) (4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl) Thiazole-4-carboxylic acid 467 [ka] [ka]

[0425] Step 1. 1-(3-(cyclopentyloxy)-4-methylphenyl)ethane-1 Synthesis of -one 3-Hydroxy-4-methylacetophenone (1 g, 0.0066 mol) was dissolved in anhydrous DMSO. F, potassium carbonate (7.35 g, 0.053 mol) and cyclopentyl bromide ( 2.8 mL, 0.026 mol) was added and the reaction was irradiated at 140 °C for 40 min. The mixture was poured into water and extracted with ethyl acetate (3 x 40 mL). The organic layer was washed with brine (2 x 5 0 mL) and dried over anhydrous magnesium sulfate. The solvent was evaporated on a rotary evaporator. and then flash chromatography (Combi-flash Rf, hexane / ethyl acetate, 0-50% gradient) to give 1-(3-(cyclopentyloxy) )-4-methylphenyl)ethan-1-one (1.20 g, 83%) was obtained.

[0426] Step 2. 1-(3-(cyclopentyloxy)-4-methylphenyl)-4-cyclopentyloxy Synthesis of 1,3-propylbutane-1,3-dione (1H-benzo[d][1,2,3]triazol-1-yl) derivative (1.20 g, To a solution of magnesium bromide (0.0055 mol) in DCM (30 mL), ester (3.55 g, 0.013 mol), followed by 1-(3-(cyclopentyloxy) (4-methylphenyl)ethan-1-one (1.44 g, 0.007 mol) and DIP EA (2.88 mL, 0.016 mol) was added, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled in an ice bath, quenched with HCl (1M) and extracted with DCM. The DCM layer was washed with HCl (1M), water, and brine. The crude product was purified by flash chromatography. graphy (Combi-flash Rf, hexane / ethyl acetate, 0-20% gradient) The compound was purified by the method described above to obtain 1-(3-(cyclopentyloxy)-4-methylphenyl)-4-cyclopentyloxy. Chloropropylbutane-1,3-dione (0.7 g, 42%) was obtained.

[0427] Step 3. 4-(2-(3-(cyclopentyloxy)-4-methylbenzoyl)- Synthesis of 4-cyclopropyl-3-oxobutyl)-benzenesulfonamide. 1-(3-(cyclopentyloxy)-4-methylphenyl)-4-cyclopropyl Tan-1,3-dione (0.7 g, 0.0023 mol) and cesium carbonate (0.9 g, 0.0028 mol) in DMSO (10 mL) was stirred at room temperature for 5 minutes, and then KI (0 0.42g, 0.0025mol) and 4-(bromomethyl)benzenesulfonamide (0 The reaction mixture was stirred at 50°C for 5 minutes. After the reaction was completed, the mixture was poured into HCl (1M) and extracted with ethyl acetate. The crude product was purified by flash chromatography (C Purification was performed by ombi-flash Rf (hexane / ethyl acetate = 0-50% gradient). 4-(2-(3-(cyclopentyloxy)-4-methylbenzoyl)-4-cyclo Propyl-3-oxobutyl)-benzenesulfonamide (0.82 g, 76%) was obtained. .

[0428] Step 4. 2-(3-(3-(cyclopentyloxy)-4-methylphenyl)-5 -(Cyclopropylmethyl)-4-(4-sulfamoylbenzyl)-1H-pyrazole -1-yl)thiazole-4-carboxylate ethyl. 4-(2-(3-(cyclopentyloxy)-4-methylbenzoyl)-4-cyclopentyl propyl-3-oxobutyl)benzenesulfonamide (0.82g, 0.0017mol ), p-toluenesulfonic acid (0.16 g, 0.0009 mol), pyrrolidine (71 μ A mixture containing 100 mL of ethanol (7 mL) was heated at 90°C for 1 hour. Ethyl 2-hydrazinylthiazole-4-carboxylate (0.41 g, 0.0 022 mol) was added and the reaction was heated to completion. The reaction mixture was diluted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated. Flash chromatography (Combi-flash Rf, hexane / ethyl acetate, 0 ~80% gradient) to obtain 2-(3-(3-(cyclopentyloxy)-4-methyl)- 4-(4-sulfamoylbenzyl)-5-(cyclopropylmethyl)-4-(4-sulfamoylbenzyl) Ethyl (1H-pyrazol-1-yl)thiazole-4-carboxylate, a mixture of positional isomers The compound was obtained as a soluble solid (0.99 g, 93%).

