TW201433567A - Indazole derivatives - Google Patents

Abstract

Disclosed are compounds of Formula 1, and pharmaceutically acceptable salts thereof, wherein R1, R2, R3, R4, R5, and R6 are defined in the specification. This disclosure also relates to materials and methods for preparing compounds of Formula 1, to pharmaceutical compositions which contain them, and to their use for treating obesity and related diseases, disorders, and conditions associated with MetAP2.

Description

Carbazole derivative

The present invention relates to a substituted carbazole which is an inhibitor of methionine aminopeptidase 2 (MetAP2); a pharmaceutical composition containing the same; and a medicament for treating diseases, disorders and diseases associated with MetAP2 Uses (including obesity).

Methionine aminopeptidase is an enzyme that binds to cobalt and manganese ions. Metalloenzymes are widely present in prokaryotic and eukaryotic cells and are present in three forms, namely MetAP1A, MetAP1D and MetAP2. See M. Leszczyniecka et al, Oncogene 25:3471-78 (2006). It is responsible for the removal of N -terminal methionine residues from nascent proteins (an important step in protein maturation) and is likely to be necessary for proper function regulation, intracellular targeting and protein conversion. See SMArfin et al, Proc. Natl. Acdd . Sci. USA 92:7714-18 (1995). Known MetAP2 (irreversible) inhibitors include the natural product fumagillin and its more potent semisynthetic analog TNP-470 (AGM-1470). See D. Ingber et al, Nature 348:555-57 (1990); see also EC Griffith et al, Chemistry & Biology 4(6): 461-471 (1997). Both compounds inhibit angiogenesis, and TNP-470 has been evaluated as a treatment for cancer in numerous clinical trials. See, for example, RS Herbst et al, J. Clin. Oncology 20 (22): 4440-47 (2002) (non-small cell lung cancer); CJ Logoothetis et al, Clin. Cancer Res. 7: 1198-1203 (2001) (progressive) Androgen-dependent prostate cancer); WMStadler et al, J. Clin . Oncology 17 (8): 2541-45 (1999) (metastatic renal cell carcinoma); APKudelka et al, N. Engl. J. Med. 338: 991 -92 (1998) (metastatic cervical cancer); APKudelka et al, Clin. Cancer Res. 3: 1501-05 (1997) (cervical squamous cell carcinoma); and P. Bhargava et al, Clin. Cancer Res. 5: 1989-95 (1999) (sarcoma, colorectal cancer and melanoma).

Numerous studies have also shown that MetAP2 inhibitors can be used to treat obesity. For example, TNP-470 was tested in various mouse obesity models and showed dose-dependent reversible weight loss and adipose tissue loss. See MARupnick et al, Proc. Natl. Acad. Sci. USA 99(16): 10730-35 (2002). It has also been shown that TNP-470 prevents diet-induced obesity in mice. See E. Bråkenhielm et al, Circulation Research 94(12): 1579-88 (2004). Treatment with fumagillin has been shown to impair diet-induced obesity in mice, as evidenced by adipocyte dystrophy, but does not significantly affect adipose tissue angiogenesis. See HRLijnen et al, Obesity 18(12): 2241-46 (2010). In addition, the MetAP2 inhibitor (CKD-732) was found to reduce food intake, body weight, fat mass, and adipocyte size in hereditary and diet-induced obese mice. See YMKim et al, J. Mol . Endocrinology , 38: 455-65 (2007). Recently, CKD-732 (beloranib hemi oxalate) has been found in adult obese patients (eg, 30) BMI Early clinical testing was performed in 45 kg/m ² ).

Certain inhibitors of MetAP2 are described in US 2012/004162 A1 and WO 2010/065883 A2.

The present invention provides substituted carbazole derivatives and related compounds and pharmaceutically acceptable salts thereof. The invention also provides a pharmaceutical composition comprising a substituted carbazole and the use thereof for the treatment of diseases, disorders and conditions associated with MetAP2 inhibition, including obesity.

One aspect of the invention provides a compound of formula 1: Or a pharmaceutically acceptable salt thereof, wherein: R ¹ is hydrogen; R ^{2 is} selected from the group consisting of hydrogen, -OH, chlorine, fluorine, -CN, methyl and hydroxymethyl; and R ^{3 is} selected from C _6-14 aryl a C _1-9 heteroaryl group and a C _2-6 heterocyclic group, each of which is optionally substituted with one to five substituents independently selected from the group consisting of halo, pendant oxy, -CN, R ⁷ And R ⁸ ; R ⁴ is hydrogen; R ⁵ is C _1-3 haloalkyl; R ^{6 is} selected from the group consisting of hydrogen, -OH, -NH ₂ , chlorine, fluorine and methyl; each R ^{7 is} independently selected from -OR ⁹ , -N(R ⁹ )R ¹⁰ , -NR ⁹ C(O)R ¹⁰ , -NHC(O)NR ⁹ R ¹⁰ , -NR ⁹ C(O)NHR ¹⁰ , -C(O)R ⁹ , -C (O)OR ⁹ , -C(O)N(R ⁹ )R ¹⁰ , -C(O)N(R ⁹ )OR ¹⁰ , -C(O)N(R ⁹ )S(O) ₂ R ⁸ , -N(R ⁹ )S(O) ₂ R ⁸ , -SR ⁹ , -S(O)R ⁸ , -S(O) ₂ R ⁸ and -S(O) ₂ N(R ⁹ )R ¹⁰ ; R ^{8 is} independently selected from the group consisting of: (a) a C _1-6 alkyl group, a C _2-6 alkenyl group, and a C _2-6 alkynyl group, each of which is optionally one to five substituents independently selected from the group consisting of Substituted: halo, pendant oxy, -CN and R ¹¹ ; and (b) C _3-8 cycloalkyl-(CH ₂ ) _m -, C _2-6 heterocyclyl-(CH ₂ ) _m -, C _6-14 aryl-(CH ₂ ) _m - and C _1-9 heteroaryl-(CH ₂ ) _m -, each of which is as appropriate Substituting one to five substituents independently selected from the group consisting of halo, pendant oxy, -CN, R ¹¹ and C _1-6 alkyl, the C _1-6 alkyl optionally being one to five independently Substituents selected from the group consisting of halo, pendant oxy, -CN and R ¹¹ ; each R ⁹ and R ^{10 are} independently selected from: (a) hydrogen; (b) C _1-6 alkyl, C _{2 6} alkenyl and C _2-6 alkynyl, each of which is optionally substituted with one to five substituents independently selected from the group consisting of halo, pendant oxy, -CN and R ¹¹ ; and (c)C _3-8 cycloalkyl-(CH ₂ ) _m -, C _2-6 heterocyclyl-(CH ₂ ) _m -, C _6-14 aryl-(CH ₂ ) _m - and C _1-9 heteroaryl -(CH ₂ ) _m -, each of these groups being optionally substituted with one to five substituents independently selected from the group consisting of halo, pendant oxy, -CN, R ¹¹ and C _1-6 alkyl, The C _1-6 alkyl group is optionally substituted with one to five substituents independently selected from the group consisting of halo, pendant oxy, -CN and R ¹¹ ; each R ^{11 is} independently selected from -OR ¹² , -N(R ¹² ) R ¹³ , -N(R ¹² )C(O)R ¹³ , -NHC(O)NR ¹² R ¹³ , -NR ¹² C(O)NHR ¹³ , -C(O)R ¹² , -C(O )OR ¹² , -C(O)N(R ¹² )R ¹³ , -C(O)N(R ¹² )OR ¹³ , -C(O)N(R ¹² )S(O) ₂ R ¹⁴ , -NR ¹² S(O) ₂ R ¹⁴ , -SR ¹² , -S(O)R ¹⁴ , -S(O) ₂ R ¹⁴ and -S(O) ₂ N(R ¹² )R ¹³ ; ¹² and R ^{13 are} independently selected from: (a) hydrogen; and (b) C _1-6 alkyl and C _3-8 cycloalkyl-(CH ₂ ) _m -, each of which is optionally one to five Substituents independently selected from the group consisting of halo, pendant, -CN, -OH, and -NH ₂ ; each R ^{14 is} independently selected from C _1-6 alkyl and C _3-8 cycloalkyl- (CH ₂ ) _m -, each of these groups being optionally substituted with one to five substituents independently selected from the group consisting of halo, pendant oxy, -CN, -OH and -NH ₂ ; and each m independently It is selected from the group consisting of 0, 1, 2, 3 and 4; wherein each heteroaryl and heterocyclic moiety has from one to four heteroatoms independently selected from N, O and S.

Another aspect of the present invention provides a compound selected from the group consisting of the compounds described in the Examples; a pharmaceutically acceptable salt thereof; and a stereoisomer of any of the compounds in the Examples and A pharmaceutically acceptable salt.

A further aspect of the invention provides a pharmaceutical composition comprising: a compound of formula 1 or a pharmaceutically acceptable salt thereof or a compound selected from the group consisting of the above, and pharmaceutically acceptable a compound of the group of salts; and a pharmaceutically acceptable excipient.

An additional aspect of the present invention provides a compound of the formula 1, or a pharmaceutically acceptable salt thereof, or a compound selected from the group consisting of a compound as defined above and a pharmaceutically acceptable salt thereof, for use as a medicament.

Another aspect of the present invention provides a compound of Formula 1, or a pharmaceutically acceptable salt thereof, or a compound selected from the group consisting of a compound as defined above and a pharmaceutically acceptable salt thereof, for use in the treatment selected from the group consisting of Disease, condition or condition: hyperglycemia, diabetes, abnormal dyslipidemia, obesity, insulin resistance, metabolic syndrome X, impaired glucose tolerance, polycystic ovarian syndrome, cardiovascular disease, nonalcoholic liver steatosis Atherosclerosis.

A further aspect of the invention provides the use of a compound of formula 1, or a pharmaceutically acceptable salt thereof, or a compound selected from the group consisting of a compound as defined above and a pharmaceutically acceptable salt thereof, for use in the manufacture of a compound An agent for a disease, disorder, or condition associated with MetAP2.

An additional aspect of the invention provides a method of treating a disease, disorder or condition associated with MetAP2, the method comprising administering to the subject an effective amount of a compound of formula 1 or A pharmaceutically acceptable salt thereof or a compound selected from the group consisting of a compound as defined above and a pharmaceutically acceptable salt thereof.

Another aspect of the invention provides a method of treating a disease, disorder or condition in a subject, the method comprising administering to the subject an effective amount of a compound of formula 1, or a pharmaceutically acceptable salt thereof, or A compound selected from the group consisting of a compound as defined above and a pharmaceutically acceptable salt thereof, wherein the disease, disorder or condition is selected from the group consisting of hyperglycemia, diabetes, dyslipidemia, obesity, insulin resistance, metabolic syndrome X, impaired glucose tolerance, polycystic ovarian syndrome, cardiovascular disease, nonalcoholic hepatic steatosis and atherosclerosis.

A further aspect of the invention provides an effective amount of a compound of formula 1, or a pharmaceutically acceptable salt thereof, or a compound selected from the group consisting of a compound as defined above and a pharmaceutically acceptable salt thereof; and at least one additional pharmacological agent Learn the active agent.

Unless otherwise indicated, this disclosure uses the definitions provided below.

When used in reference to a chemical substituent or moiety (eg, _C1-6 alkyl), "substituted" means that one or more hydrogen atoms of the substituent or moiety are replaced by one or more non-hydrogen atoms or groups, The limitation is that the valence requirement is met and a chemically stable compound is produced by the substitution.

When used in relation to a measurable numerical variable, "about" or "roughly" means the indicated value of the variable and all variables within the experimental error of the indicated value or within ±10% of the indicated value, whichever is larger .

"Alkyl" means a straight-chain or branched-chain saturated hydrocarbon group which generally has a specified number of carbon atoms (for example, a C _1-3 alkyl group means having 1 to 3 (ie 1, 2 or 3) carbon atoms. The alkyl group, C _1-6 alkyl means an alkyl group having 1 to 6 carbon atoms, and the like. Examples of the alkyl group include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, t-butyl, penten-1-yl, pentan-2-yl, pentyl 3-yl, 3-methylbut-1-yl, 3-methylbut-2-yl, 2-methylbut-2-yl, 2,2,2-trimethyleth-1-yl, Is a hexyl group and its like.

"Alkenyl" means a straight-chain or branched hydrocarbon group having one or more carbon-carbon double bonds and which generally has a specified number of carbon atoms. Examples of alkenyl groups include vinyl, 1-propene-1- Base, 1-propen-2-yl, 2-propen-1-yl, 1-buten-1-yl, 1-buten-2-yl, 3-buten-1-yl, 3-butene- 2-yl, 2-buten-1-yl, 2-buten-2-yl, 2-methyl-1-propen-1-yl, 2-methyl-2-propen-1-yl, 1, 3-butadien-1-yl, 1,3-butadien-2-yl and the like.

"Alkynyl" means a straight or branched chain hydrocarbon radical having one or more carbon-carbon reference bonds and which generally has the indicated number of carbon atoms. Examples of alkynyl groups include ethynyl, 1-propyn-1-yl, 2-propyn-1-yl, 1-butyn-1-yl, 3-butyn-1-yl, 3-butyne-2 a group, a 2-butyn-1-yl group and the like.

"Halo", "halogen" and "halo" are used interchangeably and mean fluoro, chloro, bromo and iodo.

"Haloalkyl", "haloalkenyl" and "haloalkynyl" respectively mean alkyl, alkenyl and alkynyl substituted by one or more halogen atoms, wherein alkyl, alkenyl and alkynyl are attached A carbon atom is defined and generally has a specified number of carbon atoms. Examples of haloalkyl groups include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 1 -Chloroethyl, 1,1-dichloroethyl, 1-fluoro-1-methylethyl, 1-chloro-1-methylethyl and the like.

"Cycloalkyl" means a saturated monocyclic and bicyclic hydrocarbon group which generally has a specified number of carbon atoms constituting a ring or a plurality of rings (for example, a C _3-8 cycloalkyl group means having from 3 to 8 carbon atoms as a ring) Member of the cycloalkyl group). Bicyclic hydrocarbyl groups may include isolated rings (two rings that do not share an atom), spiro rings (two rings that share one atom), fused rings (two rings that share two atoms and a bond between two shared atoms) ), as well as bridging rings (two rings that share two atoms but do not share a shared key). A cycloalkyl group can be attached via any ring atom unless such linkage would violate the valence requirement. Additionally, a cycloalkyl group can include one or more non-hydrogen substituents unless such substitution would violate the valence requirement.

Examples of the monocyclic cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and the like. Examples of fused bicyclic cycloalkyl groups include bicyclo[2.1.0]pentyl (i.e., bicyclo[2.1.0]pent-1-yl, bicyclo[2.1.0]pentan-2-yl and bicyclo[2.1.0] Pent-5-yl), bicyclo[3.1.0]hexyl, bicyclo[3.2.0]heptyl, bicyclo[4.1.0]heptyl, bicyclo[3.3.0]octyl, bicyclo[4.2.0]octyl Bicyclo [4.3.0] fluorenyl, bicyclo [4.4.0] fluorenyl and the like. Examples of bridged cycloalkyl groups include bicyclo [2.1.1] hexyl, bicyclo [2.2.1] heptyl, bicyclo [3.1.1] heptyl, bicyclo [2.2.2] octyl, bicyclo [3.2.1] Octyl, bicyclo [4.1.1] octyl, bicyclo [3.3.1] fluorenyl, bicyclo [4.2.1] fluorenyl, bicyclo [3.3.2] fluorenyl, bicyclo [4.2.2] fluorenyl, bicyclo [ 4.3.1] mercapto, bicyclo [3.3.3] undecyl, bicyclo [4.3.2] undecyl, Bicyclo[4.3.3]dodecyl and the like. Examples of spirocycloalkyl groups include spiro[3.3]heptyl, spiro[2.4]heptyl, spiro[3.4]octyl, spiro[2.5]octyl, spiro[3.5]fluorenyl and the like. Examples of isolated bicyclic cycloalkyl groups include those derived from bis(cyclobutane), cyclobutane cyclopentane, bis(cyclopentane), cyclobutane cyclohexane, cyclopentane ring Hexane, bis(cyclohexane), and the like.

"Cycloalkylene" means a divalent monocyclic cycloalkyl group wherein cycloalkyl is as defined above, which is attached via a single carbon atom of the group and generally has a specified number of carbons constituting the ring An atom (for example, a C _3-6 cycloalkylene group means a cycloalkylene group having 3 to 6 carbon atoms as a ring member). Examples include cyclopropylene, cyclobutylene, cyclopentylene, and cyclohexylene.

"Cycloalkenyl" refers to partially unsaturated monocyclic and bicyclic hydrocarbon radicals which generally have the indicated number of carbon atoms which form the ring or rings. Like a cycloalkyl group, a bicyclic cycloalkenyl group can include an isolated ring, a spiro ring, a fused ring, or a bridged ring. Similarly, a cycloalkenyl group can be attached via any ring atom and can include one or more non-hydrogen substituents unless such linkage or substitution would violate valence requirements. Examples of cycloalkenyl groups include the partially unsaturated analogs of the cycloalkyl groups described above, such as cyclobutenyl (i.e., cyclobuten-1-yl and cyclobuten-3-yl), cyclopentenyl, Cyclohexenyl, bicyclo[2.2.1]hept-2-enyl and the like.

"Aryl" means a fully unsaturated monocyclic aromatic hydrocarbon and a polycyclic hydrocarbon having at least one aromatic ring, and the monocyclic and polycyclic aryl groups generally have a specified number of carbon atoms constituting their ring members (for example, The C _6-14 aryl group means an aryl group having 6 to 14 carbon atoms as a ring member). The group may be attached via any ring atom and may include one or more non-hydrogen substituents unless such linkage or substitution would violate the valence requirement. Examples of the aryl group include a phenyl group, a biphenyl group, a cyclobutabenzenyl group, a fluorenyl group, a naphthyl group, a benzocycloheptyl group, a biphenyl group, a fluorenyl group, and a group derived from a cycloheptatriene cation. And similar groups.

"Extylene" means a divalent aryl group wherein the aryl group is as defined above. Examples of the aryl group include a phenyl group (i.e., a benzene-1,2-diyl group).

"Heterocycle" and "heterocyclyl" are used interchangeably and refer to a saturated or partially unsaturated monocyclic or bicyclic group having a ring atom consisting of a carbon atom and 1 to 4 heteroatoms, such The atoms are independently selected from the group consisting of nitrogen, oxygen and sulfur. Monocyclic and bicyclic groups generally have a specified number of carbon atoms in their ring or rings (for example, a C _2-6 heterocyclyl group refers to a ring having 2 to 6 carbon atoms and 1 to 4 heteroatoms). Member of the heterocyclic group). Like the bicyclic cycloalkyl group, the bicyclic heterocyclic group may include an isolated ring, a spiro ring, a fused ring, and a bridged ring. Heterocyclyl groups can be attached via any ring atom and can include one or more non-hydrogen substituents unless such linkage or substitution would violate the valence requirements or result in a chemically labile compound. Examples of the monocyclic heterocyclic group include an oxiranyl group, a thiocyclopropyl group, an aziridine group (for example, aziridine-1-yl and aziridine-2-yl), an oxetane group, Thiocyclobutane, azetidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, 1,4-dioxyl, 1,4-oxathiane, morpholinyl, 1,4-dithiazide, piperazinyl, 1,4-azetidinyl, oxetanyl, thia Cycloheptyl, azepanyl, 1,4-dioxepane, 1,4-oxathiazepine, 1,4-oxazacycloheptyl, 1, 4-dithiaheptanyl, 1,4-thiazepine, 1,4-diazepanyl, 3,4-dihydro- 2H -pyranyl, 3, 6-Dihydro- 2H -piperidyl, 2 H -piperidyl, 1,2-dihydropyridyl, 1,2,3,4-tetrahydropyridyl, 1,2,5,6-tetra Hydropyridyl, 1,6-dihydropyrimidinyl, 1,2,3,4-tetrahydropyrimidinyl and 1,2-dihydropyrazolo[1,5- d ][1,2,4] Azinyl.

"Heterocycle-diyl" refers to a heterocyclic group attached through two ring atoms of a group, wherein the heterocyclic group is as defined above. It generally has a specified number of carbon atoms in its ring or rings (for example, C _2-6 heterocycle-diyl refers to a heterocyclic ring having 2 to 6 carbon atoms and 1 to 4 heteroatoms as ring members). - Diji). Examples of heterocyclic-diyl groups include the polyvalent analogs of the heterocyclic groups described above, such as morpholine-3,4-diyl, pyrrolidine-1,2-diyl, 1-pyrrolidin-2- Subunit, 1-pyridyl-2-ylidene, 1-( 4H )-pyrazolyl-5-ylidene, 1-( 3H )-imidazolyl-2-ylidene, 3-oxazolyl- 2-subunit, 1-piperidinyl-2-ylidene, 1-piperazinyl-6-ylidene and the like.

"Heteroaromatic" and "heteroaryl" are used interchangeably and refer to an unsaturated monocyclic aromatic group and a polycyclic group having at least one aromatic ring, each of which has A ring atom composed of a carbon atom and 1 to 4 hetero atoms, which are independently selected from the group consisting of nitrogen, oxygen, and sulfur. Monocyclic and polycyclic groups generally have a specified number of carbon atoms as ring members (for example, a C _1-9 heteroaryl group refers to a heteroaryl having 1 to 9 carbon atoms and 1 to 4 heteroatoms as ring members). And may include any bicyclic group fused to any of the monocyclic heterocycles listed above to the phenyl ring. A heteroaryl group can be attached via any ring atom (or a plurality of ring atoms for a fused ring) and can include one or more non-hydrogen substituents unless such linkage or substitution would violate valence requirements or result chemically Stable compound. Examples of heteroaryl groups include monocyclic groups such as pyrrolyl (for example, pyrrol-1-yl, pyrrol-2-yl and pyrrol-3-yl), furyl, thienyl, pyrazolyl, imidazolyl, iso Oxazolyl, oxazolyl, isothiazolyl, thiazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl, 1-oxa-2,3-diazolyl, 1- Oxa-2,4-diazolyl, 1-oxa-2,5-oxadiazolyl, 1-oxa-3,4-oxadiazole, 1-thia-2,3-diazolyl, 1-thia-2,4-oxadiazolyl, 1-thia-2,5-diazolyl, 1-thia-3,4-oxadiazole, tetrazolyl, pyridyl, pyridazinyl, Pyrimidinyl and pyrazinyl.

Examples of heteroaryl groups also include bicyclic groups such as benzofuranyl, isobenzofuranyl, benzothienyl, benzo[ c ]thienyl, 1 H -indenyl, 3 H -indolyl, Isoindolyl, 1 H -isoindolyl, porphyrinyl, isoindolyl, benzimidazolyl, oxazolyl, benzotriazolyl, 1 H -pyrrolo[2,3- b Pyridyl, 1 H -pyrrolo[2,3- c ]pyridyl, 1 H -pyrrolo[3,2- c ]pyridyl, 1 H -pyrrolo[3,2- b ]pyridyl, 3 H -imidazo[4,5- b ]pyridinyl, 3 H -imidazo[4,5- c ]pyridinyl, 1 H -pyrazolo[4,3- b ]pyridyl, 1 H -pyrazole And [4,3- c ]pyridyl, 1 H -pyrazolo[3,4- c ]pyridinyl, 1 H -pyrazolo[3,4- b ]pyridinyl, 7 H -indolyl, anthracene Pyridazinyl, imidazo[1,2- a ]pyridyl, imidazo[1,5- a ]pyridyl, pyrazolo[1,5- a ]pyridyl, pyrrolo[1,2- b ] Pyridazinyl, imidazo[1,2- c ]pyrimidinyl, quinolinyl, isoquinolinyl, Lolinyl, quinazolinyl, quinoxalinyl, pyridazinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl, 1,8-naphthyridinyl, 1,5-naphthyridinyl, 2 , 6-naphthyridinyl, 2,7-naphthyridinyl, pyrido[3,2- d ]pyrimidinyl, pyrido[4,3- d ]pyrimidinyl, pyrido[3,4- d ]pyrimidinyl , pyrido[2,3- d ]pyrimidinyl, pyrido[2,3- b ]pyrazinyl, pyrido[3,4- b ]pyrazinyl,pyrimido[5,4- d ]pyrimidinyl , pyrazino[2,3- b ]pyrazinyl, pyrimido[4,5- d ]pyrimidinyl, 1,2,3,4-tetrahydropyrido[2,3- b ]pyrazinyl, 2,3-Dihydrobenzo[ b ][1,4]dioxin, 3,4-dihydro- 2H -pyrido[3,2- b ][1,4]oxazinyl, 2 , 3-dihydro-1 H -benzo[ d ]imidazolyl, benzo[ d ]thiazolyl, 2,3-dihydro-1 H -pyrrolo[2,3- b ]pyridinyl, [1, 2,4]triazolo[1,5- a ]pyridyl, 2,3-dihydro-1 H -imidazo[4,5- b ]pyridyl, tetrazolo[1,5- a ]pyridine , 7 H -pyrrolo[2,3- d ]pyrimidinyl, pyrazolo[1,5- a ]pyrimidinyl, imidazo[1,2- a ]pyrimidinyl, 4,5-dihydro-1 H -pyrazolo[3,4- d ]pyrimidinyl, 2,3,6,7-tetrahydro-1 H -indenyl, 5 H -pyrrolo[2,3- b ]pyrazinyl, imidazo [1,2- a ] Pyrazinyl and imidazo[1,2- b ]pyridazinyl.

"Heteroaryl" refers to a heteroaryl group attached through two ring atoms of a group, wherein heteroaryl is as defined above. It generally has a specified number of carbon atoms in its ring or rings (for example, C _3-5 heteroaryl refers to a heterodyne having 3 to 5 carbon atoms and 1 to 4 heteroatoms as ring members). base). Examples of heteroaryl groups include the polyvalent analogs of the above heteroaryl groups, such as pyridine-2,3-diyl, pyridine-3,4-diyl, pyrazole-4,5-diyl, pyridyl Oxazol-3,4-diyl and the like.

"Side oxy" refers to oxygen (=O) bonded by a double bond.

"Leaving group" means any group that leaves the molecule during the breaking process, and the breaking process includes a substitution reaction, an elimination reaction, and an addition-elimination reaction. The leaving group can be nucleated, wherein the group carries a pair of electrons that originally acted as a bond between the leaving group and the molecule; or can be off-electron, where the group does not carry a pair of electrons Leave. The ability to leave the leaving group depends on its basic strength, with the strongest base being the worst leaving group. Common leaving leaving groups include nitrogen (eg, from diazonium salts); sulfonates, including alkyl sulfonates (eg, mesylate), fluoroalkyl sulfonates (eg, trifluoromethyl) Sulfonic acid salts, hexaflate, perfluorobutane sulfonate and trifluoroethyl sulfonate, and aryl sulfonates (eg, tosylate, p-bromobenzenesulfonic acid) Salt, chlorobenzenesulfonate and m-nitrobenzenesulfonate). Other leaving leaving groups include carbonates, halides, carboxylate anions, phenate ions, and alcoholates. Some stronger bases such as NH ₂ ^- and OH ^- can be prepared by treatment with an acid to give a preferred leaving group. Common ion leaving groups include protons, CO _{2 ,} and metals.

"Relative mirror image isomer" refers to a molecule that is a non-superimposable mirror image of a reference molecule, which can be obtained by inverting all stereocenters of a reference molecule. For example, if the reference molecule has an S absolute stereochemical configuration, the opposite mirror image isomer has an R absolute stereochemical configuration. Similarly, if the reference molecule has an S , S absolute stereochemical configuration, the opposite mirror image isomer has the R , R stereochemical configuration, and the like.

"Stereoisomers" and "multiple stereoisomers" of a compound having a given stereochemical configuration refer to the opposite mirror image isomers of the compound and any non-mirromeric isomers, including geometric isomers of the compounds ( Z / E ). For example, if a compound has the S , R , Z stereochemical configuration, its stereoisomers will include the opposite mirror image isomers of the R , S , and Z configurations and have S , S , Z configurations, R , R , Z configuration, S , R , E configuration, R , S , E configuration, S , S , E configuration and non-image isomers of R , R , E configurations. If the stereochemical configuration of a compound is not specified, "stereoisomer" means any of the possible stereochemical configurations of the compound.

"Substantially pure stereoisomers" and variants thereof refer to a sample containing a compound having a particular stereochemical configuration and which constitutes at least about 95% of the sample.

"Pure stereoisomers" and their variants are meant to have a specific stereochemistry A sample of a compound of the type and the compound constitutes at least about 99.5% of the sample.

"Subject" means a mammal, including a human.

"Pharmaceutically acceptable" means those substances which are suitable for administration to a subject.

"treating" means reversing, alleviating, inhibiting the progression of, or preventing the progression of, a disease, condition or condition in which the term is applied, or reversing, alleviating, inhibiting, or inhibiting the disease, condition or condition. Progression of one or more symptoms or prevention of one or more symptoms of the disease, disorder or condition.

"Treatment" means the act of "treating" as just defined above.

"Drug", "drug substance", "active pharmaceutical ingredient" and the like means a compound which can be used to treat a subject in need of treatment (for example, a compound of formula 1, including sub-genus compounds and exactly named in the specification) Compound).

An "effective amount" of a drug, a "therapeutically effective amount" of a drug, and the like, mean an amount of a drug that can be used to treat a subject and which may depend, inter alia, on the subject's weight and age, and the route of administration.

"Excipient" means any diluent or vehicle used in medicine.

"Pharmaceutical composition" means a combination of one or more pharmaceutical substances with one or more excipients.

"Pharmaceutical product", "medical dosage form", "dosage form", "final dosage form" and the like are used to treat a subject in need of treatment and are generally in the form of tablets, capsules, capsules containing powders or granules. A pharmaceutical composition in the form of a liquid solution or suspension, a patch, a film, and the like.

"MetAP2-related conditions" and similar terms refer to a disease, disorder, or condition in a subject in which MetAP2 inhibits a therapeutic or prophylactic benefit.

The following abbreviations can be used in the specification: Ac (acetamido); ACN (acetonitrile); AIBN (azo-bis-isobutyronitrile); API (active pharmaceutical ingredient); aq (aqueous); Boc (third butoxide) Carbonyl); Cbz (benzyloxycarbonyl); dba (dibenzylideneacetone); DCC (1,3-dicyclohexylcarbodiimide); DCM (dichloromethane); DIPEA ( N , N -diisopropyl) Ethylethylamine, Hünig's base); DMA ( N , N -dimethylacetamide); DMAP (4-dimethylaminopyridine); DMARD (anti-rheumatic drug for relieving disease); DME (1,2- Dimethoxyethane); DMF ( N , N -dimethylformamide); DMSO (dimethyl hydrazine); dppf (1,1'-bis(diphenylphosphino)ferrocene); DTT (dithiothreitol); EC ₅₀ (half the maximum effective concentration); EDA (ethoxylated lauryl alcohol, Brj® 35); EDC ( N- (3-dimethylaminopropyl) - N '-ethylcarbodiimide); EDTA (ethylenediaminetetraacetic acid); ee (excessive image isomerism); eq (equivalent); Et (ethyl); Et ₃ N (triethylamine); EtOAc (ethyl acetate); EtOH (ethanol); HATU (2- (3 H - [1,2,3] triazolo [4,5- b] pyridin-3-yl) -1, 1, 3-tetramethylurea hexafluorophosphate (V)); HEPES (4-(2-hydroxyethyl) piperazine-1-ethanesulfonic acid); AcOH ( Acid); HOBt (1 H - benzo [d] [1,2,3] triazol-1-ol); the concentration at which IC _{50 (50%} inhibition); of IPA (isopropyl alcohol); IPAc (isopropyl acetate Propyl ester); IPE (isopropyl ether); LDA (diisopropylamino lithium); LiHMDS (bis(trimethyldecyl)amine lithium); mCPBA (m-chloroperoxybenzoic acid); Me (A) MeOH (methanol); MTBE (methyl tert-butyl ether); mp (melting point); NaO t -Bu (sodium butoxide); NMM (N-methylmorpholine); PE (petroleum ether) Ph; (Phenyl); pIC ₅₀ (-log ₁₀ (IC ₅₀ ), wherein IC ₅₀ is given in moles (M) units); Pr (propyl); i -Pr (isopropyl); PTFE (polytetrafluoroethylene); RT (room temperature, approximately 20 ° C to 25 ° C); TCEP ( parameter (2-carbonylethyl) phosphine); TFA (trifluoroacetic acid); TFAA (2, 2, 2-trifluoro) Acetic anhydride); THF (tetrahydrofuran); TMS (trimethyldecyl); and Tris buffer (2-amino-2-hydroxymethyl-propane-1,3-diol buffer).

As described below, the present disclosure relates to compounds of formula 1 and pharmaceutically acceptable salts thereof. The present disclosure also relates to materials and methods for the preparation of compounds of formula 1; pharmaceutical compositions containing the same; and compounds of formula 1 and pharmaceutically acceptable salts thereof (optionally in combination with other pharmacologically active agents) are used Use of the treatment of obesity and other diseases, disorders or conditions associated with MetAP2.

In addition to the specific compounds in the examples, the compounds of formula 1 also include those compounds wherein: (i) R ³ is a C _6-14 aryl group, which is optionally substituted with one to five substituents independently selected from the group consisting of: a halo group, a pendant oxy group, -CN, R ⁷ and R ⁸ ; (ii) R ³ is a C _1-9 heteroaryl group, which is optionally substituted with one to five substituents independently selected from the group consisting of halo, a pendant oxy group, -CN, R ⁷ and R ⁸ ; or (iii) R ³ is a C _2-6 heterocyclic group, which is optionally substituted with one to five substituents independently selected from the group consisting of halo, side oxygen Base, -CN, R ⁷ and R ⁸ .

The compounds of formula 1 also include those compounds wherein: (iv) R ^{3 is} selected from the group consisting of phenyl, naphthyl, anthryl, pyrrolyl and furyl, each of which is optionally selected from one to five, as the case may be, substituents: halo, -CN, R ⁷ and R ^8; (v) R ³ is selected from phenyl and naphthyl group, these groups are each optionally substituted with one to five substituents independently selected from the substituents: Halo, -CN, R ⁷ and R ⁸ ; (vi) R ³ is phenyl, which is optionally substituted with one to five substituents independently selected from the group consisting of halo, -CN, R ⁷ and R ⁸ ; Or (vii) R ³ is phenyl optionally substituted with one to three substituents independently selected from the group consisting of halo, -CN, R ⁷ and R ⁸ .

The compounds of formula 1 also include such compounds wherein: (viii) R ^{3 is} selected from the group consisting of thienyl, pyrazolyl, imidazolyl, isoxazolyl, oxazolyl, isothiazolyl, thiazolyl, 1,2,3- Triazolyl, 1,3,4-triazolyl, 1-oxa-2,3-oxadiazole, 1-oxa-2,4-oxadiazole, 1-oxa-2,5-di Azyl, 1-oxa-3,4-oxadiazolyl, 1-thia-2,3-oxadiazole, 1-thia-2,4-oxadiazole, 1-thia-2,5 -diazolyl, 1-thia-3,4-diazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzofuranyl, isobenzofuranyl, benzothiophene Benzo, benzo[ c ]thienyl, 1 H -indenyl, isodecyl, benzimidazolyl, oxazolyl, benzotriazolyl, 1 H -pyrrolo[2,3- b ]pyridine 1, H -pyrrolo[2,3- c ]pyridinyl, 1 H -pyrrolo[3,2- c ]pyridinyl, 1 H -pyrrolo[3,2- b ]pyridinyl, 3 H - Imidazo[4,5- b ]pyridinyl, 3 H -imidazo[4,5- c ]pyridinyl, 1 H -pyrazolo[4,3- b ]pyridinyl, 1 H -pyrazolo[ 4,3- c ]pyridyl, 1 H -pyrazolo[3,4- c ]pyridyl, 1 H -pyrazolo[3,4- b ]pyridinyl, 7 H -indolyl, pyridazine Imidazole [1,2- a] pyridyl, imidazo [1,5- a] pyridinyl, pyrazolo [1,5- a] pyridinyl, pyrrolo [1,2- b] pyridazinyl, imidazo [1,2- c ]pyrimidinyl, quinolyl, isoquinolinyl, Lolinyl, quinazolinyl, quinoxalinyl, pyridazinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl, 1,8-naphthyridinyl, 1,5-naphthyridinyl, 2 , 6-naphthyridinyl, 2,7-naphthyridinyl, pyrido[3,2- d ]pyrimidinyl, pyrido[4,3- d ]pyrimidinyl, pyrido[3,4- d ]pyrimidinyl , pyrido[2,3- d ]pyrimidinyl, pyrido[2,3- b ]pyrazinyl, pyrido[3,4- b ]pyrazinyl,pyrimido[5,4- d ]pyrimidinyl , pyrazino[2,3- b ]pyrazinyl, pyrimido[4,5- d ]pyrimidinyl, benzo[ d ]thiazolyl,[1,2,4]triazolo[1,5- a ] pyridyl, tetrazolo[1,5- a ]pyridyl, 7 H -pyrrolo[2,3- d ]pyrimidinyl, pyrazolo[1,5- a ]pyrimidinyl, imidazo[1 , 2- a ]pyrimidinyl, 5 H -pyrrolo[2,3- b ]pyrazinyl, imidazo[1,2- a ]pyrazinyl and imidazo[1,2- b ]pyridazinyl, such groups are each optionally substituted with one to five substituents independently selected from the substituents: halo, -CN, R ⁷ and R ^8.

The compounds of formula 1 also include those compounds wherein: (ix) R ^{3 is} selected from pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, tetrazolyl, thiazolyl, isoxazolyl , quinolyl, isoquinolyl, 1,7-naphthyridinyl, 1 H -indolyl, benzimidazolyl, benzo[ d ]thiazolyl, 1 H -pyrrolo[2,3- b ] Pyridyl, 1 H -pyrrolo[2,3- c ]pyridyl, imidazo[1,2- a ]pyridyl, pyrazolo[1,5- a ]pyridyl, 3 H -imidazo[4 ,5- b ]pyridyl,[1,2,4]triazolo[1,5- a ]pyridyl, tetrazolo[1,5- a ]pyridyl, 7 H -pyrrolo[2,3 - d ] pyrimidinyl, pyrazolo[1,5- a ]pyrimidinyl, imidazo[1,2- a ]pyrimidinyl, imidazo[1,2- a ]pyrazinyl, imidazo[1,2 - b ] pyrazinyl, and each of these groups is optionally substituted with one to five substituents independently selected from the group consisting of halo, -CN, R ⁷ and R ⁸ ; (x) R ^{3 is} selected from pyridyl a pyrimidinyl, pyrazolyl and 3H -imidazo[4,5- b ]pyridinyl group, each of which is optionally substituted with one to three substituents independently selected from the group consisting of halo, -CN, R ⁷ and R ⁸ ; (xi) R ³ is pyridyl, depending on The situation is substituted with one to three substituents independently selected from the group consisting of halo, -CN, R ⁷ and R ⁸ ; (xii) R ³ is pyrimidinyl, optionally substituted by one to three, as selected below Substituents: halo, -CN, R ⁷ and R ⁸ ; (xiii) R ³ is pyrazolyl, optionally substituted with one to three substituents independently selected from the group consisting of halo, -CN, R ⁷ And R ⁸ ; or (xiv) R ³ is 3 H -imidazo[4,5- b ]pyridinyl, which is optionally substituted with one to three substituents independently selected from the group consisting of halo, -CN, R ⁷ and R ⁸ .

The compounds of formula 1 also include those compounds wherein: (xv) R ^{3 is} selected from the group consisting of 3 H -indolyl, 1 H -isoindolyl, porphyrinyl, isoindolyl, 1,2,3, 4-tetrahydropyrido[2,3- b ]pyrazinyl, 2,3-dihydrobenzo[ b ][1,4]dioxaoctyl, 3,4-dihydro- 2H -pyridine [3,2- b ][1,4]oxazinyl, 2,3-dihydro-1 H -benzo[ d ]imidazolyl, 2,3-dihydro-1 H -pyrrolo[2,3 - b ] pyridyl, 2,3-dihydro-1 H -imidazo[4,5- b ]pyridyl, 4,5-dihydro-1 H -pyrazolo[3,4- d ]pyrimidinyl , 2,3,6,7-tetrahydro-1 H -indenyl and 1,2-dihydropyrazolo[1,5- d ][1,2,4]triazinyl, each of these groups optionally substituted with one to five substituents independently selected from the substituents: halo, oxo, -CN, R ⁷ and R ^8.

The compounds of formula 1 also include those compounds wherein: (xvi) R ^{3 is} selected from the group consisting of 1,2,3,4-tetrahydropyrido[2,3- b ]pyrazinyl, 2,3-dihydrobenzo[ b ][1,4]dioctyl, 3,4-dihydro- 2H -pyrido[3,2- b ][1,4]oxazinyl, porphyrinyl, isoindolyl , 2,3-dihydro-1 H -benzo[ d ]imidazolyl, 2,3-dihydro-1 H -pyrrolo[2,3- b ]pyridinyl, 2,3-dihydro-1 H -Imidazo[4,5- b ]pyridyl, 4,5-dihydro-1 H -pyrazolo[3,4- d ]pyrimidinyl, 2,3,6,7-tetrahydro-1 H - Mercapto, 5 H -pyrrolo[2,3- b ]pyrazinyl and 1,2-dihydropyrazolo[1,5- d ][1,2,4]triazinyl, such groups each optionally substituted with one to five substituents independently selected from the substituents: halo, oxo, -CN, R ⁷ and R ^8.

The compounds of formula 1 also include those compounds wherein: (xvii) R ^{3 is} selected from the group consisting of oxiranyl, thiocyclopropyl, aziridine, oxetanyl, thiocyclobutane, nitrogen heterocycle Butyryl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, 1,4-dioxyl, 1,4-oxothio Alkyl, morpholinyl, 1,4-dithiaalkyl, piperazinyl, 1,4-azetidinyl, oxetanyl, thiaheptanyl, azepan Alkyl, 1,4-dioxanyl, 1,4-oxecycloheptyl, 1,4-oxazepanyl, 1,4-dithiaheptanyl , 1,4-thiazepine, 1,4-diazepanyl, 3,4-dihydro-2 H -pyranyl, 3,6-dihydro-2 H -peri Cyclol, 2 H -piperidyl, 1,2-dihydropyridyl, 1,2,3,4-tetrahydropyridyl, 1,2,5,6-tetrahydropyridyl, 1,6-di a pyrimidinyl group and a 1,2,3,4-tetrahydropyrimidinyl group, and each of these groups is optionally substituted with one to five substituents independently selected from the group consisting of halo, pendant oxy, -CN, R ⁷ and R ⁸ .

The compounds of formula 1 also include those compounds wherein: (xviii) R ^{3 is} selected from the group consisting of 1,2-dihydropyridyl, 1,6-dihydropyrimidinyl and 1,2,3,4-tetrahydropyrimidinyl, and other groups are each optionally substituted with one to five substituents independently selected from the substituents: halo, oxo, -CN, R ⁷ and R ^8; or (xix) R ³ is 1,2-dihydro-pyridine group, which is optionally substituted with one to five substituents independently selected from the substituents: halo, oxo, -CN, R ⁷ and R ^8.

Alternatively, or as an alternative to one of the examples (i) to (xix) in the above paragraphs, the compound of formula 1 includes the compounds wherein: (xx) R ^{2 is} selected from the group consisting of hydrogen, -OH, chlorine and fluorine; Xxi) R ^{2 is} selected from the group consisting of hydrogen, chlorine and fluorine; (xxii) R ^{2 is} selected from hydrogen and fluorine; or (xxiii) R ² is hydrogen.

Alternatively, or as an alternative to one of the embodiments (i) to (xix) in the above paragraphs and one of the embodiments (xx) to (xxiii) in the above paragraphs, the compound of the formula 1 includes the compounds thereof, wherein: (xxiv) R ^{6 is} selected from the group consisting of hydrogen, -OH, -NH ₂ , chlorine and fluorine; (xxv) R ^{6 is} selected from the group consisting of hydrogen, chlorine and fluorine; (xxvi) R ^{6 is} selected from hydrogen and fluorine; or (xxvii) R ⁶ It is hydrogen.

In addition, or as an alternative to one or more of the embodiments (i) to (xix) in the above paragraphs and the examples (xx) to (xxvii) in the above paragraphs, the compound of the formula 1 includes the compounds Wherein: (xxviii) R ^{3 is} optionally substituted with one to three substituents; (xxix) R ^{3 is} optionally substituted with one or two substituents; (xxx) R ^{3 is} optionally substituted with one substituent; or (xxxi R ^{3 is} unsubstituted (ie, free of optional substituents as appropriate).

Alternatively, or as an alternative to one or more of the examples (i) to (xix) in the above paragraphs and the examples (xx) to (xxxi) in the above paragraphs, the compound of formula 1 includes the compounds Wherein: (xxxii) each of the R ⁸ , R ⁹ and R ¹⁰ substituents is optionally substituted with one or two substituents; (xxxiii) each of the R ⁸ , R ⁹ and R ¹⁰ substituents is optionally substituted with one substituent; Or (xxxiv) each of the R ⁸ , R ⁹ and R ¹⁰ substituents is unsubstituted (ie, free of optional substituents as appropriate).

Alternatively, or as an alternative to one or more of the examples (i) to (xix) in the above paragraphs and the examples (xx) to (xxxiv) in the above paragraphs, the compound of formula 1 includes the compounds Wherein: (xxxv) each of the R ¹² , R ¹³ and R ¹⁴ substituents is optionally substituted with one or two substituents; (xxxvi) each of the R ¹² , R ¹³ and R ¹⁴ substituents is optionally substituted with one substituent; Or (xxxvii) each of the R ¹² , R ¹³ and R ¹⁴ substituents is unsubstituted.

Alternatively, or as an alternative to one or more of the embodiments (i) to (xix) in the above paragraphs and the examples (xx) to (xxxvii) in the above paragraphs, the compound of formula 1 includes the compounds Wherein: (xxxviii) each m is independently selected from 0, 1, 2, and 3; (xxxix) each m is independently selected from 0, 1, and 2; (xxxx) each m is independently selected from 0 and 1; Xxxxi) Each m is 0.

Alternatively, or as an alternative to one or more of the examples (i) to (xix) in the above paragraphs and the examples (xx) to (xxxxi) in the above paragraphs, the compound of formula 1 includes the compounds Wherein: (xxxxii) R ^{5 is} selected from the group consisting of fluoromethyl, difluoromethyl and trifluoromethyl; or (xxxxiii) R ⁵ is trifluoromethyl.

Alternatively, or as an alternative to one or more of the examples (i) to (xix) in the above paragraphs and the examples (xxviii) to (xxxxi) in the above paragraphs, the compound of formula 1 includes the compounds Wherein: (xxxxiv) R ² is hydrogen, R ⁵ is trifluoromethyl, and R ⁶ is hydrogen.

The compound of the formula 1 includes all of the compounds (i) to (xxxxiv) described in the above paragraphs and specifically named in the examples, and may be present in the form of a salt, a complex, a solvate, a hydrate, and a liquid crystal. Also, the compound of the formula 1 as a salt may exist in the form of a complex, a solvate, a hydrate, and a liquid crystal.

The compounds of formula 1 form pharmaceutically acceptable complexes, salts, solvates and hydrates. Such salts include acid addition salts (including diacids) and base salts. Pharmaceutically acceptable acid addition salts include salts derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, and phosphorous acid, as well as organic acids such as Non-toxic salts of aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxyalkanoic acids, alkanedioic acids, aromatic acids, aliphatic sulfonic acids and aromatic sulfonic acids, and the like. Such salts include acetate, hexanoate, aspartate, benzoate, benzene Sulfonate, hydrogencarbonate, carbonate, hydrogen sulfate, sulfate, borate, camphorsulfonate, citrate, cyclohexylamine sulfonate, ethanedisulfonate, ethanesulfonate, A Acid salt, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromic acid Salt/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methyl sulfate, naphthate , 2-naphthalene sulfonate, nicotinic acid salt, nitrate, orotate, oxalate, palmitate, pamoate, phosphate, hydrogen phosphate, dihydrogen phosphate, pyroguanamine Acid salts, sucrose salts, stearates, succinates, tannins, tartrates, tosylates, trifluoroacetates, and xinafoates.