[0429] Step 5. 2-(3-(3-(cyclopentyloxy)-4-methylphenyl)-5 -(Cyclopropylmethyl)-4-(4-sulfamoylbenzyl)-1H-pyrazole -1-yl)thiazole-4-carboxylic acid 467. 2-(3-(3-(cyclopentyloxy)-4-methylphenyl)-5-(cyclopentyloxy) (4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl) Ethyl thiazole-4-carboxylate (110 mg, 0.18 mmol) in THF / MeO The reaction mixture was dissolved in 2 mL of HCl (2 mL:2 mL) and LiOH (5 M, 500 μL) was added. The mixture was stirred at room temperature overnight. The reaction mixture was neutralized by the addition of hydrochloric acid (1.2 M) and ethyl acetate was added. The mixture was diluted with ethanol (15 mL), washed with water (10 mL), and dried over anhydrous magnesium sulfate. The organic layer was concentrated using a rotary evaporator and added to a mixture of DMSO and MEOH. Dissolve and analyze by HPLC (Phenomenex Gemini C18, 55%-90% C Purification by H₃CN to H₂O / CH₃CN gradient over 4 min, 0.1% TFA) The title compound 467 (35 mg, 33%) was obtained. 1 H-NMR(d 6 -DMSO)δ8. 07(s,1H),7.53(d,2H,J=8Hz),7.12-7.07(m,5H ),6.95(d,1H,J=8Hz),6.87(d,1H,J=8Hz),6.63 (s,1H),4.16(m,1H),3.90(s,2H),2.93(m,2H), 1.87(s,3H),1.40-1.29(m,8H),0.91(m,1H),0. 11(m,2H),0.014(m,2H);MS(ES)593.4(M+H) + LC MS RT=0.81 min.

[0430] <Example 121> 2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-((tetrahydrofuran) (2-yl)methoxy)phenyl)-4-(3-fluoro-4-sulfamoylbenzene (1H-pyrazol-1-yl)thiazole-4-carboxylic acid 469 [ka]

[0431] The title compound was prepared using a procedure similar to that described for the preparation of 467, and purified by HPLC. Purified by C: 2-(5-(cyclopropylmethyl)-3-(4-fluoro-3- ((tetrahydrofuran-2-yl)methoxy)phenyl)-4-(3-fluoro-4- Sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid 469; 1 H-NMR(d 6 -DMSO) δ 8.07 (s, 1H), 7.44 (m, 1H ),7.35(s,2H),7.05-6.82(m,5H),3.93(s,2H), 3.87-3.43(m,6H),2.93(m,2H),1.75-159(m,3H ),1.38(m,1H),0.90(m,1H),0.013(m,2H)0.010 (m, 2H); MS(ES) 630.9 (M+H) + LCMS RT=1.10 min.

[0432] <Example 122> 2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-((tetrahydrofuran) (3-fluoro-4-sulfamoyl)phenyl-4-(3-yl)methoxy)phenyl (1H-pyrazol-1-yl)thiazole-4-carboxylic acid 470 [ka]

[0433] The title compound was prepared using a procedure similar to that described for the preparation of 467, and purified by HPLC. Purified by C: 2-(5-(cyclopropylmethyl)-3-(4-fluoro-3- ((tetrahydrofuran-3-yl)methoxy)phenyl)-4-(3-fluoro-4- Sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid 470 1 H-NMR(d 6 -DMSO) δ 8.07 (s, 1H), 7.44 (m, 1H ),7.35(s,2H),7.04-7.01(m,1H),6.95-6.91(m ,3H),6.84-6.82(m,1H),3.92(s,2H),3.52-3.5 0(m,4H),3.40-3.35(m,2H),3.20(m,1H),2.93( m,2H),2.4(m,1H),1.77(m,1H),1.39(m,1H),0. 91(m,1H),0.013(m,2H)0.010(m,2H);MS(ES)55 2.9(M+H) + LCMS RT=1.12 min.

[0434] <Example 123> 2-(3-(3-cyclopropoxy-4-fluorophenyl)-5-(cyclopropyl Methyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1H-pyrazole-1 -yl)thiazole-4-carboxylic acid 471 [ka]

[0435] The title compound was prepared using a procedure similar to that described for the preparation of 467, and purified by HPLC. Purified by C: 2-(3-(3-cyclopropoxy-4-fluorophenyl)-5 -(cyclopropylmethyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1 H-pyrazol-1-yl)thiazole-4-carboxylic acid 471 1 H-NMR(d 6 - DMSO)δ8.07(s,1H),7.46(m,1H),7.37(s,2H),7 .19(m,1H),7.05-6.85(m,5H),3.92(s,2H),3.5 0(m,1H),2.93(m,2H),0.91(m,1H),0.013(m,2H ) 0.010 (m, 2H); MS (ES) 586.9 (M+H) + LCMS RT=1. 12 minutes.