Pharmaceutically acceptable base salts include those derived from bases including metal cations (such as alkali metal cations or alkaline earth metal cations) and amines. Examples of suitable metal cations include sodium, potassium, magnesium, calcium, zinc, and aluminum. Examples of suitable amines include arginine, N , N '-dibenzylethylenediamine, chloroprocaine, choline, diethylamine, diethanolamine, dicyclohexylamine, ethylenediamine, glycine , lysine, N -methylglucamine, olamine, 2-amino-2-hydroxymethyl-propane-1,3-diol, and procaine. For a discussion of useful acid addition salts and base salts, see SMSGerge et al, J. Pharm. Sci. (1977) 66: 1-19; see also Stahl and Wermuth, Handbook of Pharmaceutical Salts: Properties, Selection, and Use (2002).

Pharmaceutically acceptable salts can be prepared using a variety of methods. For example, a compound of formula 1 can be reacted with a suitable acid or base to provide the desired salt. Alternatively, the precursor of the compound of Formula 1 can be reacted with an acid or base to remove the acid labile or base labile protecting group or to open the lactone or indoleamine group of the precursor. Alternatively, a salt of a compound of formula 1 can be converted to another salt (or free form) by treatment with a suitable acid or base or by contact with an ion exchange resin. After the reaction, if the salt precipitates from the solution, it can be separated by filtration or by evaporation to recover the salt. The degree of ionization of the salt can vary from fully ionized to almost non-ionized.

The compound of formula 1 can exist as a solid continuum in the fully amorphous to fully crystalline range. The term "amorphous" refers to a state in which the material lacks long-range order at the molecular level and may exhibit physical properties of a solid or liquid depending on temperature. Often such materials do not give a unique X-ray diffraction pattern and, although exhibiting solid properties, are more formally described as liquids. Once heated, a change from solid nature to liquid properties occurs. It is characterized by a change in state, usually secondary ("glass transfer"). The term "crystalline" refers to a solid phase in which the material has a regularly ordered internal structure at the molecular level and gives a unique X-ray diffraction pattern with defined peaks. When sufficiently heated, such materials will also exhibit liquid properties, but the change from solid to liquid is characterized by a phase change, usually one stage ("melting point").

The compound of formula 1 may also be present in unsolvated as well as solvated forms. The term "solvate" describes a molecular complex comprising a compound and one or more pharmaceutically acceptable solvent molecules (eg, ethanol). The term "hydrate" is a solvate wherein the solvent is water. Pharmaceutically acceptable solvates include those wherein the solvent may be isotopically substituted (e.g., D ₂ O, acetone - d _6, DMSO- d ₆₎ of their solvates.

The currently accepted classification system for solvates and hydrates of organic compounds is a classification system that distinguishes between isolated lattice points, channels, and coordination solvates and hydrates of metal ions. See, for example, KRMorris (HGBrittain ed.) Polymorphism in Pharmaceutical Solids (1995). The solvates and hydrates of the isolated lattice sites are solvates and hydrates in which the solvent (e.g., water) molecules are isolated by intervening molecules of the organic compound so as not to be in direct contact with each other. In channel solvates, solvent molecules are located in the lattice channels in which they are in close proximity to other solvent molecules. In metal ion coordinated solvates, solvent molecules are bonded to metal ions.

When the solvent or water is tightly bound, the composite will have a well-defined stereochemical structure that is independent of humidity. However, when the solvent or water is weakly bound (as in channel solvates and in hygroscopic compounds), the water or solvent content will depend on the humidity and drying conditions. In this case, non-stoichiometry will usually be observed.

The compound of formula 1 may also be present in the form of a multi-component complex (rather than a salt and a solvate) wherein the compound (drug) and at least one other component are present in stoichiometric or non-stoichiometric amounts. Complexes of this type include clathrates (drug-host inclusion complexes) and co-crystals. The latter is generally defined as a crystalline complex of neutral molecular components that are bound together via non-covalent interactions, but may also be a complex of neutral molecules and salts. The eutectic can be prepared by melt crystallization, by recrystallization from a solvent, or by physically grinding the components together. See, for example, O. Almarsson and MJ Zaworotko, Chem. Commun. (2004) 17: 1889-1896. For a general review of multi-component complexes, see JK Haleblian, J. Pharm. Sci. (1975) 64(8): 1269-88.

The compound of formula 1 may exist in a mesomorphic state (intermediate phase or liquid crystal) when subjected to suitable conditions. The mesomorphic state is between the true crystalline state and the true liquid state (melting or solution). The mesogenicity due to temperature changes is described as "hot" and the mesogenicity caused by the addition of a second component such as water or another solvent is described as "soluble". Compounds having the potential to form a readily soluble mesophase are described as "amphiphilic" and include possessing polar ion moieties (eg, -COO ^- Na ⁺ , -COO ^- K ⁺ , -SO ₃ ^- Na ⁺ ) or polar nonions Part of a molecule such as -N ^- N ⁺ (CH ₃ ) ₃ ). See, for example, NH Hartshorne and A. Stuart, Crystals and the Palarizing Microscope (4th edition, 1970).

Each of the compounds of Formula 1 may exist as a polymorph, a stereoisomer, a tautomer, or some combination thereof, may be isotopically labeled, may be produced by administration of a prodrug or may form a metabolism upon administration. Things.

"Prodrug" means a compound that has little or no pharmacological activity, and when metabolized in vivo, the compound can undergo conversion to a compound having the desired pharmacological activity. Prodrugs can be prepared by replacing the appropriate functional groups present in the pharmacologically active compound with, for example, the "precursor moiety" as described in H. Bundgaar, Design of Prodrugs (1985). Examples of prodrugs include ester, ether or decylamine derivatives of the compounds of formula 1, which have carboxylic acid, hydroxyl or amine functional groups, respectively. For further discussion of prodrugs, see, for example, T. Higuchi and V. Stella "Pro-drugs as Novel Delivery Systems," ACS Symposium Series 14 (1975) and EB Roche, Bioreversible Carriers in Drug Design (1987).

"metabolite" means a compound that is formed in vivo when a pharmacologically active compound is administered. Examples include a methylol group, a hydroxyl group, a second amine group, a first amine group, a phenol, and a carboxylic acid derivative of the compound of Formula 1, which have a methyl group, an alkoxy group, a third amine group, and a second amine, respectively. Base, phenyl and guanamine groups.

The compound of formula 1 may exist in the form of a stereoisomer resulting from the presence of one or more stereocenters, one or more double bonds, or both. Stereoisomers can be pure, substantially pure or a mixture. Such stereoisomers may also be produced by acid addition or base salts, wherein, for example, when the relative ion is D-lactate or L-isoamine, the relative ion is light. Learn to be active.

The compound of formula 1 may exist in the form of a tautomer which is an isomer produced by tautomerism. The tautomerism isomerism includes, for example, imine-enamine, keto-enol, hydrazine-nitroso, and guanamine-imidic tautomerism.

The compound of Formula 1 can exhibit more than one type of isomerism.

The geometric (cis/trans) isomers can be separated by conventional techniques such as chromatography and fractional crystallization.

Conventional techniques for preparing or isolating compounds having a particular stereochemical configuration include: performing a palmitosic synthesis from a suitable optically pure precursor or using a racemic high performance liquid chromatography (HPLC) for racemization The body (or the racemic body of the salt or derivative) is resolved. Alternatively, the racemate (or racemic precursor) can be reacted with a suitable optically active compound, such as ethanol, or with an acid or base (such as tartaric acid or in the case where the compound of formula 1 contains an acidic or basic moiety or 1-phenylethylamine) reaction. The resulting non-imagewise isomeric mixture can be separated by chromatography, fractional crystallization, and the like, and the appropriate non-image isomers are converted to compounds having the requisite stereochemical configuration. For further discussion of techniques for isolating stereoisomers, see EL Eliel and SH Wilen, Stereochemistry of Organic Compounds (1994).

The compound of Formula 1 may possess isotopic variations in which at least one atom is replaced by an atom having the same atomic number, but the atomic mass is different from the atomic mass normally found in nature. Isotopes suitable for inclusion in the compound of Formula 1 include, for example, isotopes of hydrogen such as ² H and ³ H; isotopes of carbon such as ¹¹ C, ¹³ C and ¹⁴ C; isotopes of nitrogen such as ¹³ N and ¹⁵ N; oxygen Isotopes such as ¹⁵ O, ¹⁷ O and ¹⁸ O; isotopes of sulfur such as ³⁵ S; isotopes of fluorine such as ¹⁸ F; isotopes of chlorine such as ³⁶ Cl; and isotopes of iodine such as ¹²³ I and ¹²⁵ I. The use of isotopic variations (e.g., guanidine, ² H) can provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements. In addition, certain isotopic variations of the disclosed compounds may incorporate a radioisotope (e.g., hydrazine, < ³ >H, or < ¹⁴ >C), which may be useful in drug and/or matrix distribution studies. Substitution with positron emitting isotopes such as ¹¹ C, ¹⁸ F, ¹⁵ O and ¹³ N can be useful in positron emission tomography (PET) studies for detecting receptor occupancy. Isotopically labeled compounds can be prepared by methods analogous to those described elsewhere in the disclosure, using suitable isotopically labeled reagents in place of unlabeled reagents.

The compound of formula 1 can be prepared using the techniques described below. Some processes and examples may omit common reactions (including oxidation, reduction, etc.) known to those of ordinary skill in the art of organic chemistry, separation techniques (extraction, evaporation, precipitation, chromatography, filtration, wet milling, crystallization, and Similar techniques), and details of the analysis program. Details of such reactions and techniques can be found in many monographs, including Richard Larock, Comprehensive Organic Transformations (1999), and multi-volume series by Michael B. Smith et al., Compendium of Organic Synthetic Methods (1974 and below). . Starting materials and reagents are available from commercial sources or can be prepared using literature methods. Some reaction schemes may omit minor products produced by the chemical transformation (e.g., an alcohol from the ester hydrolysis, decarboxylation of acid from CO _2, etc.). Additionally, in some cases, the reaction intermediate can be used in subsequent steps without isolation or purification (i.e., in situ).

In some of the reaction schemes and examples below, certain compounds can be prepared using protecting groups that prevent undesired chemical reactions at additional reactive sites. Protecting groups can also be used to increase solubility or otherwise modify the physical properties of the compound. For a discussion of protecting group strategies, descriptions of materials and methods for placing and removing protecting groups, and for the protection of useful protecting groups for common functional groups including amines, carboxylic acids, alcohols, ketones, aldehydes, etc., see TW Greene and PGWuts, Protecting Groups in Organic Chemistry (1999) and P. Kocienski, Protective Groups (2000).

In general, the chemical transformations described throughout the specification can be carried out using substantially stoichiometric amounts of reactants, although certain reactions can benefit from the use of excess one or more reactants. In addition, many of the reactions disclosed throughout the specification can be carried out at about room temperature (RT) and ambient pressure, but depending on the reaction kinetics, yield, etc., some reactions can be operated at elevated pressures or at higher temperatures. (eg, reflux conditions) or lower temperatures (eg, -78 ° C to 0 ° C). Any reference to stoichiometric ranges, temperature ranges, pH ranges, and the like in this disclosure, whether or not the word "range" is used explicitly, also includes the indicated endpoint.

Many chemical transformations may also employ one or more compatible solvents which may affect the rate of reaction and yield. Depending on the nature of the reactants, the one or more solvents can be polar protic solvents (including water), polar aprotic solvents, non-polar solvents, or some combination. Representative solvents include: saturated aliphatic hydrocarbons (eg, n-pentane, n-hexane, n-heptane, n-octane); aromatic hydrocarbons (eg, benzene, toluene, xylene); halogenated hydrocarbons (eg, Dichloromethane, chloroform, carbon tetrachloride); aliphatic alcohols (for example, methanol, ethanol, propan-1-ol, propan-2-ol, butan-1-ol, 2-methyl-propan-1- Alcohol, butan-2-ol, 2-methyl-propan-2-ol, pent-1-ol, 3-methyl-butan-1-ol, hex-1-ol, 2-methoxy-ethanol, 2-ethoxy-ethanol, 2-butoxy-ethanol, 2-(2-methoxy-ethoxy)-ethanol, 2-(2-ethoxy-ethoxy)-ethanol, 2- (2-butoxy-ethoxy)-ethanol); ethers (for example, diethyl ether, diisopropyl ether, dibutyl ether, 1,2-dimethoxy-ethane, 1,2-diethoxy Ethyl-ethane, 1-methoxy-2-(2-methoxy-ethoxy)-ethane, 1-ethoxy-2-(2-ethoxy-ethoxy)-ethane , tetrahydrofuran, 1,4-dioxane); ketones (eg, acetone, methyl ethyl ketone); esters (methyl acetate, ethyl acetate); nitrogen-containing solvents (eg, formamide, N , N - dimethylformamide, acetonitrile, N - methyl - pyrrolidone, pyridine, quinoline, nitrobenzene); Sulfur solvents (e.g., carbon disulfide, dimethyl sulfoxide, tetrahydro - thiophene 1,1, - dioxide); and phosphorus-containing solvents (e.g., hexamethylphosphoric triamide acyl).

In the following scheme, the substituent identifier (for example, R ¹ , R ² , R ^{3 ,} etc.) is as defined above for Formula 1. However, as mentioned earlier, some of the starting materials and intermediates may include protecting groups that are removed prior to the final product. In such cases, the substituent identifier refers to the moiety defined in Formula 1 and the moiety having the appropriate protecting group. For example, the process of starting material or intermediate thereof may be included as part of the R potentially reactive amine ^2. In such cases, R ² will include a moiety with or without, for example, a Boc or Cbz group attached to the amine.

Scheme A shows a general procedure for preparing a compound of formula 1 by reacting a halide or pseudohalide (A1, A4) with a boronic acid or ester (A2, A3) under Suzuki conditions. As shown in Scheme A, a halide or pseudohalide (A1 or A4, such as X is Br, Cl, I or a triflate) can be used in a palladium catalyst (eg, Pd(PPh ₃ ) ₄ , ( PPh ₃ ) ₂ PdCl ₂ , PdCl ₂ (dppf), etc.), a base (eg, KF, Na ₂ CO ₃ , NaHCO ₃ , Cs ₂ CO ₃ ) and one or more solvents (eg, dioxane, DMF, H _{2 )} In the presence of O, etc., at a high temperature (for example, 90 ° C to 145 ° C) with a boronic acid or ester (A2 or A3, such as Y is -B(OR') ₂ , wherein each R' is H or C _1-4 alkyl Or each R' together form a C _1-8 alkanediyl group such as a 2,3-dimethylbutane-2,3-diyl group. The method described in Flow A can be varied as needed. For example, a halide or pseudohalide (A1, A4) can be reacted with boric acid or a boronic acid ester (A2, A3), and the resulting intermediate (not shown) is passed, for example, alkylated, deuterated, hydrolyzed, oxidized. , reduction, amide amide, sulfonation, acetylation, alkynation and the like are further elaborated to give a compound of formula 1.

Process A

The biopharmaceutical properties of the compounds of formula 1 (including the above named compounds) and their pharmaceutically acceptable complexes, salts, solvates and hydrates should be evaluated in order to select the appropriate dosage form and route of administration, such as solubility. And solution stability, permeability and similar properties at various pH values. The compound intended for medical use may be administered in the form of a crystalline or amorphous product, and may be formed by methods such as precipitation, crystallization, freeze drying, spray drying, evaporative drying, microwave drying, or radio frequency drying, for example, solid plugs, powders. Or obtained in the form of a film.

The compounds of formula 1 may be administered alone or in combination with one another or in combination with one or more pharmacologically active compounds which are different from the compound of formula 1. Typically, one or more such compounds are administered in the form of a pharmaceutical composition (formulation) with one or more pharmaceutically acceptable excipients. The choice of excipient depends, inter alia, on the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form. Suitable pharmaceutical compositions and methods for their preparation can be found, for example, in ARGennaro (ed.), Remington: The Science and Practice of Pharmacy (20th edition, 2000).

The compound of formula 1 can be administered orally. Oral administration can involve swallowing, in which case the compound enters the bloodstream via the gastrointestinal tract. Alternatively or additionally, oral administration can involve mucosal administration (eg, buccal administration, sublingual administration, sublingual administration) to allow the compound to enter the bloodstream via the oral mucosa.

Formulations suitable for oral administration include: solid, semi-solid, and liquid systems, such as lozenges; soft or hard capsules containing multiparticulate or nanoparticulates, liquids, or powders; buccal agents, which can be filled Liquid; chewable; gel; fast dispersing dosage form; film; ovoid; spray; and buccal or mucoadhesive patch. Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules (eg, made of gelatin or hydroxypropyl methylcellulose) and typically comprise a carrier (eg, water, ethanol, polyethylene glycol, Propylene glycol, methylcellulose, or a suitable oil) and one or more emulsifiers, suspending agents, or both. Liquid formulations can also be prepared by reconstitution of a solid (eg, from a sachet).

The compounds of formula 1 are also useful in fast dissolving, fast disintegrating dosage forms such as those described in Liang and Chen, Expert Opinion in Therapeutic Patents (2001) 11(6): 981-986.

For lozenge dosage forms, the active pharmaceutical ingredient (API) may comprise from about 1% to about 80% by weight of the dosage form or more typically from about 5% to about 60% by weight of the dosage form, depending on the dosage. In addition to the API, the tablet may also include one or more disintegrants, binders, diluents, surfactants, glidants, lubricants, antioxidants, colorants, flavoring agents, preservatives, and taste masking agents. . Examples of the disintegrant include sodium starch glycolate, sodium carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, crosslinked polyvinylpyrrolidone, polyvinylpyrrolidone, methylcellulose. , microcrystalline cellulose, C _1-6 alkyl substituted hydroxypropyl cellulose, starch, pregelatinized starch, and sodium alginate. Typically, the disintegrant will comprise from about 1% to about 25% or from about 5% to about 20% by weight of the dosage form.

Adhesives are generally used to impart cohesive qualities to tablet formulations. Suitable binders include microcrystalline cellulose, gelatin, sugar, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinized starch, hydroxypropyl cellulose, and hydroxypropyl methylcellulose. Tablets may also contain diluents such as lactose (monohydrate, spray dried monohydrate, anhydrous), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, Starch and calcium hydrogen phosphate dihydrate.

Tablets may also include: surfactants such as sodium lauryl sulfate and polysorbate 80; and glidants such as ceria and talc. When present, the surfactant can comprise from about 0.2% to about 5% by weight of the tablet, and the flow aid can comprise from about 0.2% to about 1% by weight of the tablet.

Tablets may also contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate and sodium lauryl sulfate. The lubricant can constitute from about 0.25 wt% to about 10 wt% or from about 0.5 wt% to about 3 wt% of the tablet.

The tablet blend can be compressed directly or by rolling to form a tablet. The portion of the tablet blend or blend may alternatively be wet granulated, dry granulated, or melt granulated prior to tableting; melt coagulation; or extruded. If desired, the size can be adjusted by screening or milling or both before blending one or more of the components. The final dosage form can include one or more layers and can be coated, uncoated, or encapsulated. Exemplary lozenges can contain up to about 80% by weight of API, from about 10% to about 90% by weight of binder, from about 0% to about 85% by weight of diluent, from about 2% to about 10% by weight of disintegrant, and about 0.25. From wt% to about 10% by weight of the lubricant. For a description of blending, granulating, milling, screening, tableting, coating, and alternative techniques for preparing pharmaceutical products, see ARGennaro (ed.), Remington: The Science and Practice of Pharmacy (20th edition, 2000); HALieberman et al. (eds.), Pharmaceutical Dosage Forms: Tablets, Vol. 1-3 (2nd ed., 1990); and DK Parikh & CK Parikh, Handbook of Pharmaceutical Granulation Technology, Vol. 81 (1997).

A consumable oral film for human or veterinary use is a pliable water-soluble or water-swellable film dosage form which dissolves rapidly or adheres to the mucosa. In addition to the API, typical films also include one or more film forming polymers, binders, solvents, wetting agents, plasticizers, stabilizers or emulsifiers, viscosity modifiers, and solvents. Other film ingredients may include antioxidants, colorants, flavoring and flavoring agents, preservatives, saliva stimulating agents, coolants, cosolvents (including oils), softeners, accumulators, defoamers, surfactants And taste masking agents. Some components of the formulation may perform more than one function.

In addition to the requirements for administration, the amount of API in the film may depend on its solubility. If water soluble, the API will typically comprise from about 1% to about 80% by weight of the nonsolvent component (solute) or from about 20% to about 50% by weight of the solute in the film. The less soluble API can constitute a larger proportion of the composition, typically up to about 88% by weight of the non-solvent component of the film.

The film forming polymer can be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and typically constitutes from about 0.01 wt% to about 99 wt% or from about 30 wt% to about 80 wt% of the filming agent.

Membrane dosage forms are typically prepared by evaporative drying of an aqueous film coated on a peelable backing support or paper, which may be in a drying oven or drying tunnel (eg, in a combined coating drying device), in a freezer Dry the equipment or in a vacuum oven.

Solid formulations suitable for oral administration can include immediate release formulations and modified release formulations. Regulated release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release. For a general description of suitable regulatory release formulations, see U.S. Patent No. 6,106,864. For details on other suitable release techniques such as high energy dispersion and permeability and coated particles see Verma et al, Pharmaceutical Technology On-line (2001) 25(2): 1-14.

The compound of formula 1 can also be administered directly to the bloodstream, muscle or internal organs of the subject. in. Suitable techniques for parenteral administration include intravenous administration, intra-arterial administration, intraperitoneal administration, intrathecal administration, intraventricular administration, intraurethral administration, intrathoracic administration, intracranial administration, Intramuscular administration, intrasynovial administration, and subcutaneous administration. Suitable devices for parenteral administration include needle-type injectors, including microneedle injectors, needle-free injectors, and infusion devices.

Parenteral formulations are typically aqueous solutions, which may contain excipients such as salts, carbohydrates, and buffers (e.g., a pH of from about 3 to about 9). However, for some applications, the compound of Formula 1 may be more suitably formulated as a sterile non-aqueous solution or as a dry form to be used with a suitable vehicle such as sterile pyrogen-free water. Preparation of parenteral formulations under sterile conditions (e.g., by lyophilization) can be readily accomplished using standard pharmaceutical techniques.

The solubility of a compound for parenteral solution preparation can be increased by appropriate formulation techniques, such as incorporation of a solubilizing agent. Formulations for parenteral administration can be formulated for immediate release or modified release. Regulated release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release. Thus, the compound of Formula 1 can be formulated as a suspension, solid, semi-solid, or thixotropic liquid for administration in the form of an implantable reservoir that provides controlled release of the active compound. Examples of such formulations include drug coated stents and semi-solids and suspensions comprising drug-loaded poly( DL -lactic-glycolic acid) copolymer (PGLA) microspheres.

The compound of formula 1 can also be administered topically, intradermally or transdermally to the skin or mucosa. Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, spreaders, dressings, foams, films, skin patches, wafers, implants Things, sponges, fibers, bandages and microemulsions. Liposomes can also be used. Typical carriers can include ethanol, water, mineral oil, liquid paraffin, white petrolatum, glycerin, polyethylene glycol, and propylene glycol. Topical formulations may also include penetration enhancers. See, for example, Finnin and Morgan, J. Pharm. Sci. 88(10): 955-958 (1999).

Other means of topical administration include therewith by electroporation, iontophoresis, swimming sound therapy, sonophoresis and microneedle or needle-free (e.g. Powderject ^TM and Bioject ^TM) delivered. Formulations for topical administration can be formulated as immediate release or modified release as described above.

The compound of formula 1 can also be administered intranasally in the form of a dry powder, an aerosol spray or a nasal drop or by inhalation. An inhalant can be used to administer a dry powder, the dry powder A powder blend comprising a separate API, an API with a diluent such as lactose, or a mixed component comprising an API and a phospholipid such as phospholipid choline. For intranasal use, the powder may include a bioadhesive such as polyglucosamine or cyclodextrin. A pressurized container, pump, nebulizer, nebulizer or sprinkler can be used to produce an aerosol spray from a solution or suspension comprising: an API; one or more reagents for dispersing, dissolving, or extending API release (eg EtOH with or without water); one or more solvents acting as propellants (eg 1,1,1,2-tetrafluoroethane or 1,1,1,2,3,3,3-heptafluoropropane) And optionally a surfactant (such as sorbitan trioleate, oleic acid, or oligomeric lactic acid). A nebulizer using electrohydrodynamics can be used to create a fine mist.

Prior to use in a dry powder or suspension formulation, the pharmaceutical product is typically comminuted to a particle size suitable for delivery by inhalation (typically 90% of the particles have a maximum size of less than 5 microns by volume). This can be accomplished by any suitable size reduction method such as spiral jet milling, fluidized bed jet milling, supercritical fluid processing, high pressure homogenization, or spray drying.

Capsules, blister and cartridges (for example made of gelatin or hydroxypropylmethylcellulose) for use in an inhaler or insufflator can be formulated to contain a powder mixture of the active compound, a suitable powder base such as Lactose or starch, and a potency improver such as L-leucine, mannitol, or magnesium stearate. Lactose can be anhydrous or monohydrated. Other suitable excipients include polyglucose, glucose, maltose, sorbitol, xylitol, fructose, sucrose, and trehalose.

Suitable solution formulations for use in nebulizers that use electrohydrodynamics to produce fine mist can contain an API that is actuated from about 1 [mu]g to about 20 mg per actuation and the actuation volume can vary from about 1 [mu]L to about 100 [mu]L. A typical formulation may comprise one or more compounds of formula 1, propylene glycol, sterile water, EtOH, and NaCl. Alternative solvents that can be used in place of propylene glycol include glycerin and polyethylene glycol.

Formulations for administration by inhalation, intranasal administration, or both may be formulated, for example, as immediate release or modified release using PGLA. Suitable fragrances (such as methanol and levomentin) or sweeteners (such as saccharin or sodium saccharin) can be added to the formulation intended for inhalation/intranasal administration.

In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of delivering a metered amount of valve. The unit is typically arranged to administer a metered dose or "puff" containing from about 10 [mu]g to about 1000 [mu]g of API. The total daily dose will generally be in the range of from about 100 [mu]g to about 10 mg, which may be in a single dose, or more usually in divided doses throughout the day. Come to vote.

The active compound can be administered, for example, in the form of a suppository, pessary, or enemas, either rectally or vaginally. Cocoa butter is a traditional suppository base, but various alternatives can be used as appropriate. Formulations for rectal or vaginal administration can be formulated as immediate release or modified release as described above.

The compound of formula 1 can also be administered directly to the eye or ear in the form of a micronized suspension or drop of solution in a sterile saline solution adjusted to an isotonic pH. Other formulations suitable for ophthalmic administration and oto-injection include ointments, gels, biodegradable implants (eg, absorbable gel sponges, collagen), non-biodegradable implants (eg, polypeptone) Oxygen), wafers, lenses, and microparticles or porous systems (such as vesicles or liposomes). The formulation may include one or more polymers and a preservative such as benzalkonium chloride. Typical polymers include crosslinked polyacrylic acid, polyvinyl alcohol, hyaluronic acid, cellulosic polymers (eg, hydroxypropyl methylcellulose, hydroxyethylcellulose, methylcellulose), and heteropolysaccharide polymers ( For example, agarose gum). Such formulations can also be delivered by iontophoresis. Formulations for administration to the eye or ear can be formulated into immediate release or modified release as described above.

To improve the solubility, solubility, taste masking, bioavailability, or stability of a compound of Formula 1, a compound of Formula 1 can be combined with a soluble macromolecular entity, including cyclodextrins and derivatives thereof, and A polymer of polyethylene glycol. For example, API-cyclodextrin complexes are generally suitable for most dosage forms and routes of administration. Both clad and non-inclusion complexes can be used. As an alternative to direct compounding with API, cyclodextrin can be used as an auxiliary additive, ie as a carrier, diluent or solubilizer. --cyclodextrin, β-cyclodextrin and γ-cyclodextrin are often used for these purposes. See, for example, WO 91/11172, WO 94/02518 and WO 98/55148.

As indicated above, one or more compounds of formula 1, including the above specifically named compounds, and pharmaceutically active complexes, salts, solvates and hydrates thereof, may be combined with one another or with one or more other active pharmaceutically active compounds for treatment. Various diseases, conditions and conditions. In such cases, the active compounds may be combined in a single dosage form as described above or may be presented in the form of a kit suitable for co-administering the compositions. The kit comprises (1) two or more different pharmaceutical compositions, at least one of which comprises a compound of formula 1; and (2) a device for separately retaining two pharmaceutical compositions, such as Disfilled bottles or sub-packed foil bags. An example of such a kit is a familiar bubble drum package for packaging tablets or capsules. This kit is suitable for donating Dosage forms of the same type (for example, orally and parenterally) or for administration of different pharmaceutical compositions at separate administration intervals, or for titration of pharmaceutical compositions different from one another. To aid patient compliance, the kit typically includes instructions for administration and can be equipped with a memory aid.

For administration to human patients, the total daily dose of the claimed and disclosed compound will generally range from about 0.1 mg to about 3000 mg, depending on the route of administration. For example, oral administration may require a total daily dose of from about 1 mg to about 3000 mg, while intravenous administration may require only a total daily dose of from about 0.1 mg to about 300 mg. The total daily dose may be administered in a single or divided dose form and may be outside the typical ranges given above at the discretion of the physician. While such doses are based on an average human subject having a mass of from about 60 kg to about 70 kg, the physician will be able to determine the appropriate dose for a patient (eg, an infant) whose mass is outside of this weight range.

As indicated above, the compound of formula 1 can be used to treat diseases, disorders and conditions indicative of inhibition of MetAP2. Such diseases, disorders, and conditions typically involve any unhealthy or abnormal state in a subject for which inhibition of MetAP2 provides a therapeutic benefit. More specifically, the compound of Formula 1 can be used to treat obesity or overweight conditions in a subject, or to treat a disease, disorder, or condition associated with obesity or an overweight condition, including cardiovascular disease, hypertension, diabetes, Hyperglycemia, insulin resistance, metabolic syndrome X, impaired glucose tolerance, nonalcoholic hepatic steatosis, abnormal dyslipidemia (including high total cholesterol or high levels of triglycerides), atherosclerosis, stroke, sleep breathing , osteoarthritis, infertility, and polycystic ovarian syndrome.

According to The Practical Guide: Identification, Evaluation, and Treatment of Overweight and Obesity in Adults , published by the International Heart, Lung, and Blood Institute in 2000, adults can be classified as overweight or based on the subject's body mass index (BMI). obesity. BMI is calculated by dividing the subject's mass (in kg) by the square of the subject's height (in meters). In this guidance (Guide), 25-29.9kg / m BMI based classified as overweight of ^2, and ^{30-34.9kg / m 2, 35-39.9kg / m} 2 and The body mass index of 40 kg/m ² is classified into type 1 obesity, type 2 obesity, and type 3 (extreme) obesity, respectively.

The claimed and disclosed compounds can be combined with one or more other pharmacologically active compounds or therapies to treat one or more conditions, diseases or conditions (including obesity) indicative of MetAP2. For example, a compound of Formula 1 (including the specifically named compounds above) and pharmaceutically acceptable complexes, salts, solvates, and hydrates thereof may be combined with one or more compounds or therapies. Time-injection, sequential administration, or separate administration for the treatment of cardiovascular disease, hypertension, diabetes, hyperglycemia, insulin resistance, metabolic syndrome X, impaired glucose tolerance, nonalcoholic hepatic steatosis, abnormal blood lipids Symptoms, atherosclerosis, stroke, sleep and breathing, osteoarthritis, infertility, and polycystic ovarian syndrome. Such combinations may provide significant therapeutic advantages, including fewer side effects, increased ability to treat a population of underserved patients, or synergistic activity.

For example, a compound of Formula 1 can be used in combination with one or more agents for the treatment of obesity, diabetes, hyperglycemia, insulin resistance, metabolic syndrome X, impaired glucose tolerance, and nonalcoholic hepatic steatosis. Such agents include pancreatic lipase inhibitors (eg, orlistat); insulin; insulin sensitizers, including biguanides (eg, buformin, metformin, and phenformin) and glitazones (eg, Pioglitazone and rosiglitazone; insulin secretagogues, including sulfonylureas (eg, acesulfame, chlorpropamide, tolazamide, tolbutamide, grid Gliclazide, glimepiride, glipizide, and glyburide (glyburide) and glinide (eg, nateglinide and repaglinide) Repaginide)); alpha-glucosidase inhibitors (eg, acarbose and miglitol); glucagon-like peptide analogs and antagonists (eg, exenatide) ), liraglutide and taspoglutide; dipeptidyl peptidase-4 inhibitors (eg, alogliptin, linagliptin, saxagliptin) (saxagliptin), sitagliptin and vildagliptin; and amylin analogues (eg, pramling) (Pramlinitide)).

In addition, the compound of Formula 1 can be used in combination with one or more agents for the treatment of osteoarthritis, such agents include non-steroidal anti-inflammatory drugs (NSAIDs) (eg, apazone, aspirin, sedative). Celecoxib, diclofenac (with and without misoprostol), diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, Indomethacin, ketoprofen, meclofenac sodium, mefenamic acid, meloxicam, nabumetone, naproxen, Oxaprozin, phenylbutazone, piroxicam, choline and magnesium salicylate, salicylate and sulindac; analgesics (for example, Acetaminophen and morphine sulfate; and codeine, hydrocodone, oxycodone, propoxyphene, and tramadol, all of which have or do not have acetamidine amine Corticosteroids (eg, betamethasone, cortisone acetate, dexamethasone, hydrocortisone, methylprednisolone, prednisolone, and prednisone) And osteoporosis agents (eg, alendronate, clodronate, etidronate, ibandronate, neridronate, Olpadronate, pamidronate, risedronate, tiludronate, and zoledronate.

The compound of Formula 1 can also be used in combination with one or more agents for the treatment of cardiovascular disease, hypertension, dyslipidemia, atherosclerosis and stroke, such agents including calcium channel blockers (eg, amlodipine) , aralidipine, azelnidipine, barnidipine, bepridil, benidipine, cilnidipine, clevidipine, Diltiazem, isradipine, efonidipine, felodipine, fendiline, fluspirilene, lacidipine, luxa Lecanidiidipine, manidipine, mibefradil, nicardipine, nifedipine, nilvadipine, nimodipine, nisol Ligustin (nitoldipine), nitrendipine, pranidipine, and verapamil; statins (eg, atorvastatin, fluvastatin, lovastatin) Ruvastatin Tin), mevastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin; PPAR alpha activators (eg, fibrates) , such as bezafibrate, ciprofibrate, clofibrate, fenofibrate and gemfibrozil; bile acid sequestrants (eg, Cholestyramine, colesevelam and colestipol; other lipid lowering agents (eg, niacin and ezetimibe); beta-blockers (eg, aprenolol, atenolol, betaxolol, bisoprolol, bucindolol, carteolol, Carvedilol, celiprolol, esmolol, eucommia bark, labetalol, metoprolol, nadolol (nadolol), nebivolol, oxprenolol, penbutolol, pindolol, propranolol (propranolol), sotalol (timolol); angiotensin-converting enzyme (ACE) inhibitors (benazepril, captopril, enalapril) Elenapril, imidapril, lisinopril, perindopril, quinapril, ramirril, trandolapril (trandolapril) and zofenopril; and platelet aggregation inhibitors (abciximab, aspirin, cilostazol, clopidogrel, dipyridamole) Dipyridamole, dipyridamole, eptifibatide, ifetroban, picotamide, prasugrel, terutroban ), ticagrelor, ticlopidine, and tirofiban.

Biological activity

The biological activity of the compound of formula 1 can be determined using a variety of in vitro and in vivo methods. The following in vitro assays measure the ability of test compounds to inhibit MetAP2.

MetAP2 protein purification

The DNA encoding the full length sequence of the human MetAP2 enzyme was amplified by PCR and cloned into the pFastBac expression vector (Invitrogen). Recombinant baculoviruses incorporating the MetAP2 construct were generated by translocation using the Bac-to-Bac system (Invitrogen). The performance of the recombinant protein was performed by transfecting Spodoptera frugiperda Sf9 cells (Invitrogen) in a 5 L microwave bioreactor (Wave Biotech). The recombinant protein was isolated from the cell extract by binding to a SP Hitrap Fast Flow or SP Sepharose (Sigma) column and a NaCl gradient was used to dissolve the protein. A partially purified extract of MetAP2 was further purified by AKTA FPLC via a Superdex-200 column (GE). The purity of the MetAP2 protein was determined on a denaturing SDS-PAGE gel. The purified MetAP2 protein was concentrated to a final concentration of 17 mg/mL or 2.5 mg/mL. The protein was stored at -78 ° C in a buffer containing 10 mM HEPES (pH 7.4), 150 mM NaCl, and 1 mM CoCl ₂ , or a buffer containing 20 mM HEPES (pH 7.4), 120 mM NaCl, and 5 mM MnCl ₂ .

Enzyme analysis

The inhibition of MetAP2 was determined using the black 384-well plate format under the following reaction conditions: 50 mM Hepes pH 7.5, 100 mM NaCl, 10 μM MnCl ₂ or 10 μM CoCl ₂ , 0.005% Brij35®, 1 mM TCEP, 1% DMSO. To initiate the assay, 4 μL of 5 nM to 50 nM MetAP2 enzyme solution (end enzyme concentration of 2 nM to 20 nM) was added to each well followed by 2 μL of test compound in buffer solution containing 5% DMSO (for each test) 11 data points of the compound were subjected to 2.5-fold serial dilution). Next, 4 μL of the substrate solution (K _{m of} 2.5 xMet-AMC) was added to each well of the plate (final substrate concentration at K _m value). The reaction rate was monitored by using a fluorescence plate reader to read fluorescence at 460 nm at an excitation wavelength of 330 nm for 10 to 30 minutes. The results for each well are expressed as percent inhibition and are calculated using the following equation: among them Is the average of all the rates on the plate in the absence of the test compound, The rate of 10 [mu]M tool compound (100% inhibition of MetAP2 activity), and x is the rate in the presence of the test compound (raw data). IC ₅₀ of each test compounds by using a standard 4-parameter fit equation to obtain the percent inhibition data, and the IC ₅₀ is reported as pIC _50, i.e. -log (IC _50), where IC ₅₀ is at 50% inhibition of Molar concentration.

MetAP2 cell activity: Western blotting method of NMet-14-3-3γ

HUVEC cells (Lonza) were seeded in 96-well tissue culture microplates and cultured for 24 hours prior to the addition of test compounds (11 point range of serial dilutions) or DMSO vehicle. After 24 hours, the entire cell extract was prepared by dissolving the cells in a cell extraction buffer (Cell Signaling) containing a protease and a phosphatase inhibitor (Calbiochem). The insoluble material was removed by centrifugation and the sample was diluted in SDS-PAGE buffer and boiled therein. The protein was resolved by SDS-PAGE and transferred to the PVDF membrane. The membrane was blocked and then incubated with the appropriate primary antibody NMet-14-3-3γ (Novus) and β-actin (Sigma) followed by incubation with IRDye 680 binding or 800 CW-conjugated secondary antibody (Li-Cor). Membranes were scanned on Odyssey (Li-Cor) and LiCor software was used to quantify signals corresponding to N-Met14-3-3γ and β-actin. Compound EC ₅₀ lines by using XLfit4 Microsoft Excel curve-fitting software, the N-Met14-3-3γ untreated and β- actin protein signaling protein ratio of protein signal obtained by curve fitting.

Instance

The following examples are intended to be illustrative and not limiting, and represent specific embodiments of the invention.

¹ H nuclear magnetic resonance (NMR) spectra of many of these compounds were obtained in the following examples. Using the abbreviations used to indicate the main peaks, the characteristic chemical shifts (δ) are given in parts per million from the low magnetic field of tetramethylnonane, including s (single peak), d (double peak), t (triplet), q (quadruple), m (multiplet), and br (broad). The following abbreviations are used for common solvents: CDCl ₃ (deuterated chloroform), DMSO- d ₆ (deuterated dimethyl hydrazine), CD ₃ OD (deuterated methanol), CD ₃ CN (deuterated acetonitrile), and THF- d ₈ (deuterated tetrahydrofuran). Mass spectra (for m/z of [M+H] ⁺ ) were recorded using electrospray ionization (ESI-MS) or atmospheric pressure chemical ionization (APCI-MS) mass spectrometry.

When indicated, the product lines and some examples of the preparation by the mass triggered HPLC ^{(Pump: Waters TM 2525; MS: ZQ} TM; Software: MassLynx ^TM), flash chromatography or preparative thin layer chromatography (TLC ) to purify. Reverse phase chromatography is usually carried out under acidic conditions ("acid mode") with ACN and water mobile phases containing 0.035% and 0.05% trifluoroacetic acid (TFA), respectively; or under alkaline conditions ("alkaline mode") under water with contain of 10mM NH ₄ HCO ₃ and 20/80 (v / v) water / acetonitrile and a flow from the compatible column ^{(e.g., Gemini TM 5μ C18 110A, Axia} TM, 30 × 75mm, 5μ) on get on. Preparative TLC is typically carried out on a silicone 60 F ₂₅₄ tray. After separation by chromatography, the solvent was removed by centrifugation and the evaporator (e.g., GeneVac ^TM), a rotary evaporator, the flask was evacuated like dried product is obtained. Inert (e.g., nitrogen) or reactive (e.g., H ₂₎ atmosphere for the reaction is usually carried out at about 1 atmosphere (14.7 psi) of pressure.

Preparation of x1: 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)-1 H -carbazole

4-Bromo-6-(trifluoromethyl)-1 H -indazole (0.5 g, 1.887 mmol), bis(pinacolato)diboron (0.958 g, 3.77 mmol), PdCl ₂ (dppf) ( A mixture of 0.028 g, 0.038 mmol) and potassium acetate (0.741 g, 7.55 mmol) in DMSO (10 mL) was taken in a microwave vial, which was sealed and heated in an oil bath at 100 ° C for 13 hours. LCMS indicated the presence of the bromide starting material, so the reaction mixture was heated for an additional 7 hours before LCMS showed that the bromide starting material had been consumed. The reaction mixture followed by the product from an earlier round were combined, and then partitioned between ethyl acetate (30mL) and saturated aqueous NH ₄ Cl (30mL). Successively with saturated aqueous NH ₄ Cl (30mL) and brine (30mL) The organic phase was washed, and dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the obtained dark brown residue was purified eluting with EtOAc EtOAc EtOAc The title compound (468 mg, 72% in two rounds). ESI-MS m / z [M + H] + for _{C 14 H 16 BF 3 N 2} O ₂ calculated sum value: 313.1; Found: 313.2.

Preparation of x2: (4-bromo-1-methyl-1 H -pyrazol-5-yl)methanol

Methyl 4-bromo-1-methyl-1 H -pyrazole-5-carboxylate (2 g, 9.13 mmol) in DCM (40 mL) was cooled to -78. Diisobutylaluminum hydride (36.5 mL, 36.5 mmol) in DCM was added and the mixture was stirred at the same temperature for 2 hr. Followed by saturated aqueous sodium potassium tartrate was quenched reaction mixture was transferred to a separatory funnel, washed with water and brine in the separatory funnel, dried over Na ₂ SO ₄ dried and concentrated to give a white solid of the title compound ( 0.76g, 44%).

Preparation of x3:5-bromo- N -methylpyrimidine-4-carboxamide

HOBt (0.260 g, 1.921 mmol), EDC (0.397 g, 2.069 mmol), methylamine hydrochloride (H.sub.2). 0.200 g, 2.96 mmol) followed by N -ethyl- N -isopropylpropan-2-amine (0.772 mL, 4.43 mmol). The reaction mixture was stirred at room temperature for 18 hours. The crude residue was purified by preparative HPLC (Waters: EtOAc, EtOAc, EtOAc, EtOAc (EtOAc) The title compound (0.11 g, 35%). ESI-MS m / z [M + H] + calcd for C ₆ H ₇ BrN ₃ O of: 216.0, Found: 216.0.

Preparation of x4: N- (5-bromo-6-methylpyridin-2-yl)methanesulfonamide

To 5-bromo-6-methylpyridin-2-amine (0.3 g, 1.604 mmol) and N -ethyl- N -isopropylpropan-2-amine (0.559 mL, 3.21 mmol) at 0 °C Methane sulfonium chloride (0.137 mL, 1.764 mmol) was added to the mixture in DCM (10 mL). The reaction mixture was stirred at room temperature for 48 hours and then concentrated in vacuo to give title compound.

Preparation of x5: 4-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridinecarboxylic acid

4-Bromo-6-(trifluoromethyl)-1 H -indazole (0.302 g, 1.140 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxo dioxaborolan-2-yl) picolinate (0.3g, 1.140mmol), and _{PdCl 2 (dppf) (0.042g,} 0.057mmol) in a mixture of dioxane (10 mL) and in the saturated aqueous NaHCO ₃ (3mL) Combine to give a light brown suspension. The reaction mixture was heated in a microwave reactor at 140 ° C for 45 minutes, followed by cooling, filtration, concentration in vacuo and by using a gradient of 15% to 55% ACN (containing 0.035% TFA). Purification by preparative HPLC (Waters SunFire C18, 5 [mu]m, 30 <RTI ID=0.0> ESI-MS m / z [M + H] + for _{C 14 H 8 F 3 N 3} O ₂ calculated sum values: 308.1, Found: 308.1.

Preparation of x6: 4-(6-chloro-2-methylpyridin-3-yl)-6-(trifluoromethyl)-1 H -carbazole

The TFA salt of the title compound was replaced by (6-chloro-2-methylpyridin-3-yl)boronic acid using 4-(4,4,5,5-tetramethyl-1,3). Methyl 2-dioxaborolan-2-yl)pyridinecarboxylate was prepared. ESI-MS m / z [M + H] + calculated for C ₁₄ H ₉ ClF ₃ N ₃ The Found: 312.1; Found: 312.1.

Preparation of x7:6-methyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridinecarboxylic acid

Addition of Hydroxide to 6-Methyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl) 2-cyanopyridine (1.7 g, 5.62 mmol) in EtOH (20 mL) Sodium (14.06 mL, 28.1 mmol), and the obtained mixture was stirred under reflux for 16 hr. The mixture was then cooled to room temperature and acidified with cone. HCl. Volatiles were evaporated and the residue was purified by CombiFlash® chromatography eluting with 5% to 40% MeOH in EtOAc. The title compound (1.6 g, 89%). ESI-MS m / z [M + H] + calculated for _{C 15 H 10 F 3 N 3} O2 of values: 322.1, Found: 322.06.

Preparation of x8: 3-bromo-5-(4-methylpiperazine-1-carbonyl)pyridine-2(1 H )-one

To 5-bromo-6-o-oxy-1,6-dihydropyridine-3-carboxylic acid (500 mg, 2.294 mmol) and 2-( 1H -benzo[ d ][1,2,3]triazole- 1-Methyl-1,1,3,3-tetramethyluronium hexafluorophosphate (V) (1044 mg, 2.75 mmol) in a mixture of DMF (6 mL), 1-methylpiperazine (0.382 mL, 3.44 mmol). The mixture was stirred at room temperature for 2 hours, and containing 10% by to 50% ACN (containing 0.035% TFA) gradient of H ₂ O (containing 0.05% TFA) solution was purified by preparative HPLC isolated. The fractions containing the product were dried under vacuum to give the title compound.

Preparation of x9: 3-bromo-5-(morpholin-4-carbonyl)pyridine-2(1 H )-one

The title compound was prepared in a similar manner to the preparation of x8 using morpholine instead of 1-methylpiperazine.

Preparation of x10:5-bromo- N- (2-hydroxyethyl)-6-oxooxy-1,6-dihydropyridine-3-carboxamide

The title compound was prepared in a similar manner to the preparation of x8 using 2-aminoethanol instead of 1-methylpiperazine.

Preparation of x11: 2-(5-bromo-3-methyl-2,6-di- oxo-2,3-dihydropyrimidin-1(6 H )-yl)acetamide

5-Bromo-1-methylpyrimidine-2,4(1 H ,3 H )-dione (200 mg, 0.976 mmol), 2-bromoacetamide (162 mg, 1.171 mmol) and K at room temperature ₂ CO ₃ (162mg, _1.171mmol) was stirred in a mixture (4mL) in the DMSO 4 hours. The reaction mixture was then filtered, and the via with 1% to 40% ACN (containing 0.035% TFA) gradient of H ₂ O (containing 0.05% TFA) was purified from the solution by preparative HPLC to give the title compound.

Preparation of x12: 2-(5-bromo-3-methyl-2,6-di-oxo-2,3-dihydropyrimidin-1(6 H )-yl) -N -methylacetamide

The title compound was prepared in a similar manner to the preparation of x11 using 2-bromo- N -methylacetamide instead of 2-bromoethylamine.