[0436] Example 124 2-(5-(cyclopropylmethyl)-3-(6-fluoro-4'-methyl-[1,1 '-biphenyl]-3-yl)-4-(2-fluoro-4-sulfamoylbenzyl)- 1H-Pyrazol-1-yl)thiazole-4-carboxylic acid 472 [ka]

[0437] Step 1: 1-(6-fluoro-4'-methyl-[1,1'-biphenyl]-3-yl) )ethan-1-one. In a 20 mL microwave vial, add 3-bromo-4-fluoro-acetamide. phenol (1 g, 0.0046 mol), 4-methylphenylboronic acid (0.75 g, 0. 0.0055 mol), potassium carbonate (1.27 g, 0.009 mol), bis-(di-t- (butylphosphinoferrocene)dichloropalladium(II) (150 mg, 5% mol) DMSO (12 mL), and water (4 mL) were added, and the vial was perfused with argon for 5 minutes. The vial was irradiated at 150°C for 15 minutes. After the reaction was complete, the reaction mixture was poured into water. The organic layer was washed with brine and dried over magnesium sulfate. The crude product was purified by flash chromatography (Combi-flash Rf, hexane / ethyl acetate, 0-20% gradient) to give 1-(6-fluoro-4'-methyl- To obtain [1,1'-biphenyl]-3-yl)ethan-1-one (1 g, 90%).

[0438] 467, steps 2-5 were prepared using procedures similar to those described in The compound was treated with 1-(6-fluoro-4'-methyl-[1,1'-biphenyl]-3-yl) ethyl acetate. Prepared from tan-1-one: 2-(5-(cyclopropylmethyl)-3-(6-fluoromethyl)-2-methyl-2-propanol 4-(2-fluoro-4'-methyl-[1,1'-biphenyl]-3-yl)-4-(2-fluoro-4- Sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid 472; 1 H-NMR(d 6 -DMSO) δ 8.31 (s, 1H), 7.59-7.35 (m,11H),7.17(m,1H),4.13(s,2H),3.02(m,2H) ,2.35(s,3H),1.15(m,1H),0.033(m,2H)0.021( m, 2H); MS (ES) 621.4 (M+H) + LCMS RT=0.79 min.

[0439] Example 125 2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-((5-(trifluoromethyl)methyl)methyl) (3-fluoromethyl)furan-2-yl)methoxy)phenyl)-4-(3-fluoro-4-sulfur Famoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid 47 3 [ka]

[0440] Step 1: 1-(4-fluoro-3-((5-(trifluoromethyl)furan-2- yl)methoxy)phenyl)ethan-1-one. Di-t-butyl diazocarboxylate (480 mg, 2 mmol) dissolved in THF (11 mL) The solution was cooled to 0°C, and triphenylphosphine (553 mg, 2 mmol) was added. 5-(trifluoromethyl)furan-2-yl)methanol (350 mg, 2 mmol) and 3-hydroxy-4-fluoroacetophenone (250 mg, 1.6 mmol) in order. The reaction mixture was stirred for 30 minutes and then rotary evaporated. The extract was concentrated and subjected to flash chromatography (Combi-flash Rf, hexane / ethyl acetate, 0-30% gradient) to give 1-(4-fluoro-3-((5-( Trifluoromethyl)furan-2-yl)methoxy)phenyl)ethan-1-one (0. Yield: 66g, 95%)

[0441] 467, steps 2-5 were prepared using procedures similar to those described in Compound 473 was reacted with 1-(4-fluoro-3-((5-(trifluoromethyl)furan-2- Prepared from (methyl)methoxy)phenyl)ethan-1-one; MS(ES) 694.9( M+H) + LCMS RT=1.20 min.

[0442] <Example 126> 2-(3-(3-(cyclopentyloxy)phenyl)-5-(cyclopropylmethyl) )-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole- 4-Carboxylic acid 477 [ka]

[0443] The title compound was prepared using a procedure similar to that described for the preparation of 467, and purified by HPLC. Purified by C: 2-(3-(3-(cyclopentyloxy)phenyl)-5-(cyclopentyloxy)phenyl)- (chloropropylmethyl)-4-(4-sulfamoylbenzyl)-1H-pyrazole-1- (I)thiazole-4-carboxylic acid 477 1 H-NMR(CDCl3) δ 8.10(s ,1H(,7.84(d,J=8.4Hz,2H),7.23-7.31(m,4H), 7.02-7.07(m,2H),6.88(dd,J=1.76,1.8Hz,1H) 4.97(s,2H),4.11(s,2H),3.15(d,J=6.64Hz,2H ),1.58-1.79(m,9H),1.12-1.16(m,1H),0.43(d ,J=8Hz,2H),0.21(d,J=5.4Hz,2H),MS(ES)579( M+H) + LCMS RT 1.15 min.