Preparation of x13: 2-(5-bromo-3-methyl-2,6-di-oxo-2,3-dihydropyrimidin-1(6 H )-yl) -N -ethylacetamide

The title compound was prepared in a similar manner to the preparation of x11 using 2-bromo- N -ethylacetamide instead of 2-bromoethylamine.

Preparation of x14:5-bromo-3-(2-hydroxyethyl)-1-methylpyrimidine-2,4(1 H ,3 H )-dione

The title compound was prepared in a similar manner to the preparation of x11 using 2-bromoethanol instead of 2-bromoethylamine.

Preparation of x15: 2-(5-bromo-3-methyl-2,6-di- oxy-2,3-dihydropyrimidin-1(6H)-yl) -N , N -dimethylacetamide

5-Bromo-1-methylpyrimidine-2,4(1 H ,3 H )-dione (80 mg, 0.390 mmol), 2-chloro- N , N -dimethylacetamide at room temperature (47.4 mg, 0.390 mmol) and a mixture of potassium carbonate (64.7 mg, 0.468 mmol) in DMSO (3 mL) The reaction mixture was then filtered, and the via with 5% to 70% ACN (containing 0.035% TFA) gradient of H ₂ O (containing 0.05% TFA) was purified from the solution by preparative HPLC to give the title compound.

Preparation of x16:5-bromo-1-methyl-3-(2-(N-morpholinyl)-2-oxoethyl)pyrimidine-2,4(1 H ,3 H )-dione

The title compound was prepared in a similar manner to the preparation of x15 using 2-chloro-1-(N-morpholinyl) ethyl ketone instead of 2-chloro- N , N -dimethylacetamide.

Preparation of x17:5-bromo-3-(4-fluorobenzyl)-1-methylpyrimidine-2,4(1 H ,3 H )-dione

The title compound was prepared in a similar manner to the preparation of x15 using 1-(bromomethyl)-4-fluorobenzene instead of 2-chloro- N , N -dimethylacetamide.

Preparation of x18: 2-(5-bromo-3-methyl-2,6-di- oxy-2,3-dihydropyrimidin-1(6 H )-yl)acetonitrile

The title compound was prepared in a similar manner to the preparation of x15 using 2-bromoacetonitrile instead of 2-chloro- N , N -dimethylacetamide.

Preparation of x19:5-bromo-1-methyl-3-(2-(N-morpholinyl)ethyl)pyrimidine-2,4(1 H ,3 H )-dione

The title compound was prepared in a similar manner to the preparation of x15 using 4-(2-chloroethyl) morpholine hydrochloride instead of 2-chloro- N , N -dimethylacetamide.

Preparation of x20: 5-bromo-3-(2-(dimethylamino)ethyl)-1-methylpyrimidine-2,4(1 H ,3 H )-dione

The title compound was prepared in a similar manner to the preparation of x15 using 2-chloro- N , N -dimethylethylamine hydrochloride instead of 2-chloro- N , N -dimethylacetamide.

Preparation of x21: 3-bromo-1-methyl-5-(morpholin-4-carbonyl)pyridine-2(1 H )-one

3-Bromo-5-(morpholine-4-carbonyl)pyridine-2(1 H )-one (430 mg, 1.498 mmol), methyl iodide (0.112 mL, 1.797 mmol) and potassium carbonate (207 mg) The mixture in DMSO (5 mL) was stirred overnight. The reaction mixture was then filtered, and the via with 30% to 70% ACN gradient of H ₂ O (containing 10mM NH ₄ HCO ₃₎ was purified by preparative HPLC eluting to give the title compound.

Preparation of x22:5-bromo- N- (2-hydroxyethyl)-1-methyl-6-o-oxy-1,6-dihydropyridine-3-carboxamide

5-Bromo- N- (2-hydroxyethyl)-6-o-oxy-1,6-dihydropyridine-3-carboxamide (400 mg, 1.532 mmol), iodomethane (0.114) at room temperature A mixture of EtOAc (5. <RTI ID=0.0></RTI></RTI><RTIgt; The reaction mixture was then filtered, and the via with 1% to 30% ACN gradient of H ₂ O (containing 10mM NH ₄ HCO ₃₎ was purified by preparative HPLC eluting to give the title compound.

Preparation of x23:5-bromo- N -cyclopropyl-6-o-oxy-1,6-dihydropyridine-3-carboxamide

The bromo-6-oxo-1,6-dihydropyridine-3-carboxylic acid _{(200mg, 0.917mmol), Et 3} N (0.1mL) and 2- (1 H - benzo [d] [1 , 2,3]triazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (V) (348 mg, 0.917 mmol) in a mixture of DMF (5 mL) (52.4 mg, 0.917 mmol). The mixture was stirred at room temperature for 2 hours, and by containing 1% to 50% ACN (containing 0.035% TFA) gradient of H ₂ O (containing 0.05% TFA) solution was purified by preparative HPLC isolated. The product was dried under vacuum to give the title compound.

Preparation of x24:5-bromo- N- (cyanomethyl)-6-oxooxy-1,6-dihydropyridine-3-carboxamide

The title compound was prepared in a similar manner to the preparation of x23 using 2-aminoacetonitrile hydrochloride instead of cyclopropylamine.

Preparation of x25:5-bromo- N , N -dimethyl-6-oxirane-1,6-dihydropyridine-3-carboxamide

The title compound was prepared in a similar manner to the preparation of x23 using dimethylamine instead of cyclopropylamine.

Preparation of x26:( S )-5-bromo- N- (2-hydroxypropyl)-6-sidedoxy-1,6-dihydropyridine-3-carboxamide

The title compound was prepared in a similar manner to the preparation of x23 using ( S )-l-aminopropan-2-ol in place of cyclopropylamine.

Preparation of x27:( R )-5-bromo- N- (2-hydroxypropyl)-6-oxooxy-1,6-dihydropyridine-3-carboxamide

The title compound was prepared in a similar manner to the preparation of x23 using ( R )-1-aminopropan-2-ol in place of cyclopropylamine.

Preparation of x28: 5-bromo- N- (2,3-dihydroxypropyl)-6-o-oxy-1,6-dihydropyridine-3-carboxamide

The title compound was prepared in a similar manner to the preparation of x23 using 3-aminopropane-1,2-diol instead of cyclopropylamine.

Preparation of x29:5-bromo- N- (2,2-difluoroethyl)-6-o-oxy-1,6-dihydropyridine-3-carboxamide

The title compound was prepared in a similar manner to the preparation of x23 using 2,2-difluoroethylamine instead of cyclopropylamine.

Preparation of x30:5-bromo- N , N ,1-trimethyl-6-oxirane-1,6-dihydropyridine-3-carboxamide

To 5-bromo- N , N -dimethyl-6-o-oxy-1,6-dihydropyridine-3-carboxamide (100 mg, 0.408 mmol) and methyl iodide (57.9 mg, 0.408 mmol) in DMSO Potassium carbonate (56.4 mg, 0.408 mmol) was added to the solution in (3 mL). The mixture was stirred overnight at rt, filtered and purified via preparative HPLC eluting with &_lt;RTIID=0.0&gt_;0&gt_; The product was dried under vacuum to give the title compound.

Preparation of x31:5-bromo- N- (cyanomethyl)-1-methyl-6-o-oxy-1,6-dihydropyridine-3-carboxamide

In a manner similar to the preparation of x30, 5-bromo- N- (cyanomethyl)-6-oxo-1,6-dihydropyridine-3-carboxamide was used instead of 5-bromo- N , N- The title compound was prepared from dimethyl-6-o-oxo-1,6-dihydropyridine-3-carboxamide.

Preparation of x32:5-bromo- N- (2,2-difluoroethyl)-1-methyl-6-oxirane-1,6-dihydropyridine-3-carboxamide

In a manner similar to the preparation of x30, 5-bromo- N- (2,2-difluoroethyl)-6-o-oxy-1,6-dihydropyridine-3-carboxamide was used instead of 5-bromo- N , N -Dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide to prepare the title compound.

Preparation of x33: 5-bromo- N- (2,3-dihydroxypropyl)-1-methyl-6-oxirane-1,6-dihydropyridine-3-carboxamide

In a manner similar to the preparation of x30, 5-bromo- N- (2,3-dihydroxypropyl)-6-o-oxy-1,6-dihydropyridine-3-carboxamide was used instead of 5-bromo- N , N -Dimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide to prepare the title compound.

Preparation of x34:5-bromo- N -cyclopropyl-1-methyl-6-o-oxy-1,6-dihydropyridine-3-carboxamide

Substituting 5-bromo- N -cyclopropyl-6-o-oxy-1,6-dihydropyridine-3-carboxamide for 5-bromo- N , N -dimethyl in a similar manner to the preparation of x30 -6-Phenoxy-1,6-dihydropyridine-3-carboxamide to prepare the title compound.

Preparation of x35:( R )-5-bromo-N-(2-hydroxypropyl)-1-methyl-6-oxirane-1,6-dihydropyridine-3-carboxamide

In a manner similar to the preparation of x30, ( R )-5-bromo- N- (2-hydroxypropyl)-6-oxo-1,6-dihydropyridine-3-carboxamide was used instead of 5-bromo. - N , N -Dimethyl-6-o-oxy-1,6-dihydropyridine-3-carboxamide to prepare the title compound.

Preparation of x36:( S )-5-bromo- N- (2-hydroxypropyl)-1-methyl-6-oxirane-1,6-dihydropyridine-3-carboxamide

In a manner similar to the preparation of x30, ( S )-5-bromo- N- (2-hydroxypropyl)-6-oxo-1,6-dihydropyridine-3-carboxamide was used instead of 5-bromo. - N , N -Dimethyl-6-o-oxy-1,6-dihydropyridine-3-carboxamide to prepare the title compound.

Preparation of x37: methyl 2-(5-bromo-2-p-oxypyridine-1( 2H )-yl)acetate

Add K ₂ CO ₃ (2.383) to a solution of 5-bromopyridine-2(1 H )-one (2.5 g, 14.37 mmol) and 2-bromoacetic acid methyl ester (2.418 g, 15.81 mmol) in DMSO (12 mL) g, 17.24 mmol). The mixture was stirred at 60 ℃ 4 hours, filtered, and through with 10% to 90% ACN (containing 0.035% TFA) gradient of H ₂ O (containing 0.05% TFA) was purified soluble preparative HPLC off to give the title compound .

Preparation of x38: 3-bromo-1-methyl-5-(4-methylpiperazine-1-carbonyl)pyridine-2(1 H )-one

5-Iodo-1-methyl-6-oxooxy-1,6-dihydropyridine-3-carboxylic acid (80 mg, 0.287 mmol), 1-methylpiperazine (28.7 mg, 0.287) at room temperature Ment) and 2-(1 H -benzo[ d ][1,2,3]triazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (V) (109 mg The mixture was stirred for 2 hours in DMF (3 mL). The reaction mixture was then filtered, and the via with 10% to 50% ACN gradient of H ₂ O (containing 10mM NH ₄ HCO ₃₎ was purified by preparative HPLC eluting to give the title compound.

Preparation of x39: 1-(5-bromo-6-methylpyridin-2-yl)-4-methylpiperazine

In a microwave reactor, 3-bromo-6-chloro-2-methylpyridine (700 mg, 3.39 mmol) and 1-methylpiperazine (0.753 mL, 6.78 mmol) in DMF (4 mL) The solution was heated for 50 minutes. Subsequently, the mixture containing 10% through to 70% ACN (containing 0.035% TFA) gradient of H ₂ O (containing 0.05% TFA) was purified from the solution by preparative HPLC to give the title compound.

Preparation of x40: 3-bromo-1,6-dimethyl-5-(4-methylpiperazine-1-carbonyl)pyridine-2(1 H )-one

5-Bromo-1,2-dimethyl-6-o-oxy-1,6-dihydropyridine-3-carboxylic acid (70 mg, 0.284 mmol), 1-methylpiperazine (28.5) at room temperature Mg, 0.284 mmol), Et ₃ N (0.1 mL) and 2-(1 H -benzo[ d ][1,2,3]triazol-1-yl)-1,1,3,3-tetramethyl A mixture of the urea hexafluorophosphate (V) (108 mg, 0.284 mmol) in DMF (3 mL) was stirred for 2 hr. Subsequently, through the reaction mixture with 20% to 70% ACN gradient of H ₂ O (containing 10mM NH ₄ HCO ₃₎ was purified from the solution by preparative HPLC to give the title compound.

Preparation of x41: 5-bromo- N- (2-hydroxyethyl)-1,2-dimethyl-6-oxirane-1,6-dihydropyridine-3-carboxamide

The title compound was prepared in a similar manner to the preparation of x40 using 2-aminoethanol instead of 1-methylpiperazine.

Preparation of x42:5-'bromo-1,6-lutidine-2(1 H )-one

Add K ₂ CO ₃ (145 mg) to a solution of 5-bromo-6-methylpyridine-2(1 H )-one (164 mg, 0.872 mmol) and methyl iodide (0.065 mL, 1.047 mmol) in DMSO (3 mL) , 1.047mmol). At 60 deg.] C and the mixture was stirred overnight, filtered, and through with 20% to 70% ACN (containing 0.035% TFA) gradient of H ₂ O (containing 0.05% TFA) was purified soluble preparative HPLC off to give the title compound.

Preparation of x43: 2-(5-bromo-6-methyl-2-oxopyridine-1( 2H )-yl)acetonitrile

The title compound was prepared in a similar manner to the preparation of x42 using 2-bromoacetonitrile instead of methyl iodide.

Preparation of x44:5-bromo-6-methyl-1-(pyridin-2-ylmethyl)pyridine-2(1 H )-one

The title compound was prepared in a similar manner to the preparation of x42 using 2-(chloromethyl)pyridine hydrochloride instead of methyl iodide.

Preparation of x45:5-bromo-1,4-dimethylpyridine-2(1 H )-one

Add potassium carbonate (121 mg, 0.872 mmol) to a solution of 5-bromo-4-methylpyridine-2( 1H )-one (164 mg, 0.872 mmol) and iodomethane (124 mg, 0.872 mmol) in DMSO (3 mL) ). At 60 deg.] C and the mixture was stirred overnight, filtered, and through with 20% to 70% ACN (containing 0.035% TFA) gradient of H ₂ O (containing 0.05% TFA) was purified soluble preparative HPLC off to give the title compound.

Preparation of x46:5-bromo-4-methyl-1-(pyridin-2-ylmethyl)pyridine-2(1 H )-one

In a manner similar to the preparation of x45, 2-(chloromethyl)pyridine hydrochloride was used instead. Methyl iodide was used to prepare the title compound.

Preparation of x47: 2-(5-bromo-4-methyl-2-oxo-pyridine-1( 2H )-yl)acetonitrile

The title compound was prepared in a similar manner to the preparation of x45 using 2-bromoacetonitrile instead of methyl iodide.

Preparation of x48:5-bromopyridine-2-sulfonamide

Add 5-bromopyridine-2-sulfonium chloride hydrochloride (250 mg, 0.853 mmol) and ammonium hydroxide (1329 μL, 34.1 mmol) to a 4 mL vial equipped with a magnetic stir bar to give a white suspension in a sand bath The white suspension was heated to 70 ° C overnight. The solvent was then evaporated to give the title compound which was used without further purification.

Preparation of x49: 2-(4-bromo-3,5-dimethyl-1 H -pyrazol-1-yl) -N -isopropylacetamide

Add 4-bromo-3,5-dimethyl-1 H -pyrazole (50 mg, 0.286 mmol), 2-bromo- N -isopropylacetamide (51.4 mg) to a 4 mL vial equipped with a magnetic stir bar , 0.286 mmol), K ₂ CO ₃ (118 mg, 0.857 mmol) and acetonitrile (2 mL). The contents of the vial were stirred to give a white suspension. In a sand bath, the vial was heated to 70 ° C for 24 hours. Subsequently, the reaction mixture was partitioned between water (10 mL) and ethyl acetate (15 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (15 mL). The combined organic layers were evaporated to dryness crystals

Preparation of x50:( S )-5-((4-bromo-3,5-dimethyl-1 H -pyrazol-1-yl)methyl)pyrrolidin-2-one

The title compound was prepared in a manner analogous to the preparation of x49 using ( S )-5-(bromomethyl)pyrrolidin-2-one instead of 2-bromo- N -isopropylacetamide.

Preparation of x51: 5-bromo- N- (2-hydroxyethyl)pyridine-2-sulfonamide

5-Bromopyridine-2-sulfonium chloride hydrochloride (50 mg, 0.171 mmol), 2-aminoethanol (0.015 mL, 0.256 mmol), Et ₃ N (0.071 mL) in a 4 mL vial equipped with a magnetic stir bar , 0.512 mmol) and acetonitrile (1 mL). The resulting yellow solution was stirred overnight at room temperature. Subsequently, the reaction mixture was partitioned between water (10 mL) and ethyl acetate (15 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (15 mL). The combined organic layer was evaporated to dryness crystals

Preparation of x52: 4-bromo-3,5-dimethyl-1-((3-methyloxetan-3-yl)methyl)-1 H -pyrazole

Add 4-bromo-3,5-dimethyl-1 H -pyrazole (150 mg, 0.857 mmol), 3-(bromomethyl)-3-methyloxocycle to a 4 mL vial equipped with a magnetic stir bar Butane (283 mg, 1.714 mmol), K ₂ CO ₃ (355 mg, 2.57 mmol), and acetonitrile (2 mL). The contents of the vial were stirred to give a white suspension. The vial was heated to 70 °C in a sand bath for 24 h, and then the reaction mixture was partitioned between water (15 mL) and ethyl acetate (20 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layers were concentrated and the residue was purified eluting eluting eluting eluting eluting The pure fractions were combined and concentrated to give crystall

Preparation of x53: 3-(6-(trifluoromethyl)-1 H -indazol-4-yl)imidazo[1,2- b ]pyridazine-6-carboxylic acid

Add 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)-1 H -吲 to a 10 mL vial Oxazole (0.066 g, 0.211 mmol), 3-bromoimidazo[1,2- b ]pyridazine-6-carboxylic acid methyl ester (0.054 g, 0.211 mmol) and PdCl ₂ (dppf) (7.74 mg, 10.57 μmol) dioxane (2mL) and saturated NaHCO ₃ aqueous solution of the (1 mL) mixture. The resulting orange suspension was heated in a microwave reactor at 140 °C for 30 minutes. The main peak by LCMS is the decarboxylation product. The reaction mixture was extracted into EtOAc and aq. The aqueous layer was extracted with EtOAc. The organic layers were combined, dried over Na ₂ SO _4, filtered and concentrated to give an oil (36 mg of), which was used without further purification of the.

Preparation of x54: (5-bromopyridin-3-yl)(4-methylpiperazin-1-yl)methanone

5-bromonicotinic acid (0.020 g, 0.10 mmol), 1-methylpiperazine (0.015 g, 0.15 mmol), HATU (0.046 g, 0.12 mmol), DIPEA (0.052 g, 0.40 mmol) and dioxane (2 mL) was added to a 20 mL vial. The vial was sealed and placed on a heater/vibrator at 40 °C for 3 days. The reaction mixture containing the title compound was used without purification.

Preparation of x55: (5-bromo-2-methoxypyridin-3-yl)(4-methylpiperazin-1-yl)methanone

The title compound was prepared in a similar manner to the preparation of x54 using 5-bromo-2-methoxynicotinic acid instead of 5-bromonicotinic acid.

Preparation of x56: (2-amino-5-bromopyridin-3-yl)(4-methylpiperazin-1-yl)methanone

The title compound was prepared in a similar manner to the preparation of x54 using 2-amino-5-bromonicotinic acid instead of 5-bromonicotinic acid.

Preparation of x57: (5-bromo-2-fluoropyridin-3-yl)(4-methylpiperazin-1-yl)methanone

The title compound was prepared in a similar manner to the preparation of x54 using 5-bromo-2-fluoronicotinic acid instead of 5-bromonicotinic acid.

Preparation of x58:5-bromo- N- (2-hydroxyethyl)nicotinamide

5-bromonicotinic acid (0.020 g, 0.10 mmol), 2-aminoethanol (9.16 mg, 0.15 mmol), HATU (0.046 g, 0.12 mmol), DIPEA (0.052 g, 0.40 mmol) and dioxane 2 mL) was added to a 20 mL vial. The vial was sealed and placed on a heater/vibrator at 40 °C for 3 days. The reaction mixture containing the title compound was used without purification.

Preparation of x59: 5-bromo- N- (2-hydroxyethyl)-2-methoxynicotinamide

The title compound was prepared in a similar manner to the preparation of x58 using 5-bromo-2-methoxynicotinic acid instead of 5-bromonicotinic acid.

Preparation of x60: 4-bromo- N- (2-hydroxyethyl)pyridinium

Add 2-aminoethanol (0.181 g, 2.97 mmol), HOBt (0.301 g, 2.228 mmol) and EDC (0.456 g, 2.376 mmol) to 4-bromopicolinic acid (0.3 g, 1.485 mmol) in DMF (4 mL) And followed by N -ethyl- N -isopropylpropan-2-amine (1.293 mL, 7.43 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted with EtOAc EtOAc m.

Preparation of x61: 4-bromo-1,3-dimethyl-1 H -pyrazole-5-carboxamide

Add ammonium chloride (0.293 g, 5.48 mmol), HOBt (4-bromo-1,3-dimethyl-1 H -pyrazole-5-carboxylic acid (0.3 g, 1.370 mmol) in DMF (5 mL) 0.222 g, 1.644 mmol) and EDC (0.368 g, 1.917 mmol) followed by N -ethyl- N -isopropylpropan-2-amine (1.193 mL, 6.85 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was then diluted with EtOAc, washed with brine, dried over Na ₂ SO ₄ dried and concentrated to give the title compound (0.28 g of), which was used without further purification of the.

Preparation of x62: 3-methoxy-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzoic acid

4-Bromo-6-(trifluoromethyl)-1 H -indazole (0.5 g, 1.887 mmol), 5-dihydroxyboryl-4-methoxypyrimidine-2-carboxylic acid (0.560 g, 2.83 mmol) And a mixture of PdCl ₂ (dppf) (0.014 g, 0.019 mmol) in dioxane (10 mL) was added 2N sodium carbonate (1.887 mL, 3.77 mmol). The reaction mixture was heated at 130 ° C for 1 hour in a microwave reactor. The white precipitate was then filtered off and rinsed with methanol. The solvent was removed in vacuo. The residue was taken up in DMSO/methanol (1:1) and purified by preparative HPLC eluting with &_lt;RTIID=0.0&gt_;0&gt_; The product was taken up in vacuo to dryness crystals crystals crystals ESI-MS m / z [M + H] + for C ₁₆ H ₁₁ F ₃ N ₂ O ₃ The calculated value: 337.1; Found: 337.2.

Preparation of x63: 2-(3,5-dimethyl-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1 H -pyrazol-1-yl)acetic acid

Add 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)-1 H -indole to a microwave vial Ethyl azole (0.3 g, 0.961 mmol), ethyl 2-(4-bromo-3,5-dimethyl-1 H -pyrazol-1-yl)acetate (0.351 g, 1.346 mmol) and PdCl ₂ (dppf) (0.035g, 0.048mmol) in dioxane (10 mL) and saturated aqueous NaHCO ₃ in the (3mL) mixtures thereof. The resulting pale yellow suspension was heated in a microwave reactor at 140 °C for 45 minutes. The reaction mixture was then concentrated and the residue was purified by preparative HPLC eluting with &_lt;RTIID=0.0&gt_;0&gt_; Two products were isolated. The fractions containing the product are combined and the volatiles are removed in vacuo to give the title compound. ESI-MS m / z [M + H] + calculated for C ₁₅ value of the _{2 H 13 F 3 N 4 O:} 339.1; Found: 339.2.

Preparation of x64: methyl 2-(4-methoxy-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)phenyl)acetate

4-Bromo-6-(trifluoromethyl)-1 H -indazole (0.433 g, 1.633 mmol), 2-(4-methoxy-3-(4,4,5,5-tetramethyl) Methyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (0.5 g, 1.633 mmol) and PdCl ₂ (dppt) (0.060 g, 0.082 mmol) in dioxane (10 mL) The mixture was filled with a mixture of saturated aqueous NaHCO ₃ (3 mL). The resulting light brown suspension was heated in a microwave reactor at 140 °C for 45 minutes. The reaction mixture was then concentrated. The crude residue was taken up in EtOAc (EtOAc)EtOAc. The title compound (0.47 g, 79%) was obtained. ESI-MS m / z [M + H] + for C ₁₈ F ₃ N ₂ O ₃ The calculated value H _15: 365.1; Found: 365.2.

Preparation of methyl 3-65:3-fluoro-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzoate

4-Bromo-6-(trifluoromethyl)-1 H -indazole (0.402 g, 1.515 mmol), (2-fluoro-4-(methoxycarbonyl)phenyl)boronic acid (0.3 g, 1.515 mmol) ) and _{PdCl 2 (dppf) (0.055g,} 0.076mmol) in a mixture of _aqueous solution (3mL) in dioxane (10 mL) and saturated NaHCO filled vial. The resulting pale yellow suspension was heated in a microwave reactor at 140 °C for 45 minutes. The reaction mixture was then concentrated. The crude residue was diluted with EtOAc and washed with water, ₂ SO ₄ dried and the volatiles were removed via rotary evaporation to give the title compound (0.4g, 78%), which was used without further purification of the by Na. ESI-MS m / z [M + H] + for _{C 16 H 10 F 4 N 2} O ₂ calculated sum value: 339.1; Found: 339.1.

Preparation of x66: methyl 3-methyl-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzoate

To the microwave vial was added 4-bromo-6-(trifluoromethyl)-1 H -indazole (0.478 g, 1.804 mmol), (4-(methoxycarbonyl)-2-methylphenyl)boronic acid ( 0.35g, 1.804mmol), and _{PdCl 2 (dppf) (0.066g,} 0.090mmol) in dioxane (10 mL) and saturated NaHCO mixture of (3mL) ₃ solution. The resulting pale yellow suspension was heated in a microwave reactor at 140 °C for 60 minutes. The reaction mixture was then concentrated and the residue was diluted with EtOAc The volatiles were removed via EtOAc (EtOAc) elute ESI-MS m / z [M + H] + for _{C 17 H 13 F 3 N 2} O ₂ calculated sum value: 335.1; Found: 335.2.

Preparation of x67: ethyl 4-fluoro-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzoate

The title compound was prepared in a similar manner to the preparation of x66 using (5-(ethoxycarbonyl)-2-fluorophenyl)boronic acid instead of (4-(methoxycarbonyl)-2-methylphenyl)boronic acid. ESI-MS m / z [M + H] + for ₁₂ F ₄ N ₂ O ₂ calculated values of C ₁₇ H: 353.1; Found: 353.2.

Preparation of x68: methyl 4-methyl-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzoate

The title compound was prepared in a similar manner to the preparation of x66 using (5-(methoxycarbonyl)-2-methylphenyl)boronic acid instead of (4-(methoxycarbonyl)-2-methylphenyl)boronic acid. . ESI-MS m / z [M + H] + for _{C 17 H 13 F 3 N 2} O ₂ calculated sum value: 335.1; Found: 335.1.

Preparation of x69: 1-(2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 H -imidazo[4 ,5- b ]pyridin-1-yl)ethanone

To a 250 mL round bottom flask was added 1-(6-bromo-2-methyl- 1H -imidazo[4,5- b ]pyridin-1-yl)ethanone (1.032 g, 4.06 mmol), 4, 4 , 4',4',5,5,5',5'-octamethyl-2,2'-bis(1,3,2-dioxaborane) (1.547 g, 6.09 mmol), PdCl ₂ (dppf) (0.149 g, 0.203 mmol), potassium acetate (0.797 g, 8.12 mmol) and dioxane (40 mL). The resulting brown suspension was purged with nitrogen for 5 minutes and then heated to reflux under nitrogen for 12 hours. The reaction mixture was treated with water and filtered. The filtrate was extracted with EtOAc. The combined organic layer was dried over MgSO _4, filtered and concentrated to give the title compound as a brown solid (1.82g). This crude product was used without further purification.

Preparation of x70: 2-(4-bromo-3,5-dimethyl-1 H -pyrazol-1-yl)-1-(3-hydroxyazetidin-1-yl)ethanone

Add azetidine-3- to 2-(4-bromo-3,5-dimethyl-1 H -pyrazol-1-yl)acetic acid (0.4 g, 1.716 mmol) in DMF (6 mL) Alcohol (0.151 g, 2.060 mmol), HOBt (0.301 g, 2.231 mmol) and EDC (0.461 g, 2.403 mmol), followed by N -ethyl- N -isopropylpropan-2-amine (1.495 mL, 8.58 mmol) ). The reaction mixture was stirred at room temperature for 18 hours. The crude reaction mixture was then diluted with EtOAc, washed with brine, ₂ SO ₄ dried and concentrated to give the title compound, which was used without further purification of the by Na.

Preparation of x71: 2-(4-bromo-3,5-dimethyl-1 H -pyrazol-1-yl) -N -methylacetamide

The title compound was prepared in a similar manner to the preparation of x70 using methylamine hydrochloride instead of azetidine-3-ol.

Preparation x72: 2- (4- bromo-3,5-dimethyl -1 H - pyrazol-1-yl) - N - (2- hydroxyethyl) amine acetyl

The title compound was prepared in a similar manner to the preparation of x70 using 2-aminoethanol instead of azetidin-3-ol.

Preparation of x73: (5-bromo-6-methyl-2-(methylamino)pyridin-3-yl)(3-hydroxyazetidin-1-yl)methanone

Add azetidin-3-ol (0.119 g, 1.632) to 5-bromo-6-methyl-2-(methylamino)nicotinic acid (0.2 g, 0.816 mmol) in DMF (3 mL) Methyl), HOBt (0.154 g, 1.143 mmol) and EDC (0.235 g, 1.224 mmol), followed by N -ethyl- N -isopropylpropan-2-amine (0.426 mL, 2.448 mmol). The reaction mixture was stirred at room temperature for 18 hours. The crude reaction mixture was then diluted with EtOAc, washed with brine, ₂ SO ₄ dried and concentrated by rotary evaporation to give the title compound (0.15g), which was used without further purification of the by Na.

Preparation of x74:6-methoxy-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridinecarboxylic acid

Adding hydrogen to 6-methoxy-5-(6-(trifluoromethyl)-1 H -indazol-4-yl) 2-cyanopyridine (0.5 g, 1.571 mmol) in EtOH (20 mL) Sodium oxide (3.93 mL, 7.86 mmol). The reaction mixture was stirred for 50 minutes under reflux and then diluted with water and acidified with cone. Volatiles were evaporated and the residue was purified by preparative HPLC eluting with &_lt;RTIID=0.0&gt_;0&gt_; The product-containing fractions were combined and the volatiles were evaporated to afford title compound.

Example 1: 4-Phenyl-6-(trifluoromethyl)-1 H -carbazole

4-Bromo-6-(trifluoromethyl)-1 H -carbazole (0.1 g, 0.377 mmol), phenylboronic acid (0.069 g, 0.566 mmol), PdCl ₂ (dppf) (0.014 g, 0.019 mmol) And dioxane (3mL) filling container. A 2N aqueous sodium carbonate solution (0.377 mL, 0.755 mmol) was added to the obtained slurry. The mixture was purged with nitrogen and heated in a microwave reactor at 120 ° C for 30 minutes, then filtered through a pad of Celite, and rinsed with methanol. Removed the solvent in vacuo, and the resulting residue was taken up in DMSO and methanol (1: 1), and the via containing 55% to 80% ACN (containing 0.035% TFA) gradient of H ₂ O (containing 0.05% TFA) was purified by acidic preparative HPLC (Waters SunFire C18, 5 [mu]m, 30 mm ID x 75 mm column). The collected fractions were dried <RTI ID=0.0> ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 7.43-7.62 (m, 4 H), 7.71 (d, J = 7.07 Hz, 2 H), 7.83 (s, 1 H), 8.23 - 8.38 (m, 1 H) ), 8.47 (br s, 1 H); ESI-MS m / z [m + H] + for C ₁₄ H ₉ F ₃ N ₂ calculated sum value: 263.1; Found: 263.1.

The compounds of Examples 2 to 52 below were prepared according to Scheme B using a procedure similar to that of Example 1.

Reaction conditions: 4-bromo-6-(trifluoromethyl)-1 H -indazole (B-1) (40 mg, 0.151 mmol), boric acid (B-2, R' and R" = H) or ester ( B-2, R' and R" are common = 2,3-dimethylbutane-2,3-diyl) (1.5 equivalents), PdCl ₂ (dppf) (0.1 equivalent), aqueous Na ₂ CO ₃ (2N, 2 to 3 equivalents), dioxane (1.2 mL to 1.5 mL) was continued at 130 ° C for 30 minutes to 1 hour. Unless otherwise stated, the title compound was isolated as the TFA salt.

Example 2: 4-(3-Methylpyridin-4-yl)-6-(trifluoromethyl)-1 H -carbazole

ESI-MS m / z [M + H] + calculated for C ₁₄ H ₁₀ F ₃ N ₃ The Found: 278.1; Found: 278.1.

Example 3: 4-(Imidazo[1,2-a]pyridin-6-yl)-6-(trifluoromethyl)-1 H -carbazole

ESI-MS m / z [M + H] + for C ₁₅ H ₉ F ₃ N ₄ of the calculated value: 303.1; Found: 303.1.

Example 4: 7-(6-(Trifluoromethyl)-1 H -indazol-4-yl)-3,4-dihydro- 2H -pyrido[3,2- b ][1,4] Oxazine

ESI-MS m / z [M + H] + for C ₁₅ H ₁₁ F ₃ N ₄ O Calcd of: 321.1; Found: 321.2.

Example 5: 5-(6-(Trifluoromethyl)-1 H -indazol-4-yl)nicotinonitrile

¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.71 (d, J = 1.01 Hz, 1 H), 8.06 (s, 1 H), 8.48 (t, J = 1.26 Hz, 1 H), 8.78 (t , J = 2.15 Hz, 1 H), 9.15 (d, J = 2.02 Hz, 1 H), 9.29 (d, J = 2.27 Hz, 1 H), 13.83 (s, 1 H); ESI-MS m/z [M ⁺ H] + for C ₁₄ H ₇ F ₃ N ₄ of the calculated value: 289.1; Found: 289.1.

Example 6: 4-(pyrimidin-5-yl)-6-(trifluoromethyl)-1 H -carbazole

ESI-MS m / z [M + H] + for C ₁₂ H ₇ F ₃ N ₄ of the calculated value: 265.1; Found: 265.1.

Example 7: 4-(6-(Trifluoromethyl)-1 H -indazol-4-yl)benzamide

¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.47 (s, 1 H), 7.53 (d, J = 1.01 Hz, 1 H), 7.89 (d, J = 8.59 Hz, 2 H), 7.98 (s , 1 H), 8.07 (d, J = 8.34 Hz, 2 H), 8.12 (s, 1 H), 8.37 (s, 1 H), 13.76 (s, 1 H); ESI-MS m/z [M + H] ⁺ calcd for _{C 15 H 10 F 3 N 3} O of: 306.1; Found: 306.1.

Example 8: (3-(6-(Trifluoromethyl)-1 H -indazol-4-yl)phenyl)methanol

ESI-MS m / z [M + H] + for _{C 15 H 11 F 3 N 2} O of Calcd: 293.1; Found: 293.1.

Example 9: 5-(6-(Trifluoromethyl)-1 H -indazol-4-yl)pyrimidin-2-amine

^{1 H NMR (400MHz, DMSO- d} 6) δ ppm 7.08 (br s, 2 H), 7.47 (s, 1 H), 7.88 (s, 1 H), 8.39 (s, 1 H), 8.71 (s, 2 H), 13.33-14.00 (m, 1 H); ESI-MS m / z [m + H] + calculated for C ₁₂ H ₈ F ₃ N ₅ the Found: 280.1; Found: 280.1.

Example 10: 2-(6-(Trifluoromethyl)-1 H -indazol-4-yl)benzamide

ESI-MS m / z [M + H] + calcd for C ₁₅ H ₁₀ F ₃ N ₃ O of: 306.1; Found: 306.1.

Example 11: (4-(6-(Trifluoromethyl)-1 H -indazol-4-yl)phenyl)methanol

ESI-MS m / z [M + H] + for _{C 15 H 11 F 3 N 2} O of Calcd: 293.1; Found: 293.1.

Example 12: (2-(6-(Trifluoromethyl)-1 H -indazol-4-yl)phenyl)methanol

ESI-MS m / z [M + H] + for _{C 15 H 11 F 3 N 2} O of Calcd: 293.1; Found: 293.

Example 13: 4-( 1H -pyrazol-3-yl)-6-(trifluoromethyl)-1 H -carbazole

ESI-MS m / z [M + H] + for C ₁₁ H ₇ F ₃ N ₄ of the calculated value: 253.1; Found: 2531.

Example 14: 4-(Pyridin-4-yl)-6-(trifluoromethyl)-1 H -carbazole

ESI-MS m / z [M + H] + calculated for C ₁₃ H ₈ F ₃ N ₃ The Found: 264.1; Found: 264.1.

Example 15: 2'-Methyl-6-(trifluoromethyl)-1 H , 2' H -4,4'-dicarbazole

ESI-MS m / z [M + H] + for C ₁₆ H ₁₁ F ₃ N ₄ of the calculated value: 317.1; Found: 317.2.

Example 16: 5-(6-(Trifluoromethyl)-1 H -indazol-4-yl)pyridin-2-amine

ESI-MS m / z [M + H] + for C ₁₃ H ₉ F ₃ N ₄ of the calculated value: 279.1; Found: 279.1.

Example 17: 4-( 1H -Benzo[ d ]imidazol-5-yl)-6-(trifluoromethyl)-1 H -carbazole

¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.52 (s, 1 H), 7.77-7.85 (m, 1 H), 7.85-7.94 (m, 1 H), 7.96 (s, 1 H), 8.10 (s, 1 H), 8.36 (s, 1 H), 8.98 (br s, 1 H), 13.76 (br s, 1 H); ESI-MS m/z [M+H] ⁺ for C ₁₅ H ₉ Calculated for F ₃ N ₄ : 303.1; found: 303.1.

Example 18: 3-(6-(Trifluoromethyl)-1 H -indazol-4-yl)benzamide

¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.51 (br s, 1 H), 7.56 (d, J = 1.01 Hz, 1 H), 7.66 (t, J = 7.83 Hz, 1 H), 7.93 8.03 (m, 3 H), 8.18 (s, 1 H), 8.23 (s, 1 H), 8.36 (s, 1 H), 13.75 (s, 1 H); ESI-MS m/z [M+H ] ⁺ calcd for _{C 15 H 10 F 3 N 3} O of: 306.1; Found: 306.2.

Example 19: 4-(Pyridin-3-yl)-6-(trifluoromethyl)-1 H -carbazole

ESI-MS m / z [M + H] + calculated for C ₁₃ H ₈ F ₃ N ₃ The Found: 264.1; Found: 264.1.

Example 20: 4-(1-Methyl-1 H -pyrazol-5-yl)-6-(trifluoromethyl)-1 H -carbazole

ESI-MS m / z [M + H] + for C ₁₂ H ₉ F ₃ N ₄ of the calculated value: 267.1; Found: 267.1.

Example 21: 4-(1-Methyl-1 H -pyrazol-5-yl)-6-(trifluoromethyl)-1 H -carbazole

The title compound was isolated as the free base. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 3.87 (s, 3 H), 6.67 (d, J = 1.77 Hz, 1 H), 7.51 (s, 1 H), 7.63 (d, J = 1.77 Hz , 1 H), 8.03 (s, 1 H), 8.19 (s, 1 H), 13.81 (s, 1 H); ESI-MS m/z [M+H] ⁺ for C ₁₂ H ₉ F ₃ N ₄ Calculated: 267.1; found: 267.1.

Example 22: 4-(3-Methyl-1 H -pyrazol-4-yl)-6-(trifluoromethyl)-1 H -carbazole

ESI-MS m / z [M + H] + for C ₁₂ H ₉ F ₃ N ₄ of the calculated value: 267.1; Found: 267.1.

Example 23: 4-( 1H -pyrazol-4-yl)-6-(trifluoromethyl)-1 H -carbazole

ESI-MS m / z [M + H] + for C ₁₁ H ₇ F ₃ N ₄ of the calculated value: 253.1; Found: 253.1.

Example 24: 1'-Methyl-6-(trifluoromethyl)-1 H , 1' H -4,6'-dicarbazole

ESI-MS m / z [M + H] + for C ₁₆ H ₁₁ F ₃ N ₄ of the calculated value: 317.1; Found: 317.2.

Example 25: 4-(6-(Trifluoromethyl)-1 H -indazol-4-yl)benzenesulfonamide

ESI-MS m / z [M + H] + for _{C 14 H 10 F 3 N 3} O ₂ S calculated sum value: 342.0; Found: 342.1.

Example 26: 7-(6-(Trifluoromethyl)-1 H -indazol-4-yl)isoquinoline

ESI-MS m / z [M + H] + calculated for C ₁₇ H ₁₀ F ₃ N ₃ The Found: 314.1; Found: 314.2.

Example 27: 4-(Benzo[ d ][1,3]dioxol-4-yl)-6-(trifluoromethyl)-1 H -carbazole

ESI-MS m / z [M + H] + calculated for C N ₂ O ₂ value of ₁₅ H ₉ F _3: 307.1; Found: 307.1.

Example 28: N -isobutyl-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzamide

ESI-MS m / z [M + H] + calcd for _{C 19 H 18 F 3 N 3} O of: 362.1; Found: 362.3.

Example 29: (5-(6-(Trifluoromethyl)-1 H -indazol-4-yl)pyridin-3-yl)methanol

ESI-MS m / z [M + H] + calcd for C ₁₄ H ₁₀ F ₃ N ₃ O of: 294.1; Found: 294.1.

Example 30: 4-(4-Methoxypyridin-3-yl)-6-(trifluoromethyl)-1 H -carbazole

ESI-MS m / z [M + H] + calcd for C ₁₄ H ₁₀ F ₃ N ₃ O of: 294.1; Found: 294.2.

Example 31: 8-(6-(Trifluoromethyl)-1 H -indazol-4-yl)quinoline

¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.51 (d, J = 1.01 Hz, 1 H), 7.61 (dd, J = 8.34, 4.29 Hz, 1 H), 7.71-7.77 (m, 1 H) , 7.76-7.83 (m, 1 H), 7.94 (dd, J = 7.20, 1.39 Hz, 1 H), 7.98 (s, 1 H), 8.15 (dd, J = 8.21, 1.39 Hz, 1 H), 8.52 (dd, J = 8.59, 1.77 Hz, 1 H), 8.83 (dd, J = 4.29, 1.77 Hz, 1 H), 13.62 (s, 1 H); ESI-MS m/z [M+H] ⁺ Calcd for C ₁₇ H ₁₀ F ₃ N ₃ : 314.1; found: 314.1.

Example 32: N , N -Diethyl-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzamide

ESI-MS m / z [M + H] + calcd for _{C 19 H 18 F 3 N 3} O of: 362.1; Found: 362.3.

Example 33: 3-(6-(Trifluoromethyl)-1 H -indazol-4-yl)benzonitrile

ESI-MS m / z [M + H] + calculated for C ₁₅ H ₈ F ₃ N ₃ the values: 288.1; Found: 288.1.

Example 34: N -Benzyl-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzamide

ESI-MS m / z [M + H] + calcd for C ₂₂ H ₁₆ F ₃ N ₃ O of: 396.1; Found: 396.3.

Example 35: N -cyclopropyl-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzamide

ESI-MS m / z [M + H] + calcd for _{C 18 H 14 F 3 N 3} O of: 346.1; Found: 346.2.

Example 36: 1'-Methyl-6-(trifluoromethyl)-1 H , 1' H -4,5'-dicarbazole

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 4.14 (s, 3 H), 7.47 (d, J = 1.26 Hz, 1 H), 7.74 (d, J = 8.59 Hz, 1 H), 7.80-7.85 ( m,1 H), 7.87 (s, 1 H), 8.11-8.16 (m, 2 H), 8.29 (d, J = 1.01 Hz, 1 H); ESI-MS m/z [M+H] ⁺ Calcd for C ₁₆ H ₁₁ F ₃ N ₄ : 317.1; found: 317.2.

Example 37: 2-Methyl-5-(3-(6-(trifluoromethyl)-1 H -indazol-4-yl)phenyl)-1,3,4-oxadiazole

¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 2.62 (s, 3 H), 7.58 (s, 1 H), 7.80 (t, J = 7.83 Hz, 1 H), 8.01 (s, 1 H), 8.03-8.08 (m, 1 H), 8.11 (d, J = 7.58 Hz, 1 H), 8.29 (t, J = 1.52 Hz, 1 H), 8.37 (s, 1 H), 13.81 (s, 1 H) ); ESI-MS m / z [m + H] + calcd for _{C 17 H 11 F 3 N 4} O of: 345.1; Found: 345.2.

Example 38: 2-(3-(6-(Trifluoromethyl)-1 H -indazol-4-yl)phenyl)acetamide

ESI-MS m / z [M + H] + calcd for C ₁₆ H ₁₂ F ₃ N ₃ O of: 320.1; Found: 320.2.

Example 39: 4-(1,3-Dimethyl-1 H -pyrazol-4-yl)-6-(trifluoromethyl)-1 H -carbazole

ESI-MS m / z [M + H] + for C ₁₃ H ₁₁ F ₃ N ₄ of the calculated value: 281.1; Found: 281.2.

Example 40: 2,4-Dimethyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)thiazole

ESI-MS m / z [M + H] + calculated for C ₁₃ H ₁₀ F ₃ N ₃ S The value: 298.1; Found: 298.1.

Example 41: 4-(pyrazolo[1,5- a ]pyridin-3-yl)-6-(trifluoromethyl)-1 H -carbazole

ESI-MS m / z [M + H] + for C ₁₅ H ₉ F ₃ N ₄ of the calculated value: 303.1; Found: 303.1.

Example 42: 4-(5-Methoxypyridin-3-yl)-6-(trifluoromethyl)-1 H -carbazole

^{1 H NMR (400MHz, DMSO- d} 6) δ ppm 3.97 (s, 3 H), 7.61 (s, 1 H), 7.83 (d, J = 2.02Hz, 1 H), 8.02 (s, 1 H), 8.42 (d, J = 0.76 Hz, 1 H), 8.46 (d, J = 2.53 Hz, 1 H), 8.62 (d, J = 1.01 Hz, 1 H), 13.81 (s, 1 H); ESI-MS m / z [m + H] + calcd for C ₁₄ H ₁₀ F ₃ N ₃ O of: 294.1; Found: 294.1.

Example 43: 4-(1-(Pyridin-4-ylmethyl)-1 H -pyrazol-4-yl)-6-(trifluoromethyl)-1 H -carbazole

ESI-MS m / z [M + H] + calculated for C ₁₇ H ₁₂ F ₃ N ₅ The Found: 344.1; Found: 344.2.

Example 44; N- (2-(6-(Trifluoromethyl)-1 H -indazol-4-yl)phenyl)methanesulfonamide

^{1 H NMR (400MHz, DMSO- d} 6) δ ppm 2.79 (s, 3 H), 7.34-7.45 (m, 2 H), 7.45-7.60 (m, 3 H), 7.89-7.97 (m, 2 H) , 9.08 (s, 1 H), 13.61 (s, 1 H); ESI-MS m/z [M+H] ⁺ Calculated for C ₁₅ H ₁₂ F ₃ N ₃ O ₂ S: 356.1; 356.2.

Example 45: 4-(3-Methoxypyridin-4-yl)-6-(trifluoromethyl)-1 H -carbazole

ESI-MS m / z [M + H] + calcd for C ₁₄ H ₁₀ F ₃ N ₃ O of: 294.1; Found: 294.2.

Example 46: 4-(3-Fluoropyridin-4-yl)-6-(trifluoromethyl)-1 H -carbazole

ESI-MS m / z [M + H] + calculated for C ₁₃ H ₇ F ₄ N ₃ of values: 282.1; Found: 282.1.

Example 47: N , N -Dimethyl-2-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzamide

ESI-MS m / z [M + H] + calcd for C ₁₇ H ₁₄ F ₃ N ₃ O of: 334.1; Found: 334.2.

Example 48: 4-(4-(Methoxymethyl)phenyl)-6-(trifluoromethyl)-1 H -carbazole

ESI-MS m / z [M + H] + for _{C 16 H 13 F 3 N 2} O of Calcd: 307.1; Found: 307.2.