[0444] <Example 127> 2-(3-(3-(benzyloxy)-4-fluorophenyl)-5-(cyclopropyl) (4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thia 4-diol-4-carboxylic acid 480 [ka]

[0445] The title compound was prepared using a procedure similar to that described for the preparation of 467, and purified by HPLC. Purified by C: 2-(3-(3-(benzyloxy)-4-fluorophenyl)- 5-(cyclopropylmethyl)-4-(4-sulfamoylbenzyl)-1H-pyrazoline (1-(1-yl)thiazole-4-carboxylic acid) 480 1 H-NMR(CDCl3) δ8. 11(s,1H),7.84(d,J=8Hz,2H),7.24-7.38(m,8H ),7.15(d,J=7.4Hz,1H)7.08(d,J=8Hz,2H),5.0 1(s,2H),4.95(s,3H),4.02(s,2H),3.16(d,J=6 .7Hz,2H),1.11-1.15(m,1H),0.42(d,J=7Hz,2H ),0.21(d,J=5.24Hz,2H);MS(ES)619(M+H) + LCM S RT=1.28 minutes.

[0446] Example 128 2-(5-(cyclopropylmethyl)-4-(4-sulfamoylbenzyl)-3-( 3-(4-(trifluoromethyl)phenoxy)-phenyl)-1H-pyrazole-1- (I)thiazole-4-carboxylic acid 481 [ka]

[0447] The title compound was prepared using a procedure similar to that described for the preparation of 467, and purified by HPLC. Purified by C: 2-(5-(cyclopropylmethyl)-4-(4-sulfamoyl) benzyl)-3-(3-(4-(trifluoromethyl)phenoxy)-phenyl)-1H -pyrazol-1-yl)thiazole-4-carboxylic acid 481: 1 NMR (CDCl3) δ8.11(s,1H),7.8(d,J=8Hz,2H),7.6(d,J=8Hz, 2H),7.21-7.40(m,5H),7.01-7.06(m,3H),5.04 (s,2H),4.08(s,2H),3.16(d,J=6Hz,2H),1.09- 1.15(m,1H)0.42(d,J=8.Hz,2H),0.21(d,J=5Hz ,2H), MS(ES) 655(M+H) + LCMS RT=1.38 min.

[0448] Example 129 2-(5-(cyclopropylmethyl)-3-(3-phenoxyphenyl)-4-(4- Sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid 503 [ka]

[0449] The title compound was prepared using a procedure similar to that described for the preparation of 467, and purified by HPLC. Purified by C: 2-(5-(cyclopropylmethyl)-3-(3-phenoxyphenyl)-2-(4-methyl-2-propanol)-3-one (4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazo le-4-carboxylic acid 503; 1 H-NMR(MeOD) δ 8.19(s,1H), 7.7 5(d,J=8.4Hz,2H),7.38-7.31(m,4H),7.20(d,J =8.4Hz,2H),7.15-7.10(m,2H),7.02-6.97(m,1 H),7.00(dd,J=8.0,1.2Hz,2H),4.10(s,2H),3. 22(d,J=6.8Hz,2H),1.12-1.06(m,1H),0.39-0. 33(m,2H),0.21(dt,J=6.0,5.2Hz,2H);MS(ES)5 87.7(M+H) + ;LCMS RT=1.00 min.

[0450] Example 130 2-(5-(cyclopropylmethyl)-3-(3-isopropoxyphenyl)-4-( 4-Sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole-4-carbo Phosphoric Acid 504 [ka]

[0451] The title compound was prepared using a procedure similar to that described for the preparation of 467, and purified by HPLC. Purified by C: 2-(5-(cyclopropylmethyl)-3-(3-isopropoxy)- (phenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thia 4-diol-carboxylic acid 504; MS(ES) 552.6(M+H) + ;LCMS RT =0.98 minutes.