Example 49: 4-(3-Chloropyridin-4-yl)-6-(trifluoromethyl)-1 H -carbazole

ESI-MS m / z [M + H] + calculated for C ₁₃ H ₇ ClF ₃ N ₃ The Found: 298.0; Found: 298.1.

Example 50: 4-(2-Methylpyridin-3-yl)-6-(trifluoromethyl)-1 H -carbazole

ESI-MS m / z [M + H] + calculated for C ₁₄ H ₁₀ F ₃ N ₃ The Found: 278.1; Found: 278.1.

Example 51: 4-(1-Methyl-1 H -indol-2-yl)-6-(trifluoromethyl)-1 H -carbazole

ESI-MS m / z [M + H] + calculated for C ₁₇ H ₁₂ F ₃ N ₃ of values: 3161; Found: 316.2.

Example 52: 2-(6-(Trifluoromethyl)-1 H -indazol-4-yl)benzonitrile

ESI-MS m / z [M + H] + calculated for C ₁₅ H ₈ F ₃ N ₃ the values: 288.1; Found: 288.1.

Example 53: 4-(2-Methoxypyridin-3-yl)-6-(trifluoromethyl)-1 H -carbazole

ESI-MS m / z [M + H] + calcd for C ₁₄ H ₁₀ F ₃ N ₃ O of: 294.1; Found: 294.2.

Example 54: 5-(6-(Trifluoromethyl)-1 H -indazol-4-yl)pyrimidine-2,4(1 H ,3 H )-dione

ESI-MS m / z [M + H] + for _{C 12 H 7 F 3 N 4} O ₂ computing the values: 297.1; Found: 297.1.

Example 55: 4-(2,6-Dimethoxypyridin-3-yl)-6-(trifluoromethyl)-1 H -carbazole

^{1 H NMR (400MHz, DMSO- d} 6) δ ppm 3.91 (s, 3 H), 3.96 (s, 3 H), 6.57 (d, J = 8.08Hz, 1 H), 7.36 (s, 1 H), 7.79-7.96 (m, 2 H), 8.04 (s, 1 H), 13.58 (s, 1 H); ESI-MS m/z [M+H] ⁺ for C ₁₅ H ₁₂ F ₃ N ₃ O ₂ Calculated: 324.1; found: 324.2.

Example 56: N- (4-(6-(Trifluoromethyl)-1 H -indazol-4-yl)phenyl)methanesulfonamide

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 3.05 (s, 3 H), 7.43 (d, J = 1.26 Hz, 1 H), 7.43-7.48 (m, 2 H), 7.71-7.78 (m, 2) H), 7.87 (s, 1 H), 8.29 (d, J = 1.01 Hz, 1 H); ESI-MS m/z [M+H] ⁺ for C ₁₅ H ₁₂ F ₃ N ₃ O ₂ S Value: 356.1; Found: 356.2.

Example 57: 4-(3-(6-(Trifluoromethyl)-1 H -indazol-4-yl)phenyl)morpholine

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 3.39-3.47 (m, 4 H), 3.91-3.98 (m, 4 H), 7.32 (ddd, J = 8.34, 2.53, 1.01 Hz, 1 H), 7.42 -7.48 (m, 2 H), 7.49-7.52 (m, 1 H), 7.53-7.60 (m, 1 H), 7.88-7.92 (m, 1 H), 8.26 (d, J = 1.01 Hz, 1 H ); ESI-MS m / z [m + H] + calculated for _{C 18 H 16 F 3 N 3} O of values: 348.1; Found: 348.2.

Example 58: 4-(6-(Cyclopropylmethoxy)pyridin-3-yl)-6-(trifluoromethyl)-1 H -carbazole

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 0.34-0.44 (m, 2 H), 0.56-0.71 (m, 2 H), 1.24-1.44 (m, 1 H), 4.22 (d, J = 7.07 Hz) , 2 H), 6.99-7.08 (m, 1 H), 7.43 (d, J = 1.01 Hz, 1 H), 7.90 (s, 1 H), 8.12 (dd, J = 8.72, 2.65 Hz, 1 H) , 8.27 (d, J = 1.01 Hz, 1 H), 8.50 (d, J = 2.02 Hz, 1 H); ESI-MS m/z [M+H] ⁺ for C ₁₇ H ₁₄ F ₃ N ₃ O Calculated: 334.1; found: 334.2.

Example 59: 4-( 1H -pyrrolo[2,3-b]pyridin-5-yl)-6-(trifluoromethyl)-1 H -carbazole

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 6.80 (d, J = 3.54 Hz, 1 H), 7.50-7.60 (m, 1 H), 7.64 (d, J = 3.54 Hz, 1 H), 7.96 ( s, 1 H), 8.33 (d, J = 1.01 Hz, 1 H), 8.67 (s, 2 H); ESI-MS m/z [M+H] ⁺ for C ₁₅ H ₉ F ₃ N ₄ Value: 303.1; found: 303.2.

Example 60: 4-(4-(6-(Trifluoromethyl)-1 H -indazol-4-yl)thiazol-2-yl)morpholine

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 3.55-3.63 (m, 4 H), 3.81-3.91 (m, 4 H), 7.42 (s, 1 H), 7.84 (d, J = 9.60 Hz, 2 H), 8.68 (s, 1 H); ESI-MS m / z [m + H] + ₃ N calcd for C ₁₅ H ₁₃ F ₄ OS of: 355.1; Found: 355.2.

Example 61: 4-(3-( 1H -pyrazol-3-yl)phenyl)-6-(trifluoromethyl)-1 H -carbazole

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 6.83 (d, J = 2.53 Hz, 1 H), 7.52 (d, J = 1.01 Hz, 1 H), 7.61-7.68 (m, 1 H), 7.72 7.76 (m, 1 H), 7.77 (d, J = 2.27 Hz, 1 H), 7.87-7.91 (m, 1 H), 7.92 (s, 1 H), 8.17 (t, J = 1.52 Hz, 1 H ), 8.33 (d, J = 1.01Hz, 1 H); ESI-MS m / z [m + H] + for C ₁₇ H ₁₁ F ₃ N ₄ of the calculated value: 329.1; Found: 329.2.

Example 62: 4-(4-( 1H -pyrazol-5-yl)phenyl)-6-(trifluoromethyl)-1 H -carbazole

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 6.81 (d, J = 2.27 Hz, 1 H), 7.49 (d, J = 1.01 Hz, 1 H), 7.76 (d, J = 2.27 Hz, 1 H) , 7.81-7.83 (m, 1 H), 7.83-7.86 (m, 1 H), 7.89-7.91 (m, 1 H), 7.97-7.99 (m, 1 H), 7.99-8.01 (m, 1 H) , 8.32 (d, J = 1.01Hz , 1 H); ESI-MS m / z [m + H] + for C ₁₇ H ₁₁ F ₃ N ₄ of the calculated value: 329.1; Found: 329.2.

Example 63: 2-Chloro-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzamide

The title compound was isolated as the free base. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 7.50 (s, 1 H), 7.68 (d, J = 8.34 Hz, 1 H), 7.80-7.85 (m, 1 H), 7.86 (d, J = 2.27) Hz, 1 H), 7.94 (s, 1 H), 8.31-8.36 (m, 1 H); ESI-MS m/z [M+H] ⁺ calculated for C ₁₅ H ₉ ClF ₃ N ₃ O: 340.0; Found: 340.1.

Example 64: 4-(1-Methyl-1 H -benzo[ d ]imidazol-6-yl)-6-(trifluoromethyl)-1 H -carbazole

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 4.21 (s, 3 H), 7.60 (d, J = 1.26 Hz, 1 H), 7.98 (s, 1 H), 7.99-8.06 (m, 2 H) , 8.26 (s, 1 H), 8.35 (d, J = 1.01 Hz, 1 H), 9.32 (s, 1 H); ESI-MS m/z [M+H] ⁺ for C ₁₆ H ₁₁ F ₃ N Calculated for ₄ : 317.1; found: 317.2.

Example 65: 4-(3-Fluoro-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridin-2-yl)morpholine

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 3.51-3.57 (m, 4 H), 3.83-3.89 (m, 4 H), 7.11-7.15 (m, 1 H), 7.51 (s, 1 H), 8.02 (d, J = 1.26 Hz, 1 H), 8.10 (dd, J = 2.27, 1.01 Hz, 1 H), 8.13 (d, J = 5.05 Hz, 1 H); ESI-MS m/z [M+ H) ⁺ calcd for C ₁₇ H ₁₄ F ₄ N ₄ O: 367.1; Found: 367.2.

Example 66: 4-(5-Fluoro-1 H -pyrrolo[2,3- b ]pyridin-4-yl)-6-(trifluoromethyl)-1 H -carbazole

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 6.32 (d, J = 3.54 Hz, 1 H), 7.55 (d, J = 3.54 Hz, 1 H), 7.61 (s, 1 H), 7.97 (dd, J = 2.27, 1.01 Hz, 1 H), 8.05 (s, 1 H), 8.33 (d, J = 3.03 Hz, 1 H); ESI-MS m/z [M+H] ⁺ for C ₁₅ H ₈ F Calculated for ₄ N ₄ : 321.1; found: 321.1.

Example 67: 1 ',3'-Dimethyl-6-(trifluoromethyl)-1 H , 1' H -4,6'-dicarbazole

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 2.60 (s, 3 H), 4.07 (s, 3 H), 7.52 (dd, J = 8.46, 1.39 Hz, 1 H), 7.54 (d, J = 1.01) Hz, 1 H), 7.80-7.82 (m, 1 H), 7.88 (dd, J = 8.34, 0.76 Hz, 1 H), 7.92 (s, 1 H), 8.32 (d, J = 1.01 Hz, 1 H ); ESI-MS m / z [m + H] + calculated for ₃ N ₄ values of C ₁₇ H ₁₃ F: 331.1; Found: 331.2.

Example 68: 1 ',3'-Dimethyl-6-(trifluoromethyl)-1 H , 1' H -4,6'-dicarbazole

The title compound was isolated as the free base. ^{1 H NMR (400MHz, DMSO- d} 6) δ ppm 2.54 (s, 3 H), 4.06 (s, 3 H), 7.52 (d, J = 8.34Hz, 1 H), 7.58 (s, 1 H), 7.88 (d, J = 8.08 Hz, 1 H), 7.96 (br s, 2 H), 8.43 (s, 1 H); ESI-MS m/z [M+H] ⁺ for C ₁₇ H ₁₃ F ₃ N Calculated for ₄ : 331.1; found: 331.2.

Example 69: 4-(3-( 1H -pyrazol-1-yl)phenyl)-6-(trifluoromethyl)-1 H -carbazole

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 6.56 (dd, J = 2.40, 1.89 Hz, 1 H), 7.54 (d, J = 1.01 Hz, 1 H), 7.64-7.74 (m, 2 H), 7.77 (d, J = 1.77 Hz, 1 H), 7.83 (dt, J = 7.45, 1.96 Hz, 1 H), 7.92 (s, 1 H), 8.11 (t, J = 1.64 Hz, 1 H), 8.34 (td, J = 3.03,0.76Hz, 2 H); ESI-MS m / z [m + H] + for C ₁₇ H ₁₁ F ₃ N ₄ of the calculated value: 329.1; Found: 329.2.

Example 70: 4-(5-Methyl-1-phenyl-1 H -pyrazol-4-yl)-6-(trifluoromethyl)-1 H -carbazole

The title compound was isolated as the free base. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 2.41 (s, 3 H), 7.36 (s, 1 H), 7.53 (dt, J = 6.19, 2.59 Hz, 1 H), 7.56-7.66 (m, 4) H), 7.86 (s, 1 H), 8.00 (s, 1 H), 8.25 (s, 1 H); ESI-MS m/z [M+H] ⁺ for C ₁₈ H ₁₃ F ₃ N ₄ Value: 343.1; found: 343.2.

Example 71: 4-(5-Methyl-1-phenyl-1 H -pyrazol-4-yl)-6-(trifluoromethyl)-1 H -carbazole

ESI-MS m / z [M + H] + calculated for ₃ N ₄ values of C ₁₈ H ₁₃ F: 343.1; Found: 343.2.

Example 72: 4-(1-(Pyridin-2-ylmethyl)-1 H -pyrazol-4-yl)-6-(trifluoromethyl)-1 H -carbazole

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 5.68 (s, 2 H), 7.44 (d, J = 7.83 Hz, 1 H), 7.55-7.61 (m, 2 H), 7.76-7.81 (m, 1 H), 8.08 (td, J = 7.77, 1.64 Hz, 1 H), 8.18 (d, J = 0.76 Hz, 1 H), 8.47 (d, J = 1.01 Hz, 1 H), 8.53 (d, J = 0.76Hz, 1 H), 8.63-8.69 ( m, 1 H); ESI-MS m / z [m + H] + calculated for C ₁₇ H ₁₂ F ₃ N ₅ the Found: 344.1; Found: 344.2.

Example 73: N- (3-(6-(Trifluoromethyl)-1 H -indazol-4-yl)pyridin-2-yl)trimethylacetamide

ESI-MS m / z [M + H] + for C ₁₈ H ₁₇ F ₃ N ₄ O Calcd of: 363.1; Found: 363.3.

Example 74: 4-(2-(4-(6-(Trifluoromethyl)-1 H -indazol-4-yl)-1 H -pyrazol-1-yl)ethyl)morpholine

ESI-MS m / z [M + H] + calcd for C ₁₇ H ₁₈ F ₃ N ₅ O of: 366.1; Found: 366.3.

Example 75: 5-Fluoro-2-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzonitrile

The title compound was isolated as the free base. ESI-MS m / z [M + H] + calculated for C ₁₅ H ₇ F ₄ N ₃ of values: 306.1; Found: 306.1.

Example 76: 4-( 1H -indol-7-yl)-6-(trifluoromethyl)-1 H -carbazole

ESI-MS m / z [M + H] + calculated for C ₁₆ H ₁₀ F ₃ N ₃ The Found: 302.1; Found: 302.2.

Example 77: 4-(1-Methyl-1 H -indol-4-yl)-6-(trifluoromethyl)-1 H -carbazole

ESI-MS m / z [M + H] + calculated for C ₁₇ H ₁₂ F ₃ N ₃ The Found: 316.1; Found: 316.2.

Example 78: 3-(6-(Trifluoromethyl)-1 H -indazol-4-yl)pyridin-2-amine

ESI-MS m / z [M + H] + for C ₁₃ H ₉ F ₃ N ₄ of the calculated value: 279.1; Found: 279.1.

Example 79: 4-(1,5-Dimethyl-1 H -pyrazol-4-yl)-6-(trifluoromethyl)-1 H -carbazole

The title compound was isolated as the free base. ESI-MS m / z [M + H] + for C ₁₃ H ₁₁ F ₃ N ₄ of the calculated value: 281.1; Found: 281.2.

Example 80: 3,5-Dimethyl-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)isoxazole

ESI-MS m / z [M + H] + calcd for C ₁₃ H ₁₀ F ₃ N ₃ O of: 282.1; Found: 282.1.

Example 81: 4-( 1H -indol-4-yl)-6-(trifluoromethyl)-1 H -carbazole

ESI-MS m / z [M + H] + calculated for C ₁₆ H ₁₀ F ₃ N ₃ The Found: 302.1; Found: 302.2.

Example 82: 1,3-Dimethyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyrimidine-2,4(1 H ,3 H )-dione

¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 3.30 (s, 3 H), 3.45 (s, 3 H), 7.48 (s, 1 H), 7.89 (s, 1 H), 8.17 (s, 1) H), 8.21 (s, 1 H), 13.55 (s, 1 H); ESI-MS m/z [M+H] ⁺ Calculated for C ₁₄ H ₁₁ F ₃ N ₄ O ₂ : 325.1; :325.2.

Example 83: 4-(3,5-Dimethyl-1 H -pyrazol-4-yl)-6-(trifluoromethyl)-1 H -carbazole

The title compound was isolated as the free base. ESI-MS m / z [M + H] + for C ₁₃ H ₁₁ F ₃ N ₄ of the calculated value: 281.1; Found: 281.2.

Example 84: (4-Methylpiperazin-1-yl)(3-(6-(trifluoromethyl)-1 H -indazol-4-yl)phenyl)methanone

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 2.96 (s, 3 H), 3.13 - 3.29 (m, 4 H), 3.33 - 3.44 (m, 1 H), 3.44 - 3.72 (m, 3 H), 7.48-7.51 (m, 1 H), 7.59-7.64 (m, 1 H), 7.69-7.75 (m, 1 H), 7.85-7.89 (m, 1 H), 7.91-7.96 (m, 2 H), 8.30 (d, J = 1.01Hz, 1 H); ESI-MS m / z [m + H] + for _{C 20 H 19 F 3 N 4} O of Calcd: 389.2; Found: 389.3.

Example 85: Pyrrolidin-1-yl (3-(6-(trifluoromethyl)-1 H -indazol-4-yl)phenyl)methanone

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.89-1.98 (m, 2 H), 1.98-2.08 (m, 2 H), 3.55 (t, J = 6.69 Hz, 2 H), 3.64 (t, J =6.95 Hz, 2 H), 7.47 (d, J = 1.01 Hz, 1 H), 7.62-7.70 (m, 2 H), 7.83-7.89 (m, 2 H), 7.92 (d, J = 0.76 Hz, 1 H), 8.31 (d, J = 1.01 Hz, 1 H); ESI-MS m/z (M+H) ⁺ Calculated for C ₁₉ H ₁₆ F ₃ N ₃ O: 360.1;

Example 86: 4-(2,5-Dimethoxyphenyl)-6-(trifluoromethyl)-1 H -carbazole

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 3.73 (s, 3 H), 3.81 (s, 3 H), 6.97 (d, J = 2.78 Hz, 1 H), 7.02 (dd, J = 8.84, 3.03) Hz, 1 H), 7.11 (d, J = 8.84 Hz, 1 H), 7.34 (d, J = 1.77 Hz, 1 H), 7.84 - 7.87 (m, 1 H), 7.92 (d, J = 1.01 Hz) , 1 H); ESI-MS m / z [m + H] + ₂ of the value calculated for _{C 16 H 13 F 3 N 2} O: 323.1; Found: 323.2.

Example 87: 4-(2,3-Dimethoxyphenyl)-6-(trifluoromethyl)-1 H -carbazole

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 3.49 (s, 3 H), 3.94 (s, 3 H), 7.04 (dd, J = 7.45, 1.64 Hz, 1 H), 7.16 (dd, J = 8.34) , 1.52 Hz, 1 H), 7.23 (dd, J = 8.34, 7.58 Hz, 1 H), 7.39 (d, J = 1.26 Hz, 1 H), 7.87-7.90 (m, 1 H), 7.97 (d, J = 0.76Hz, 1 H); ESI-MS m / z [m + H] + ₂ of the value calculated for _{C 16 H 13 F 3 N 2} O: 323.1; Found: 323.2.

Example 88: N -Ethyl-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzamide

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.20-1.33 (m, 3 H), 3.46 (q, J = 7.33 Hz, 2 H), 7.52-7.55 (m, 1 H), 7.65-7.70 (m) , 1 H), 7.91-7.94 (m, 2 H), 7.94-7.96 (m, 1 H), 8.17-8.21 (m, 1 H), 8.32 (d, J = 1.01 Hz, 1 H); MS m / z [m + H ] + calcd for _{C 17 H 14 F 3 N 3} O of: 334.1; Found: 334.2.

Example 89: 4-(5-(6-(Trifluoromethyl)-1 H -indazol-4-yl)pyridin-2-yl)morpholine

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 3.68-3.78 (m, 4 H), 3.86-3.94 (m, 4 H), 7.43 (dd, J = 9.35, 0.76 Hz, 1 H), 7.51 (d) , J = 1.01 Hz, 1 H), 7.93-7.99 (m, 1 H), 8.31 (d, J = 1.01 Hz, 1 H), 8.34 (dd, J = 9.35, 2.53 Hz, 1 H), 8.38 ( dd, J = 2.53,0.76Hz, 1 H ); ESI-MS m / z [m + H] + calcd for _{C 17 H 15 F 3 N 4} O of: 349.1; Found: 349.2.

Example 90: 2-(3-(6-(Trifluoromethyl)-1 H -indazol-4-yl)phenyl)acetonitrile

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 4.05 (s, 2 H), 7.45 (d, J = 1.01 Hz, 1 H), 7.48-7.53 (m, 1 H), 7.60 (t, J = 7.71) Hz, 1 H), 7.69-7.74 (m, 1 H), 7.74-7.77 (m, 1 H), 7.91 (s, 1 H), 8.28 (d, J = 1.01 Hz, 1 H); ESI-MS m / z [m + H] + calculated for C ₁₆ H ₁₀ F ₃ N ₃ the Found: 302.1; Found: 302.2.

Example 91: 4-(6-Methoxypyridin-2-yl)-6-(trifluoromethyl)-1 H -carbazole

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 4.08 (s, 3 H), 6.85 (d, J = 8.34 Hz, 1 H), 7.63 (d, J = 7.33 Hz, 1 H), 7.83 (t, J = 7.83 Hz, 1 H), 7.90 (s, 1 H), 7.94 (s, 1 H), 8.80 (s, 1 H); ESI-MS m/z [M+H] ⁺ for C ₁₄ H ₁₀ Calculated for F ₃ N ₃ O: 294.1; found: 294.2.

Example 92: 2-Fluoro- N -methyl-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzamide

The title compound was isolated as the free base. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 2.98 (s, 3 H), 7.52 (d, J = 1.01 Hz, 1 H), 7.62 (dd, J = 11.87, 1.52 Hz, 1 H), 7.69 ( Dd, J = 8.08, 1.77 Hz, 1 H), 7.91 - 7.95 (m, 1 H), 7.96 (s, 1 H), 8.31 (s, 1 H); ESI-MS m/z [M+H] ⁺ calculated for _{C 16 H 11 F 4 N 3} O of values: 338.1; Found: 338.2.

Example 93: 2-(2-(6-(Trifluoromethyl)-1 H -indazol-4-yl)phenoxy)acetonitrile

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 4.94 (s, 2 H), 7.27 (td, J = 7.45, 1.01 Hz, 1 H), 7.32 (dd, J = 8.34, 0.76 Hz, 1 H), 7.35 (d, J = 1.01 Hz, 1 H), 7.50 (dd, J = 7.58, 1.52 Hz, 1 H), 7.51-7.57 (m, 1 H), 7.89 (s, 1 H), 7.94 (d, J = 1.01Hz, 1 H); ESI-MS m / z [m + H] + calcd for _{C 16 H 10 F 3 N 3} O of: 318.1; Found: 318.2.

Example 94: 4-(5-(6-(Trifluoromethyl)-1 H -indazol-4-yl)pyrazin-2-yl)morpholine

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 3.68-3.74 (m, 4 H), 3.82-3.88 (m, 4 H), 7.79-7.83 (m, 1 H), 7.88 (s, 1 H), 8.43 (d, J = 1.52 Hz, 1 H), 8.68 (d, J = 1.01 Hz, 1 H), 8.78 (d, J = 1.52 Hz, 1 H); ESI-MS m/z [M+H] ⁺ calculated for _{C 16 H 14 F 3 N 5} O of values: 350.1; Found: 350.2.

Example 95: N- (4-(6-(Trifluoromethyl)-1 H -indazol-4-yl)benzyl)methanesulfonamide

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 2.92 (s, 3 H), 4.36 (s, 2 H), 7.40-7.46 (m, 1 H), 7.56-7.62 (m, 2 H), 7.72 7.79 (m, 2 H), 7.88 (s, 1 H), 8.26 (s, 1 H); ESI-MS m/z [M+H] ⁺ for C ₁₆ H ₁₄ F ₃ N ₃ O ₂ S Value: 370.1; found: 370.2.

Example 96: 4-(1-(Pyridin-3-ylmethyl)-1 H -pyrazol-4-yl)-6-(trifluoromethyl)-1 H -carbazole

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 5.67 (s, 2 H), 7.55 (dd, J = 1.26, 0.51 Hz, 1 H), 7.77-7.80 (m, 1 H), 7.84-7.91 (m , 1 H), 8.19 (d, J = 0.76 Hz, 1 H), 8.29-8.34 (m, 1 H), 8.45 (d, J = 1.01 Hz, 1 H), 8.54 (d, J = 0.76 Hz, 1 H), 8.72 (d, J = 5.05 Hz, 1 H), 8.77 (s, 1 H): ESI-MS m/z [M+H] ⁺ calculated for C ₁₇ H ₁₂ F ₃ N ₅ : 344.1; Found: 344.2.

Example 97: N -Methyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridinium

The title compound was isolated as the free base. ESI-MS m / z [M + H] + for C ₁₅ H ₁₁ F ₃ N ₄ O Calcd of: 321.1; Found: 321.2.

Example 98: 4-(2-(Cyclopentyloxy)pyridin-3-yl)-6-(trifluoromethyl)-1 H -carbazole

ESI-MS m / z [M + H] + calcd for _{C 18 H 16 F 3 N 3} O of: 348.1; Found: 348.2.

Example 99: 4-(2-(Benzyloxy)pyridin-3-yl)-6-(trifluoromethyl)-1 H -carbazole

ESI-MS m / z [M + H] + calcd for C ₂₀ H ₁₄ F ₃ N ₃ O of: 370.1; Found: 370.2.

Example 100: 4-(2-(2,2,2-Trifluoroethoxy)pyridin-3-yl)-6-(trifluoromethyl)-1 H -carbazole

ESI-MS m / z [M + H] + calcd for _{C 15 H 9 F 6 N 3} O of: 362.1; Found: 362.2.

Example 101: 5-(6-(Trifluoromethyl)-1 H -indazol-4-yl)quinoline

ESI-MS m / z [M + H] + calculated for C ₁₇ H ₁₀ F ₃ N ₃ The Found: 314.1; Found: 314.2.

Example 102: 4-Fluoro- N -methyl-2-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzamide

The title compound was isolated as the free base. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 2.48 (s, 2 H), 3.17 (d, J = 5.31 Hz, 1 H), 7.31 (s, 1 H), 7.33-7.49 (m, 2 H ), 7.61 (dd, J = 8.46, 5.94 Hz, 1 H), 7.93 (s, 1 H), 8.05 (s, 1 H), 8.32 (d, J = 4.55 Hz, 1 H), 13.64 (br s , 1 H); ESI-MS m / z [m + H] + calcd for _{C 16 H 11 F 4 N 3} O of: 338.1; Found: 338.2.

Example 103: 4-(3-(Methylsulfonyl)phenyl)-6-(trifluoromethyl)-1 H -carbazole

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 3.23 (s, 3 H), 7.54 (d, J = 1.26 Hz, 1 H), 7.82-7.88 (m, 1 H), 7.96-7.99 (m, 1 H), 8.08 (ddd, J = 7.89, 1.83, 1.14 Hz, 1 H), 8.12 (dq, J = 7.71, 0.97 Hz, 1 H), 8.27-8.31 (m, 2 H); ESI-MS m/ z [M ⁺ H] + for _{15 H 11 F 3 N 2 O} 2 S of the calculated values C: 341.0; Found: 341.2.

Example 104: N -Methyl-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzenesulfonamide

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 2.60 (s, 3 H), 7.51 (d, J = 1.01 Hz, 1 H), 7.75-7.83 (m, 1 H), 7.93-7.99 (m, 2) H), 8.03 (dq, J = 7.71, 0.97 Hz, 1 H), 8.17-8.21 (m, 1 H), 8.28 (d, J = 1.01 Hz, 1 H); ESI-MS m/z [M+ H) ⁺ calcd for C ₁₅ H ₁₂ F ₃ N ₃ O ₂ S: 356.1; found: 356.2.

Example 105: 4-(5-(Methylsulfonyl)pyridin-3-yl)-6-(trifluoromethyl)-1 H -carbazole

The title compound was isolated as the free base. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 3.33 (s, 3 H), 7.65 (d, J = 1.01 Hz, 1 H), 8.05 (d, J = 1.01 Hz, 1 H), 8.33 (d, J = 1.01 Hz, 1 H), 8.68 (t, J = 2.15 Hz, 1 H), 9.20 (d, J = 2.02 Hz, 1 H), 9.27 (d, J = 2.02 Hz, 1 H); ESI- MS m / z [m + H ] + for _{C 14 H 10 F 3 N 3} O ₂ S calculated sum value: 342.0; Found: 342.1.

Example 106: 2-(3-(6-(Trifluoromethyl)-1 H -indazol-4-yl)phenyl)ethanol

The title compound was isolated as the free base. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 2.95 (t, J = 6.82 Hz, 2 H), 3.85 (t, J = 6.69 Hz, 2 H), 7.37 (d, J = 7.33 Hz, 1 H) , 7.43 (s, 1 H), 7.49 (t, J = 7.58 Hz, 1 H), 7.55-7.60 (m, 1 H), 7.62 (s, 1 H), 7.87 (s, 1 H), 8.26 ( s, 1 H); ESI- MS m / z [m + H] + for _{C 16 H 13 F 3 N 2} O of Calcd: 307.1; Found: 307.2.

Example 107: 5-(6-(Trifluoromethyl)-1 H -indazol-4-yl)benzo[ d ]thiazole

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 7.55 (d, J = 1.01 Hz, 1 H), 7.87-7.92 (m, 1 H), 7.92-7.96 (m, 1 H), 8.27 (dd, J =8.34, 0.51 Hz, 1 H), 8.32 (d, J = 1.01 Hz, 1 H), 8.42 (dd, J = 1.77, 0.51 Hz, 1 H), 9.36 (s, 1 H); ESI-MS m / z [M ⁺ H] + calcd for _{C 15 H 8 F 3 N 3} S 's: 320.0; Found: 320.1.

Example 108: N , N -Dimethyl-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzenesulfonamide

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 2.76 (s, 6 H), 7.48-7.51 (m, 1 H), 7.80-7.87 (m, 1 H), 7.89-7.94 (m, 1 H), 7.96-7.99 (m, 1 H), 8.05-8.10 (m, 2 H), 8.25 (d, J = 1.01 Hz, 1 H); ESI-MS m/z [M+H] ⁺ for C ₁₆ H ₁₄ F ₃ N ₃ O ₂ S Calcd of: 370.1; Found: 370.2.

Example 109: 2-Fluoro- N- (2-hydroxyethyl)-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzamide

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 3.57 (t, J = 5.81 Hz, 2 H), 3.75 (t, J = 5.81 Hz, 2 H), 7.52 (d, J = 1.01 Hz, 1 H) , 7.62 (dd, J = 11.75, 1.64 Hz, 1 H), 7.69 (dd, J = 7.96, 1.64 Hz, 1 H), 7.94 - 8.00 (m, 2 H), 8.31 (d, J = 1.01 Hz, 1 H); ESI-MS m / z [m + H] + for _{C 17 H 13 F 4 N 3} O ₂ calculated sum value: 368.1; Found: 368.2.

Example 110: 2-Fluoro-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzamide

The title compound was isolated as the free base. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 7.44 (dd, J = 10.61, 8.59 Hz, 1 H), 7.48 (d, J = 1.26 Hz, 1 H), 7.93 (s, 1 H), 7.93 7.97 (m, 1 H), 8.17 (dd, J = 6.95, 2.40 Hz, 1 H), 8.31 (d, J = 1.01 Hz, 1 H); ESI-MS m/z [M+H] ⁺ for C ₁₅ H ₉ F ₄ N ₃ O of Calcd: 324.1; Found: 324.2.

Example 111: 4-(6-(Trifluoromethyl)-1 H -indazol-4-yl)isoquinoline

The title compound was isolated as the free base. ESI-MS m / z [M + H] + calculated for C ₁₇ H ₁₀ F ₃ N ₃ The Found: 314.1; Found: 314.2.

Example 112: 4-(6-(Trifluoromethyl)-1 H -indazol-4-yl)quinoline

ESI-MS m / z [M + H] + calculated for C ₁₇ H ₁₀ F ₃ N ₃ The Found: 314.1; Found: 314.2.

Example 113: 8-Methoxy-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)quinoline

¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 4.11 (s, 3 H), 7.34-7.51 (m, 2 H), 7.63 (dd, J = 8.46, 4.17 Hz, 1 H), 7.69-7.86 ( m, 2 H), 8.06 (s, 1 H), 8.12 (d, J = 8.59 Hz, 1 H), 8.91-9.06 (m, 1 H); ESI-MS m/z [M+H] ⁺ _{C 18 H 12 F 3 N 3} O of Calcd: 344.1; Found: 344.2.

Example 114: 4-Fluoro- N -methyl-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzamide

ESI-MS m / z [M + H] + calcd for C ₁₆ H ₁₁ F ₄ N ₃ O of: 338.1; Found: 338.2.

Example 115: 3-Fluoro- N , N -dimethyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzamide

¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 3.01 (d, J = 13.39 Hz, 6 H), 7.41 (d, J = 9.09 Hz, 1 H), 7.57 (s, 1 H), 7.64 (s) , 1 H), 7.74 (d, J = 9.35 Hz, 1 H), 8.01 (s, 1 H), 8.36 (s, 1 H), 13.80 (s, 1 H); ESI-MS m/z [M + H] ⁺ calcd for _{C 17 H 13 F 4 N 3} O of: 352.1; Found: 352.2.

Example 116: 4-(2-(Pyrrolidin-1-yl)pyrimidin-5-yl)-6-(trifluoromethyl)-1 H -carbazole

ESI-MS m / z [M + H] + calculated for C ₁₆ H ₁₄ F ₃ N ₅ The Found: 334.1; Found: 334.2.

Example 117: N -Methyl-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzamide

¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 2.83 (d, J = 4.55 Hz, 3 H), 7.54 (s, 1 H), 7.90 (d, J = 8.34 Hz, 2 H), 7.98 (s , 1 H), 8.03 (d, J = 8.08 Hz, 2 H), 8.37 (s, 1 H), 13.76 (s, 1 H); ESI-MS m/z [M+H] ⁺ for C ₁₆ H Calculated for ₁₂ F ₃ N ₃ O: 320.1; found: 320.2.

Example 118: 4-(5-(6-(Trifluoromethyl)-1 H -indazol-4-yl)pyrimidin-2-yl)morpholine

ESI-MS m / z [M + H] + calcd for C ₁₆ H ₁₄ F ₃ N ₅ O of: 350.1; Found: 350.3.

Example 119: N , N -Dimethyl-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzamide

ESI-MS m / z [M + H] + calcd for C ₁₇ H ₁₄ F ₃ N ₃ O of: 334.1; Found: 334.2.

Example 120: 2-Methyl-5-(4-(6-(trifluoromethyl)-1 H -indazol-4-yl)phenyl)-1,3,4-oxadiazole

ESI-MS m / z [M + H] + for C ₁₇ H ₁₁ F ₃ N ₄ O Calcd of: 345.1; Found: 345.2.

Example 121: N , N -Dimethyl-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzamide

ESI-MS m / z [M + H] + calcd for C ₁₇ H ₁₄ F ₃ N ₃ O of: 334.1; Found: 334.2.

Example 122: 4-Methyl-7-(6-(trifluoromethyl)-1 H -indazol-4-yl)-3,4-dihydro- 2H -pyrido[3,2- b ] [1,4]oxazine

ESI-MS m / z [M + H] + ₃ N calcd for C ₁₆ H ₁₃ F ₄ O of: 335.1; Found: 335.2.

Example 123: 4-(2-Methoxy-4-methylpyridin-3-yl)-6-(trifluoromethyl)-1 H -carbazole

ESI-MS m / z [M + H] + calcd for C ₁₅ H ₁₂ F ₃ N ₃ O of: 308.1; Found: 308.2.

Example 124: 4-(3-Chloro-2-methoxypyridin-4-yl)-6-(trifluoromethyl)-1 H -carbazole

ESI-MS m / z [M + H] + calcd for C ₁₄ H ₉ ClF ₃ N ₃ O of: 328.1; Found: 328.1.

Example 125: N , N ,3-Trimethyl-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzenesulfonamide

¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 2.26 (s, 3 H), 2.70 (s, 6 H), 7.35 (s, 1 H), 7.58-7.65 (m, 1 H), 7.66-7.73 (m, 1 H), 7.79 (s, 1 H), 7.96 (s, 1 H), 8.01 (s, 1 H), 13.75 (s, 1 H); ESI-MS m/z [M+H] ⁺ for _{C 17 H 16 F 3 N 3} O ₂ S calculated sum value: 384.1; Found: 384.2.

Example 126: 4-(1,3-Dimethyl-1 H -pyrazol-5-yl)-6-(trifluoromethyl)-1 H -carbazole

ESI-MS m / z [M + H] + for C ₁₃ H ₁₁ F ₃ N ₄ of the calculated value: 281.1; Found: 281.2.

Example 127: N , N ,4-Trimethyl-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzenesulfonamide

ESI-MS m / z [M + H] + for _{C 17 H 16 F 3 N 3} O ₂ S calculated sum value: 384.1; Found: 384.2.

Example 128: (4-Chloro-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)phenyl)methanol

ESI-MS m / z [M + H] + for _{C 15 H 10 ClF 3 N 2} O of Calcd: 327.0; Found: 327.1.

Example 129: 4-(6-(Trifluoromethyl)-1 H -indazol-4-yl)porphyrin-2-one

4-Bromo-6-(trifluoromethyl)-1 H -indazole (0.026 g, 0.096 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxo dioxaborolan-2-yl) indol-2-one (0.025g, 0.096mmol), and _{PdCl 2 (dppf) (3.53mg,} 4.82μmol) in dioxane (4mL) and saturated aqueous NaHCO (3mL) ₃ The mixture is filled in a vial. The resulting light brown suspension was heated in a microwave reactor at 140 °C for 45 minutes. The reaction mixture was then concentrated, and the crude residue was purified by containing 30% ACN (containing 0.035% TFA) of H ₂ O (containing 0.05% TFA) was purified by preparative HPLC 10 minutes of fractions. The product-containing fractions were combined and evaporated EtOAcjjjjjjjjjj ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 3.50 (s, 2 H), 6.94 (d, J = 7.58 Hz, 1 H), 7.17 (dd, J = 7.96, 0.88 Hz, 1 H), 7.29 -7.44 (m, 1 H), 7.46-7.53 (m, 1 H), 7.94 (s, 1 H), 8.15 (s, 1 H), 10.55 (s, 1 H), 13.70 (s, 1 H) ; ESI-MS m / z [ m + H] + calcd for C ₁₆ H ₁₀ F ₃ N ₃ O of: 318.1; Found: 318.15.

Example 130: N- (2-Hydroxyethyl)-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzamide

Using 4-bromo-6-(trifluoromethyl)-1 H -carbazole (0.300 g, 1.132 mmol), (4-((2-hydroxyethyl)amine-carbamoyl)phenyl)boronic acid (0.237 g) , 1.132mmol), and _{PdCl 2 (dppf) (0.041g,} 0.057mmol) in a mixture of _aqueous solution (3mL) in dioxane (10 mL) and saturated NaHCO filled vial. The resulting yellow suspension was heated in a microwave reactor at 140 ° C for 60 minutes. The reaction mixture was then concentrated and the crude residue was purified by preparative HPLC eluting with &_lt;RTIgt;&lt;/RTI&gt;&gt_;< / RTI></RTI> with 40% ACN (containing 0.035% TFA) in H2O (containing 0.05% TFA) over a period of 4.5 minutes. The title compound was obtained as a white solid. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 3.56 (t, J = 5.81 Hz, 2 H), 3.75 (t, J = 5.81 Hz, 2 H), 7.49 (d, J = 1.01 Hz, 1 H) , 7.78-7.89 (m, 2 H), 7.93 (s, 1 H), 8.00-8.10 (m, 2 H), 8.21-8.32 (m, 1 H); ESI-MS m/z [M+H] ⁺ for _{C 17 H 14 F 3 N 3} O ₂ calculated values of: 350.1: Found: 350.1.

Example 131: 4-(2,4-Dimethoxypyrimidin-5-yl)-6-(trifluoromethyl)-1 H -carbazole

4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)-1 H -indazole (35 mg, 0.112 mmol), 5-bromo-2,4-dimethoxypyrimidine (24.56 mg, 0.112 mmol) and PdCl ₂ (dppf) (8.21 mg, 0.011 mmol) were dissolved in dioxane (1.5 mL). A 2N aqueous sodium carbonate solution (0.112 mL, 0.224 mmol) was added to the obtained slurry. The mixture was purged with nitrogen and heated in a microwave reactor at 130 ° C for 50 minutes, followed by filtration through a microfilter frit. The dioxane was stripped with nitrogen. The resulting residue was taken up in DMSO and methanol (1: 1), and the via containing ACN (containing 0.035% TFA) gradient of H ₂ O (containing 0.05% TFA) and purified by preparative HPLC eluting in. The purified fractions were collected to give the title compound <RTI ID=0.0> ESI-MS m / z [M + H] + for _{C 14 H 11 F 3 N 4} O ₂ computing the values: 325.1; Found: 325.2.

Example 132: 4-(2,4-Dimethoxypyrimidin-5-yl)-6-(trifluoromethyl)-1 H -indazole

4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)-1 H -indazole (100 mg, 0.320 mmol), 5-iodo-2,4-dimethoxypyrimidine (57 mg, 0.215 mmol) and PdCl ₂ (dppf) (23 mg, 0.032 mmol) were dissolved in dioxane (3 mL). A 2N aqueous sodium carbonate solution (0.320 mL, 0.641 mmol) was added to the obtained slurry. The mixture was heated in a microwave reactor at 130 ° C for 1 hour, then filtered through a microfiltration frit and the microfiltration frit was rinsed with methanol. Removed the solvent in vacuo and the resulting residue was taken up in DMSO and methanol (1: 1), and the via with 40% to 45% ACN (containing 0.1% formic acid) gradient of H ₂ O (containing 0.1% formic acid Purification by preparative HPLC with dissolution. The purified fractions were collected to give the title compound (33.5 mg, 32.2%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 3.95 (s, 3 H), 4.00 (s, 3 H), 7.43 (s, 1 H), 7.95 (s, 1 H), 8.12 (s, 1) H), 8.52 (s, 1 H), 13.64 (br s, 1 H); ESI-MS m/z [M+H] ⁺ Calculated for C ₁₄ H ₁₁ F ₃ N ₄ O ₂ : 325.1; Value: 325.2.

The compounds of Examples 133 through 244 below were prepared according to Scheme C using procedures analogous to those in Example 131.

Reaction conditions: 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)-1 H -indazole ( C-1) (19 mg to 40 mg, 0.061 mmol to 0.128 mmol), halide (C-2, X = Br, Cl or I) (0.67 to 1.5 equivalents), PdCl ₂ (dppf) or PdCl ₂ (dppf) CH ₂ Cl ₂ (0.1 eq.), aqueous Na ₂ CO ₃ (2N, 2 to 4 equivalents), dioxane (1.5 mL to 2.0 mL) at 130 ° C to 135 ° C for 30 to 60 minutes (Examples 144 to 158) The exception is 90 ° C for 60 minutes). Unless otherwise stated, the title compound was isolated as the TFA salt.

Example 133: 4-(2-ethoxypyridin-3-yl)-6-(trifluoromethyl)-1 H -carbazole

¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.20 (t, J = 6.95 Hz, 3 H), 4.38 (q, J = 6.99 Hz, 2 H), 7.16 (dd, J = 7.33, 5.05 Hz, 1 H), 7.46 (s, 1 H), 7.88-7.99 (m, 2 H), 8.07 (s, 1 H), 8.28 (dd, J = 4.93, 1.89 Hz, 1 H), 13.61 (br s, 1 H); ESI-MS m / z [m + H] + calcd for C ₁₅ H ₁₂ F ₃ N ₃ O of: 308.1; Found: 308.2.

Example 134: 4-(2-propoxypyridin-3-yl)-6-(trifluoromethyl)-1 H -carbazole

¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 0.83 (t, J = 7.33 Hz, 3 H), 1.60 (q, J = 6.82 Hz, 2 H), 4.28 (t, J = 6.44 Hz, 2 H ), 7.16 (dd, J = 7.33, 5.05 Hz, 1 H), 7.48 (s, 1 H), 7.89-8.00 (m, 2 H), 8.08 (s, 1 H), 8.28 (dd, J = 4.80) , 1.77Hz, 1 H), 13.63 (s, 1 H); ESI-MS m / z [m + H] + calcd for C ₁₆ H ₁₄ F ₃ N ₃ O of: 322.1; Found: 322.2.

Example 135: 4-(3-Methylpyridin-2-yl)-6-(trifluoromethyl)-1 H -carbazole

¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 2.28 (s, 3 H), 7.48 (s, 1 H), 7.49-7.56 (m, 1 H), 7.94 (d, J = 7.58 Hz, 1 H ), 8.03 (s, 2 H), 8.62 (d, J = 4.29 Hz, 1 H); ESI-MS m/z [M+H] ⁺ Calculated for C ₁₄ H ₁₀ F ₃ N ₃ : 278.1; Found: 278.2.

Example 136: 7-(6-(Trifluoromethyl)-1 H -indazol-4-yl)porphyrin-2-one

ESI-MS m / z [M + H] + calcd for C ₁₆ H ₁₀ F ₃ N ₃ O of: 318.1; Found: 318.2.

Example 137: 5-Chloro-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridin-2-amine

ESI-MS m / z [M + H] + for C ₁₃ H ₈ ClF ₃ N ₄ of the calculated value: 313.0; Found: 313.1.

Example 138: 4-Methoxy-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyrimidin-2-amine

ESI-MS m / z [M + H] + calcd for C ₁₃ H ₁₀ F ₃ N ₅ O of: 310.1; Found: 310.2.

Example 139: 8-(6-(Trifluoromethyl)-1 H -indazol-4-yl)-2 H -benzo[ b ][1,4]oxazin-3( 4H )-one

ESI-MS m / z [M + H] + for _{C 16 H 10 F 3 N 3} O ₂ calculated sum value: 334.1; Found: 334.2.

Example 140: 4-(Hydroxymethyl)-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzonitrile

^{1 H NMR (400MHz, DMSO- d} 6) δ ppm 4.36 (s, 2 H), 7.39 (s, 1 H), 7.83-7.92 (m, 2 H), 7.93-8.06 (m, 3 H), 13.76 (br s, 1 H); ESI-MS m / z [m + H] + calcd for _{C 16 H 10 F 3 N 3} O of: 318.1; Found: 318.2.

Example 141: 4-(6-(Trifluoromethyl)-1 H -indazol-4-yl)isoindolin-1-one

¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 4.41 (s, 2 H), 7.59 (s, 1 H), 7.64-7.75 (m, 1 H), 7.77-7.89 (m, 2 H), 8.00 (s, 1 H), 8.16 (s, 1 H), 8.67 (s, 1 H), 13.76 (s, 1 H); ESI-MS m/z [M+H] ⁺ for C ₁₆ H ₁₀ F ₃ Calculated for N ₃ O: 318.1; found: 318.2.

Example 142: 5-(6-(Trifluoromethyl)-1 H -indazol-4-yl)-1,7-naphthyridin-8-amine

ESI-MS m / z [M + H] + calculated for C ₁₆ H ₁₀ F ₃ N ₅ The Found: 330.1; Found: 330.2.

Example 143: 4-(2-Isopropoxypyridin-3-yl)-6-(trifluoromethyl)-1 H -indazole

ESI-MS m / z [M + H] + calcd for C ₁₆ H ₁₄ F ₃ N ₃ O of: 322.1; Found: 322.2.

Example 144: 1-Methyl-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1H-pyrazol-3-amine

ESI-MS m / z [M + H] + calculated for C ₁₂ H ₁₀ F ₃ N ₅ The Found: 282.1; Found: 282.1.

Example 145: 4-(1-(Ethoxymethyl)-1 H -imidazol-2-yl)-6-(trifluoromethyl)-1 H -carbazole

ESI-MS m / z [M + H] + ₃ N calcd for C ₁₄ H ₁₃ F ₄ O of: 311.1; Found: 311.2.

Example 146: 4-(1,2-Dimethyl-1 H -imidazol-5-yl)-6-(trifluoromethyl)-1 H -indazole

^{1 H NMR (400MHz, DMSO- d} 6) δ ppm 2.70 (s, 3 H), 3.63 (s, 3 H), 7.56 (s, 1 H), 7.97 (s, 1 H), 8.17 (s, 1 H), 8.30 (s, 1 H): ESI-MS m / z [m + H] + for C ₁₃ H ₁₁ F ₃ N ₄ of the calculated value: 281.1; Found: 281.2.

Example 147: 4-(1-Methyl-1 H -imidazol-2-yl)-6-(trifluoromethyl)-1 H -carbazole

ESI-MS m / z [M + H] + for C ₁₂ H ₉ F ₃ N ₄ calculates the values: 267.1; Found: 267.2.

Example 148: 4-(6-(Trifluoromethyl)-1 H -indazol-4-yl)-1 H -pyrazole-3-carbonitrile

ESI-MS m / z [M + H] + calculated for C ₁₂ H ₆ F ₃ N ₅ The Found: 278.1; Found: 278.2.

Example 149: 4-(Imidazo[1,2- a ]pyridin-3-yl)-6-(trifluoromethyl)-1 H -carbazole

ESI-MS m / z [M + H] + for C ₁₅ H ₉ F ₃ N ₄ of the calculated value: 303.1; Found: 303.2.

Example 150: 4-(2-Methylimidazo[1,2- a ]pyridin-3-yl)-6-(trifluoromethyl)-1 H -indazole

ESI-MS m / z [M + H] + for C ₁₆ H ₁₁ F ₃ N ₄ of the calculated value: 317.1; Found: 317.2.

Example 151: 3-(6-(Trifluoromethyl)-1 H -indazol-4-yl)imidazo[1,2- a ]pyrimidine

ESI-MS m / z [M + H] + calculated for C ₁₄ H ₈ F ₃ N ₅ The Found: 304.1; Found: 304.2.

Example 152: 3-(6-(Trifluoromethyl)-1 H -indazol-4-yl)imidazo[1,2- a ]pyrazine

¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.74 (s, 1 H), 8.1 (d, J = 4.80 Hz, 1 H), 8.10 (s, 1 H), 8.25 (s, 1 H), 8.32(s,1 H), 8.49 (dd, J = 4.80, 1.26 Hz, 1H), 9.26 (d, J = 1.26 Hz, 1 H); ESI-MS m/z [M+H] ⁺ for C ₁₄ Calculated for H ₈ F ₃ N ₅ : 304.1; found: 304.2.

Example 153: 3-(6-(Trifluoromethyl)-1 H -indazol-4-yl)imidazo[1,2- a ]pyridine-6-carbonitrile

ESI-MS m / z [M + H] + calculated for C ₁₆ H ₈ F ₃ N ₅ The Found: 328.1; Found: 328.2.

Example 154: 4-(Imidazo[1,5- a ]pyridin-1-yl)-6-(trifluoromethyl)-1 H -carbazole

¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 6.86 (t, J = 6.69 Hz, 1 H), 7.08 (dd, J = 9.09, 6.32 Hz, 1 H), 7.62 (s, 1 H), 7.81 (s, 1 H), 7.90 (d, J = 9.09 Hz, 1 H), 8.51 (d, J = 7.07 Hz, 1 H), 8.70 (d, J = 8.08 Hz, 2 H); ESI-MS m / z [M ⁺ H] + for C ₁₅ H ₉ F ₃ N ₄ of the calculated value: 303.1; Found: 303.2.

Example 155: 5-(6-(Trifluoromethyl)-1 H -indazol-4-yl)-7 H -pyrrolo[2,3- d ]pyrimidine

ESI-MS m / z [M + H] + calculated for C ₁₄ H ₈ F ₃ N ₅ The Found: 304.1; Found: 304.1.

Example 156: 3-(6-(Trifluoromethyl)-1 H -indazol-4-yl)-1 H -pyrazolo[3,4- d ]pyrimidin-4( 5H )-one

ESI-MS m / z [M + H] + calcd for _{C 13 H 7 F 3 N 6} O 's: 321.1; Found: 321.2.

Example 157: 7-(6-(Trifluoromethyl)-1 H -indazol-4-yl)-5 H -pyrrolo[2,3- b ]pyrazine

ESI-MS m / z [M + H] + calculated for C ₁₄ H ₈ F ₃ N ₅ The Found: 304.1; Found: 304.2.

Example 158: 4-(6-(Trifluoromethyl)-1 H -indazol-4-yl)-1 H -pyrazole-5-carbonitrile

ESI-MS m / z [M + H] + calculated for C ₁₂ H ₆ F ₃ N ₅ The Found: 278.1; Found: 278.1.

Example 159: 7-Amino-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyrazolo[1,5- a ]pyrimidine-6-carbonitrile

ESI-MS m / z [M + H] + for C ₁₅ H ₈ F ₃ N ₇ of calculated value: 344.1; Found: 344.1.

Example 160: 7-Methoxy-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)imidazo[1,2- a ]pyridine-8-carbonitrile

ESI-MS m / z [M + H] + calcd for C ₁₇ H ₁₀ F ₃ N ₅ O of: 358.1; Found: 358.2.

Example 161: 4-(5-Methyl-1 H -imidazol-4-yl)-6-(trifluoromethyl)-1 H -carbazole

ESI-MS m / z [M + H] + for C ₁₂ H ₉ F ₃ N ₄ of the calculated value: 267.1; Found: 267.1.

Example 162: 4-(1,5-Dimethyl-1 H -imidazol-2-yl)-6-(trifluoromethyl)-1 H -carbazole

ESI-MS m / z [M + H] + for C ₁₃ H ₁₁ F ₃ N ₄ calculates the values: 281.1; Found: 281.1.

Example 163: 4-(1,4-Dimethyl-1 H -imidazol-2-yl)-6-(trifluoromethyl)-1 H -carbazole

ESI-MS m / z [M + H] + for C ₁₃ H ₁₁ F ₃ N ₄ of the calculated value: 281.1; Found: 281.1.

Example 164: 6-(Trifluoromethyl)-4-(1,3,5-trimethyl-1 H -pyrazol-4-yl)-1 H -carbazole

ESI-MS m / z [M + H] + calculated for ₃ N ₄ values of C ₁₄ H ₁₃ F: 295.1; Found: 295.2.

Example 165: 1-Methyl-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1H-pyrazole-5-amine

ESI-MS m / z [M + H] + calculated for C ₁₂ H ₁₀ F ₃ N ₅ The Found: 282.1; Found: 282.1.

Example 166: 5-Methyl-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)isoxazole-3-amine

ESI-MS m / z [M + H] + calcd for _{C 12 H 9 F 3 N 4} O of: 283.1; Found: 283.1.

Example 167: 3,7-dimethyl-8- (6- (trifluoromethyl) -1 H - indazol-4-yl) -1 H - purine -2,6 (3 H, 7 H) - Diketone

ESI-MS m / z [M + H] + calculated for C N ₆ O ₂ value of ₁₅ H ₁₁ F _3: 365.1; Found: 365.2.

Example 168: 4-(1-Ethyl-3,5-dimethyl-1 H -pyrazol-4-yl)-6-(trifluoromethyl)-1 H -carbazole

¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.37 (t, J = 7.20 Hz, 3 H), 2.09 (s, 3 H), 2.19 (s, 3 H), 4.08 (q, J = 7.07 Hz) , 2 H), 7.14 (s, 1 H), 7.85 (s, 1 H), 8.00 (s, 1 H); ESI-MS m/z [M+H] ⁺ for C ₁₅ H ₁₅ F ₃ N ₄ Calculated value: 309.1; found: 309.3.

Example 169: 4-(3,5-Dimethyl-1-(1 H -tetrazol-5-yl)-1 H -pyrazol-4-yl)-6-(trifluoromethyl)-1 H -carbazole

ESI-MS m / z [M + H] + for C ₁₄ H ₁₁ F ₃ N ₈ calculates the values: 349.1; Found: 349.2.

Example 170: 2-(3,5-Dimethyl-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1 H -pyrazol-1-yl)acetonitrile

ESI-MS m / z [M + H] + for C ₁₅ H ₁₂ F ₃ N ₅ calculates the values: 320.1; Found: 320.1.

Example 171: 4-(1-Ethyl-3-methyl-1 H -pyrazol-4-yl)-6-(trifluoromethyl)-1 H -carbazole

ESI-MS m / z [M + H] + calculated for ₃ N ₄ values of C ₁₄ H ₁₃ F: 295.1; Found: 295.2.

Example 172: 3-(3,5-Dimethyl-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1 H -pyrazol-1-yl)propanamide

ESI-MS m / z [M + H] + calcd for C ₁₆ H ₁₆ F ₃ N ₅ O of: 352.1; Found: 352.1.

Example 173: 2-(3,5-Dimethyl-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1 H -pyrazol-1-yl)acetamide

¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 2.09 (s, 3 H), 2.14 (s, 3 H), 4.73 (s, 2 H), 7.15 (d, J = 1.01 Hz, 1 H), 7.30 (s, 1 H), 7.52 (br s, 1 H), 7.87 (s, 1 H), 7.98 (d, J = 1.01 Hz, 1 H); ESI-MS m/z [M+H] ⁺ Calcd for C ₁₅ H ₁₄ F ₃ N ₅ O: 338.1; found: 338.2.

Example 174: 3-(3,5-Dimethyl-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1 H -pyrazol-1-yl)propanenitrile

¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 2.11 (s, 3 H), 2.23 (s, 3 H), 3.08 (t, J = 6.44 Hz, 2 H), 4.36 (t, J = 6.44 Hz , 2 H), 7.16 (s, 1 H), 7.88 (s, 1 H), 7.97 (s, 1 H); ESI-MS m/z [M+H] ⁺ for C ₁₆ H ₁₄ F ₃ N ₅ Calculated: 334.1; found: 334.1.

Example 175: 4-(1-Ethyl-5-methyl-1 H -pyrazol-4-yl)-6-(trifluoromethyl)-1 H -carbazole

ESI-MS m / z [M + H] + calculated for ₃ N ₄ values of C ₁₄ H ₁₃ F: 295.1; Found: 295.1.

Example 176: 2-(3,5-Dimethyl-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1 H -pyrazol-1-yl)ethylamine

¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 2.09-2.16 (m, 3 H), 2.17-2.24 (m, 3 H), 3.27-3.36 (m, 2 H), 4.28 (t, J = 6.19) Hz, 2 H), 7.15 (s, 1 H), 7.89 (s, 1H), 7.93 (br s, 2 H), 8.03 (s, 1 H), 13.64 (br s, 1 H); ESI-MS m / z [m + H] + for C ₁₅ H ₁₆ F ₃ N ₅ calculates the values: 324.1; Found: 324.1.

Example 177: 4-Methyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)thiazole

ESI-MS m / z [M + H] + calcd for C ₁₂ H ₈ F ₃ N ₃ S's: 284.1; Found: 284.1.

Example 178: N- (6-Methyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridin-2-yl)acetamide

¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 2.13 (s, 3 H), 2.31 (s, 3 H), 7.33 (s, 1 H), 7.77 (d, J = 8.59 Hz, 1 H), 7.99 (d, J = 13.89 Hz, 2 H), 8.07 (d, J = 8.34 Hz, 1 H), 10.66 (s, 1 H); ESI-MS m/z [M+H] ⁺ for C ₁₆ H Calculated for ₁₃ F ₃ N ₄ O: 335.1; found: 335.2.

Example 179: N- (4-Methyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridin-2-yl)acetamide

ESI-MS m / z [M + H] + ₃ N calcd for C ₁₆ H ₁₃ F ₄ O of: 335.1; Found: 335.2.

Example 180: 1-(N-morpholinyl)-3-(2-(6-(trifluoromethyl)-1 H -indazol-4-yl)phenoxy)propan-2-ol

ESI-MS m / z [M + H] + calculated for F _{3 3} O ₃ value of C ₂₁ H ₂₂ N: 422.2; Found: 422.3.

Example 181: 4-Methoxy- N -methyl-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzamide

¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 2.78 (d, J = 4.29 Hz, 3 H), 3.82 (s, 3 H), 7.30 (d, J = 8.84 Hz, 1 H), 7.38 (s) , 1 H), 7.88-8.05 (m, 4 H), 8.41 (d, J = 4.55 Hz, 1 H), 13.59 (s, 1 H); ESI-MS m/z [M+H] ⁺ for C ₁₇ H ₁₄ F ₃ N ₃ O ₂ calculated sum value: 350.1; Found: 350.2.

Example 182: 2-(2-(6-(Trifluoromethyl)-1 H -indazol-4-yl)phenylsulfonyl)ethanol

¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 3.54 (t, J = 6.19 Hz, 2 H), 3.57 - 3.62 (m, 2 H), 7.43 (s, 1 H), 7.53 (dd, J = 7.33, 1.26 Hz, 1 H), 7.72-7.89 (m, 3 H), 8.01 (s, 1 H), 8.15 (dd, J = 7.71, 1.14 Hz, 1 H); ESI-MS m/z [M + H] ⁺ for ₃ N ₂ O ₃ S Calcd of C ₁₆ H ₁₃ F: 371.1; Found: 371.1.

Example 183: N , N -Dimethyl-2-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzenesulfonamide

ESI-MS m / z [M + H] + for _{C 16 H 14 F 3 N 3} O ₂ S calculated sum value: 370.1; Found: 370.2.

Example 184: 6-Methoxy-2-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridin-3-amine

ESI-MS m / z [M + H] + for C ₁₄ H ₁₁ F ₃ N ₄ O Calcd of: 309.1; Found: 309.2.

Example 185: (4-Methoxy-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)phenyl)methanol

ESI-MS m / z [M + H] + ₂ of the value calculated for _{C 16 H 13 F 3 N 2} O: 323.1; Found: 323.2.

Example 186: 3-Methyl-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzenesulfonamide

ESI-MS m / z [M + H] + for C ₁₅ H ₁₂ F ₃ N ₃ O ₂ S calculated values of: 356.1; Found: 356.1.

Example 187: 6-Methoxy-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridin-3-amine

ESI-MS m / z [M + H] + for C ₁₄ H ₁₁ F ₃ N ₄ O Calcd of: 309.1; Found: 309.1.

Example 188: 6-Methyl-2-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridin-3-amine

ESI-MS m / z [M + H] + for C ₁₄ H ₁₁ F ₃ N ₄ of the calculated value: 293.1; Found: 293.1.

Example 189: (5-Methoxy-2-(6-(trifluoromethyl)-1 H -indazol-4-yl)phenyl)methanol

ESI-MS m / z [M + H] + ₂ of the value calculated for _{C 16 H 13 F 3 N 2} O: 323.1; Found: 323.1.

Example 190: 4,6-Dimethyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyrimidin-2-amine

¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 2.00 (s, 6 H), 7.31 (s, 1 H), 7.98 (d, J = 10.11 Hz, 2 H), 8.03 (s, 1 H); ESI-MS m / z [m + H] + calculated for C _{14 3} N ₅ value of H ₁₂ F: 308.1; Found: 308.2.

Example 191: 2-Chloro-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyrimidine-4-amine

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 7.42 (d, J = 1.01 Hz, 1 H), 7.99 (s, 1 H), 8.03-8.09 (m, 2 H); ESI-MS m/z [ M ⁺ H] + calculated C ₁₂ H ₇ ClF ₃ N ₅ the values for: 314.0; Found: 314.09.

Example 192: 5-(6-(Trifluoromethyl)-1 H -indazol-4-yl)pyrimidine-4-carboxylic acid

¹ H NMR (400 MHz, CD ₃ OD) δ ppm 7.43 (d, J = 1.01 Hz, 1 H), 7.94-8.11 (m, 2 H), 9.10 (s, 1 H), 9.35 (s, 1 H) ; ESI-MS m / z [ m + H] + for _{C 13 H 7 F 3 N 4} O ₂ computing the values: 309.1; Found: 309.12.

Example 193: 5-Methyl-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridin-2-amine

ESI-MS m / z [M + H] + for C ₁₄ H ₁₁ F ₃ N ₄ of the calculated value: 293.1; Found: 293.2.

Example 194: 5-Fluoro-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridin-2-amine

ESI-MS m / z [M + H] + for C ₁₃ H ₈ F ₄ N ₄ calculates the values: 297.1; Found: 297.2.

Example 195: 5-Methyl-6- (6- (trifluoromethyl) -1 H - indazol-4-yl) -3 H - imidazo [4,5- b] pyridine

ESI-MS m / z [M + H] + calculated for C ₁₅ H _{10 3} N ₅ value of F: 318.1; Found: 318.2.

Example 196: N -Methyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyrimidin-2-amine

ESI-MS m / z [M + H] + calcd for C ₁₃ H ₁₀ F ₃ N ₅ of: 294.1; Found: 294.2.

Example 197: N -cyclopropyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyrimidin-2-amine

ESI-MS m / z [M + H] + for C ₁₅ H ₁₂ F ₃ N ₅ calculates the values: 320.1; Found: 320.2.

Example 198: 5-(6-(Trifluoromethyl)-1 H -indazol-4-yl)pyrimidine-2-carbonitrile

ESI-MS m / z [M + H] + calculated for C ₁₃ H ₆ F ₃ N ₅ The Found: 290.1; Found: 290.2.

Example 199: 1-Ethyl-5-methyl-7-(6-(trifluoromethyl)-1 H -indazol-4-yl)porphyrin-2,3-dione

^{1 H NMR (400MHz, DMSO- d} 6) δ ppm 0.56 (t, J = 6.95Hz, 3 H), 2.34 (s, 3 H), 3.4 (m, 2 H), 7.43 (s, 1 H), 7.51 (s, 1 H), 7.54 (s, 1 H), 8.06 (s, 1 H), 8.13 (s, 1 H); ESI-MS m/z [M+H] ⁺ for C ₁₉ H ₁₄ F Calculated for ₃ N ₃ O ₂ : 374.1; found: 374.3.

Example 200: 4-(3-Methoxy-6-methylpyridin-2-yl)-6-(trifluoromethyl)-1 H -carbazole

ESI-MS m / z [M + H] + calcd for C ₁₅ H ₁₂ F ₃ N ₃ O of: 308.1; Found: 308.2.

Example 201: 6-Methoxy-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridinium

ESI-MS m / z [M + H] + for _{C 15 H 11 F 3 N 4} O ₂ computing the values: 337.1; Found: 337.2.

Example 202: 2- (1 H -1,2,4- triazol-1-yl) - N - (2- (6- ( trifluoromethyl) -1 H - indazol-4-yl) benzyl Ethylamine

ESI-MS m / z [M + H] + for C _{19 6} O Calcd of H ₁₅ F ₃ N: 401.1; Found: 401.3.

Example 203: 5-Fluoro-2-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzamide

ESI-MS m / z [M + H] + calcd for _{C 15 H 9 F 4 N 3} O of: 324.1; Found: 324.1.

Example 204: 6-Methyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyrimidine-2,4(1 H ,3 H )-dione

ESI-MS m / z [M + H] + ₂ of the value calculated for _{C 13 H 9 F 3 N 4} O: 311.1; Found: 311.1.

Example 205: 2-Amino-1-(2-(6-(trifluoromethyl)-1 H -indazol-4-yl)phenyl)ethanol

¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 3.50 (s, 2 H), 6.01 (d, J = 2.78 Hz, 1 H), 7.40 (t, J = 7.58 Hz, 1 H), 7.51 (t , J = 7.20 Hz, 2 H), 7.59 (br s, 3 H), 7.68 (br s, 1 H), 7.93 (s, 1 H), 13.67 (br s, 1 H); ESI-MS m/ z [M ⁺ H] + calcd for C ₁₆ H ₁₄ F ₃ N ₃ O of: 322.1; Found: 322.1.

Example 206: ( R )-2-(5-(6-(Trifluoromethyl)-1 H -indazol-4-yl)pyrimidin-2-ylamino)propan-1-ol

ESI-MS m / z [M + H] + calcd for C ₁₅ H ₁₄ F ₃ N ₅ O of: 338.1; Found: 338.1.

Example 207: ( R )-1-(5-(6-(Trifluoromethyl)-1 H -indazol-4-yl)pyrimidin-2-ylamino)propan-2-ol

¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.11 (d, J = 6.06 Hz, 3 H), 1.74-2.11 (m, 1 H), 3.32 (br s, 2 H), 3.86 (sxt, J =6.21 Hz, 1 H), 7.48 (s, 2 H), 7.89 (s, 1 H), 8.40 (s, 1 H), 8.75 (s, 2 H); ESI-MS m/z [M+H ] ⁺ calcd for _{C 15 H 14 F 3 N 5} O of: 338.1; Found: 338.1.

Example 208: ( S )-1-(5-(6-(Trifluoromethyl)-1 H -indazol-4-yl)pyrimidin-2-ylamino)propan-2-ol

ESI-MS m / z [M + H] + calcd for C ₁₅ H ₁₄ F ₃ N ₅ O of: 338.1; Found: 338.1.

Example 209: 2-(5-(6-(Trifluoromethyl)-1 H -indazol-4-yl)pyrimidin-2-ylamino)ethanol

ESI-MS m / z [M + H] + for C _{14 5} O Calcd of H ₁₂ F ₃ N: 324.1; Found: 324.4.

Example 210: 3-(6-(Trifluoromethyl)-1 H -indazol-4-yl)pyridin-2-ol

ESI-MS m / z [M + H] + calcd for C ₁₃ H ₈ F ₃ N ₃ O of: 280.1; Found: 280.1.

Example 211: 6-Methyl-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridin-2-amine

ESI-MS m / z [M + H] + for C ₁₄ H ₁₁ F ₃ N ₄ of the calculated value: 293.1; Found: 293.1.

Example 212: 6-Amino-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)nicotinonitrile

ESI-MS m / z [M + H] + calculated for C ₁₄ H ₈ F ₃ N ₅ The Found: 304.1; Found: 304.1.

Example 213: 4-(3-Methoxypyridin-2-yl)-6-(trifluoromethyl)-1 H -carbazole

ESI-MS m / z [M + H] + calcd for C ₁₄ H ₁₀ F ₃ N ₃ O of: 294.1; Found: 294.1.

Example 214: 2-(6-(Trifluoromethyl)-1 H -indazol-4-yl)pyridin-3-ol

ESI-MS m / z [M + H] + calcd for C ₁₃ H ₈ F ₃ N ₃ O of: 280.1; Found: 280.0.

Example 215: 4-(2,6-Dimethylpyridin-3-yl)-6-(trifluoromethyl)-1 H -carbazole

ESI-MS m / z [M + H] + calculated for C ₁₅ H ₁₂ F ₃ N ₃ The Found: 292.1; Found: 292.1.

Example 216: 5-Chloro-2-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridin-3-amine

ESI-MS m / z [M + H] + for C ₁₃ H ₈ ClF ₃ N ₄ of the calculated value: 313.0; Found: 313.0.

Example 217: 4-(2-( 1H -imidazol-1-yl)pyrimidin-5-yl)-6-(trifluoromethyl)-1 H -carbazole

ESI-MS m / z [M + H] + for C ₁₅ H ₉ F ₃ N ₆ The calculated value: 331.1; Found: 331.1.

Example 218: N- (2-(6-(Trifluoromethyl)-1 H -indazol-4-yl)pyridin-3-yl)acetamide

ESI-MS m / z [M + H] + for C ₁₅ H ₁₁ F ₃ N ₄ O Calcd of: 321.1; Found: 321.1.

Example 219: 2-(3,5-Dimethyl-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1 H -pyrazol-1-yl) -N , N -dimethylethylamine

ESI-MS m / z [M + H] + for C ₁₇ H ₂₀ F ₃ N ₅ calculates the values: 352.2; Found: 352.2.

Example 220: (1-Methyl-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1 H -pyrazol-3-yl)methanol

ESI-MS m / z [M + H] + calcd for _{C 13 H 11 F 3 N 4} O of: 297.1; Found: 297.1.

Example 221: (6-Amino-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridin-3-yl)(4-methylpiperazin-1-yl)- ketone

ESI-MS m / z [M + H] + for C _{19 6} O Calcd of H ₁₉ F ₃ N: 405.2; Found: 405.3.

Example 222: 2-Methyl-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyrazolo[1,5- d ][1,2,4]triazine- 7(6 H )-ketone

ESI-MS m / z [M + H] + for _{C 14 H 9 F 3 N 6} O of Calcd: 335.1; Found: 335.2.

Example 223: 4-(4-( 1H -pyrazol-1-ylsulfonyl)phenyl)-6-(trifluoromethyl)-1 H -carbazole

¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 6.67 (dd, J = 2.65, 1.64 Hz, 1 H), 7.61 (s, 1 H), 7.97 (d, J = 1.26 Hz, 1 H), 8.04 (s, 1 H), 8.08-8.21 (m, 4 H), 8.40 (s, 1 H), 8.59 (d, J = 2.78 Hz, 1 H), 13.84 (s, 1 H); ESI-MS m / z [M ⁺ H] + for _{C 17 H 11 F 3 N 4} O ₂ S Calcd of: 393.1; Found: 393.2.

Example 224: N- (2-Hydroxyethyl)-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzenesulfonamide

ESI-MS m / z [M + H] + for C ₁₆ H ₁₄ F ₃ N ₃ O ₃ S The calculated values: 386.1; Found: 386.2.

Example 225: 4-(4-(6-(Trifluoromethyl)-1 H -indazol-4-yl)phenylsulfonyl)morpholine

ESI-MS m / z [M + H] + for _{C 18 H 16 F 3 N 3} O ₃ S The calculated values: 412.1; Found: 412.3.

Example 226: 4-(3-Methyl-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)phenylsulfonyl)morpholine

¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 2.27 (s, 3 H), 2.92-3.03 (m, 4 H), 3.63-3.75 (m, 4 H), 7.38 (s, 1 H), 7.59 -7.73 (m, 2 H), 7.77 (s, 1 H), 8.00 (d, J = 13.39 Hz, 2 H), 13.76 (br s, 1 H); ESI-MS m/z [M+H] ⁺ ₃ S calculated for C ₁₉ value of _{H 18 F 3 N 3 O:} 426.1; Found: 426.3.

Example 227: 3-(4-Methylpiperazine-1-carbonyl)-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridine-2(1 H )-one

The title compound was isolated as the free base. ESI-MS m / z [M + H] + calculated for C ₁₉ value of the _{2 H 18 F 3 N 5 O:} 406.1; Found: 406.2.

Example 228: N- (2-Hydroxyethyl)-2-oxo-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1,2-dihydropyridine- 3-methylamine

The title compound was isolated as the free base. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 3.35 (q, J = 5.56 Hz, 2 H), 3.43-3.51 (m, 2 H), 7.42 (s, 1 H), 7.85 (s, 1 H) ), 8.11 (dd, J = 6.57, 2.78 Hz, 1 H), 8.24 (s, 1 H), 8.60-8.66 (m, 1 H), 9.81 (t, J = 5.56 Hz, 1 H), 12.89 ( d, J = 6.32 Hz, 1 H), 13.68 (br s, 1 H); ESI-MS m/z [M+H] ⁺ calculated for C ₁₆ H ₁₃ F ₃ N ₄ O ₃ : 367.1; Value: 367.2.

Example 229: N- (2-Hydroxyethyl)-2-methoxy-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)nicotinate

The title compound was isolated as the free base. ESI-MS m / z [M + H] + for _{C 17 H 15 F 3 N 4} O ₃ The calculated value: 381.1; Found: 381.2.

Example 230: 2-Amino- N- (2-hydroxyethyl)-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)nicotinate

The title compound was isolated as the free base. ESI-MS m / z [M + H] + for _{C 16 H 14 F 3 N 5} O ₂ computing the values: 366.1; Found: 366.2.

Example 231: 2-Sideoxy-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1,2-dihydropyridine-3-carboxamide

The title compound was isolated as the free base. ESI-MS m / z [M + H] + for _{C 14 H 9 F 3 N 4} O ₂ computing the values: 323.1; Found: 323.1.

Example 232: 2-Methoxy-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)nicotinamide

The title compound was isolated as the free base. ESI-MS m / z [M + H] + for _{C 15 H 11 F 3 N 4} O ₂ computing the values: 337.1; Found: 337.1.

Example 233: 2-Amino-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)nicotinate

The title compound was isolated as the free base. ESI-MS m / z [M + H] + calcd for C ₁₄ H ₁₀ F ₃ N ₅ O of: 322.1; Found: 322.1.

Example 234: 1-Methyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)porphyrin-2-one

¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 3.20 (s, 3 H), 3.68 (s, 2 H), 7.17 (d, J = 8.08 Hz, 1 H), 7.43 (s, 1 H), 7.71-7.76 (m, 2 H), 7.89 (s, 1 H), 8.35 (s, 1H), 13.69 (s, 1 H); ESI-MS m/z [M+H] ⁺ for C ₁₇ H ₁₂ Calculated for F ₃ N ₃ O: 332.1; found: 332.2.

Example 235: 5-(6-(Trifluoromethyl)-1 H -indazol-4-yl)porphyrin-2-one

ESI-MS m / z [M + H] + calcd for C ₁₆ H ₁₀ F ₃ N ₃ O of: 318.1; Found: 318.1.

Example 236: 6-(Trifluoromethyl)-1 H , 1' H -4,5'-dicarbazole

ESI-MS m / z [M + H] + for C ₁₅ H ₉ F ₃ N ₄ of the calculated value: 303.1; Found: 303.1.

Example 237: 5-(6-(Trifluoromethyl)-1 H -indazol-4-yl)-1 H -benzo[ d ]imidazole-2( 3H )-one

ESI-MS m / z [M + H] + for C ₁₅ H ₉ F ₃ N ₄ O Calcd of: 319.1; Found: 319.1.

Example 238: 5-(6-(Trifluoromethyl)-1 H -indazol-4-yl)-1 H -pyrrolo[2,3- b ]pyridine-2( 3H )-one

ESI-MS m / z [M + H] + for C ₁₅ H ₉ F ₃ N ₄ O Calcd of: 319.1; Found: 319.1.

Example 239: 6-(6-(Trifluoromethyl)-1 H -indazol-4-yl)porphyrin-2-one

¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 3.59 (s, 2 H), 7.17 (s, 1 H), 7.33-7.45 (m, 3 H), 7.93 (s, 1 H), 8.30 (s) , 1 H), 10.47 (s, 1 H), 13.73 (s, 1 H); ESI-MS m/z [M+H] ⁺ Calculated for C ₁₆ H ₁₀ F ₃ N ₃ O: 318.1; Value: 318.1.

Example 240: 2-(6-(Trifluoromethyl)-1 H -indazol-4-yl)-5 H -pyrrolo[2,3- b ]pyrazine

ESI-MS m / z [M + H] + calculated for C ₁₄ H ₈ F ₃ N ₅ The Found: 304.1; Found: 304.1.

Example 241: 6-(6-(Trifluoromethyl)-1 H -indazol-4-yl)-1 H -imidazo[4,5- b ]pyridine-2(3 H )-one

ESI-MS m / z [M + H] + calcd for C ₁₄ H ₈ F ₃ N ₅ O of: 320.1; Found: 320.1.

Example 242: 2- (trifluoromethyl) -6- (6- (trifluoromethyl) -1 H - indazol-4-yl) -3 H - imidazo [4,5- b] pyridine

ESI-MS m / z [M + H] + calculated for C ₁₅ H ₇ F ₆ N ₅ The Found: 372.1; Found: 372.1.

Example 243: 5-(6-(Trifluoromethyl)-1 H -indazol-4-yl)-1 H -pyrazolo[3,4- b ]pyridine

ESI-MS m / z [M + H] + calculated for C ₁₄ H ₈ F ₃ N ₅ The Found: 304.1; Found: 304.1.

Example 244: 7-(6-(Trifluoromethyl)-1H-indazol-4-yl)-3,4-dihydropyrido[2,3-b]pyrazine-2(1H)-one

ESI-MS m / z [M + H] + calcd for C ₁₅ H ₁₀ F ₃ N ₅ O of: 334.1; Found: 334.1.

Example 245: 6-Amino-3-methyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyrimidin-4( 3H )-one

4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)-1 H -indazole (0.05 g , 0.160 mmol), 6-amino-5-bromo-3-methylpyrimidin-4(3 H )-one (0.042 g, 0.208 mmol) and PdCl ₂ (dppf) (5.86 mg, 8.01 μmol) in dioxins dioxane (8 mL) and saturated NaHCO ₃ the mixture was filled in a vial aqueous solution (2mL). The resulting light brown suspension was heated in a microwave reactor at 140 °C for 45 minutes. The reaction mixture was then concentrated and the crude residue was purified by preparative HPLC eluting with &_lt;RTIID=0.0&gt_;0&gt_; The product-containing fractions were combined and evaporated to dryness crystals ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 3.45 (s, 3 H), 7.33 (d, J = 1.01 Hz, 1 H), 7.83 (s, 1 H), 7.89 (d, J = 0.76 Hz, 1 H), 8.19 (s, 1 H); ESI-MS m / z [m + H] + for C _{13 5} O Calcd of H ₁₀ F ₃ N: 310.1; Found: 310.2.

Example 246: 4-(2-Methoxypyrimidin-5-yl)-6-(trifluoromethyl)-1 H -carbazole

4-Bromo-6-(trifluoromethyl)-1 H -indazole (0.1 g, 0.377 mmol), (2-methoxypyrimidin-5-yl)boronic acid (0.076 g, 0.491 mmol) and PdCl ₂ (dppf) (0.014g, 0.019mmol) in dioxane (8 mL) and saturated NaHCO ₃ the mixture was filled in a vial aqueous solution (2mL). The resulting light brown suspension was heated in a microwave reactor at 140 °C for 45 minutes. The reaction mixture was then concentrated and the crude residue was purified by preparative HPLC eluting with &_lt;RTIID=0.0&gt_;0&gt_; The volatiles were removed in vacuo to give a crystallite. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 4.03 (s, 3 H), 7.60 (d, J = 1.01 Hz, 1 H), 8.00 (s, 1 H), 8.34 - 8.52 (m, 1 H) ), 9.06 (s, 2 H ); ESI-MS m / z [m + H] + calcd for _{C 13 H 9 F 3 N 4} O of: 295.1; Found: 295.15.

Example 247: N , N -Dimethyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyrimidin-2-amine

4-Bromo-6-(trifluoromethyl)-1 H -indazole (0.1 g, 0.377 mmol), N , N -dimethyl-5-(4,4,5,5-tetramethyl- 1,3,2-Dioxaborolan-2-ylpyrimidin-2-amine (0.122 g, 0.491 mmol) and PdCl ₂ (dppf) (0.014 g, 0.019 mmol) in dioxane (8 mL) and sat. The mixture in a NaHCO ₃ aqueous solution (2 mL) was filled with a vial. The resulting light brown suspension was heated in a microwave reactor at 140 °C for 45 minutes. The reaction mixture was then concentrated, and the crude residue was purified by a 30% to 40% ACN (containing 0.035% TFA) gradient of H ₂ O (containing 0.05% TFA) and purified by preparative HPLC eluting in eight minutes. The product-containing fractions were combined and evaporated to dryness crystals crystals crystals ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 3.23 (s, 6 H), 7.48 (d, J = 1.01 Hz, 1 H), 7.89 (s, 1 H), 8.40 (d, J = 0.76 Hz) , 1 H), 8.82 (s , 2 H); ESI-MS m / z [m + H] + for C ₁₄ F ₃ N ₅ calculates the values H _12: 308.1; Found: 308.15.

Example 248: 4-(3,6-Dimethoxypyridazin-4-yl)-6-(trifluoromethyl)-1 H -carbazole

4-Bromo-6-(trifluoromethyl)-1 H -indazole (0.15 g, 0.566 mmol), (3,6-dimethoxypyridazin-4-yl)boronic acid (0.135 g, 0.736 mmol) ) and _{PdCl 2 (dppf) (0.021g,} 0.028mmol) in a mixture of _aqueous solution (3mL) in dioxane (10 mL) and saturated NaHCO filled vial. The resulting light brown suspension was heated in a microwave reactor at 140 °C for 45 minutes. The reaction mixture was then concentrated, and the crude residue was purified by a 40% to 45% ACN (containing 0.035% TFA) gradient of H ₂ O (containing 0.05% TFA) and purified by preparative HPLC eluting time of 6.5 minutes. The volatiles were removed in vacuo to give a crystallite. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 3.97 (s, 3 H), 4.03 (s, 3 H), 7.42 (s, 1 H), 7.55 (d, J = 1.01 Hz, 1 H), 8.05(s,1 H), 8.14(s,1 H), 13.74(s,1 H); ESI-MS m/z[M+H] ⁺ calculated for C ₁₄ H ₁₁ F ₃ N ₄ O ₂ : 325.1; Found: 325.16.

Example 249: 4-(6-Methoxy-2-methylpyridin-3-yl)-6-(trifluoromethyl)-1 H -carbazole

4-Bromo-6-(trifluoromethyl)-1 H -indazole (0.15 g, 0.566 mmol), (6-methoxy-2-methylpyridin-3-yl)boronic acid (0.123 g, 0.736) mmol) and _{PdCl 2 (dppf) (0.021g,} 0.028mmol) in dioxane (10 mL) and saturated NaHCO ₃ the mixture was filled in a vial aqueous solution (3mL). The resulting light brown suspension was heated in a microwave reactor at 140 °C for 45 minutes. The reaction mixture was then concentrated, and the crude residue was purified by containing 45% ACN (containing 0.035% TFA) of H ₂ O (containing 0.05% TFA) was purified by preparative HPLC 6.5 minutes of fractions. The volatiles were removed in vacuo to give a crystallite. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 2.30 (s, 3 H), 3.93 (s, 3 H), 6.75-6.86 (m, 1 H), 7.29 (d, J = 1.26 Hz, 1 H ), 7.72 (d, J = 8.34 Hz, 1 H), 7.90-8.03 (m, 2 H); ESI-MS m/z [M+H] ⁺ calculated for C ₁₅ H ₁₂ F ₃ N ₃ O : 308.1; Found: 308.15.

Example 250: (1-Methyl-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1 H -pyrazol-5-yl)methanol

4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)-1 H -indazole (0.1 g , 0.320 mmol), (4-bromo-1-methyl-1 H -pyrazol-5-yl)methanol (0.086 g, 0.449 mmol) and PdCl ₂ (dppf) (0.012 g, 0.016 mmol) in dioxane A mixture of (8 mL) and a saturated aqueous solution of NaHCO ₃ (2 mL) was used to fill the vial. The resulting light brown suspension was heated in a microwave reactor at 140 °C for 45 minutes. The reaction mixture was then concentrated, and the crude residue was purified by containing 30% ACN (containing 0.035% TFA) of H ₂ O (containing 0.05% TFA) was purified by preparative HPLC 6 fractions of minutes. The product-containing fractions were combined with EtOAc (EtOAc m. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 3.96 (s, 3 H), 4.56 (d, J = 4.80 Hz, 2 H), 5.53 (t, J = 4.93 Hz, 1 H), 7.43 (s) , 1 H), 7.78-7.92 (m, 2 H), 8.30 (s, 1 H), 13.62 (s, 1 H); ESI-MS m/z [M+H] ⁺ for C ₁₃ H ₁₁ F ₃ Calculated for N ₄ O: 297.1; found: 297.14.

Example 251: 5-(6-(Trifluoromethyl)-1 H -indazol-4-yl)pyridiniumamine

4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)-1 H -indazole (0.05 g a mixture of 0.125 mmol), 5-bromopyridiniumamine (0.042 g, 0.208 mmol) and PdCl ₂ (dppf) (5.86 mg, 8.01 μmol) in dioxane (8 mL) and saturated aqueous NaHCO ₃ (2 mL) Vial. The resulting light brown suspension was heated in a microwave reactor at 140 °C for 45 minutes. The reaction mixture was then concentrated and the crude residue was purified by preparative HPLC eluting with &_lt;RTIID=0.0&gt_;0&gt_; The volatiles were removed in vacuo to give a crystallite. ^{1 H NMR (400MHz, DMSO- d} 6) δ ppm 7.66 (s, 1 H), 7.77 (br s, 1 H), 8.06 (s, 1 H), 8.14-8.33 (m, 1 H), 8.37- 8.49 (m, 1 H), 9.00-9.08 (m, 1 H), 13.84 (br s, 1 H); ESI-MS m/z [M+H] ⁺ for C ₁₄ H ₉ F ₃ N ₄ O Calculated: 307.1; found: 307.15.

Example 252: 2-Methyl-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridin-4-amine

4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)-1 H -indazole (0.1 g , 0.320 mmol), 3-bromo-2-methylpyridin-4-amine (0.078 g, 0.417 mmol) and PdCl ₂ (dppf) (0.012 g, 0.016 mmol) in dioxane (8 mL) and saturated aqueous NaHCO ₃ The mixture in (2 mL) was filled with vials. The resulting light brown suspension was heated in a microwave reactor at 140 °C for 45 minutes. The reaction mixture was then concentrated, and the crude residue was purified by containing 20% ACN (containing 0.035% TFA) of H ₂ O (containing 0.05% TFA) was purified by preparative HPLC 5 minutes of fractions. The volatiles were removed in vacuo to afford titled <RTI ID=0.0> ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 2.11 (s, 3 H), 6.69 (br s, 1 H), 6.90 (d, J = 7.07 Hz, 1 H), 7.38 (s, 1 H) , 8.01 (s, 1 H), 8.08 (s, 1 H), 8.17 (t, J = 6.44 Hz, 1 H), 13.51 (br s, 1 H); ESI-MS m/z [M+H] ⁺ calculated for C ₁₄ H ₁₁ F ₃ N ₄ of the values: 293.1; Found: 293.14.

Example 253: 4-(6-Methoxy-4-methylpyridin-3-yl)-6-(trifluoromethyl)-1 H -carbazole

4-Bromo-6-(trifluoromethyl)-1 H -indazole (0.1 g, 0.377 mmol), (6-methoxy-4-methylpyridin-3-yl)boronic acid (0.082 g, 0.491) mmol) and _{PdCl 2 (dppf) (0.014g,} 0.019mmol) in dioxane (8 mL) and saturated NaHCO ₃ the mixture was filled in a vial aqueous solution (2mL). The resulting light brown suspension was heated in a microwave reactor at 140 °C for 45 minutes. The reaction mixture was then concentrated, and the crude residue was purified by a 40% to 45% ACN (containing 0.035% TFA) gradient of H ₂ O (containing 0.05% TFA) and purified by preparative HPLC eluting time of 6.5 minutes. The fractions containing the product were combined and the solvent was removed on a rotary evaporator. The crude product was extracted into DCM, and washed sequentially with saturated aqueous NaHCO _3, water and brine, and dried over Na ₂ SO _4. The title compound (0.053 g, 0.172 mmol, 46%) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 2.14 (s, 3 H), 3.91 (s, 3 H), 6.88 (s, 1 H), 7.29 (s, 1 H), 7.97 (s, 2) H), 8.12 (s, 1 H), 13.71 (s, 1 H); ESI-MS m/z [M+H] ⁺ Calculated for C ₁₅ H ₁₂ F ₃ N ₃ O: 308.1; 308.15.

Example 254: N -Methyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyrimidine-4-carboxamide

4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)-1 H -indazole (0.144 g) , 0.463 mmol), 5-bromo- N -methylpyrimidine-4-carboxamide (0.1 g, 0.463 mmol) and PdCl ₂ (dppf) (0.017 g, 0.023 mmol) in dioxane (8 mL) and sat. NaHCO A mixture of ₃ aqueous solutions (2 mL) was filled with vials. The resulting light brown suspension was heated in a microwave reactor at 140 °C for 45 minutes. The reaction mixture was then concentrated, and the crude residue was purified by a 25% to 30% ACN gradient of H ₂ O (containing 10mMol NH ₄ HCO ₃₎ was purified by preparative HPLC 8 fractions of minutes. The fractions containing the product were combined and the solvent was removed via rotary evaporation. The crude product was extracted into DCM and washed with water. The volatiles were removed in vacuo to give crystalljjjjjjjjj ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 2.62 (d, J = 4.80 Hz, 3 H), 7.43 (s, 1 H), 8.04 (s, 1 H), 8.01 (s, 1 H), 8.89 (d, J = 4.29 Hz, 1 H), 9.09 (s, 1 H), 9.38 (s, 1 H), 13.72 (br s, 1 H); ESI-MS m/z [M+H] ⁺ Calcd for C ₁₄ H ₁₀ F ₃ N ₅ O: 322.1; found: 322.2.

Example 255: 6-Methyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridin-2-amine

To 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)-1 H -indazole (0.05 g , 0.160 mmol), 5-iodo-6-methylpyridin-2-amine (0.025 g, 0.107 mmol) and PdCl ₂ (dppf) (0.012 g, 0.016 mmol) in a mixture of dioxane (1.5 mL) 2N sodium carbonate (0.160 mL, 0.320 mmol) was added. The reaction mixture was heated at 130 ° C for 50 minutes in a microwave reactor. LCMS showed incomplete conversion of the starting material, so the reaction mixture was heated at 130 ° C for an additional 50 min. LCMS again showed incomplete conversion. More catalyst was added and the reaction mixture was heated again at 130 °C for 50 minutes. The reaction mixture was then filtered through a microfiltration frit and the microfilter frit was rinsed with methanol. The solvent was removed in vacuo. The residue was taken up in DMSO and methanol (1: 1), and by containing with 25% ACN (containing 0.035% TFA) of H ₂ O (containing 0.05% TFA) and purified by preparative HPLC eluting in. The product-containing fractions were dried <RTI ID=0.0></RTI> to <RTI ID=0.0> ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 2.32 (s, 3 H), 6.94 (d, J = 9.35 Hz, 1 H), 7.37 (s, 1 H), 7.97 (d, J = 8.84 Hz) , 1 H), 8.02 (s, 1 H), 8.14 (s, 1 H); ESI-MS m/z [M+H] ⁺ Calculated for C ₁₄ H ₁₁ F ₃ N ₄ : 293.1; :293.2.

Example 256: 2-Methoxy-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyrimidine-4-amine

4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)-1 H -indazole (0.1 g , 0.320mmol), 5- bromo-2-methoxy-pyrimidin-4-amine (0.131g, 0.641mmol), and _{PdCl 2 (dppf) (0.012g,} 0.016mmol) in dioxane (8 mL) and saturated NaHCO ₃ The mixture in the aqueous solution (2 mL) was filled with vials. The resulting light brown suspension was heated in a microwave reactor at 140 °C for 45 minutes. The reaction mixture was then concentrated, and the crude residue was purified by a 15% to 25% ACN (containing 0.035% TFA) gradient of H ₂ O (containing 0.05% TFA) and purified by preparative HPLC eluting in 5 minutes. The product-containing fractions were combined with EtOAc EtOAcjjjjjjjj ^{1 H NMR (400MHz, DMSO- d} 6) δ ppm 4.04 (s, 3 H), 7.35-7.41 (m, 1 H), 8.03 (s, 1 H), 8.06-8.15 (m, 1 H), 8.21 (s, 1 H); ESI -MS m / z [m + H] + for _{C 13 H 10 F 3 N 5} O of Calcd: 310.1; Found: 310.13.

Example 257: N-(6-Methyl-5-(6-(trifluoromethyl)-1H-indazol-4-yl)pyridin-2-yl)methanesulfonamide

4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)-1 H -indazole (0.1 g , 0.320 mmol), N- (5-bromo-6-methylpyridin-2-yl)methanesulfonamide (0.170 g, 0.641 mmol) and PdCl ₂ (dppf) (0.012 g, 0.016 mmol) in dioxane A mixture of (8 mL) and a saturated aqueous solution of NaHCO ₃ (2 mL) was used to fill the vial. The resulting light brown suspension was heated in a microwave reactor at 140 °C for 45 minutes. The reaction mixture was then concentrated, and the crude residue was purified by containing 30% ACN (containing 0.035% TFA) of H ₂ O (containing 0.05% TFA) was purified by preparative HPLC 8 fractions of minutes. The product-containing fractions were combined with EtOAc EtOAcjjjjjjjj ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 2.30 (s, 3 H), 3.31 (br s, 3 H), 7.02 (d, J = 8.08 Hz, 1 H), 7.32 (d, J = 1.01) Hz, 1 H), 7.76 (d, J = 8.34 Hz, 1 H), 7.97 (s, 1 H), 8.02 (s, 1 H); ESI-MS m/z [M+H] ⁺ for C ₁₅ H ₁₃ F ₃ N ₄ O ₂ S calcd.

Example 258: 2-Methoxy- N- (6-methyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridin-2-yl)acetamide

In a similar manner to Example 257, N- (5-bromo-6-methylpyridin-2-yl)-2-methoxyacetamidine was used instead of N- (5-bromo-6-methylpyridine-2 Methyl sulfoximine to prepare the TFA salt of the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 2.31 (s, 3 H), 3.39 (s, 3 H), 4.11 (s, 2 H), 7.34 (d, J = 1.26 Hz, 1 H), 7.82 (d, J = 8.34 Hz, 1 H), 7.93 - 8.02 (m, 2 H), 8.07 (d, J = 8.59 Hz, 1 H), 10.19 (s, 1 H); ESI-MS m/z [M ⁺ H] + for _{C 17 H 15 F 3 N 4} O ₂ computing the values: 365.1; Found: 365.2.