[0452] <Example 131> 2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-((4-fluorobenzyl)methyl)methyl) (4-phenyl)-4-(4-sulfamoylbenzyl)-1H-pyrazole -1-yl)thiazole-4-carboxylic acid 527 [ka]

[0453] The title compound was prepared using a procedure similar to that described for the preparation of 467, and purified by HPLC. Purified by C: 2-(5-(cyclopropylmethyl)-3-(4-fluoro-3- ((4-fluorobenzyl)oxy)phenyl)-4-(4-sulfamoylbenzyl) -1H-pyrazol-1-yl)thiazole-4-carboxylic acid 527; 1 H-NMR (M eOD)δ8.21(s,1H),7.83(d,J=8.4Hz,2H),7.40( m,2H),7.31(d,J=8.3Hz,2H),7.23(m,1H),7.17 (m,1H),7.107(m,3H),4.96(s,2H),4.13(s,2H) ,3.25(d,J=6.83Hz,2H),1.12(m,1H),0.38(d,J =8.1Hz,2H),0.23(d,J=5.1Hz,2H);MS(ES)636. 9(M+H) + ;LCMS RT=1.12 min.

[0454] <Example 132> 2-(5-(cyclopropylmethyl)-3-(4-fluoro-3-((3-fluorobenzyl)methyl)methyl) benzyl)oxy)phenyl)-4-(3-fluoro-4-sulfamoylbenzyl)-1 H-pyrazol-1-yl)thiazole-4-carboxylic acid 528 [ka]

[0455] The title compound was prepared using a procedure similar to that described for the preparation of 467, and purified by HPLC. Purified by C: 2-(5-(cyclopropylmethyl)-3-(4-fluoro-3- ((3-fluorobenzyl)oxy)phenyl)-4-(3-fluoro-4-sulfamo (Ilbenzyl)-1H-pyrazol-1-yl)thiazole-4-carboxylic acid 528; 1 H-NMR(MeOD)δ8.19(s,1H),7.77(t,J=7.7Hz,1H ),7.40(m,1H),7.23(m,3H),7.16(m,2H),7.04( m,3H),5.08(s,2H),4.11(s,2H),3.25(d,J=6.5 Hz),1.11(m,1H),0.39(d,J=7.8Hz),0.23(d,J= 4.6Hz); MS(ES) 655.0(M+H) + ;LCMS RT=1.19 min.

[0456] Example 133: 4-((3-(cyclopropylmethyl)-5-(3',5-difluoromethyl)methyl)- 1-(4-((oxo-1,1'-biphenyl)-3-yl)-[1,1'-biphenyl]-3-yl]- 1H-pyrazol-4-yl)methyl) Benzenesulfonamide 525 [ka]

[0457] The title compound was prepared using a procedure similar to that described for the preparation of 482, and purified by HPLC. Purified by C: 4-((3-(cyclopropylmethyl)-5-(3',5-difluoromethyl)- ... Oro-[1,1'-biphenyl]-3-yl)-1-(4-((oxo-1-methyl) -1H-pyrazol-4-yl)methyl (1H-3-oxidanyl)thiazol-2-yl) )Benzenesulfonamide 525: 1 H-NMR(CDCl3) δ 7.96(s,1H) ,7.84(d,J=8.4Hz,2H),7.39(m,2H),7.24(m,4H )7.06(m,4H),3.93(s,2H)2.53(d,J=6.8Hz,2H) ,1.05(m,1H),0.55(m,2H),0.22(d,J=5.8Hz,2H ); MS(ES) 607.0(M+H) + ;LCMS RT=0.95 min.

[0458] Example 134 2-(5-(cyclopropylmethyl)-3-(3-(4-fluorophenoxy)phenyl) (4-sulfamoylbenzyl)-1H-pyrazol-1-yl)thiazole -4-carboxylic acid 507 [ka]

[0459] Step 1: 1-(3-(4-fluorophenoxy)phenyl)ethan-1-one: 1-(3-hydroxyphenyl)ethan-1-one (1.0 g, 7.34 mmol), (4-Fluorophenyl)boronic acid (2.06 g, 14.7 mmol), Cu(OAc) 2 (2.67 g, 14.7 mmol), and pyridine (1.18 mL, 14.7 mmol) ...

Claims

1. A compound selected from the following compounds or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 【Chemistry 2】 【Transformation 3】 【Chemistry 4】 【Transformation 5】 【Transformation 6】 【Transformation 7】

2. 10. A pharmaceutical composition comprising at least one compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

3. 10. The compound of claim 1 or the pharmaceutical composition of claim 2 for use in a method for treating a patient having cancer cells resistant to an anti-cancer drug, wherein the patient is administered the compound or pharmaceutical composition and the anti-cancer drug, and wherein the compound resensitizes the cancer cells to the anti-cancer drug.

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