Example 259: 1-Methyl- N- (6-methyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridin-2-yl)-1 H -pyrazole -4-sulfonamide

In a manner similar to Example 257, N- (5-bromo-6-methylpyridin-2-yl)-1-methyl-1 H -pyrazole-4-sulfonamide was used instead of N- (5-bromo) -6-Methylpyridin-2-yl)methanesulfonamide to prepare the TFA salt of the title compound. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 2.31 (s, 3 H), 3.92 (s, 3 H), 7.15-7.32 (m, 2 H), 7.72 (d, J = 8.84 Hz, 1 H) , 7.86 (d, J = 0.51 Hz, 1 H), 7.89-7.99 (m, 2 H), 8.20 (s, 1 H); ESI-MS m/z [M+H] ⁺ for C ₁₈ H ₁₅ F Calculated for ₃ N ₆ O ₂ S: 437.1; found: 437.18.

Example 260: Ethyl 2-(4-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1 H -pyrazol-1-yl)acetate

4-Bromo-6-(trifluoromethyl)-1 H -indazole (0.3 g, 1.132 mmol), 2-(4-(4,4,5,5-tetramethyl-1,3,2) -Dioxaborolan-2-yl)-1 H -pyrazol-1-yl)acetate (0.349 g, 1.245 mmol) and PdCl ₂ (dppf) (0.041 g, 0.057 mmol) in dioxane ( A vial was filled with a mixture of 10 mL) and saturated aqueous NaHCO ₃ (3 mL). The resulting light brown suspension was heated in a microwave reactor at 140 °C for 45 minutes. The reaction mixture was then concentrated, and the crude residue was purified by a 40% to 45% ACN (containing 0.035% TFA) gradient of H ₂ O (containing 0.05% TFA) and purified by preparative HPLC eluting time of 6.5 minutes. The product-containing fractions were combined and evaporated to dryness crystals crystals crystals ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.24 (t, J = 7.07 Hz, 3 H), 4.19 (q, J = 7.16 Hz, 2 H), 5.15 (s, 2 H), 7.60 (d) , J = 1.01 Hz, 1 H), 7.77 (s, 1 H), 8.27 (d, J = 0.76 Hz, 1 H), 8.53 (s, 1 H), 8.63 (s, 1 H), 13.64 (s , 1 H); ESI-MS m / z [m + H] + calculated for C ₁₅ value of the _{2 H 13 F 3 N 4 O:} 339.1; Found: 339.

Example 261: 2-(4-(6-(Trifluoromethyl)-1 H -indazol-4-yl)-1 H -pyrazol-1-yl)acetic acid

Ethyl 2-(4-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1 H -pyrazol-1-yl)acetate (0.14 g, 0.414) Addition of lithium hydroxide (0.621 mL, 1.242 mmol) to a mixture of THF-H ₂ O (5:1, 4 mL). The reaction mixture was stirred for 1 h then EtOAcqqqqqqm ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 4.97 (s, 2 H), 7.58 (s, 1 H), 7.76 (s, 1 H), 8.22 (s, 1 H), 8.54 (s, 1) H), 8.59 (s, 1 H), 13.70 (br s, 1 H); ESI-MS m/z [M+H] ⁺ Calculated for C ₁₃ H ₉ F ₃ N ₄ O ₂ : 311.1; Value: 311.15.

Example 262: (N-morpholinyl)(5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridin-2-yl)methanone

4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)-1 H -indazole (0.1 g , 0.320 mmol), (5-bromopyridin-2-yl)(N-morpholinyl)methanone (0.174 g, 0.641 mmol) and PdCl ₂ (dppf) (0.012 g, 0.016 mmol) in dioxane (10 mL) The mixture was filled with a mixture of saturated aqueous NaHCO ₃ (3 mL). The resulting light brown suspension was heated in a microwave reactor at 140 °C for 45 minutes. The reaction mixture was then concentrated, and the crude residue was purified by a 35% to 45% ACN (containing 0.035% TFA) gradient of H ₂ O (containing 0.05% TFA) and purified by preparative HPLC eluting in 5 minutes. The product-containing fractions were combined with EtOAc EtOAcjjjjjjj ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 3.49-3.67 (m, 4 H), 3.71 (s, 4 H), 7.63 (s, 1 H), 7.80 (dd, J = 8.08, 0.76 Hz, 1 H), 8.03 (s, 1 H), 8.28-8.48 (m, 2 H), 9.01 (dd, J = 2.40, 0.88 Hz, 1 H), 13.82 (br s, 1 H); ESI-MS m / z [M ⁺ H] + calculated for C ₁₈ value of the _{2 H 15 F 3 N 4 O:} 377.1; Found: 377.

Example 263: Methyl 4-methoxy-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzoate

4-Bromo-6-(trifluoromethyl)-1 H -indazole (0.631 g, 2.381 mmol), (2-methoxy-5-(methoxycarbonyl)phenyl)boronic acid (0.5 g, 2.381mmol), and _{PdCl 2 (dppf) (0.087g,} 0.119mmol) in dioxane (10 mL) and saturated NaHCO ₃ the mixture was filled in a vial aqueous solution (3mL). The resulting light brown suspension was heated in a microwave reactor at 140 °C for 45 minutes. The reaction mixture was then concentrated and EtOAc EtOAc m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m m The title compound (0.592 g, 71.0%) was obtained. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 3.85 (s, 3 H), 3.84 (s, 3 H), 7.21-7.46 (m, 2 H), 7.89-7.99 (m, 3 H), 8.10 (dd, J = 8.59, 2.27 Hz, 1 H), 13.62 (s, 1 H); ESI-MS m/z [M+H] ⁺ Calculated for C ₁₇ H ₁₃ F ₃ N ₂ O ₃ : 351.1 ;Measured value: 351.16.

Example 264: 2-(4-(6-(Trifluoromethyl)-1 H -indazol-4-yl)-1 H -pyrazol-1-yl)acetamide

2-(4-(6-(Trifluoromethyl)-1 H -pyrazol-4-yl)-1 H -pyrazol-1-yl)acetic acid (0.052 g, 0.168 mmol) in DMF (3 mL) Add HOBt (0.029 g, 0.218 mmol), EDC (0.045 g, 0.235 mmol), ammonium chloride (0.045 g, 0.838 mmol), followed by N -ethyl- N -isopropylpropan-2-amine ( 0.146 mL, 0.838 mmol). The reaction mixture was stirred at room temperature for 18 hours. The crude mixture was then purified by preparative HPLC (Waters SunFire C18, 5 μm, 30 mm ID x 75 mm column) eluting with water containing 20% to 30% ACN (containing 0.035% TFA) gradient (containing 0.05% TFA). The title compound (0.016 g, 31%) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 4.84 (s, 2 H), 7.33 (br s, 1 H), 7.51-7.68 (m, 2 H), 7.75 (s, 1 H), 8.23 ( d, J = 0.76 Hz, 1 H), 8.56 (d, J = 4.29 Hz, 2 H), 13.62 (s, 1 H); ESI-MS m/z [M+H] ⁺ for C ₁₃ H ₁₀ F Calculated for ₃ N ₅ O: 310.1; found: 310.

Example 265: 6-Sideoxy-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1,6-dihydropyridine-3-carboxylic acid methyl ester

4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl) in a microwave reactor at 140 °C -1 H -carbazole (43 mg, 0.138 mmol), 5-iodo-6-oxo-1,6-dihydropyridine-3-carboxylic acid methyl ester (38.4 mg, 0.138 mmol) and PdCl ₂ (dppf) ) (5.04mg, 6.89μmol) in dioxane (2mL) and the mixture of saturated NaHCO ₃ aq (0.5mL) was heated for 30 minutes. Then reaction mixture was filtered, and the via with 20% to 90% ACN (containing 0.035% TFA) gradient of H ₂ O (containing 0.05% TFA) was purified soluble preparative HPLC isolated, to give the title compound as a white solid of (7 mg of , 15%). ^{1 H NMR (400MHz, DMSO- d} 6) δ ppm 8.19 (s, 1H), 8.09-8.14 (m, 2H), 7.94 (s, 1H), 7.62 (s, 1H), 3.82 (s, 3H); ESI-MS m / z [m + H] + for _{C 15 H 10 F 3 N 3} O ₃ calculated sum value: 338.1; Found: 338.2.

Example 266: (4-Methoxy-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)phenyl)(4-methylpiperazin-1-yl)methanone

To a 10 mL microwave vial containing 1-methylpiperazine (0.029 g, 0.285 mmol) in dioxane (2 mL) was added dropwise and trimethylaluminum (0.428 mL) 0.856 mmol). After stirring at room temperature for 15 minutes, methyl 4-methoxy-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzoate (0.1 g, 0.285 mmol) was added. The reaction mixture was heated in a microwave reactor at 110 °C for 1 hour and then transferred to a round bottom flask which was quenched with concentrated HCl. The reaction mixture was concentrated, and the crude residue was purified by preparative HPLC (Waters &lt;RTI ID=0.0&gt; Purification afforded the title compound <RTI ID=0.0> ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 2.83 (s, 3 H), 3.11 (br s, 2 H), 3.33 (br s, 2 H), 3.45 (br s, 2 H), 3.83 ( s, 3 H), 4.27 (br s, 2 H), 7.32 (d, J = 8.59 Hz, 1 H), 7.37-7.44 (m, 1 H), 7.54 (d, J = 2.02 Hz, 1 H) , 7.62 (dd, J = 8.59, 2.02 Hz, 1 H), 7.93 - 8.05 (m, 2 H), 10.29 (br s, 1 H); ESI-MS m/z [M+H] ⁺ for C ₂₁ H ₂₁ F ₃ N ₄ O ₂ computing the values: 419.2; Found: 419.21.

Example 267: (4-Methoxy-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)phenyl)(N-morpholinyl)methanone

The title compound was prepared as a TFA salt using morpholine instead of 1-methylpiperazine. ^{1 H NMR (400MHz, DMSO- d} 6) δ ppm 3.55 (br s, 4 H), 3.72 (br s, 4 H), 3.81 (s, 3 H), 7.28 (d, J = 8.59Hz, 1 H ), 7.35 (d, J = 1.01 Hz, 1 H), 7.47 (d, J = 2.27 Hz, 1 H), 7.56 (dd, J = 8.46, 2.15 Hz, 1 H), 7.87-8.02 (m, 2) H); ESI-MS m / z [m + H] + for _{C 20 H 18 F 3 N 3} O ₃ calculated sum value: 406.1; Found: 406.22.

Example 268: N- (2-Hydroxyethyl)-4-methoxy-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzamide

The TFA salt of the title compound was prepared in a manner analogous to Example 266, using 2-aminoethanol instead of 1-methylpiperazine. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 3.44-3.55 (m, 2 H), 3.65-3.75 (m, 2 H), 3.83-3.92 (m, 3 H), 7.19-7.33 (m, 1 H ), 7.39 (s, 1 H), 7.85-7.97 (m, 3 H), 8.01 (dd, J = 8.72, 2.40 Hz, 1 H); ESI-MS m/z [M+H] ⁺ for C ₁₈ H ₁₆ F ₃ N ₃ O ₃ calcd.: 380.1;

Example 269: Methyl 5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridinecarboxylate

4-Bromo-6-(trifluoromethyl)-1 H -indazole (0.732 g, 2.76 mmol), (6-(methoxycarbonyl)pyridin-3-yl)boronic acid (0.5 g, 2.76 mmol) and _{PdCl 2 (dppf) (0.101g,} 0.138mmol) in dioxane (10 mL) and saturated NaHCO ₃ the mixture was filled in a vial aqueous solution (3mL). The resulting light brown suspension was heated in a microwave reactor at 140 °C for 45 minutes. The reaction mixture was then concentrated. The residue was diluted with DCM, washed with water and EtOAc evaporated. The crude product was purified by CombiFlash® chromatography (EtOAc (EtOAc) The fractions containing the product were combined and concentrated by rotary evaporation to give a product (0.28 g). Portion of the product (20mg) by containing 40% ACN (containing 0.035% TFA) of H ₂ O (containing 0.05% TFA) and purified by preparative HPLC 6.5 minutes eluting to give the TFA salt of the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 3.95 (s, 3 H), 7.69 (s, 1 H), 8.07 (s, 1 H), 8.23 (dd, J = 8.21, 0.63 Hz, 1 H ), 8.39-8.57 (m, 2 H), 9.10-9.26 (m, 1 H), 13.86 (br s, 1 H); ESI-MS m/z [M+H] ⁺ for C ₁₅ H ₁₀ F ₃ Calculated for N ₃ O ₂ : 322.1; found: 322.11.

Example 270: N- (2-Hydroxyethyl)-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridinium

Trimethylaluminum (0.467 mL, 0.934 mmol) in toluene was added dropwise to a 10 mL vial containing 2-aminoethanol (0.057 g, 0.934 mmol) in dioxane (2 mL). The mixture was stirred for 15 minutes at room temperature. Add methyl 5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridinecarboxylate (0.1 g, 0.285 mmol) and heat the reaction mixture at 110 ° C in a microwave reactor. hour. The reaction mixture was transferred to a round-br. The crude residue was purified by a 30% to 35% ACN (containing 0.035% TFA) gradient of H ₂ O (containing 0.05% TFA) and purified by preparative HPLC eluting time of 6 minutes. The solution containing the product were combined from parts and volatiles were removed in vacuo to give the TFA salt of the title compound ^{(0.023g, 42%) 1 H} NMR (400MHz, DMSO- d 6) δ ppm 3.44 (q, J = 5.98Hz, 2 H), 3.57 (d, J = 4.80 Hz, 2 H), 4.86 (br s, 1 H), 7.66 (s, 1 H), 8.06 (s, 1 H), 8.21 (d, J = 8.08 Hz, 1 H), 8.37-8.51 (m, 2 H), 8.79 (t, J = 5.81 Hz, 1 H), 9.06 (dd, J = 2.27, 0.76 Hz, 1 H), 13.85 (s, 1 H); ESI-MS m / z [m + H] + ₂ of the value calculated for _{C 16 H 13 F 3 N 4} O: 351.1; Found: 351.16.

Example 271: (4-Methylpiperazin-1-yl)(5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridin-2-yl)methanone

In a similar manner to Example 270, 1-methylpiperazine was used instead of 2-aminoethanol to prepare the title compound as a TFA salt. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 2.81-2.90 (m, 3 H), 3.17 (br s, 3 H), 3.42 (br s, 1 H), 3.54 (d, J = 16.17 Hz, 2 H), 4.25 (br s, 1 H), 4.64 (br s, 1 H), 7.63 (d, J = 1.01 Hz, 1 H), 7.86 (dd, J = 8.08, 0.76 Hz, 1 H), 8.06 (s, 1 H), 8.38-8.49 (m, 2 H), 9.03 (d, J = 1.77 Hz, 1 H), 10.27 (br s, 1 H); ESI-MS m/z [M+H ] ⁺ for C _{19 5} O Calcd of H ₁₈ F ₃ N: 390.1; Found: 390.25.

Example 272: 4-Methoxy- N , N -dimethyl-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzamide

The TFA salt of the title compound was prepared in a procedure analogous to Example 266 using dimethylamine hydrochloride instead of 1-methylpiperazine. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 3.00 (br s, 6 H), 3.81 (s, 3 H), 7.26 (d, J = 8.59 Hz, 1 H), 7.35 (d, J = 1.01) Hz, 1 H), 7.47 (d, J = 2.02 Hz, 1 H), 7.56 (dd, J = 8.46, 2.15 Hz, 1 H), 7.96 (s, 1 H), 7.93 (s, 1 H), 13.59 (br s, 1 H) ; ESI-MS m / z [m + H] + for _{C 18 H 16 F 3 N 3} O ₂ calculated sum value: 364.1; Found: 364.2.

Example 273: 4-Methoxy-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzamide

The TFA salt of the title compound was prepared in a procedure analogous to Example 266 using &lt ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 3.82 (s, 3 H), 7.28 (d, J = 8.59 Hz, 2 H), 7.37 (d, J = 1.26 Hz, 1 H), 7.83-8.11 (m, 5 H), 13.58 (s, 1 H); ESI-MS m / z [m + H] + for _{C 16 H 12 F 3 N 3} O ₂ calculated sum value: 336.1; Found: 336.16.

Example 274: 2-(3-Methyl-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1 H -pyrazol-1-yl)acetamide

In a similar manner to Example 257, 2-(4-bromo-3-methyl-1 H -pyrazol-1-yl)acetamide was used instead of N- (5-bromo-6-methylpyridine-2- Methanesulfonamide to prepare the TFA salt of the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 2.32 (s, 3 H), 4.77 (s, 2 H), 7.21-7.37 (m, 2 H), 7.52 (br s, 1 H), 7.81 ( s, 1 H), 8.16-8.33 (m, 2 H), 13.62 (s, 1 H); ESI-MS m/z [M+H] ⁺ calculated for C ₁₄ H ₁₂ F ₃ N ₅ O: 324.1; Found: 324.1.

Example 275: 6-(6-(Trifluoromethyl)-1 H -indazol-4-yl)pyrazolo[1,5- a ]pyrimidine

The title compound was prepared in a similar manner to Example 257 using 6-bromopyrazolo[1,5- a ]pyrimidine instead of N- (5-bromo-6-methylpyridin-2-yl)methanesulfonamide. TFA salt. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 6.86 (dd, J = 2.40, 0.88 Hz, 1 H), 7.73 (d, J = 1.01 Hz, 1 H), 8.03 (s, 1 H), 8.35 (d, J = 2.53 Hz, 1 H), 8.49 (t, J = 1.26 Hz, 1 H), 8.98 (d, J = 2.27 Hz, 1 H), 9.57 (dd, J = 2.27, 0.76 Hz, 1 H), 13.80 (s, 1 H); ESI-MS m / z [m + H] + for C ₁₄ H ₈ F ₃ N ₅ calculates the values: 304.1; Found: 304.2.

Example 276: 3-(6-(Trifluoromethyl)-1 H -indazol-4-yl)imidazo[1,2- b ]pyridazine-6-carboxamide

3-(6-(Trifluoromethyl)-1 H -indazol-4-yl)imidazo[1,2- b ]pyridazine-6-carboxylic acid (0.036 g, 0.104 mmol) in DMF (3 mL) Adding O- (benzotriazol-1-yl) -N , N , N ', N '-tetramethyluronium tetrafluoroborate (0.028 g, 0.073 mmol), ammonium chloride (8.32 mg, 0.156 mmol) and Et ₃ N (0.013 g, 0.124 mmol). The reaction mixture was stirred at room temperature overnight and then filtered, and by using 25% to 50% ACN (containing 0.035% TFA) gradient of H ₂ O (containing 0.05% TFA) was purified from the solution by preparative HPLC to give The TFA salt of the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.35-7.46 (m, 1 H), 7.53 (t, J = 7.58 Hz, 1 H), 7.71 (d, J = 8.59 Hz, 1 H), 7.82 (dd, J = 18.32, 9.47 Hz, 1 H), 7.95-8.05 (m, 2 H), 8.40 (t, J = 9.35 Hz, 1 H), 8.50 (br s, 1 H), 8.57-8.66 ( m, 1 H), 8.70 ( s, 1 H); ESI-MS m / z [m + H] + for _{C 15 H 9 F 3 N 6} O of Calcd: 347.1; Found: 347.2.

Example 277: 2-(3-Methyl-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1 H -pyrazol-1-yl)-1-(N- Morpholinyl)ketone

In a manner similar to Example 257, 2-(4-bromo-3-methyl-1 H -pyrazol-1-yl)-1-(N-morpholinyl)ethanone was used instead of N- (5-bromo) -6-Methylpyridin-2-yl)methanesulfonamide to prepare the TFA salt of the title compound. ^{1 H NMR (400MHz, DMSO- d} 6) δ ppm 2.32 (s, 3 H), 3.48 (d, J = 4.55Hz, 2 H), 3.52-3.69 (m, 6 H), 5.16 (s, 2 H ), 7.28 (d, J = 1.01 Hz, 1 H), 7.82 (s, 1 H), 8.11-8.28 (m, 2 H); ESI-MS m/z [M+H] ⁺ for C ₁₈ H ₁₈ F ₃ N ₅ O ₂ computing the values: 394.1; Found: 394.2.

Example 278: 1-Methyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyrimidine-2,4(1 H ,3 H )-dione

In a manner similar to Example 265, 5-bromo-1-methylpyrimidine-2,4(1 H ,3 H )-dione was used in place of 5-iodo-6-o-oxy-1,6-dihydropyridine. The title compound was prepared from methyl 3-carboxylate. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.18 (s, 1H), 7.97 (s, 1H), 7.86 (s, 1H), 7.48 (s, 1H), 3.46 (s, 3H); ESI-MS m / z [m + H] + ₂ of the value calculated for _{C 13 H 9 F 3 N 4} O: 311.1; Found: 311.2.

Example 279: N- (2-Hydroxyethyl)-2-(3-methyl-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1 H -pyrazole- 1-yl)acetamide

In a similar manner to Example 257, 2-(4-bromo-3-methyl-1 H -pyrazol-1-yl)acetamide was used instead of N- (5-bromo-6-methylpyridine-2- Methanesulfonamide to prepare the TFA salt of the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 2.31 (s, 3 H), 3.18 (q, J = 5.89 Hz, 2 H), 3.44 (q, J = 5.73 Hz, 2 H), 4.65-4.86 (m, 3 H), 7.28 (s, 1 H), 7.81 (s, 1 H), 8.06-8.31 (m, 3 H), 13.62 (s, 1 H); ESI-MS m/z [M+ H] ⁺ for _{C 16 H 16 F 3 N 5} O ₂ computing the values: 368.1; Found: 368.

Example 280: N , N -Dimethyl-2-(4-(6-(trifluoromethyl)-1 H -indazol-4-yl)phenoxy)ethylamine

In a similar manner to Example 247, N , N -dimethyl-2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) was used. Phenoxy)ethylamine in place of N , N -dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2 -Amine to prepare the TFA salt of the title compound. ^{1 H NMR (400MHz, DMSO- d} 6) δ ppm 2.83-2.96 (m, 6 H), 3.58 (d, J = 4.55Hz, 2 H), 4.31-4.48 (m, 2 H), 7.12-7.30 ( m, 2 H), 7.41 (d, J = 1.26 Hz, 1H), 7.71-7.86 (m, 2 H), 7.91 (s, 1 H), 8.32 (d, J = 0.76 Hz, 1 H), 9.78 (br s, 1 H); ESI-MS m / z [m + H] + calcd for _{C 18 H 18 F 3 N 3} O of: 350.1; Found: 350.

Example 281: 4-(2-(4-(6-(Trifluoromethyl)-1 H -indazol-4-yl)phenoxy)ethyl)morpholine

In a similar manner to Example 247, 4-(2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy) was used. Ethyl)morpholine instead of N , N -dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine To prepare the TFA salt of the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 3.26 (br s, 2 H), 3.57 (d, J = 12.13 Hz, 2 H), 3.61-3.69 (m, 2 H), 3.74 (t, J =11.24 Hz, 2 H), 4.02 (d, J = 11.87 Hz, 2 H), 4.36-4.54 (m, 2 H), 7.11-7.29 (m, 2 H), 7.41 (d, J = 1.01 Hz, 1 H), 7.72-7.86 (m, 2 H), 7.91 (s, 1 H), 8.32 (d, J = 1.01 Hz, 1 H), 10.27 (br s, 1 H); ESI-MS m/z [M ⁺ H] + for _{C 20 H 20 F 3 N 3} O ₂ calculated sum value: 392.2; Found: 392.

Example 282: (2-Amino-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridin-3-yl)(4-methylpiperazin-1-yl)- ketone

4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)-1 H -indazole (20 mg, 0.064 mmol), (2-amino-5-bromopyridin-3-yl)(4-methylpiperazin-1-yl)methanone (preparation x56, 1 mL, 0.096 mmol), sodium carbonate (27.2 mg, 0.256) Methyl) and PdCl ₂ (dppf) CH ₂ Cl ₂ (5.23 mg, 6.41 μmol) were sealed in a vial and the vial was heated to 135 ° C for 30 minutes in a microwave reactor. The reaction mixture was purified by preparative HPLC eluting with ACN / H ₂ O (containing 0.05% TFA). The product-containing fractions were dried to give the title compound <RTIgt; ESI-MS m / z [M + H] + for C _{19 6} O Calcd of H ₁₉ F ₃ N: 405.2; Found: 405.3.

Example 283: 4-(6-(Trifluoromethyl)-1 H -indazol-4-yl)pyridinium

Add ammonium chloride (0.024 g, 0.456) to a mixture of 4-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridinecarboxylic acid (0.028 g, 0.091 mmol) in DMF (3 mL Eth), HOBt (0.018 g, 0.137 mmol) and EDC (0.028 g, 0.146 mmol), followed by N -ethyl- N -isopropylpropan-2-amine (0.079 mL, 0.456 mmol). The reaction mixture was stirred at room temperature for 18 hours. The crude reaction mixture was then purified by preparative HPLC eluting time of 6.5 minutes by containing 30 to 35% acetonitrile (containing 0.035% TFA) gradient of H ₂ O (containing 0.05% TFA). The product-containing fractions were combined with EtOAcqqqqqqqqqq ^{1 H NMR (400MHz, DMSO- d} 6) δ ppm 7.68 (s, 1 H), 7.80 (br s, 1 H), 7.95-8.15 (m, 2 H), 8.27 (br s, 1 H), 8.32 -8.47 (m, 2 H), 8.81 (d, J = 5.05 Hz, 1 H), 13.89 (br s, 1 H); ESI-MS m/z [M+H] ⁺ for C ₁₄ H ₉ F ₃ Calculated for N ₄ O: 307.1; found: 307.11.

Example 284: (4-Methylpiperazin-1-yl)(4-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridin-2-yl)methanone

The TFA salt of the title compound was prepared in a manner analogous to Example 283 using 1-methylpiperazine instead of ammonium chloride. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 2.79-2.90 (m, 3 H), 3.08-3.24 (m, 2 H), 3.33 - 3.53 (m, 3 H), 3.58 (d, J = 11.12) Hz, 1 H), 4.12 (d, J = 15.16 Hz, 1 H), 4.64 (d, J = 12.13 Hz, 1 H), 7.59-7.74 (m, 1 H), 7.95-8.07 (m, 2 H) ), 8.11 (s, 1 H), 8.40-8.48 (m, 1 H), 8.69-8.85 (m, 1 H), 9.96 (br s, 1 H); ESI-MS m/z [M+H] ⁺ for C _{19 5} O Calcd of H ₁₈ F ₃ N: 390.1; Found: 390.25.

Example 285: N- (2-Hydroxyethyl)-2-methoxy-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)nicotinamide

In a similar manner to Example 282, 5-bromo- N- (2-hydroxyethyl)-2-methoxynicotinium amide (preparation x59) was used instead of (2-amino-5-bromopyridine-3- (4-Methylpiperazin-1-yl)methanone to prepare the title compound as a TFA salt. ESI-MS m / z [M + H] + for _{C 17 H 15 F 3 N 4} O ₃ The calculated value: 381.1; Found: 381.2.

Example 286: N- (2-Hydroxyethyl)-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyrimidine-2-carboxamide

In a similar manner to Example 257, 5-bromo- N- (2-hydroxyethyl)pyrimidine-2-carboxamide was used instead of N- (5-bromo-6-methylpyridin-2-yl)methanesulfonate. The amine was used to prepare the TFA salt of the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 3.44 (q, J = 6.06 Hz, 2 H), 3.50 - 3.63 (m, 2 H), 3.67 - 3.79 (m, 1 H), 4.58 (t, J = 5.31 Hz, 1 H), 7.71-7.85 (m, 1 H), 8.10 (s, 1 H), 8.50 (s, 1 H), 8.90 (t, J = 5.94 Hz, 1 H), 9.35- 9.44 (m, 2 H); ESI-MS m / z [m + H] + calculated for C ₁₅ value of the _{2 H 12 F 3 N 5 O:} 352.1; Found: 352.19.

Example 287: (4-Methylpiperazin-1-yl)(5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridin-3-yl)methanone

In a similar manner to Example 282, (5-bromopyridin-3-yl)(4-methylpiperazin-1-yl)methanone (preparation x54) was used instead of (2-amino-5-bromopyridine-3) -Based (4-methylpiperazin-1-yl)methanone to prepare the title compound as a TFA salt. ESI-MS m / z [M + H] + for C _{19 5} O Calcd of H ₁₈ F ₃ N: 390.1; Found: 390.3.

Example 288: (2-Methoxy-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridin-3-yl)(4-methylpiperazin-1-yl) Ketone

In a similar manner to Example 282, (5-bromo-2-methoxypyridin-3-yl)(4-methylpiperazin-1-yl)methanone (preparation x55) was used instead of (2-amino)- 5-Bromopyridin-3-yl)(4-methylpiperazin-1-yl)methanone to give the title compound as a TFA salt. ESI-MS m / z [M + H] + for _{C 20 H 20 F 3 N 5} O ₂ computing the values: 420.2; Found: 420.3.

Example 289: (2-Fluoro-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridin-3-yl)(4-methylpiperazin-1-yl)methanone

In a similar manner to Example 282, (5-bromo-2-fluoropyridin-3-yl)(4-methylpiperazin-1-yl)methanone (preparation x57) was used instead of (2-amino-5-) Bromopyridin-3-yl)(4-methylpiperazin-1-yl)methanone to give the title compound as a TFA salt. ESI-MS m / z [M + H] + calcd for _{C 19 H 17 F 4 N 5} O of: 408.1; Found: 408.2.

Example 290: N- (2-Hydroxyethyl)-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)nicotinate

In a similar manner to Example 282, 5-bromo- N- (2-hydroxyethyl)nicotinium amide (preparation x58) was used instead of (2-amino-5-bromopyridin-3-yl) (4-A) The piperazine-1-yl)methanone was used to prepare the TFA salt of the title compound. ESI-MS m / z [M + H] + ₂ of the value calculated for _{C 16 H 13 F 3 N 4} O: 351.1; Found: 351.2.

Example 291: 4-(7-Methoxy-1 H -pyrrolo[2,3- c ]pyridin-4-yl)-6-(trifluoromethyl)-1 H -carbazole

In a similar manner to Example 247, (1-ethylindolyl-7-methoxy- 1H -pyrrolo[2,3- c ]pyridin-4-yl)boronic acid was used instead of N , N -dimethyl- 5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine-2-amine to give the title compound as a TFA salt. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 4.12 (s, 3 H), 6.28-6.50 (m, 1 H), 7.51 (d, J = 1.01 Hz, 1 H), 7.58 (t, J = 2.78 Hz, 1 H), 7.86-8.03 (m, 2 H), 8.14 (d, J = 0.76 Hz, 1 H), 12.11 (br s, 1 H); ESI-MS m/z [M+H] ⁺ for _{C 16 H 11 F 3 N 4} O of Calcd: 333.1; Found: 333.19.

Example 292: 4-(7-Methyl-1 H -pyrrolo[2,3- c ]pyridin-4-yl)-6-(trifluoromethyl)-1 H -indazole

In a similar manner to Example 247, 1-(7-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 was used. H -pyrrolo[2,3- c ]pyridin-1-yl)ethanone in place of N , N -dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-di Oxaborolan-2-yl)pyrimidin-2-amine to give the title compound as a TFA salt. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 3.03 (s, 3 H), 6.57 (br s, 1 H), 6.71 (d, J = 1.26 Hz, 1 H), 7.64 (s, 1 H) , 8.12 (d, J = 9.85 Hz, 1 H), 8.33 (br s, 1 H), 8.52 (s, 1 H), 13.36 (br s, 1 H), 13.91 (br s, 1 H); ESI -MS m / z [m + H ] + for C ₁₆ H ₁₁ F ₃ N ₄ of the calculated value: 317.1; Found: 317.16.

Example 293: N- (2-Methoxyethyl)-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyrimidin-2-amine

In a similar manner to Example 257, 5-bromo- N- (2-methoxyethyl)pyrimidin-2-amine was used in place of N- (5-bromo-6-methylpyridin-2-yl)methanesulfonate. The amine was used to prepare the TFA salt of the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 3.29 (s, 3 H), 3.44 - 3.60 (m, 4 H), 7.48 (d, J = 1.01 Hz, 1 H), 7.61 (br s, 1 H), 7.89 (s, 1 H), 8.40 (d, J = 1.01 Hz, 1 H), 8.76 (s, 2 H); ESI-MS m/z [M+H] ⁺ for C ₁₅ H ₁₄ F Calculated for ₃ N ₅ O: 338.1; found: 338.2.

Example 294: (N-morpholinyl)(5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyrimidin-2-yl)methanone

Substituting (5-bromopyrimidin-2-yl)(N-morpholinyl)methanone for N- (5-bromo-6-methylpyridin-2-yl)methanesulfonamide in a similar manner to Example 257 To prepare the TFA salt of the title compound. ^{1 H NMR (400MHz, DMSO- d} 6) δ ppm 3.24-3.37 (m, 2 H), 3.53-3.64 (m, 2 H), 3.71 (s, 4 H), 7.74 (d, J = 1.01Hz, 1 H), 8.08 (s, 1 H), 8.52 (d, J = 0.76 Hz, 1 H), 9.33 (s, 2 H); ESI-MS m/z [M+H] ⁺ for C ₁₇ H ₁₄ F ₃ N ₅ O ₂ computing the values: 378.1; Found: 378.21.

Example 295: 5-(6-(Trifluoromethyl)-1 H -indazol-4-yl)pyrimidine-2-carboxamide

The title compound as a TFA salt was prepared in a procedure analogous to Example 257, using 5-bromopyrimidine-2-carbamide as the N- (5-bromo-6-methylpyridin-2-yl)methanesulfonamide. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.77 (s, 1 H), 7.91 (br s, 1 H), 8.09 (s, 1 H), 8.32 (br s, 1 H), 8.49 (s , 1 H), 9.37 (s, 2 H), 13.87 (br s, 1 H); ESI-MS m/z [M+H] ⁺ Calculated for C ₁₃ H ₈ F ₃ N ₅ O: 308.1; Found: 308.11.

Example 296: 4-Methyl-6-(6-(trifluoromethyl)-1 H -indazol-4-yl)-2 H -benzo[ b ][1,4]oxazine-3 (4 H )-ketone

In a manner analogous to Example 247, the 4-methyl-6- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -2 H - benzene And [ b ][1,4]oxazin-3( 4H )-one replaces N , N -dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-di Oxaborolan-2-yl)pyrimidin-2-amine to give the title compound as a TFA salt. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 3.41 (s, 3 H), 4.75 (s, 2 H), 7.18 (d, J = 8.34 Hz, 1 H), 7.36-7.59 (m, 3 H ), 7.92 (s, 1 H), 8.39 (s, 1 H), 13.71 (br s, 1 H); ESI-MS m/z [M+H] ⁺ for C ₁₇ H ₁₂ F ₃ N ₃ O ₂ Calculated: 348.1; found: 348.16.

Example 297: 5-(4-Methylpiperazine-1-carbonyl)-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridine-2(1 H )-one

In a similar manner to Example 265, 3-bromo-5-(4-methylpiperazine-1-carbonyl)pyridine-2(1 H )-one was used in place of 5-iodo-6-sideoxy-1,6. Methyl dihydropyridine-3-carboxylate to prepare the TFA salt of the title compound. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.15 (s, 1H), 7.95 (d, J = 4.0 Hz, 1H), 7.92 (s, 1H), 7.87 (d, J = 4.0 Hz, 1H), 7.60 (s, 1H), 4.35-4.58 (m, 2H), 3.38-3.66 (m, 4H), 3.08-3.25 (m, 2H), 2.94 (s, 3H); ESI-MS m/z [M+ H] ⁺ for C ₁₉ F _{3 5} O ₂ calculates the value N H _18: 406.1; Found: 406.4.

Example 298: 5-(morpholine-4-carbonyl)-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridine-2(1 H )-one

In a manner similar to Example 265, 3-bromo-5-(morpholin-4-carbonyl)pyridine-2( 1H )-one was used in place of 5-iodo-6-o-oxy-1,6-dihydropyridine. The title compound was prepared from methyl 3-carboxylate. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.16 (s, 1H), 7.92 (d, J = 4.0 Hz, 1H), 7.91 (s, 1H), 7.80 (d, J = 4.0 Hz, 1H), 7.60 (s, 1H), 3.71 (br s, 8 H); ESI-MS m / z [m + H] + for C ₁₈ F _{3 4} O _Computation of the value H ₁₅ N: 393.1; Found: 393.3.

Example 299: N- (2-Hydroxyethyl)-6-oxo-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1,6-dihydropyridine- 3-methylamine

In a manner similar to Example 265, 5-bromo- N- (2-hydroxyethyl)-6-oxo-1,6-dihydropyridine-3-carboxamide was used instead of 5-iodo-6-side. The title compound was prepared from methyl oxy-1,6-dihydropyridine-3-carboxylate. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.30 (d, J = 2.0 Hz, 1H), 8.18 (d, J = 2.0 Hz, 1H), 8.15 (s, 1H), 7.91 (s, 1H), 7.60 (s, 1H), 3.70 (t, J = 4.0, 8.0 Hz, 2H), 3.48 (t, J = 4.0, 8.0 Hz, 2H); ESI-MS m/z [M+H] ⁺ for C ₁₆ H ₁₃ F ₃ N ₄ O ₃ calcd.: 367.1; Found: 367.3.

Example 300: 2-(3-Methyl-2,6-di-oxy-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)-2,3-dihydropyrimidine -1(6 H )-yl)acetamide

In a manner analogous to Example 265, the use of 2- (5-bromo-3-oxo-2,3-methyl-2,6-dihydropyrimidine -1 (6 H) - yl) amine instead of acetyl The title compound was prepared as 5-iodo-6-oxooxy-1,6-dihydropyridine-3-carboxylic acid methyl ester. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.15 (s, 1H), 8.00 (s, 1H), 7.86 (s, 1H), 7.48 (s, 1H), 4.72 (s, 2H), 3.51 (s) , 3H); ESI-MS m / z [m + H] + for C ₁₅ F _{3 5} O ₃ the calculated value N H _12: 368.1; Found: 368.3.

Example 301: N -Methyl-2-(3-methyl-2,6-di-oxy-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)-2, 3-dihydropyrimidin-1(6 H )-yl)acetamide

In a similar manner to Example 265, 2-(5-bromo-3-methyl-2,6-di- oxo-2,3-dihydropyrimidin-1(6 H )-yl) -N -A was used. The title compound was prepared by substituting methyl acetalamine for methyl 5-iodo-6-oxo-1,6-dihydropyridine-3-carboxylate. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.15 (s, 1H), 8.01 (s, 1H), 7.86 (s, 1H), 7.48 (s, 1H), 4.69 (s, 2H), 3.51 (s) , 3H), 2.78 (s, 3H); ESI-MS m / z [m + H] + for _{C 16 H 14 F 3 N 5} O ₃ the calculated value: 382.1; Found: 382.3.

Example 302: N -ethyl-2-(3-methyl-2,6-di-oxy-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)-2, 3-dihydropyrimidin-1(6 H )-yl)acetamide

In a similar manner to Example 265, 2-(5-bromo-3-methyl-2,6-di- oxo-2,3-dihydropyrimidin-1(6 H )-yl) -N -B was used. The title compound was prepared by substituting methyl acetalamine for methyl 5-iodo-6-oxo-1,6-dihydropyridine-3-carboxylate. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.15 (s, 1H), 8.01 (s, 1H), 7.86 (s, 1H), 7.48 (s, 1H), 4.68 (s, 2H), 3.26 (q) , J = 4.0, 8.0 Hz, 2H), 1.15 (t, J = 8.0, 8.0 Hz, 3H); ESI-MS m/z [M+H] ⁺ for C ₁₇ H ₁₆ F ₃ N ₅ O ₃ Value: 396.1; Found: 396.3.

Example 303: 3-(2-Hydroxyethyl)-1-methyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyrimidine-2,4 (1 H , 3 H )-dione

In a manner similar to Example 265, 5-bromo-3-(2-hydroxyethyl)-1-methylpyrimidine-2,4(1 H ,3 H )-dione was used in place of 5-iodo-6-side The title compound was prepared from methyl oxy-1,6-dihydropyridine-3-carboxylate. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.15 (s, 1H), 7.98 (s, 1H), 7.86 (s, 1H), 7.47 (s, 1H), 4.71 (t, J = 4.0, 8.0 Hz , 1 H), 4.44 (t, J = 4.0, 8.0 Hz, 1H), 4.22 (t, J = 4.0, 8.0 Hz, 1H), 3.81 (t, J = 8.0, 8.0 Hz, 1H), 3.49 (s) , 3H); ESI-MS m / z [m + H] + calculated for F _{3 4} O ₃ value of N C ₁₅ H _13: 355.1; Found: 355.3.

Example 304: 3-methoxy- N -methyl-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzamide

3-methoxy-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzoic acid (0.04 g, 0.119 mmol), EDC (0.034 g, 0.178 mmol), HOBt 0.027 g, 0.178 mmol), methylamine (0.178 mL, 0.357 mmol), DMA (1 mL) and DIPEA (0.062 mL, 0.357 mmol). The vial was capped and the reaction mixture was stirred at room temperature for 2 days. The reaction mixture was then diluted with MeOH and purified by preparative HPLC eluting with _&lt; RTI ID=0.0&gt _; 0&gt _; The product was taken up in vacuo to dryness crystals crystals crystals ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 2.84 (d, J = 4.29 Hz, 3 H), 3.83 (s, 3 H), 7.37 (s, 1 H), 7.49-7.56 (m, 1 H) ), 7.56-7.62 (m, 1 H), 7.65 (s, 1 H), 7.94 (s, 1 H), 7.97 (s, 1 H), 8.60 (d, J = 4.55 Hz, 1 H), 13.61 (br s, 1 H); ESI-MS m / z [m + H] + for _{C 17 H 14 F 3 N 3} O ₂ calculated sum value: 350.1; Found: 350.2.

Example 305: N- (2-Hydroxyethyl)-3-methoxy-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzamide

The title compound of the title compound was prepared in a similar manner to Example 304 using ethanolamine instead of methylamine. ^{1 H NMR (400MHz, DMSO- d} 6) δ ppm 3.37-3.43 (m, 2 H), 3.56 (q, J = 5.89Hz, 2 H), 3.83 (s, 3 H), 7.36 (s, 1 H ), 7.53 (d, J = 7.83 Hz, 1 H), 7.58-7.65 (m, 1 H), 7.67 (s, 1 H), 7.94 (s, 1 H), 7.97 (s, 1 H), 8.62 (t, J = 5.56Hz, 1 H); ESI-MS m / z [m + H] + for _{C 18 H 16 F 3 N 3} O ₃ calculated sum value: 380.1; Found: 380.3.

Example 306: 3-Methoxy-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzamide

The title compound of the title compound was prepared in a similar manner to Example 304 using ammonium chloride instead of methylamine. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 3.83 (s, 3 H), 7.37 (s, 1 H), 7.52 (d, J = 7.83 Hz, 2 H), 7.60-7.67 (m, 1 H) ), 7.69 (s, 1 H), 7.94 (s, 1 H), 7.97 (s, 1 H), 8.14 (s, 1 H), 13.60 (br s, 1 H); ESI-MS m/z [ M ⁺ H] + for _{C 16 H 12 F 3 N 3} O ₂ calculated sum value: 336.1; Found: 336.2.

Example 307: N- (2-Hydroxyethyl)-4-methyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridinium

In a similar manner to Example 270, methyl 4-methyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridinecarboxylate was used instead of 5-(6-(trifluoromethyl). The methyl ester of -1 H -indazol-4-yl)pyridinecarboxylate afforded the title compound as a TFA salt. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 2.29 (br s, 3 H), 3.57 (br s, 2 H), 3.72-3.78 (m, 2 H), 7.27-7.40 (m, 1 H), 7.91 (br s, 1 H), 8.00 (br s, 1 H), 8.12 (br s, 1 H), 8.60 (s, 1 H); ESI-MS m/z [M+H] ⁺ for C ₁₇ H ₁₅ F ₃ N ₄ O ₂ calcd.: 365.1; found: 365.

Example 308: N- (2-Hydroxyethyl)-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridinium

The title was prepared in a similar manner to Example 257 using 4-bromo- N- (2-hydroxyethyl)pyridiniumamine instead of N- (5-bromo-6-methylpyridin-2-yl)methanesulfonamide. a TFA salt of the compound. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 3.44 (q, J = 5.98 Hz, 2 H), 3.57 (t, J = 6.06 Hz, 2 H), 7.69 (d, J = 1.01 Hz, 1 H ), 8.00-8.14 (m, 2 H), 8.30-8.46 (m, 2 H), 8.74 - 8.91 (m, 2 H); ESI-MS m/z [M+H] ⁺ for C ₁₆ H ₁₃ F Calculated for ₃ N ₄ O ₂ : 351.1; found: 351.16.

Example 309: N , N -Dimethyl-2-(3-methyl-2,6-di-oxy-5-(6-(trifluoromethyl)-1 H -indazol-4-yl) -2,3-dihydropyrimidin-1(6 H )-yl)acetamide

In a similar manner to Example 265, 2-(5-bromo-3-methyl-2,6-di- oxo-2,3-dihydropyrimidin-1(6 H )-yl) -N , N was used. The title compound was prepared by substituting dimethylacetamide for methyl 5-iodo-6-oxo-1,6-dihydropyridine-3-carboxylate. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.15 (s, 1H), 8.02 (s, 1H), 7.87 (s, 1H), 7.49 (s, 1H), 4.92 (s, 2H), 3.57-3.79 (m, 8H), 3.51 ( s, 3H); ESI-MS m / z [m + H] + for _{C 17 H 16 F 3 N 5} O ₃ the calculated value: 396.1; Found: 396.3.

Example 310: 1-Methyl-3-(2-(N-morpholinyl)-2-oxoethyl)-5-(6-(trifluoromethyl)-1 H -indazole-4- Pyrimidine-2,4(1 H ,3 H )-dione

In a similar manner to Example 265, 5-bromo-1-methyl-3-(2-(N-morpholinyl)-2-yloxyethyl)pyrimidine-2,4( 1H , 3H was used. The title compound was prepared by substituting 5-dione for methyl 5-iodo-6-oxo-1,6-dihydropyridine-3-carboxylate. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.15 (s, 1H), 8.02 (s, 1H), 7.87 (s, 1H), 7.49 (s, 1H), 4.92 (s, 2H), 3.57-3.79 (m, 8H), 3.51 ( s, 3H); ESI-MS m / z [m + H] + for C _{19 3} N ₅ O ₄ calculated values of H ₁₈ F: 438.1; Found: 438.4.

Example 311: 3-(4-Fluorobenzyl)-1-methyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyrimidine-2,4 (1 H , 3 H )-dione

In a manner similar to Example 265, 5-bromo-3-(4-fluorobenzyl)-1-methylpyrimidine-2,4(1 H ,3 H )-dione was used in place of 5-iodo-6-side. The title compound was prepared from methyl oxy-1,6-dihydropyridine-3-carboxylate. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.09 (s, 1H), 7.97 (s, 1H), 7.86 (s, 1H), 7.46-7.52 (m, 2H), 7.00-7.06 (m, 2H) , 5.19 (s, 2H), 3.49 (s, 3H); ESI-MS m / z [m + H] + for _{C 20 H 14 F 4 N 4} O ₂ computing the values: 419.1; Found: 419.3.

Example 312: 2-(3-Methyl-2,6-di-oxy-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)-2,3-dihydropyrimidine -1(6 H )-yl)acetonitrile

In a manner similar to Example 265, 2-(5-bromo-3-methyl-2,6-di- oxo-2,3-dihydropyrimidin-1( 6H )-yl)acetonitrile was used instead of 5- The title compound was prepared from methyl iodo-6-oxo-1,6-dihydropyridine-3-carboxylate. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.17 (s, 1H), 8.04 (s, 1H), 7.88 (s, 1H), 7.51 (s, 1H), 4.99 (s, 2H), 3.53 (s) , 3H); ESI-MS m / z [m + H] + for _{C 15 H 10 F 3 N 5} O ₂ computing the values: 350.1; Found: 350.3.

Example 313: 1-Methyl-3-(2-(N-morpholinyl)ethyl)-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyrimidine-2, 4(1 H ,3 H )-dione

In a manner similar to Example 265, 5-bromo-1-methyl-3-(2-(N-morpholinyl)ethyl)pyrimidine-2,4(1 H ,3 H )-dione was used instead of 5 - Iodo-6-oxooxy-1,6-dihydropyridine-3-carboxylic acid methyl ester to give the title compound. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.21 (s, 1H), 8.03 (s, 1H), 7.88 (s, 1H), 7.48 (s, 1H), 4.46 (t, J = 8.0, 8.0 Hz , 2H), 4.00-4.13 (m, 2H), 3.69-3.89 (m, 4H), 3.57 (t, J = 8.0, 8.0 Hz, 2H), 3.52 (s, 3H), 3.13 - 3.27 (m, 2H) ); ESI-MS m / z [m + H] + for C _{19 3 5} O ₃ the calculated value N H ₂₀ F: 424.2; Found: 424.4.

Example 314: 1-Methyl-5-(morpholin-4-carbonyl)-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridine-2(1 H ) ketone

In a similar manner to Example 265, 3-bromo-1-methyl-5-(morpholine-4-carbonyl)pyridine-2(1 H )-one was used in place of 5-iodo-6-oxy-1. Methyl 6-dihydropyridine-3-carboxylate was used to prepare the title compound. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.12 (s, 1H), 8.09 (d, J = 4.0 Hz, 1H), 7.90 (s, 1H), 7.86 (d, J = 4.0 Hz, 1H), 7.58 (s, 1H), 3.71 (br s, 11H); ESI-MS m / z [m + H] + for C ₁₉ F _{3 4} O ₃ the calculated value N H _17: 407.1; Found: 407.4.

Example 315: N -(2-hydroxyethyl)-1-methyl-6-oxo-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1,6 -dihydropyridine-3-carboxamide

In a manner similar to Example 265, 5-bromo- N- (2-hydroxyethyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide was used instead of 5-. The title compound was prepared from methyl iodo-6-oxo-1,6-dihydropyridine-3-carboxylate. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.44 (d, J = 4.0 Hz, 1H), 8.22 (d, J = 4.0 Hz, 1H), 8.12 (s, 1H), 7.90 (s, 1H), 7.57 (s, 1H), 3.73 (s, 3H), 3.70 (t, J = 8.0, 8.0 Hz, 2H), 3.48 (t, J = 8.0, 8.0 Hz, 2H); ESI-MS m/z [M + H] ⁺ for _{C 17 H 15 F 3 N 4} O ₃ the calculated value: 381.1; Found: 381.3.

Example 316: 2-(4-Methoxy-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)phenyl)-1-(N-morpholinyl)ethanone

Trimethylaluminum (0.549 mL, 1.098 mmol) in toluene was added dropwise to a 20 mL vial containing morpholine (0.096 g, 1.09 mmol) in dioxane (5 mL). After stirring at room temperature for 15 minutes, methyl 2-(4-methoxy-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)phenyl)acetate (0.1 g) , 0.274 mmol). The reaction mixture was heated in a microwave reactor at 110 °C for 1 hour and then transferred to a round bottom flask which was quenched with concentrated HCl. The mixture was concentrated and the crude residue was purified by preparative HPLC eluting with &_lt;RTIgt;&lt;/RTI&gt;&gt;_&lt;/RTI&gt_;< / RTI></RTI> with 35% acetonitrile (containing 0.035% TFA) in H2O (containing 0.05% TFA) over 10 min. The product-containing fractions were combined with EtOAc EtOAcjjjjjjjj ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 3.51-3.68 (m, 8 H), 3.74-3.85 (m, 5 H), 7.15 (d, J = 8.34 Hz, 1 H), 7.28-7.40 (m) , 3 H), 7.85 (s, 1 H), 7.93 (d, J = 0.76 Hz, 1 H); ESI-MS m/z [M+H] ⁺ for C ₂₁ H ₂₀ F ₃ N ₃ O ₃ Calculated: 420.1; found: 420.2.

Example 317: 2-(3,5-Dimethyl-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1 H -pyrazol-1-yl)-1- (N-morpholinyl) ethyl ketone

In a similar manner to Example 283, 2-(3,5-dimethyl-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1 H -pyrazole-1 was used. The -TF)-acetic acid was used in place of 4-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridinecarboxylic acid to give the title compound as a TFA salt. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 2.17 (d, J = 2.53 Hz, 6 H), 3.59-3.67 (m, 4 H), 3.67-3.74 (m, 2 H), 3.74-3.81 (m) , 2 H), 5.18 (s, 2 H), 7.24 (d, J = 1.26 Hz, 1 H), 7.88 (s, 1 H), 8.00 (d, J = 1.01 Hz, 1 H); ESI-MS m / z [m + H] + calculated for C ₁₉ value of the _{2 H 20 F 3 N 5 O:} 408.2; Found: 408.21.

Example 318: (3-Methoxy-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)phenyl)(N-morpholinyl)methanone

In a similar manner to Example 283, 3-methoxy-6(6-(trifluoromethyl)-1 H -indazol-4-yl)benzoic acid was used instead of 4-(6-(trifluoromethyl) The title compound was prepared by the- 1H -oxazol-4-yl)pyridinecarboxylic acid. ¹ H NMR (400 MHz, CDCl ₃ ) δ ppm 3.58 (d, J = 8.34 Hz, 1 H), 3.63-3.92 (m, 10 H), 7.07-7.17 (m, 2 H), 7.38-7.51 (m, 2 H), 7.77-7.83 (m, 1 H), 7.99 (br s, 1 H); ESI-MS m/z [M+H] ⁺ calculated for C ₂₀ H ₁₈ F ₃ N ₃ O ₃ : 406.1; Found: 406.21.

Example 319: 3-(2-(Dimethylamino)ethyl)-1-methyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyrimidine-2, 4(1 H ,3 H )-dione

In a manner similar to Example 265, 5-bromo-3-(2-(dimethylamino)ethyl)-1-methylpyrimidine-2,4(1 H ,3 H )-dione was used instead of 5 - Iodo-6-oxooxy-1,6-dihydropyridine-3-carboxylic acid methyl ester to prepare the title compound as a TFA salt. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.19 (s, 1H), 8.04 (s, 1H), 7.89 (s, 1H), 7.50 (s, 1H), 4.44 (t, J = 4.0, 8.0 Hz , 2H), 3.49-3.54 (m, 5H), 3.02 (s, 6H); ESI-MS m/z [M+H] ⁺ calculated for C ₁₇ H ₁₈ F ₃ N ₅ O ₂ : 382.1; Value: 382.4.

Example 320: N- (2-Hydroxyethyl)-2-(4-methoxy-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)phenyl)acetamide

In a similar manner to Example 316, 2-aminoethanol was used instead of morpholine to afford the title compound as a TFA salt. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 3.49-3.63 (m, 4 H), 3.78 (d, J = 1.26 Hz, 3 H), 4.43 (t, J = 5.31 Hz, 1 H), 7.08- 7.17 (m, 1 H), 7.32-7.43 (m, 3 H), 7.84 (s, 1 H), 7.93 (dd, J = 6.82, 1.01 Hz, 1 H); ESI-MS m/z [M+ H] ⁺ for C ₁₉ F N ₃ O ₃ calculated sum values of ₃ H _18: 394.1; Found: 394.21.

Example 321: 3-Fluoro-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzamide

Trimethylaluminum (1.183 mL, 2.365 mmol) in toluene was added dropwise to a 20 mL vial containing ammonium chloride (0.127 g, 2.365 mmol) in dioxane (8 mL). After stirring at room temperature for 10 minutes, methyl 3-fluoro-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzoate (0.2 g, 0.591 mmol) was added. The mixture was heated at 110 ° C for 1 hour in a microwave reactor. The reaction mixture was transferred to a round bottom flask and quenched with cone. HCl. The mixture was then concentrated, and the crude residue was purified by a 35% acetonitrile (containing 0.035% TFA) of H ₂ O (containing 0.05% TFA) was purified by preparative HPLC 6.5 minutes of fractions. The product-containing fractions were combined with EtOAc EtOAcjjjjjjj ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.49 (s, 1 H), 7.64 (s, 1 H), 7.73-7.86 (m, 1 H), 7.86-7.96 (m, 2 H), 8.04 (s, 1 H), 8.14 (s, 1 H), 8.20 (s, 1 H); ESI-MS m/z [M+H] ⁺ Calculated for C ₁₅ H ₉ F ₄ N ₃ O: 324.1 ;Measured value: 324.11.

Example 322: 3-Fluoro- N- (2-hydroxyethyl)-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzamide

The TFA salt of the title compound was prepared in a procedure analogous to Example 321 using 2-aminoethanolamine hydrochloride instead of ammonium chloride. ^{1 H NMR (400MHz, DMSO- d} 6) δ ppm 3.38-3.46 (m, 2 H), 3.48-3.62 (m, 2 H), 4.78 (br s, 1 H), 7.49 (s, 1 H), 7.74-7.84(m,1 H), 7.89 (d, J = 9.35 Hz, 2 H), 8.04 (s, 1 H), 8.13 (s, 1 H), 8.69 (t, J = 5.56 Hz, 1 H ), 13.77 (s, 1 H ); ESI-MS m / z [m + H] + for the ₄ N ₃ O ₂ calculated values of C ₁₇ H ₁₃ F: 368.1; Found: 368.16.

Example 323: 4-(5-(Methoxymethyl)-3-methyl-1 H -pyrazol-4-yl)-6-(trifluoromethyl)-1 H -carbazole

In a similar manner to Example 257, 4-bromo-5-(methoxymethyl)-3-methyl-1 H -pyrazole was used instead of N- (5-bromo-6-methylpyridin-2-yl) Methanesulfonamide to prepare the TFA salt of the title compound. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 2.27 (s, 3 H), 3.29 (s, 3 H), 4.35 (s, 2 H), 7.33 (d, J = 1.26 Hz, 1 H), 7.89 (s, 1 H), 8.01 (d, J = 1.01 Hz, 1 H); ESI-MS m/z [M+H] ⁺ Calculated for C ₁₄ H ₁₃ F ₃ N ₄ O: 311.1; :311.15.

Example 324: 1-(3,5-Dimethyl-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1 H -pyrazol-1-yl)propane-2 -ketone

In a similar manner to Example 257, 1-(4-bromo-3,5-dimethyl-1 H -pyrazol-1-yl)propan-2-one was used instead of N- (5-bromo-6-- Pyridin-2-yl)methanesulfonamide to prepare the title compound as a TFA salt. ^{1 H NMR (400MHz, DMSO- d} 6) δ ppm 2.08 (d, J = 8.59Hz, 6 H), 2.18 (s, 3 H), 5.12 (s, 2 H), 7.17 (d, J = 1.26Hz , 1 H), 7.87 (s, 1 H), 7.96 (d, J = 0.76 Hz, 1 H); ESI-MS m/z [M+H] ⁺ for C ₁₆ H ₁₅ F ₃ N ₄ O Value: 337.1; found: 337.2.

Example 325: 4-(4-Methoxy-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzylidenyl)-1-methylpiperazin-2-one

Trimethylaluminum in toluene (0.571) was added dropwise to a vial containing 1-methylpiperazin-2-one hydrochloride (0.172 g, 1.142 mmol) in dioxane (5 mL). mL, 1.142 mmol). After stirring at room temperature for 15 minutes, methyl 4-methoxy-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzoate (0.1 g, 0.285 mmol) was added. The mixture was heated in a microwave reactor at 110 ° C for 1 hour and then transferred to a round bottom flask. The reaction mixture was quenched with cone. HCl and concentrated. The crude residue was purified by preparative HPLC eluting with &_lt;RTIID=0.0&gt_;0&gt_; The product-containing fractions were combined with EtOAc EtOAcjjjjjjj ^{1 H NMR (400MHz, DMSO- d} 6) δ ppm 2.86 (s, 3 H), 3.37 (t, J = 5.43Hz, 2 H), 3.70-3.86 (m, 5 H), 4.12 (s, 2 H ), 7.29 (d, J = 8.59 Hz, 1 H), 7.37 (d, J = 1.01 Hz, 1 H), 7.52 (d, J = 2.02 Hz, 1 H), 7.61 (dd, J = 8.59, 2.27) Hz, 1 H), 7.94 (s, 1 H), 7.99 (d, J = 0.76 Hz, 1 H); ESI-MS m/z [M+H] ⁺ for C ₂₁ H ₁₉ F ₃ N ₄ O ₃ Calculated: 433.1; found: 433.22.

Example 326: 4-Fluoro-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzamide

In a manner analogous to Example 247, (5-amine-mercapto-2-fluorophenyl)boronic acid was used instead of N , N -dimethyl-5-(4,4,5,5-tetramethyl-1, 3,2-Dioxaboran-2-yl)pyrimidine-2-amine to prepare the title compound as a TFA salt. ^{1 H NMR (400MHz, DMSO- d} 6) δ ppm 7.47-7.58 (m, 3 H), 7.96-8.11 (m, 2 H), 8.11-8.24 (m, 3 H), 13.75 (s, 1 H) ; ESI-MS m / z [ m + H] + calcd for _{C 15 H 9 F 4 N 3} O of: 324.1; Found: 324.11.

Example 327: 1,3-Dimethyl-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1 H -pyrazole-5-carboxamide

In a manner similar to Example 257, 4-bromo-1,3-dimethyl-1 H -pyrazole-5-carboxamide was used instead of N- (5-bromo-6-methylpyridin-2-yl). Methanesulfonamide to prepare the TFA salt of the title compound. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 2.18 (s, 3 H), 4.03 (s, 3 H), 7.33 (d, J = 1.01 Hz, 1 H), 7.84-7.93 (m, 1 H) , 7.96 (d, J = 1.01Hz , 1 H); ESI-MS m / z [m + H] + for C _{14 5} O Calcd of H ₁₂ F ₃ N: 324.1; Found: 324.15.

Example 328: (3-Hydroxyazetidin-1-yl)(4-methoxy-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)phenyl) A ketone

In a similar manner to Example 325, the title compound as a TFA salt was prepared using azetidine-3-ol hydrochloride. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 3.82 (s, 4 H), 4.09 (br s, 1 H), 4.24 (br s, 1 H), 4.50 (d, J = 4.29 Hz, 2 H ), 5.75 (d, J = 5.81 Hz, 1 H), 7.27 (d, J = 8.84 Hz, 1 H), 7.35 (d, J = 1.01 Hz, 1 H), 7.65 (d, J = 2.27 Hz, 1 H), 7.77 (dd, J = 8.59, 2.27 Hz, 1 H), 7.96 (s, 1 H), 7.93 (s, 1 H), 13.60 (s, 1 H); ESI-MS m/z [ M ⁺ H] + for C _{19 3 3} O ₃ calculated sum values N H ₁₆ F: 392.1; Found: 392.21.

Example 329: 3-(6-(Trifluoromethyl)-1 H -indazol-4-yl)benzenesulfonamide

4-Bromo-6-(trifluoromethyl)-1 H -indazole (40 mg, 0.151 mmol), (3-aminesulfonylphenyl)boronic acid (45.5 mg, 0.226 mmol), PdCl ₂ (dppf) (11.04 mg, 0.015 mmol), sodium bicarbonate (323 μL, 0.604 mmol) and dioxane were combined in a 10 mL vial to give an orange suspension. The vial was sealed and then heated to 140 ° C in a microwave reactor for 20 minutes. The reaction mixture was then filtered, and the product by using 35% to 70% ACN gradient of H ₂ O (containing 10mM NH ₄ HCO ₃₎ was purified from the solution by preparative HPLC. The title compound (35.8 mg, 69.5%) was obtained as a white solid. ^{1 H NMR (400MHz, DMSO- d} 6) δ ppm 7.50 (s, 2 H), 7.53 (s, 1 H), 7.75-7.80 (m, 1 H), 7.92-7.94 (m, 1 H), 8.02 (s, 1 H), 8.06 (dt, J = 8.02, 1.29 Hz, 1H), 8.21 (t, J = 1.64 Hz, 1 H), 8.40 (s, 1 H); ESI-MS m/z [M + H] ⁺ for _{C 14 H 10 F 3 N 3} O ₂ S calculated sum value: 342.0; Found: 342.2.

Example 330: N- (2-Hydroxyethyl)-3-methyl-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzamide

In a similar manner to Example 270, methyl 3-methyl-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzoate was used instead of 5-(6-(trifluoromethyl). The methyl ester of -1 H -indazol-4-yl)pyridinecarboxylate afforded the title compound as a TFA salt. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 2.23 (s, 3 H), 3.55 (t, J = 5.94 Hz, 2 H), 3.75 (t, J = 5.81 Hz, 2 H), 7.26 (d, J = 1.01 Hz, 1 H), 7.42 (d, J = 7.83 Hz, 1 H), 7.75-7.85 (m, 2 H), 7.85-7.92 (m, 1 H), 7.94 (s, 1 H); ESI-MS m / z [m + H] + for _{C 18 H 16 F 3 N 3} O ₂ calculated sum value: 364.1; Found: 364.19.

Example 331: 3-Chloro- N- (2-hydroxyethyl)-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzamide

In a similar manner to Example 270, methyl 3-chloro-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzoate was used instead of 5-(6-(trifluoromethyl) ) -1 H - indazol-4-yl) picolinate the title compound was prepared TFA salt of. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 3.47-3.60 (m, 1 H), 3.70-3.84 (m, 2 H), 4.60 (t, J = 5.31 Hz, 1 H), 7.35-7.40 (m) , 1 H), 7.55-7.69 (m, 1 H), 7.84-8.02 (m, 3 H), 8.04-8.16 (m, 1 H); ESI-MS m/z [M+H] ⁺ for C ₁₇ H ₁₃ ClF ₃ N ₃ O ₂ calculated sum value: 384.1; Found: 384.18.

Example 332: N -cyclopropyl-6-o-oxy-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1,6-dihydropyridine-3-carboxamidine amine

In a manner similar to Example 265, 5-bromo- N -cyclopropyl-6-o-oxy-1,6-dihydropyridine-3-carboxamide was used instead of 5-iodo-6-sideoxy-1. The title compound was prepared as methyl 6-dihydropyridine-3-carboxylate. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.26 (d, J = 2.0 Hz, 1H), 8.15 (d, J = 2.0 Hz, 1H), 8.12 (s, 1H), 7.91 (s, 1H), 7.59 (s, 1H), 2.79-2.87 (m, 1H), 0.76-0.83 (m, 2H), 0.59-0.65 (m, 1H); ESI-MS m/z [M+H] ⁺ for C ₁₇ H Calculated for ₁₃ F ₃ N ₄ O ₂ : 363.1; found: 363.3.

Example 333: N- (Cyanomethyl)-6-oxo-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1,6-dihydropyridine-3 -Procarbamide

In a manner similar to Example 265, 5-bromo- N- (cyanomethyl)-6-o-oxy-1,6-dihydropyridine-3-carboxamide was used instead of 5-iodo-6-side oxygen. The title compound was prepared from methyl-1,6-dihydropyridine-3-carboxylate. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.26 (d, J = 4.0 Hz, 1H), 8.21 (d, J = 4.0 Hz, 1H), 8.14 (s, 1H), 7.92 (s, 1H), 7.61 (s, 1H), 4.31 (s, 2H); ESI-MS m / z [m + H] + for _{C 16 H 10 F 3 N 5} O ₂ computing the values: 362.1; Found: 362.3.

Example 334: N , N -Dimethyl-6-oxo-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1,6-dihydropyridine-3- Formamide

In a manner similar to Example 265, 5-bromo- N,N -dimethyl-6-o-oxy-1,6-dihydropyridine-3-carboxamide was used instead of 5-iodo-6-sideoxy. The title compound was prepared using methyl-1,6-dihydropyridine-3-carboxylate. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.16 (s, 1H), 7.95 (d, J = 4.0 Hz, 1H), 7.91 (1H), 7.81 (d, J = 4.0 Hz, 1H), 7.60 ( s, 1H), 3.08-3.21 (br s, 6H); ESI-MS m/z (M+H) ⁺ Calculated for C ₁₆ H ₁₃ F ₃ N ₄ O ₂ : 351.1;

Example 335 :( S) - N - ( 2- hydroxypropyl) -6-oxo-5- (6- (trifluoromethyl) -1 H - indazol-4-yl) -1,6 Dihydropyridine-3-carboxamide

In a similar manner to Example 265, ( S )-5-bromo- N- (2-hydroxypropyl)-6-oxo-1,6-dihydropyridine-3-carboxamide was used instead of 5-iodine. The title compound was prepared from methyl-6-o-oxo-1,6-dihydropyridine-3-carboxylate. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.30 (d, J = 4.0 Hz, 1H), 8.18 (d, J = 4.0 Hz, 1H), 8.14 (s, 1H), 7.91 (s, 1H), 7.60 (s, 1H), 3.89-32.99 (m, 1H), 3.23 - 3.44 (m, 2H), 1.19 (d, J = 8.0 Hz, 3H); ESI-MS m/z [M+H] ⁺ Calcd for C ₁₇ H ₁₅ F ₃ N ₄ O ₃ : 381.1; found: 381.3.

Examples 336 :( R) - N - ( 2- hydroxypropyl) -6-oxo-5- (6- (trifluoromethyl) -1 H - indazol-4-yl) -1,6 Dihydropyridine-3-carboxamide

In a manner similar to Example 265, ( R )-5-bromo- N- (2-hydroxypropyl)-6-oxo-1,6-dihydropyridine-3-carboxamide was used instead of 5-iodine. The title compound was prepared from methyl-6-o-oxo-1,6-dihydropyridine-3-carboxylate. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.30 (d, J = 4.0 Hz, 1H), 8.18 (d, J = 4.0 Hz, 1H), 8.14 (s, 1H), 7.91 (s, 1H), 7.60 (s, 1H), 3.90-3.99 (m, 1H), 3.23 - 3.44 (m, 2H), 1.19 (d, J = 8.0 Hz, 3H); ESI-MS m/z [M+H] ⁺ Calcd for C ₁₇ H ₁₅ F ₃ N ₄ O ₃ : 381.1; found: 381.3.

Example 337: N- (2,3-Dihydroxypropyl)-6-oxo-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1,6-di Hydropyridine-3-carbamide

In a manner similar to Example 265, 5-bromo- N- (2,3-dihydroxypropyl)-6-o-oxy-1,6-dihydropyridine-3-carboxamide was used instead of 5-iodo- 6-Phenoxy-1,6-dihydropyridine-3-carboxylic acid methyl ester to give the title compound. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.29 (d, J = 4.0 Hz, 1H), 8.18 (d, J = 4.0 Hz, 1H), 8.14 (s, 1H), 7.91 (s, 1H), 7.60(s,1H), 3.75-3.86(m,1H), 3.47-3,59(m,4H),3.33-3.43(m,1H);ESI-MS m/z[M+H] ⁺ for C ₁₇ H ₁₅ F ₃ N ₄ O ₄ calculated sum value: 397.1; Found: 397.3.

Example 338: N- (2,2-Difluoroethyl)-6-oxo-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1,6-di Hydropyridine-3-carbamide

In a manner similar to Example 265, 5-bromo- N- (2,2-difluoroethyl)-6-o-oxy-1,6-dihydropyridine-3-carboxamide was used instead of 5-iodo- 6-Phenoxy-1,6-dihydropyridine-3-carboxylic acid methyl ester to give the title compound. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.29 (d, J = 4.0 Hz, 1H), 8.19 (d, J = 4.0 Hz, 1H), 8.14 (s, 1H), 7.91 (s, 1H), 7.60(s,1H), 5.83-6.16(m,1H), 3.66-3.77(m,2H); ESI-MS m/z[M+H] ⁺ for C ₁₆ H ₁₁ F ₅ N ₄ O ₂ Value: 387.1; found: 387.3.

Example 339: 4-(3-Fluoro-1 H -pyrrolo[2,3- b ]pyridin-5-yl)-6-(trifluoromethyl)-1 H -carbazole

4-Bromo-6-(trifluoromethyl)-1 H -indazole (60 mg, 0.226 mmol), (3-fluoro-1 H -pyrrolo[2,3- b ]pyridin-5-yl)boronic acid (61.1 mg, 0.340 mmol) and a mixture of PdCl ₂ (dppf) CH ₂ Cl ₂ (9.31 mg, 0.011 mmol) in dioxane (4 mL) and sat. NaHCO ₃ (2 mL). The resulting brown suspension was heated in a microwave reactor at 130 ° C for 30 minutes. Followed by containing 65 to 80% acetonitrile (containing 0.035% TFA) gradient of H ₂ O (containing 0.05% TFA) solution to preparative HPLC purification from the reaction mixture. The product was partitioned and dried to give the title compound (1. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 7.34 (d, J = 2.27 Hz, 1 H), 7.50 (d, J = 1.01 Hz, 1 H), 7.92 (s, 1 H), 8.29 (d, J = 1.01 Hz, 1 H), 8.36 (d, J = 2.02 Hz, 1 H), 8.62 (d, J = 2.02 Hz, 1 H); ESI-MS m/z [M+H] ⁺ for C ₁₅ H ₈ F ₄ N ₄ calc.: 321.1; found: 321.2.

Example 340: 4-(3-Methyl-1 H -pyrrolo[2,3- b ]pyridin-5-yl)-6-(trifluoromethyl)-1 H -carbazole

In a similar manner to Example 339, (3-methyl-1 H -pyrrolo[2,3- b ]pyridin-5-yl)boronic acid was used instead of (3-fluoro-1 H -pyrrolo[2,3- b ] Pyridin-5-yl)boronic acid to prepare the title compound as a TFA salt. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 2.43 (d, J = 1.26 Hz, 3 H), 7.40 (d, J = 1.01 Hz, 1 H), 7.56 (d, J = 1.26 Hz, 1 H) , 7.96 (s, 1 H), 8.33 (d, J = 1.01 Hz, 1 H), 8.60 (d, J = 2.02 Hz, 1 H), 8.63 (d, J = 1.77 Hz, 1 H); ESI- MS m / z [m + H ] + for C ₁₆ H ₁₁ F ₃ N ₄ of the calculated value: 317.1; Found: 317.3.

Example 341: 2-Methyl-6- (6- (trifluoromethyl) -1 H - indazol-4-yl) -3 H - imidazo [4,5- b] pyridine

In a similar manner to Example 339, 1-(2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1 was used. Preparation of the title compound TFA by H -imidazo[4,5- b ]pyridin-1-yl)ethanone instead of (3-fluoro-1 H -pyrrolo[2,3- b ]pyridin-5-yl)boronic acid salt. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 2.93 (s, 3 H), 7.61 (d, J = 1.01 Hz, 1 H), 8.02 (d, J = 1.01 Hz, 1 H), 8.33 (d, J = 1.01 Hz, 1 H), 8.54 (d, J = 2.02 Hz, 1 H), 8.97 (d, J = 2.02 Hz, 1 H); ESI-MS m/z [M+H] ⁺ for C ₁₅ H ₁₀ F ₃ N ₅ calcd.: 318.1; found: 318.3.

Example 342: 3-Fluoro-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzenesulfonamide

Add 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl) to a 5 mL vial equipped with a magnetic stir bar -1 H -carbazole (40 mg, 0.128 mmol), 4-bromo-3-fluorobenzenesulfonamide (39.1 mg, 0.154 mmol), saturated aqueous sodium hydrogencarbonate (0.274 mL, 0.513 mmol), PdCl ₂ (dppf) (9.38 mg, 0.013 mmol) and dioxane (2 mL) gave an orange suspension. The vial was sealed and then heated in a microwave reactor at 140 °C for 30 minutes. The reaction mixture was then filtered, and the product by using 35% to 60% ACN (containing 0.035% TFA) gradient of H ₂ O (containing 0.05% TFA) solution was purified by preparative HPLC isolated. The pure fractions were lyophilized to give the title compound (13.7 mg, 22. ^{1 H NMR (400MHz, DMSO- d} 6) δ ppm 7.50 (s, 2 H), 7.53 (s, 1 H), 7.75-7.80 (m, 1 H), 7.92-7.94 (m, 1 H), 8.02 (s, 1 H), 8.06 (dt, J = 8.02, 1.29 Hz, 1H), 8.21 (t, J = 1.64 Hz, 1 H), 8.40 (s, 1 H); ESI-MS m/z [M + H] ⁺ for _{C 14 H 9 F 4 N 3} O ₂ S calculated sum value: 360.0; Found: 360.1.

Example 343: 2-Chloro-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzenesulfonamide

The title compound as a TFA salt was prepared in a procedure analogous to Example 342 using 4-bromo-2-chlorobenzenesulfonamide instead of 4-bromo-3-fluorobenzenesulfonamide. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.22-1.26 (m, 2 H), 2.00-2.04 (m, 2 H), 4.10 (q, J = 7.07 Hz, 1 H), 7.54 (d, J =1.01 Hz, 1 H), 7.86 (dd, J = 8.08, 1.77 Hz, 1 H), 7.97 (d, J = 1.52 Hz, 1 H), 7.99 (s, 1 H), 8.26 (d, J = 8.34Hz, 1 H), 8.30 (d, J = 1.01 Hz, 1 H); ESI-MS m/z [M+H] ⁺ calcd for C ₁₄ H ₉ ClF ₃ N ₃ O ₂ S: 376.0; Found: 376.1.

Example 344: 2-Fluoro-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzenesulfonamide

The title compound as a TFA salt was prepared in a procedure analogous to Example 342 using 4-bromo-2-fluorobenzenesulfonamide instead of 4-bromo-3-fluorobenzenesulfonamide. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 7.54 (d, J = 1.01 Hz, 1 H), 7.71 (dd, J = 5.81, 1.26 Hz, 1 H), 7.73-7.74 (m, 1 H), 7.99 (s, 1 H), 8.04-8.09 (m, 1 H), 8.32 (d, J = 1.01 Hz, 1 H); ESI-MS m/z [M+H] ⁺ for C ₁₄ H ₉ F ₄ Calculated for N ₃ O ₂ S: 360.0; found: 360.2.

Example 345: 5-(6-(Trifluoromethyl)-1 H -indazol-4-yl)pyridine-2-sulfonamide

4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)-1 H -indazole (39.5 mg , 0.127 mmol), 5-bromopyridine-2-sulfonamide (45 mg, 0.190 mmol), PdCl ₂ (dppf) (9.26 mg, 0.013 mmol), sodium hydrogencarbonate (0.271 mL, 0.506 mmol) and dioxane ( 2 mL) was mixed in a 10 mL vial to give an orange suspension. The vial was sealed and then heated to 140 ° C in a microwave reactor for 20 minutes. The reaction mixture was then filtered, and the product by using 35% to 60% ACN (containing 0.035% TFA) gradient of H ₂ O (containing 0.05% TFA) solution was purified by preparative HPLC isolated. The pure fractions were lyophilized to give the title compound <RTI ID=0.0> ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 2.01 (s, 1 H), 7.61 (d, J = 1.26 Hz, 1 H), 8.03 (s, 1 H), 8.17-8.21 (m, 1 H) , 8.34 (d, J = 1.01 Hz, 1 H), 8.43 (dd, J = 8.08, 2.27 Hz, 1 H), 9.07 (dd, J = 2.27, 0.76 Hz, 1 H); ESI-MS m/z [M ⁺ H] + calculated for C ₁₃ value of the ₂ S _{H 9 F 3 N 4 O:} 343.0; Found: 343.2.

Example 346: 5-(6-(Trifluoromethyl)-1 H -indazol-4-yl)pyridine-3-sulfonamide

The TFA salt of the title compound was prepared in a manner analogous to Example 342, using 5-bromopyridine-3-sulfonamide as the title compound. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 7.61 (d, J = 1.26 Hz, 1 H), 8.04 (d, J = 1.01 Hz, 1 H), 8.34 (d, J = 1.01 Hz, 1 H) , 8.63 (t, J = 2.15 Hz, 1 H), 9.13 (d, J = 2.27 Hz, 1 H), 9.16 (d, J = 2.02 Hz, 1 H); ESI-MS m/z [M+H ] ⁺ calculated for C ₁₃ value of the ₂ S _{H 9 F 3 N 4 O:} 343.0; Found: 343.2.

Example 347: 4-(4-(Methylsulfonyl)phenyl)-6-(trifluoromethyl)-1 H -carbazole

The title compound was prepared as the TFA salt of the title compound, using 1-bromo-4-(methylsulfonyl)benzene instead of 4-bromo-3-fluorobenzenesulfonamide. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 3.21 (s, 3 H), 7.55 (d, J = 1.01 Hz, 1 H), 7.98 (s, 1 H), 8.01-8.05 (m, 2 H) , 8.14 - 8.18 (m, 2 H), 8.32 (d, J = 1.01 Hz, 1 H); ESI-MS m/z [M+H] ⁺ for C ₁₅ H ₁₁ F ₃ N ₂ O ₂ S Value: 341.0; found: 341.2.

Example 348: 4-(1-(Difluoromethyl)-3,5-dimethyl-1 H -pyrazol-4-yl)-6-(trifluoromethyl)-1 H -carbazole

In a similar manner to Example 257, 4-bromo-1-(difluoromethyl)-3,5-dimethyl-1 H -pyrazole was used instead of N- (5-bromo-6-methylpyridine-2 Methyl sulfoximine to prepare the TFA salt of the title compound. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 2.16 (s, 3 H), 2.35 (s, 3 H), 7.24 (d, J = 1.01 Hz, 1 H), 7.50 (s, 1 H), 7.88 -8.01 (m, 2 H); ESI-MS m / z [m + H] + calculated for C ₁₄ H ₁₁ F ₅ N ₄ of the values: 331.1; Found: 331.15.

Example 349: 2-(4-(6-(Trifluoromethyl)-1 H -indazol-4-yl)-1 H -pyrazol-1-yl)ethanol

In a similar manner to Example 257, 2-(4-bromo-1 H -pyrazol-1-yl)ethanol was used instead of N- (5-bromo-6-methylpyridin-2-yl)methanesulfonamide. The TFA salt of the title compound was prepared. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 3.97 (t, J = 5.43 Hz, 2 H), 4.35 (t, J = 5.31 Hz, 2 H), 7.52 (d, J = 1.01 Hz, 1 H) , 7.75 (s, 1 H), 8.09 (d, J = 0.76 Hz, 1 H), 8.32 (s, 1 H), 8.45 (d, J = 1.01 Hz, 1 H); ESI-MS m/z [ M ⁺ H] + calcd for _{C 13 H 11 F 3 N 4} O of: 297.1; Found: 297.14.

Example 350: 2-(4-Methoxy-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)phenyl)acetamide

In a similar manner to Example 316, ammonium chloride was used instead of morpholine to afford the title compound. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 3.53 (s, 2 H), 3.79 (s, 3 H), 7.14 (d, J = 8.84 Hz, 1 H), 7.32-7.44 (m, 3 H) , 7.84 (s, 1 H), 7.94 (d, J = 0.76 Hz, 1 H); ESI-MS m/z [M+H] ⁺ Calculated for C ₁₇ H ₁₄ F ₃ N ₃ O ₂ : 350.1 ;Measured value: 350.16.

Example 351: 3-Chloro-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzenesulfonamide

The title compound was prepared as a TFA salt using 4-bromo-3-chlorobenzenesulfonamide instead of 4-bromo-3-fluorobenzenesulfonamide. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 2.04 (s, 1 H), 7.39 (s, 1 H), 7.70 (d, J = 8.34 Hz, 1 H), 7.91 (s, 1 H), 7.96 -8.01 (m, 2 H), 8.13 (d, J = 1.52 Hz, 1 H); ESI-MS m/z [M+H] ⁺ calculated for C ₁₄ H ₉ ClF ₃ N ₃ O ₂ S: 376.0; Found: 376.1.

Example 352: 2-(3,5-Dimethyl-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1 H -pyrazol-1-yl) -N - Isopropyl acetamide

4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)-1 H -indazole (58.3 mg , 0.187mmol), 2- (4- bromo-3,5-dimethyl -1 H - pyrazol-1-yl) - N - acetyl isopropyl amine _{(77mg, 0.28mmol), PdCl 2} (dppf (13.66 mg, 0.019 mmol), sodium bicarbonate (0.399 mL, 0.747 mmol) and dioxane (2 mL) were combined in a 10 mL vial to give an orange suspension. The vial was sealed and then heated to 140 ° C in a microwave reactor for 45 minutes. The reaction mixture was then filtered, and the product by using 35% to 55% ACN (containing 0.035% TFA) gradient of H ₂ O (containing 0.05% TFA) solution was purified by preparative HPLC isolated. The pure fractions were lyophilized to give the title compound (10.2 mg, 11.1%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.20 (d, J = 6.57 Hz, 6 H), 2.15 (s, 3 H), 2.19 (s, 3 H), 2.66 (s, 1 H), 7.23 (s, 1 H), 7.87 (s, 1 H), 8.00 (d, J = 1.01 Hz, 1 H); ESI-MS m/z [M+H] ⁺ for C ₁₈ H ₂₀ F ₃ N ₅ O Calculated: 380.2; found: 380.3.

Example 353: N , N ,1-Trimethyl-6-oxo-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1,6-dihydropyridine- 3-methylamine

In a manner similar to Example 265, 5-bromo- N,N, 1-trimethyl-6-oxo-1,6-dihydropyridine-3-carboxamide was used instead of 5-iodo-6-side. The title compound was prepared from methyl oxy-1,6-dihydropyridine-3-carboxylate. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.14 (s, 1H), 8.11 (d, J = 4.0 Hz, 1H), 7.88-7.92 (m, 2H), 7.58 (s, 1H), 3.71 (s) , 3H), 3.02-3.23 (br s , 6H); ESI-MS m / z [m + H] + for _{C 17 H 15 F 3 N 4} O ₂ computing the values: 365.1; Found: 365.3.

Example 354: N- (Cyanomethyl)-1-methyl-6-oxo-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1,6- Dihydropyridine-3-carboxamide

In a manner similar to Example 265, 5-bromo- N- (cyanomethyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide was used instead of 5-iodine. The title compound was prepared from methyl-6-o-oxo-1,6-dihydropyridine-3-carboxylate. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.48 (d, J = 4.0 Hz, 1H), 8.19 (d, J = 4.0 Hz, 1H), 8.12 (s, 1H), 7.91 (s, 1H), 7.58(s,1H), 4.31(s,2H), 3.74(s,3H); ESI-MS m/z [M+H] ⁺ calcd for C ₁₇ H ₁₂ F ₃ N ₅ O ₂ : 376.1; Found: 376.3.

Example 355: N- (2,2-Difluoroethyl)-1-methyl-6-oxo-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)- 1,6-dihydropyridine-3-carboxamide

In a similar manner to Example 265, 5-bromo- N- (2,2-difluoroethyl)-1-methyl-6-o-oxy-1,6-dihydropyridine-3-carboxamide was used. The title compound was prepared by substituting methyl 5-iodo-6-oxo-1,6-dihydropyridine-3-carboxylate. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.46 (d, J = 4.0 Hz, 1H), 8.22 (d, J = 4.0 Hz, 1H), 8.11 (s, 1H), 7.91 (s, 1H), 7.58(s,1H), 5.80-6.17(m,1H), 3.66-3.78(m,5H); ESI-MS m/z[M+H] ⁺ for C ₁₇ H ₁₃ F ₅ N ₄ O ₂ Value: 401.1; found: 401.3.

Example 356: N- (2,3-Dihydroxypropyl)-1-methyl-6-oxo-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)- 1,6-dihydropyridine-3-carboxamide

In a similar manner to Example 265, 5-bromo- N- (2,3-dihydroxypropyl)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide was used. The title compound was prepared by substituting methyl 5-iodo-6-oxo-1,6-dihydropyridine-3-carboxylate. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.45 (d, J = 4.0 Hz, 1H), 8.22 (d, J = 4.0 Hz, 1H), 8.11 (s, 1H), 7.90 (s, 1H), 7.58(s,1H), 3.77-3.86(m,1H), 3.49-3.59(m,3H),3.34-3.42(m,1H);ESI-MS m/z[M+H] ⁺ for C ₁₈ H Calculated for ₁₇ F ₃ N ₄ O ₄ : 411.1; found: 411.

Example 357: N -cyclopropyl-1-methyl-6-oxo-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1,6-dihydropyridine 3-carbamamine

In a manner similar to Example 265, 5-bromo- N -cyclopropyl-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxamide was used instead of 5-iodo-6- The title compound was prepared as the pendant oxy-1,6-dihydropyridine-3-carboxylic acid methyl ester. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.42 (d, J = 4.0 Hz, 1H), 8.19 (d, J = 4.0 Hz, 1h), 8.10 (s, 1H), 7.91 (s, 1H), 7.56 (s, 1H), 3.72 (s, 2H), 2.78-2.87 (m, 1H), 0.74-0.84 (m, 2H), 0.59-0.65 (m, 2H); ESI-MS m/z [M+ H] ⁺ calculated for C ₁₈ value of the _{2 H 15 F 3 N 4 O:} 377.1; Found: 377.3.

Example 358: ( R )-N-(2-Hydroxypropyl)-1-methyl-6-oxo-5-(6-(trifluoromethyl)-1 H -indazol-4-yl) -1,6-dihydropyridine-3-carboxamide

In a similar manner to Example 265, ( R )-5-bromo- N- (2-hydroxypropyl)-1-methyl-6-o-oxy-1,6-dihydropyridine-3-carboxamidine was used. The title compound was prepared by substituting the amine for the methyl 5-iodo-6-oxo-1,6-dihydropyridine-3-carboxylate. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.44 (d, J = 4.0 Hz, 1H), 8.23 (d, J = 4.0 Hz, 1H), 8.11 (s, 1H), 7.91 (s, 1H), 7.57 (s, 1H), 3.89-3.99 (m, 1H), 3.73 (s, 3H), 3.24-3.44 (m, 2H), 1.19 (d, J = 8.0 Hz, 3H); ESI-MS m/z [M ⁺ H] + for _{C 18 H 17 F 3 N 4} O ₃ the calculated value: 395.1; Found: 395.3.

Example 359 :( S) - N - ( 2- hydroxypropyl) -1-methyl-6-oxo-5- (6- (trifluoromethyl) -1 H - indazol-4-yl) -1,6-dihydropyridine-3-carboxamide

In a similar manner to Example 265, ( S )-5-bromo- N- (2-hydroxypropyl)-1-methyl-6-o-oxy-1,6-dihydropyridine-3-carboxamidine was used. The title compound was prepared by substituting the amine for the methyl 5-iodo-6-oxo-1,6-dihydropyridine-3-carboxylate. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.44 (d, J = 4.0 Hz, 1H), 8.23 (d, J = 4.0 Hz, 1H), 8.11 (s, 1H), 7.90 (s, 1H), 7.57 (s, 1H), 3.89-3.99 (m, 1H), 3.73 (s, 3H), 3.24-3.44 (m, 2H), 1.19 (d, J = 8.0 Hz, 3H); ESI-MS m/z [M ⁺ H] + for _{C 18 H 17 F 3 N 4} O ₃ the calculated value: 395.1; Found: 395.3.

Example 360: 4-Fluoro- N- (2-hydroxyethyl)-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzamide

In a similar manner to Example 270, ethyl 4-fluoro-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzoate was used instead of 5-(6-(trifluoromethyl) ) -1 H - indazol-4-yl) picolinate the title compound was prepared TFA salt of. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 3.34-3.38 (m, 2 H), 3.52 (q, J = 5.89 Hz, 2 H), 4.75 (t, J = 5.68 Hz, 1 H), 7.40 -7.64 (m, 2 H), 7.92-8.09 (m, 2 H), 8.09-8.21 (m, 2 H), 8.62 (t, J = 5.43 Hz, 1 H), 13.76 (s, 1 H); ESI-MS m / z [m + H] + for _{C 17 H 13 F 4 N 3} O ₂ calculated sum value: 368.1; Found: 368.16.

Example 361: (3-Hydroxyazetidin-1-yl)(3-methyl-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)phenyl)methanone

To a solution of azetidin-3-ol (0.262 g, 3.59 mmol) in dioxane (8 mL) was added dropwise trimethylaluminum (1.795 mL, 3.59 mmol) in toluene at room temperature. . After stirring at room temperature for 10 minutes, methyl 3-methyl-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzoate (0.2 g, 0.598 mmol) was added. The reaction mixture was heated in a microwave reactor at 110 ° C for 1 hour and then transferred to a round bottom flask. The reaction was quenched with cone. HCl and the mixture was concentrated. The residue was purified by preparative HPLC eluting with H.sub.2O (0.035% TFA) containing & _lt The product-containing fractions were combined with EtOAc EtOAcjjjjjjjj ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 2.13-2.30 (m, 3 H), 3.99 (dd, J = 10.74, 3.41 Hz, 1 H), 4.18 - 4.29 (m, 1 H), 4.43 (dd , J = 10.36, 6.82 Hz, 1 H), 4.56-4.74 (m, 2 H), 7.26 (d, J = 1.01 Hz, 1 H), 7.43 (d, J = 7.83 Hz, 1 H), 7.59 ( Dd, J = 7.96, 1.39 Hz, 1 H), 7.67 (s, 1 H), 7.84 (s, 1 H), 7.94 (s, 1 H); ESI-MS m/z [M+H] ⁺ _{C 19 H 16 F 3 N 3} O ₂ calculated sum value: 376.1; Found: 376.21.

Example 362: 4-(6-(2-Methoxyethoxy)-2-methylpyridin-3-yl)-6-(trifluoromethyl)-1 H -carbazole

In a similar manner to Example 257, 3-bromo-6-(2-methoxyethoxy)-2-methylpyridine was used in place of N- (5-bromo-6-methylpyridin-2-yl)methane. Sulfonamide to prepare the TFA salt of the title compound. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 2.28 (s, 3 H), 3.33 (s, 3 H), 3.63-3.74 (m, 2 H), 4.35-4.53 (m, 2 H), 6.80 (d, J = 8.34 Hz, 1 H), 7.29 (s, 1 H), 7.70 (d, J = 8.34 Hz, 1 H), 7.96 (d, J = 8.08 Hz, 2 H); ESI-MS m / z [M ⁺ H] + for _{C 17 H 16 F 3 N 3} O ₂ calculated sum value: 352.1; Found: 352.2.

Example 363: 2-(3,5-Dimethyl-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1 H -pyrazol-1-yl) -N , N -dimethylacetamide

In a similar manner to Example 257, 2-(4-bromo-3,5-dimethyl-1 H -pyrazol-1-yl) -N , N -dimethylacetamide was used instead of N- (5). -Bromo-6-methylpyridin-2-yl)methanesulfonamide to prepare the title compound as a TFA salt. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 2.17 (d, J = 4.29 Hz, 6 H), 3.02 (s, 3 H), 3.18 (s, 3 H), 5.16 (s, 2 H), 7.24 (d, J = 1.26 Hz, 1 H), 7.88 (s, 1H), 8.01 (d, J = 1.01 Hz, 1 H); ESI-MS m/z [M+H] ⁺ for C ₁₇ H ₁₈ F Calculated for ₃ N ₅ O: 366.1; found: 366.2.

Example 364: (5 S )-5-((3,5-Dimethyl-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1 H -pyrazole-1 -yl)methyl)pyrrolidin-2-one

4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)-1 H -carbazole, ( S -5-((4-Bromo-3,5-dimethyl-1 H -pyrazol-1-yl)methyl)pyrrolidin-2-one, PdCl ₂ (dppf), sodium bicarbonate and dioxins The alkane (2 mL) was combined in a 10 mL vial to give an orange suspension. The vial was sealed and then heated to 140 ° C in a microwave reactor for 45 minutes. The reaction mixture was then filtered, and the product by using 35% to 55% ACN (containing 0.035% TFA) gradient of H ₂ O (containing 0.05% TFA) solution was purified by preparative HPLC isolated. The pure fractions were lyophilized to give the title compound <RTIgt; ^{1 H NMR (400MHz, DMSO- d} 6) δ ppm 1.98 (s, 3 H), 2.10 (s, 3 H), 2.16 (s, 3 H), 4.09 (d, J = 5.31Hz, 2 H), 7.16 (s, 1 H), 7.81 (s, 1 H), 7.86 (s, 1 H), 8.03 (s, 1 H); ESI-MS m/z [M+H] ⁺ for C ₁₈ H ₁₈ F Calculated for ₃ N ₅ O: 378.1; found: 378.3.

Example 365: 4-(2-(Methylsulfonyl)phenyl)-6-(trifluoromethyl)-1 H -carbazole

The title compound was prepared as the TFA salt of the title compound using 1-bromo-2-(methylsulfonyl)benzene instead of 4-bromo-3-fluorobenzenesulfonamide. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 2.86 (s, 3 H), 7.42 (d, J = 1.01 Hz, 1 H), 7.55 (dd, J = 7.33, 1.26 Hz, 1 H), 7.79 -7.87 (m, 4 H), 8.01 (s, 1 H), 8.18 (dd, J = 7.83, 1.52 Hz, 1 H); ESI-MS m/z [M+H] ⁺ for C ₁₅ H ₁₁ F Calculated for ₃ N ₂ O ₂ S: 341.0; found: 341.2.

Example 366: 2-(3,5-Dimethyl-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1 H -pyrazol-1-yl)-1- (3-hydroxyazetidin-1-yl)ethanone

In a similar manner to Example 257, 2-(4-bromo-3,5-dimethyl-1 H -pyrazol-1-yl)-1-(3-hydroxyazetidin-1-yl) was used. Ethyl ketone was used in place of N- (5-bromo-6-methylpyridin-2-yl)methanesulfonamide to prepare the title compound as a TFA salt. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 2.19 (s, 3 H), 2.16 (s, 3 H), 3.85 (dd, J = 10.99, 3.92 Hz, 1 H), 4.06 (ddd, J = 9.47) , 4.29, 1.14 Hz, 1 H), 4.29 (dd, J = 10.61, 6.82 Hz, 1 H), 4.43-4.55 (m, 1 H), 4.65 (tt, J = 6.82, 4.42 Hz, 1 H), 7.22 (d, J = 1.26 Hz, 1 H), 7.88 (s, 1 H), 7.98 (d, J = 1.01 Hz, 1 H); ESI-MS m/z [M+H] ⁺ for C ₁₈ H Calculated for ₁₈ F ₃ N ₅ O ₂ : 394.1; found: 394.21.

Example 367: 2-(3,5-Dimethyl-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1 H -pyrazol-1-yl) -N - Methylacetamide

In a similar manner to Example 257, 2-(4-bromo-3,5-dimethyl-1 H -pyrazol-1-yl) -N -methylacetamide was used instead of N- (5-bromo- 6-Methylpyridin-2-yl)methanesulfonamide to prepare the title compound as a TFA salt. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 2.20 (s, 3 H), 2.17 (s, 3 H), 2.81 (s, 3 H), 4.85 (s, 2 H), 7.24 (d, J = 1.26 Hz, 1 H), 7.88 (s, 1 H), 8.00 (d, J = 1.01 Hz, 1 H); ESI-MS m/z [M+H] ⁺ for C ₁₆ H ₁₆ F ₃ N ₅ O Calculated: 352.1; found: 352.16.

Example 368: N- (2-Hydroxyethyl)-4-methyl-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzamide

In a similar manner to Example 270, methyl 4-methyl-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzoate was used instead of 5-(6-(trifluoromethyl). The methyl ester of -1 H -indazol-4-yl)pyridinecarboxylate afforded the title compound as a TFA salt. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 2.18 (s, 3 H), 3.49 (q, J = 6.06 Hz, 2 H), 4.71 (t, J = 5.68 Hz, 1 H), 7.29 (s) , 1 H), 7.49 (d, J = 8.08 Hz, 1 H), 7.76-7.93 (m, 3 H), 7.99 (s, 1 H), 8.47 (t, J = 5.43 Hz, 1 H), 13.72 (br s, 1 H); ESI-MS m / z [m + H] + for _{C 18 H 16 F 3 N 3} O ₂ calculated sum value: 364.1; Found: 364.2.

Example 369: (3-Hydroxyazetidin-1-yl)(4-methyl-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)phenyl)methanone

In a similar manner to Example 361, methyl 4-methyl-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzoate was used instead of 3-methyl-4-(6) Methyl (-trifluoromethyl)-1 H -indazol-4-yl)benzoate to give the title compound as a TFA salt. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 2.19 (s, 3 H), 3.78 (d, J = 9.85 Hz, 1 H), 4.06 (br s, 1 H), 4.24 (br s, 1 H) ), 4.42-4.57 (m, 2 H), 5.74 (d, J = 5.81 Hz, 1 H), 7.29 (s, 1 H), 7.43-7.61 (m, 2 H), 7.64 (dd, J = 7.83) , 1.77 Hz, 1 H), 7.91 (s, 1 H), 7.98 (s, 1 H), 13.73 (br s, 1 H); ESI-MS m/z [M+H] ⁺ for C ₁₉ H ₁₆ F ₃ N ₃ O ₂ calculated sum value: 376.1; Found: 376.21.

Example 370: (3-Hydroxypyrrolidin-1-yl)(4-methyl-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)phenyl)methanone

Trimethylaluminum in toluene (0.628 mL, 1.256 mmol) was added dropwise to a microwave vial containing pyrrolidine-3-ol (0.109 g, 1.256 mmol) in dioxane (8 mL). . After stirring at room temperature for 5 minutes, methyl 4-methyl-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzoate (0.07 g, 0.209 mmol). The reaction mixture was heated in a microwave reactor at 110 ° C for 1 hour and then transferred to a round bottom flask. The reaction was quenched with cone. HCl and the mixture was concentrated. The residue was purified by preparative HPLC eluting with 35% acetonitrile (0.035% &lt;RTI ID=0.0&gt;&gt _; The fractions containing the product are combined and the volatiles are evaporated in vacuo to give the title compound as the title compound. ESI-MS m / z [M + H] + for _{C 20 H 18 F 3 N 3} O ₂ calculated sum value: 390.1; Found: 390.21.

Example 371: (3-(Hydroxymethyl)pyrrolidin-1-yl)(4-methyl-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)phenyl) A ketone

The TFA salt of the title compound was prepared in a procedure analogous to Example 370, using pyrrolidine-3-ylmethanol instead of pyrrolidine-3-ol. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.53-1.72 (m, 1 H), 1.79-1.98 (m, 2 H), 2.12-2.22 (m, 4 H), 2.26-2.38 (m, 2) H), 7.29 (s, 1 H), 7.37-7.50 (m, 2 H), 7.50-7.60 (m, 1 H), 7.90 (s, 1 H), 7.97 (s, 1 H), 13.71 (br s, 1 H); ESI- MS m / z [m + H] + for _{C 21 H 20 F 3 N 3} O ₂ calculated sum value: 404.2; Found: 404.21.

Example 372: (4-Hydroxypiperidin-1-yl)(4-methyl-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)phenyl)methanone

The TFA salt of the title compound was prepared in a procedure analogous to Example 370, using </RTI><RTIgt; ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.36 (br s, 1 H), 1.65-1.80 (m, 2 H), 1.96 (d, J = 14.40 Hz, 1 H), 2.19 (s, 3) H), 3.46 (br s, 1 H), 3.61 (br s, 1 H), 3.72 (br s, 1 H), 5.21-5.30 (m, 1 H), 7.25-7.34 (m, 1 H), 7.34-7.54 (m, 3 H), 7.82-7.94 (m, 1 H), 7.97 (s, 1 H); ESI-MS m/z [M+H] ⁺ for C ₂₁ H ₂₀ F ₃ N ₃ O ₂ calculated value: 404.2; measured value: 404.21.

Example 373: 1-Methyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridine-2(1 H )-one

In a manner similar to Example 265, 5-bromo-1-methylpyridine-2( 1H )-one was used in place of methyl 5-iodo-6-oxo-1,6-dihydropyridine-3-carboxylate. To prepare the title compound. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.34 (s, 1H), 8.14 (d, J = 4.0 Hz, 1H), 7.98 (dd, J = 4.0, 8.0 Hz, 1H), 7.87 (s, 1H) ), 7.42 (s, 1H), 6.73 (d, J = 8.0 Hz, 1H), 3.70 (s, 3H); ESI-MS m/z [M+H] ⁺ for C ₁₄ H ₁₀ F ₃ N ₃ O Calculated: 294.1; found: 294.2.

Example 374: 2-(2-Sideoxy-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridine-1( 2H )-yl)acetic acid

In a similar manner to Example 265, methyl 2-(5-bromo-2-p-oxypyridine-1( 2H )-yl)acetate was used instead of 5-iodo-6-sideoxy-1,6-di. The title compound was prepared from methyl hydropyridine-3-carboxylate. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.34 (s, 1H), 8.13 (d, J = 4.0 Hz, 1H), 8.01 (dd, J = 4.0, 8.0 Hz, 1H), 7.88 (s, 1H) ), 7.43 (s, 1H), 6.76 (d, J = 8.0 Hz, 1H); ESI-MS m/z [M+H] ⁺ calculated for C ₁₅ H ₁₀ F ₃ N ₃ O ₃ : 338.1; Found: 338.2.

Example 375: 1-Methyl-5-(4-methylpiperazine-1-carbonyl)-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridine-2 (1 H )-ketone

In a manner similar to Example 265, 3-iodo-1-methyl-5-(4-methylpiperazine-1-carbonyl)pyridine-2(1 H )-one was used in place of 5-iodo-6-side oxygen. The title compound was prepared from methyl-1,6-dihydropyridine-3-carboxylate. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.12 (s, 1H), 8.08 (d, J = 4.0 Hz, 1H), 7.90 (s, 1H), 7.85 (d, J = 4.0 Hz, 1H), 7.58 (s, 1H), 3.67-3.77 (m, 7H), 2.46-2.54 (m, 4H), 2.33 (s, 3H); ESI-MS m/z [M+H] ⁺ for C ₂₀ H ₂₀ F Calculated for ₃ N ₅ O ₂ : 420.2; found: 420.4.

Example 376: 2,5-Difluoro-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzenesulfonamide

The title compound as a TFA salt was prepared in a procedure analogous to Example 342 using 4-bromo-2,5-difluorobenzenesulfonamide instead of 4-bromo-3-fluorobenzenesulfonamide. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 7.57 (s, 1 H), 7.74-7.79 (m, 1 H), 7.86 (dd, J = 10.23, 5.68 Hz, 1 H), 7.96 (s, 1 H), 8.08 (s, 1 H), 8.20 (s, 1 H); ESI-MS m/z [M+H] ⁺ Calculated for C ₁₄ H ₈ F ₅ N ₃ O ₂ S: 378.0; Found: 378.2.

Example 377: 6-Methyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl) 2-cyanopyridine

4-(6-Chloro-2-methylpyridin-3-yl)-6-(trifluoromethyl)-1 H -indazole (0.97 g, 3.11 mmol), zinc cyanide (1.462 g) The mixture of 12.45 mmol) and hydrazine (triphenylphosphine)palladium(0) (0.360 g, 0.311 mmol) in DMF (15 mL) was then degased thoroughly and stirred at 120 ° C for 24 hours. The reaction mixture was then cooled and diluted with EtOAc then brine. The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by CombiFlash® chromatography eluting with EtOAc EtOAc EtOAc. The title compound (0.32 g, 34%) was obtained. ^{1 H NMR (400MHz, DMSO- d} 6) δ ppm 2.39 (s, 3 H), 7.45 (d, J = 1.01Hz, 1 H), 7.90-8.16 (m, 4 H), 13.81 (s, 1 H ); ESI-MS m / z [m + H] + for C ₁₅ H ₉ F ₃ N ₄ of the calculated value: 303.1; Found: 303.18.

Example 378: N -(2-Hydroxyethyl)-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridine-2-sulfonamide

4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)-1 H -indazole (40 mg, 0.128 mmol), 5-bromo- N- (2-hydroxyethyl)pyridine-2-sulfonamide (43.2 mg, 0.154 mmol), PdCl ₂ (dppf) (9.38 mg, 0.013 mmol), sodium hydrogencarbonate (0.274) mL, 0.513 mmol) and dioxane (2 mL) were combined in a 10 mL vial to give an orange suspension. The vial was sealed and then heated to 140 ° C in a microwave reactor for 20 minutes. The reaction mixture was then filtered and the product was purified by preparative HPLC eluting with &_lt;RTIID=0.0&gt_;0&gt_; The pure fractions were lyophilized to give the title compound (16.4 mg, 25. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 3.05 (q, J = 6.48 Hz, 2 H), 3.40-3.46 (m, 7 H), 7.70 (d, J = 1.01 Hz, 1 H), 7.96 (t, J = 5.81Hz, 1 H), 8.08 (dd, J = 8.21,0.88Hz, 2 H), 8.45 (s, 1 H), 8.51 (dd, J = 8.21,2.40Hz, 1 H), 9.15 (dd, J = 2.27,1.01Hz, 1 H); ESI-MS m / z [m + H] + for C ₁₅ F _{3 4} O ₃ S the calculated values N H _13: 387.1; Found: 387.2.

Example 379: 6-Methyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridinium

6-Methyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl) 2-cyanide in acetic acid (2 mL) and H ₂ SO ₄ (2 mL) at room temperature The pyridine (0.02 g, 0.066 mmol) was stirred for 18 hours. The reaction mixture was poured into an Erlenmeyer flask containing ice and treated with NaHCO ₃ and carefully neutralized, and extracted into DCM thereof. The organic layer was dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was purified by preparative HPLC (Waters SunFire C18, 5 μm, 30 mm ID x 75 mm column) eluting with water (containing 0.05% TFA) gradient from 45% to 55% ACN (containing 0.035% TFA). The title compound (0.32 g, 34%) ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 2.42 (s, 3 H), 7.42 (d, J = 1.26 Hz, 1 H), 7.73 (br s, 1 H), 7.90-8.08 (m, 3) H), 8.14 (br s, 1 H); ESI-MS m / z [m + H] + calcd for _{C 15 H 11 F 3 N 4} O of: 321.1; Found: 321.2.

Example 380: 4-(3,5-Dimethyl-1-((3-methyloxetan-3-yl)methyl)-1 H -pyrazol-4-yl)-6-( Trifluoromethyl)-1 H -carbazole

Add 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl) to a 5 mL vial equipped with a magnetic stir bar -1 H -carbazole (41.6 mg, 0.133 mmol), 4-bromo-3,5-dimethyl-1-((3-methyloxetan-3-yl)methyl)-1 H -pyrazole (51.8 mg, 0.2 mmol), sodium hydrogencarbonate (0.285 mL, 0.533 mmol), PdCl ₂ (dppf) (9.76 mg, 0.013 mmol) and dioxane (3 mL). The contents of the vial were stirred to give an orange suspension. The vial was sealed and then heated in a microwave reactor at 140 °C for 90 minutes. The reaction mixture was then filtered and the product was purified by preparative HPLC eluting with &_lt;RTIID=0.0&gt_;0&gt_; The pure fractions were lyophilized to give the title compound <RTI ID=0.0> ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 1.46 (s, 3 H), 2.37 (s, 6 H), 3.71 (s, 2 H), 4.31 (d, J = 11.37 Hz, 2 H), 4.58 (d, J = 11.37 Hz, 2 H), 7.39 (d, J = 1.01 Hz, 1 H), 8.04-8.06 (m, 1 H), 8.07 (d, J = 0.76 Hz, 1 H); MS m / z [m + H ] + for C _{18 4} O Calcd of H ₁₉ F ₃ N: 365.2; Found: 365.3.

Example 381:1, 5-Dimethyl-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1 H -pyrazol-3-amine

The title compound as a TFA salt was prepared in a procedure analogous to Example 342 using 4-bromo-1,5-dimethyl- 1H -pyrazol-3-amine instead of 4-bromo-3-fluorobenzenesulfonamide. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 2.24 (s, 3 H), 3.81 (s, 3 H), 7.32 (d, J = 1.01 Hz, 1 H), 7.92-7.94 (m, 1 H) , 8.06 (d, J = 1.01Hz , 1 H); ESI-MS m / z [m + H] + calculated for C ₁₃ value of ₅ H ₁₂ F ₃ N: 296.1; Found: 296.2.

Example 382: 5-Methyl-6- (6- (trifluoromethyl) -1 H - indazol-4-yl) -3 H - imidazo [4,5-b] pyridin-2-ol

In a similar manner to Example 257, 6-bromo-5-methyl- 3H -imidazo[4,5- b ]pyridin-2-ol was used instead of N- (5-bromo-6-methylpyridine-2 Methyl sulfoximine to prepare the TFA salt of the title compound. ¹ H NMR (400MHz, dioxane) δ ppm 2.23 (s, 3 H), 7.15 (s, 1 H), 7.29 (s, 1 H), 7.95 (d, J = 9.60Hz, 2 H), 10.81 (s, 1 H), 11.37 (s, 1 H), 13.67 (s, 1 H); ESI-MS m/z [M+H] ⁺ Calculated for C ₁₅ H ₁₀ F ₃ N ₅ O: 334.1 ;Measured value: 334.3.

Example 383: 4-(2-Methyl-6-( 4H -1,2,4-triazol-4-yl)pyridin-3-yl)-6-(trifluoromethyl)-1 H -indole Azole

In a similar manner to Example 265, 3-bromo-2-methyl-6-( 4H -1,2,4-triazol-4-yl)pyridine was used in place of 5-iodo-6-oxirane-1. Methyl 6-dihydropyridine-3-carboxylate to prepare the title compound as a TFA salt. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 9.48 (s, 2H), 7.99-8.04 (m, 2H), 7.94 (s, 1H), 7.79 (d, J = 8.0 Hz, 1H), 7.38 (s) , 1H), 2.47 (s, 3H); ESI-MS m / z [m + H] + for C ₁₆ H ₁₁ F ₃ N ₆ the calculated value: 345.1; Found: 345.3.

Example 384: 4-(2-Methyl-6-(pyrrolidin-1-yl)pyridin-3-yl)-6-(trifluoromethyl)-1 H -carbazole

In a similar manner to Example 265, 3-bromo-2-methyl-6-(pyrrolidin-1-yl)pyridine was used in place of 5-iodo-6-o-oxy-1,6-dihydropyridine-3- Methyl formate was used to prepare the TFA salt of the title compound. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 7.91-8.04 (m, 3H), 7.37 (s, 1H), 7.07 (d, J = 8.0 Hz, 1H), 3.67-3.77 (m, 4H), 2.45 (s, 3H), 2.15-2.27 ( m, 4H); ESI-MS m / z [m + H] + for C ₁₈ H ₁₇ F ₃ N ₄ of the calculated value: 347.1; Found: 347.4.

Example 385: (3-Hydroxyazetidin-1-yl)(4-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridin-2-yl)methanone

In a similar manner to Example 283, the title compound was obtained as the TFA salt using the azetidine-3-ol hydrochloride. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 3.85 (dd, J = 10.74, 4.17 Hz, 1 H), 4.22-4.43 (m, 2 H), 4.48-4.60 (m, 1 H), 4.72 4.87 (m, 1 H), 7.62-7.69 (m, 1 H), 7.98 (dd, J = 5.05, 1.77 Hz, 1 H), 8.08 (s, 1 H), 8.26 (s, 1 H), 8.39 (s, 1 H), 8.79 (d, J = 4.80 Hz, 1 H); ESI-MS m/z [M+H] ⁺ calculated for C ₁₇ H ₁₃ F ₃ N ₄ O ₂ : 363.1; Value: 363.14.

Example 386: 2-(3,5-Dimethyl-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1 H -pyrazol-1-yl) -N - (2-hydroxyethyl)acetamide

To 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)-1 H -indazole (0.1 g , 0.320mmol), 2- (4- bromo-3,5, - dimethyl -1 H - pyrazol-1-yl) - N - (2- hydroxyethyl) acetyl amine (0.133g, 0.481mmol ) and _{PdCl 2 (dppf) (0.012g,} 0.016mmol) was added in dioxane (10 mL) in a mixture of saturated aqueous NaHCO ₃ (3mL). The resulting pale yellow suspension was heated in a microwave reactor at 140 °C for 60 minutes. The reaction mixture was then concentrated, and the residue was purified by 25-30% acetonitrile (containing 0.035% TFA) gradient of H ₂ O (containing 0.05% TFA) containing purified by preparative HPLC eluting time of 5.5 minutes using. The fractions containing the product were combined and the solvent was removed by rotary evaporation. The product was lyophilized and then dissolved in MeOH (4 mL). Aqueous NaOH (1 N, 0.3 mL) was added and the mixture was stirred at room temperature for 1 hour. The mixture was acidified with concentrated HCl. The solution was concentrated by rotary evaporation then diluted with EtOAc and water. The organic layer was concentrated to give EtOAcjjjjjjjj ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 2.09 (s, 3 H), 2.15 (s, 3 H), 3.19 (q, J = 5.73 Hz, 2 H), 3.39-3.48 (m, 2 H) ), 4.77 (s, 2 H), 7.14 (d, J = 1.26 Hz, 1 H), 7.87 (s, 1 H), 7.96 (s, 1 H), 8.12-8.24 (m, 1 H); ESI -MS m / z [m + H ] + for _{C 17 H 18 F 3 N 5} O ₂ computing the values: 382.1; Found: 382.21.

Example 387: N- (2-Hydroxyethyl)-6-methyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridinium

HOBt (0.942 g, added to 6-methyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridinecarboxylic acid (1.6 g, 4.98 mmol) in DMF (20 mL) 6.97 mmol), EDC (1.432 g, 7.47 mmol), 2-aminoethanol (0.913 g, 14.94 mmol), followed by N -ethyl- N -isopropylpropan-2-amine (4.34 mL, 24.90 mmol) . The reaction mixture was stirred at room temperature for 16 h then diluted with EtOAc and brine. The volatiles were evaporated from the organic phase and the residue was purified by CombiFlash® chromatography eluting with EtOAc EtOAc. The title compound (0.658 g, 36.3%) was obtained as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 2.43 (s, 3 H), 3.44 (q, J = 5.98 Hz, 2 H), 3.57 (t, J = 5.94 Hz, 2 H), 7.38-7.44 (m, 1 H), 7.90-8.07 (m, 4 H), 8.70 (t, J = 5.81 Hz, 1 H); ESI-MS m/z [M+H] ⁺ for C ₁₇ H ₁₅ F ₃ N Calculated for ₄ O ₂ : 365.1; found: 365.2.

Example 388: 4-(7-Methylimidazo[1,5- a ]pyridin-6-yl)-6-(trifluoromethyl)-1 H -carbazole

In a similar manner to Example 257, 6-bromo-7-methylimidazo[1,5- a ]pyridine was used instead of N- (5-bromo-6-methylpyridin-2-yl)methanesulfonamide. The TFA salt of the title compound was prepared. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 2.37 (s, 3 H), 7.48 (d, J = 1.26 Hz, 1 H), 7.94 (s, 1 H), 8.02 (d, J = 1.01 Hz, 1 H), 8.04 (d, J = 2.02 Hz, 1 H), 8.07-8.11 (m, 1 H), 8.17 (d, J = 1.77 Hz, 1 H), 8.85 (s, 1 H); MS m / z [m + H ] + for C ₁₆ H ₁₁ F ₃ N ₄ of the calculated value: 317.1; Found: 317.3.

Example 389: 6-Methyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridine-2(1 H )-one

Preparation of the title compound TFA in a manner analogous to Example 257, using 5-bromo-6-methylpyridin-2-ol in place of N- (5-bromo-6-methylpyridin-2-yl)methanesulfonamide. salt. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 2.23 (s, 3 H), 6.55 (d, J = 9.35 Hz, 1 H), 7.29 (d, J = 1.26 Hz, 1 H), 7.65 (d, J = 9.35 Hz, 1 H), 7.93 (s, 1 H), 8.00 (d, J = 1.01 Hz, 1 H); ESI-MS m/z [M+H] ⁺ for C ₁₄ H ₁₀ F ₃ N Calculated value of ₃ O: 294.1; found: 294.3.

Example 390: 4-Methyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridine-2(1 H )-one

Preparation of the title compound TFA in a manner analogous to Example 257, using 5-bromo-4-methylpyridin-2-ol in place of N- (5-bromo-6-methylpyridin-2-yl)methanesulfonamide salt. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 2.06 (d, J = 1.01 Hz, 3 H), 6.55 (d, J = 0.76 Hz, 1 H), 7.18 (d, J = 1.01 Hz, 1 H) , 7.32 (s, 1 H), 7.87 (dd, J = 5.43, 0.88 Hz, 2 H); ESI-MS m/z [M+H] ⁺ calculated for C ₁₄ H ₁₀ F ₃ N ₃ O 294.1 ;Measured value: 294.3.

Example 391: 6-Methoxy-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridinium

Add ammonium chloride to 6-methoxy-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridinecarboxylic acid (0.020 g, 0.059 mmol) in DMF (3 mL) 0.016 g, 0.297 mmol), HOBt (0.011 g, 0.083 mmol) and EDC (0.017 g, 0.089 mmol), followed by N -ethyl- N -isopropylpropan-2-amine (0.052 mL, 0.297 mmol). The reaction mixture was stirred for 1 hour at room temperature. The crude reaction mixture was purified by containing 30 to 40% acetonitrile (containing 0.035% TFA) gradient of H ₂ O (containing 0.05% TFA) preparative HPLC eluting in seven minutes. The title compound was obtained as a white solid. ^{1 H NMR (400MHz, DMSO- d} 6) δ ppm 3.99 (s, 3 H), 7.45-7.51 (m, 1 H), 7.70-7.83 (m, 1 H), 7.98 (s, 1 H), 8.03 - 8.12 (m, 2 H), 8.13 (s, 1 H); ESI-MS m/z [M+H] ⁺ calcd for C ₁₅ H ₁₁ F ₃ N ₄ O ₂ : 337.1; .

Example 392: 4-(6-Chloro-2-methoxypyridin-3-yl)-6-(trifluoromethyl)-1 H -carbazole

In a similar manner to Example 247, (6-chloro-2-methoxypyridin-3-yl)boronic acid was used instead of N , N -dimethyl-5-(4,4,5,5-tetramethyl- 1,3,2-Dioxaboran-2-yl)pyrimidine-2-amine to prepare the title compound as a TFA salt. ESI-MS m / z [M + H] + calcd for C ₁₄ H ₉ ClF ₃ N ₃ O of: 328.0; Found: 328.11.

Example 393: 5-Methyl-6-(6-(trifluoromethyl)-1 H -indazol-4-yl)-[1,2,4]triazolo[1,5- a ]pyridine

In a similar manner to Example 257, 6-bromo-5-methyl-[1,2,4]triazolo[1,5- a ]pyridine was used instead of N- (5-bromo-6-methylpyridine- 2-Base) methanesulfonamide to prepare the TFA salt of the title compound. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 2.74 (s, 3 H), 7.44-7.47 (m, 1 H), 7.89 (br s, 2 H), 7.96-8.08 (m, 3 H); -MS m / z [m + H ] + calculated for C ₁₅ H _{10 3} N ₅ value of F: 318.1; Found: 318.4.

Example 394: N- (2-Hydroxyethyl)-6-methoxy-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridinium

The title compound was prepared in a similar manner to Example 391 using 2-aminoethanol instead of ammonium chloride. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 3.61 (t, J = 5.68 Hz, 2 H), 3.77 (t, J = 5.68 Hz, 2 H), 4.06 (s, 3 H), 7.47 (d, J = 1.01 Hz, 1 H), 7.88 (d, J = 7.58 Hz, 1 H), 7.94 (s, 1 H), 8.02 (t, J = 7.33 Hz, 2 H); ESI-MS m/z [ M ⁺ H] + for _{C 17 H 15 F 3 N 4} O ₃ the calculated value: 381.1; Found: 381.21.

Example 395: (3-Hydroxyazetidin-1-yl)(6-methoxy-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridine-2- Ketone

The TFA salt of the title compound was prepared in a procedure analogous to Example 391, using az. ESI-MS m / z [M + H] + for C ₁₈ F _{3 4} O ₃ The calculated value H ₁₅ N: 393.1; Found: 393.22.

Example 396: 6-Methoxy-5-(6-(trifluoromethyl)-1 H -indazol-4-yl) 2-cyanopyridine

4-(6-Chloro-2-methoxypyridin-3-yl)-6-(trifluoromethyl)-1 H -indazole (0.71 g, 2.167 mmol) and zinc cyanide (1.018 g). A mixture of 8.67 mmol) and hydrazine (triphenylphosphine) palladium (0) (0.250 g, 0.217 mmol) in DMF (15 mL) was evaporated and evaporated. The reaction mixture was then cooled, diluted with EtOAc and brine. The organic layer was dried over Na ₂ SO _4, and the volatiles were removed by rotary evaporation. The crude residue was purified by 60-65% acetonitrile (containing 0.035% TFA) gradient of H ₂ O (containing 0.05% TFA) was purified by preparative HPLC 5 minute fractions containing used. The product-containing fractions were combined and concentrated to give the title compound. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 3.99 (s, 3 H), 7.48 (s, 1 H), 7.63 (d, J = 7.58 Hz, 1 H), 7.96 (s, 1 H), 8.00 -8.07 (m, 2 H); ESI-MS m / z [m + H] + calcd for _{C 15 H 9 F 3 N 4} O of: 319.1; Found: 319.21.

Example 397: (3-Hydroxyazetidin-1-yl)(6-methyl-2-(methylamino)-5-(6-(trifluoromethyl)-1 H -indazole- 4-yl)pyridin-3-yl)methanone

In a similar manner to Example 257, (5-bromo-6-methyl-2-(methylamino)pyridin-3-yl)(3-hydroxyazetidin-1-yl)methanone was used instead. N- (5-Bromo-6-methylpyridin-2-yl)methanesulfonamide was used to prepare the title compound as a TFA salt. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 2.42 (s, 3 H), 3.18 (s, 3 H), 4.03-4.12 (m, 2 H), 4.48-4.68 (m, 3 H), 7.31 7.39 (m, 1 H), 7.91 (s, 1 H), 7.96-8.05 (m, 2 H); ESI-MS m/z [M+H] ⁺ for C ₁₉ H ₁₈ F ₃ N ₅ O ₂ Calculated: 406.1; found: 406.22.

Example 398: 5-Methyl-6-(6-(trifluoromethyl)-1 H -indazol-4-yl)tetrazolo[1,5- a ]pyridine

Add 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)-1 H - to a 20 mL microwave vial Carbazole (50 mg, 0.160 mmol), 6-bromo-5-methyltetrazolo[1,5- a ]pyridine (34.1 mg, 0.160 mmol) and PdCl ₂ (dppf) (6.59 mg, 8.01 μmol) dioxane (4mL) and saturated aqueous NaHCO ₃ in the (2mL) mixture. The resulting yellow suspension was heated in a microwave reactor at 130 ° C for 30 minutes. Then the reaction mixture by containing 45-65% acetonitrile gradient of H ₂ O (containing 10mM NH ₄ HCO ₃₎ was purified from the solution by preparative HPLC. The product was combined and dried to give the title compound. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 2.83 (s, 3 H), 7.51 (d, J = 1.01 Hz, 1 H), 7.91 (d, J = 9.09 Hz, 1 H), 8.04 (s, 1 H), 8.06 (s, 1 H), 8.10 (dd, J = 9.09, 0.76 Hz, 1 H); ESI-MS m/z [M+H] ⁺ for C ₁₄ H ₉ F ₃ N ₆ Value: 319.1; found: 319.3.

Example 399: 4-(6-Methyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridin-2-yl)morpholine

In a similar manner to Example 398, 4-(5-bromo-6-methylpyridin-2-yl)morpholine was used instead of 6-bromo-5-methyltetrazolo[1,5- a ]pyridine (34.1 Mp, 0.160 mmol) to give the title compound as a TFA salt. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 2.46 (s, 3 H), 3.75-3.82 (m, 4 H), 3.86-3.95 (m, 4 H), 7.32 (d, J = 9.09 Hz, 1 H), 7.38 (d, J = 1.26 Hz, 1 H), 7.99 (d, J = 0.76 Hz, 1 H), 8.00-8.05 (m, 2 H); ESI-MS m/z [M+H] ⁺ calcd for _{C 18 H 17 F 3 N 4} O of: 363.1; Found: 363.3.

Example 400: 4-(2-Methyl-6-(4-methylpiperazin-1-yl)pyridin-3-yl)-6-(trifluoromethyl)-1 H -carbazole

4-(6-Chloro-2-methylpyridin-3-yl)-6-(trifluoromethyl)-1 H -indazole (20 mg, 0.064 mmol) in a microwave reactor at 180 ° C A mixture of 1-methylpiperazine (19.28 mg, 0.192 mmol) in DMF (3 mL Subsequently, the reaction mixture was a gradient of H ₂ O (containing 0.05% TFA) dissolving purified isolated via preparative HPLC with 20% to 40% ACN (containing 0.035% TFA), to give the TFA salt of the title compound. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 7.93 (s, 1H), 7.89 (s, 1H), 7.75 (d, J = 8.0 Hz, 1H), 7.27 (s, 1H), 7.03 (d, J) = 8.0 Hz, 1H), 3.00-3.54 (br, 8H), 2.69, (s, 3H), 2.35 (s, 3H); ESI-MS m/z [M+H] ⁺ for C ₁₉ H ₂₀ F ₃ Calculated for N ₅ : 376.2; found: 376.4.

Example 401:1,6-Dimethyl-5-(4-methylpiperazine-1-carbonyl)-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridine- 2(1 H )-ketone

In a manner similar to Example 265, 3-bromo-1,6-dimethyl-5-(4-methylpiperazine-1-carbonyl)pyridine-2( 1H )-one was used instead of 5-iodo-6. - The pendant oxy-1,6-dihydropyridine-3-carboxylic acid methyl ester to give the title compound as a TFA salt. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.08 (s, 1H), 7.89 (s, 1H), 7.71 (s, 1H), 7.54 (s, 1H), 3.04-3.83 (broad peak, 8H), 3.71(s,3H), 2.93(s,3H), 2.51(s,3H); ESI-MS m/z [M+H] ⁺ calcd for C ₂₁ H ₂₂ F ₃ N ₅ O ₂ : 434.2; Found: 434.4.

Example 402: 1,6-Dimethyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridine-2(1 H )-one

In a manner similar to Example 265, 5-bromo-1,6-lutidine-2( 1H )-one was used in place of 5-iodo-6-o-oxy-1,6-dihydropyridine-3- Methyl formate was used to prepare the title compound. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 7.99 (s, 1H), 7.93 (s, 1H), 7.53 (d, J = 8.0 Hz, 1H), 7.27 (s, 1H), 6.61 (d, J = 8.0 Hz, 1 H), 3.71 (s, 3H), 2.32 (s, 3H); ESI-MS m/z [M+H] ⁺ calculated for C ₁₅ H ₁₂ F ₃ N ₃ O: 308.1; Found: 308.3.

Example 403: 1,4-Dimethyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridine-2(1 H )-one

In a manner similar to Example 265, 5-bromo-1,4-dimethylpyridine-2( 1H )-one was used in place of 5-iodo-6-o-oxy-1,6-dihydropyridine-3- Methyl formate was used to prepare the title compound. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.02 (s, 1H), 7.94 (s, 1H), 7.72 (s, 1H), 7.30 (s, 1H), 6.58 (s, 1, 1H), 3.61 (s, 3H), 2.07 (s, 3H); ESI-MS m/z (M+H) ⁺ Calculated for C ₁₅ H ₁₂ F ₃ N ₃ O: 308.1;

Example 404: N- (2-hydroxyethyl)-1,2-dimethyl-6-oxo-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)- 1,6-dihydropyridine-3-carboxamide

In a similar manner to Example 265, 5-bromo- N- (2-hydroxyethyl)-1,2-dimethyl-6-o-oxy-1,6-dihydropyridine-3-carboxamide was used. The title compound was prepared by substituting methyl 5-iodo-6-oxo-1,6-dihydropyridine-3-carboxylate. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.12 (s, 1H), 7.88 (s, 1H), 7.83 (s, 1H), 7.56 (s, 1H), 3.67-3.75 (m, 5H), 3.47 (t, J = 4.0, 8.0 Hz, 2H), 2.63 (s, 3H); ESI-MS m/z [M+H] ⁺ calculated for C ₁₈ H ₁₇ F ₃ N ₄ O ₃ : 395.1; Value: 395.3.

Example 405: 2-(6-Methyl-2-oxo-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridine-1( 2H )-yl)acetonitrile

In a similar manner to Example 265, 2-(5-bromo-6-methyl-2-oxopyridine-( 2H )-yl)acetonitrile was used instead of 5-iodo-6-o-oxy-1. Methyl 6-dihydropyridine-3-carboxylate was used to prepare the title compound. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.02 (s, 1H), 7.93 (s, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.31 (s, 1H), 6.60 (d, J = 8.0 Hz, 1H), 4.99 (s, 2H), 2.24 (s, 3H); ESI-MS m/z [M+H] ⁺ calculated for C ₁₆ H ₁₁ F ₃ N ₄ O: 333.1; Value: 333.3.

Example 406: 4-Methyl-1-(pyridin-2-ylmethyl)-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridine-2( 1H )- ketone

In a manner similar to Example 265, 5-bromo-4-methyl-1-(pyridin-2-ylmethyl)pyridine-2(1 H )-one was used in place of 5-iodo-6-sideoxy-1 Methyl 6-dihydropyridine-3-carboxylate to prepare the title compound as a TFA salt. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.71 (d, J = 4.0 Hz, 1H), 8.29 (t, J = 8.0, 8.0 Hz, 1H), 8.09 (s, 1H), 7.96 (s, 1H) ), 7.92 (s, 1H), 7.71-7.79 (m, 2H), 7.37 (s, 1H), 6.61 (s, 1H), 5.46 (s, 2H), 2.11 (s, 3H); ESI-MS m / z [M ⁺ H] + calcd for _{C 20 H 15 F 3 N 4} O of: 385.1; Found: 385.4.

Example 407: 6-Methyl-1-(pyridin-2-ylmethyl)-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridine-2(1 H )- ketone

In a similar manner to Example 265, 5-bromo-6-methyl-1-(pyridin-2-ylmethyl)pyridine-2(1 H )-one was used in place of 5-iodo-6-sideoxy-1 Methyl 6-dihydropyridine-3-carboxylate to prepare the title compound as a TFA salt. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.66 (d, J = 4.0 Hz, 1H), 8.15 (d, J = 8.0 Hz, 1H), 8.04 (s, 1H), 7.95 (s, 1H), 7.57-7.65 (m, 3H), 7.34 (s, 1H), 6.66 (d, J = 8.0 Hz, 1H), 5.68 (s, 2H), 2.33 (s, 3H); ESI-MS m/z [M +H] ⁺ calcd for C ₂₀ H ₁₅ F ₃ N ₄ O 385.1; found: 385.4.

Example 408: 2-(4-Methyl-2-oxo-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridine-1( 2H )-yl)acetonitrile

In a similar manner to Example 265, 2-(5-bromo-4-methyl-2-oxo-pyridine pyridine-1( 2H )-yl)acetonitrile was used instead of 5-iodo-6-o-oxy-1. Methyl 6-dihydropyridine-3-carboxylate to prepare the TFA salt of the title compound. ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 8.07 (s, 1H), 7.95 (s, 1H), 7.77 (s, 1H), 7.33 (s, 1H), 6.60 (s, 1H), 5.02 (s) , 2H), 2.08 (s, 3H); ESI-MS m / z [m + H] + for _{C 16 H 11 F 3 N 4} O of Calcd: 333.1; Found: 333.3.

Example 409: 4-(2-Methyl-6-(2-(methylsulfonyl)ethyl)pyridin-3-yl)-6-(trifluoromethyl)-1 H -indazole

Step A: 4-(6-Chloro-2-methylpyridin-3-yl)-6-(trifluoromethyl)-1 H -carbazole

The reaction was carried out in eight microwave vials. To each vial was added 4-bromo-6-(trifluoromethyl)-1 H -carbazole (0.5 g, 1.86 mmol) in (4 mL) and saturated aqueous NaHCO ₃ (3 mL). - chloro-2-methyl-pyridin-3-yl) boronic acid (0.3875g, 2.264mmol), and _{PdCl 2 (dppf) (0.069g,} 0.0944mmol). The resulting light brown suspensions were each heated in a microwave reactor at 140 ° C for 60 minutes. The reaction mixture was combined and concentrated and EtOAc evaporated Volatiles were removed via rotary evaporation and the product was purified by CombiFlash® chromatography eluting with &lt;RTI ID=0.0&gt; The title compound (3.56 g, 76%) was obtained. ESI-MS m / z [M + H] + calculated for C ₁₄ H ₉ ClF ₃ N ₃ The value: 312.05; Found: 311.89.

Step B: 4-(2-Methyl-6-(2-(methylsulfonyl)ethyl)pyridin-3-yl)-6-(trifluoromethyl)-1 H -carbazole

Add 4-(6-chloro-2-methylpyridin-3-yl)-6-(trifluoromethyl)-1 H -indazole (0.33 g, 1.059 mmol) in IPA (12 mL). , potassium vinyltrifluoroborate _{(0.312g, 2.329mmol), Et 3} N (0.298mL, 2.117mmol) , and _{PdCl 2 (dppf) (0.077g,} 0.106mmol), to give a pale brown suspension. The mixture was bubbled with nitrogen and heated in a microwave reactor at 100 ° C for 30 minutes. Sodium methanesulfinate (0.540 g, 5.29 mmol) and acetic acid (0.606 mL, 10.59 mmol) were added, and the reaction mixture was stirred at 60 ° C for 18 hr then cooled. The volatiles were evaporated and the resulting crude residue was purified by the 40% ACN containing H ₂ O (containing 10mM NH ₄ HCO ₃₎ was purified over 8 minutes eluting the LCMS. The solution containing the product were combined and used parts from GeneVac ^TM volatiles were evaporated to afford the title compound as a white solid (0.192g, 47.3%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 2.41 (s, 3 H), 3.05 (s, 3 H), 3.35-3.43 (m, 2 H), 3.59-3.72 (m, 2 H), 7.32 ( s, 1 H), 7.40 (d, J = 7.83 Hz, 1 H), 7.75 (d, J = 7.83 Hz, 1 H), 7.89 (s, 1 H), 7.98 (s, 1 H); ESI- MS m / z [m + H ] + for _{C 17 H 16 F 3 N 3} O ₂ S calculated sum value: 384.1; Found: 384.09.

Example 410: (3-Methyl-1-((1-methyl-1 H -pyrazol-4-yl)methyl)-4-(6-(trifluoromethyl)-1 H -indazole- 4-yl)-1 H -pyrazole-5-yl)methanol

Step A: 4-bromo-3-methyl-1-((1-methyl-1 H -pyrazol-4-yl)methyl)-1 H -pyrazole-5-carboxylic acid ethyl ester

Add Cs ₂ CO ₃ (8.94 g, 27.4 mmol) and 4- to 4-bromo-3-methyl-1 H -pyrazole-5-carboxylic acid ethyl ester (2.56 g, 10.98 mmol) in DMF (30 mL) (Chloromethyl)-1-methyl-1 H -pyrazole hydrochloride (2.2 g, 13.17 mmol). The reaction mixture was stirred at room temperature for 20 hours and then diluted with water. The product was extracted into EtOAc. The organic phase was dried over Na ₂ SO ₄ and concentrated. The crude residue was purified by CombiFlash® chromatography (120 g, column) eluting with 10% to 100% EtOAc gradient of Heptane over 180 min. The product-containing fractions were combined and concentrated to give the title compound (md. Ethyl H -pyrazol-4-yl)methyl)-1 H -pyrazole-3-carboxylate (1.32 g, 36.8%).

Step B: 3-methyl-1-((1-methyl-1 H -pyrazol-4-yl)methyl)-4-(1-(tetrahydro-2 H -pyran-2-yl) Ethyl 6-(trifluoromethyl)-1 H -indazol-4-yl)-1 H -pyrazole-5-carboxylate

Dioxane (25mL) in a microwave vial and saturated aqueous NaHCO ₃ (6mL) of the 1- (tetrahydro -2 H - pyran-2-yl) -4- (4,4,5,5 Methyl-1,3,2-dioxaborolan-2-yl)-6-(trifluoromethyl)-1 H -indazole (0.993 g, 2.506 mmol), 4-bromo-3-methyl Ethyl 1-((1-methyl-1 H -pyrazol-4-yl)methyl)-1 H -pyrazole-5-carboxylate (0.82 g, 2.506 mmol) and PdCl ₂ (dppf) (0.092 g, 0.125 mmol). The mixture was bubbled with nitrogen to give a pale-yellow suspension which was heated in a microwave reactor at 140 ° C for 60 minutes. The reaction mixture was then washed with water and brine and diluted with EtOAc, dried over Na ₂ SO _4, and concentrated. The crude residue was purified by CombiFlash® chromatography (120 g column) eluting with 10% to 100% EtOAc gradient of heptane over 180 min. The title compound (0.745 g, 57.5%) was obtained. ESI-MS m / z [M + H] + for C ₂₅ H ₂₇ F _{3 6} O ₃ The calculated value N: 517.22; Found: 517.20.

Step C: (3-Methyl-1-((1-methyl-1 H -pyrazol-4-yl)methyl)-4-(6-(trifluoromethyl)-1 H -indazole- 4-yl)-1 H -pyrazole-5-yl)methanol

3-methyl-1-((1-methyl-1 H -pyrazol-4-yl)methyl)-4-(1-(tetrahydro-2 H -pyran)- in THF (10 mL) 2-Base)-6-(Trifluoromethyl)-1 H -indazol-4-yl)-1 H -pyrazole-5-carboxylic acid ethyl ester (0.745 g, 1.42 mmol) was loaded in a 100 mL round bottom flask. The mixture was cooled to 0 °C. A 1M lithium aluminum hydride solution (4.33 mL, 4.33 mmol) in diethyl ether was added and the mixture was stirred at 0 ° C for one hour. The reaction was quenched with 1N EtOAc (EtOAc)EtOAc. The organic phase was washed with brine, and dried over Na ₂ SO _4. The volatiles were removed by evaporation. The crude residue was dissolved in MeOH (5 mL). HCl (0.5 mL) was added, and the mixture was stirred for 2 hr. The product containing 30% ACN by the H ₂ O (containing 10mM NH ₄ HCO ₃₎ was purified over a period of 10 minutes eluting LCMS. The solution containing the product were combined and used parts from GeneVac ^TM volatiles were evaporated to give the title compound (0.178g, 31.6%). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 2.27 (s, 3 H), 3.88 (s, 3 H), 4.51 (s, 2 H), 5.30 (s, 2 H), 7.37 (d, J = 1.26 Hz, 1 H), 7.52 (s, 1 H), 7.65 (s, 1 H), 7.88 (s, 1 H), 7.94-8.02 (m, 1 H); ESI-MS m/z [M+ H) ⁺ calcd for C ₁₈ H ₁₇ F ₃ N ₆ O: 391.15; Found: 391.

Example 411: (5-Methyl-1-((3-methylisoxazol-5-yl)methyl)-4-(6-(trifluoromethyl)-1 H -indazol-4-yl) )-1 H -pyrazol-3-yl)methanol

And Example 412: (3-Methyl-1-((3-methylisoxazol-5-yl)methyl)-4-(6-(trifluoromethyl)-1 H -indazole-4 -yl)-1 H -pyrazole-5-yl)methanol

Step A: 4-Bromo-5-methyl-1-((3-methylisoxazol-5-yl)methyl)-1 H -pyrazole-3-carboxylic acid ethyl ester and 4-bromo-3- Ethyl methyl-1-((3-methylisoxazole-5-yl)methyl)-1 H -pyrazole-5-carboxylate

and

Add Cs ₂ CO ₃ (1.157 g, 3.55 mmol) to a mixture of 4-bromo-3-methyl-1 H -pyrazole-5-carboxylate (0.331 g, 1.40 mmol) in DMF (10 mL) 5-(Bromomethyl)-3-methylisoxazole (0.5 g, 2.84 mmol). The reaction mixture was stirred at room temperature for 20 hours and then diluted with water. The product was extracted into EtOAc. The organic phase was dried over Na ₂ SO ₄ and concentrated to give a crude mixture of the title compound (0.24 g), which was used without further purification of the.

Step B: 5-Methyl-1-((3-methylisoxazol-5-yl)methyl)-4-(6-(trifluoromethyl)-1 H -indazol-4-yl) -1 H -pyrazole-3-carboxylic acid ethyl ester and 3-methyl-1-((3-methylisoxazole-5-yl)methyl)-4-(6-(trifluoromethyl)- 1 H -carbazol-4-yl)-1 H -pyrazole-5-carboxylic acid ethyl ester

and

(6-(Trifluoromethyl)-1 H -indazol-4-yl)boronic acid (0.168 g, 0.731 mmol), 4-bromo-3-methyl-1-((3-methylisoxazole) -5-yl)methyl)-1 H -pyrazole-5-carboxylic acid ethyl ester and 4-bromo-5-methyl-1-((3-methylisoxazole-5-yl)methyl)- 1 H - pyrazole-3-carboxylate (0.240 g) and _{PdCl 2 (dppf) (0.027g,} 0.037mmol) in a mixture of _aqueous solution (3mL) in dioxane (12 mL) and saturated NaHCO charged microwave vial. The solution was bubbled with nitrogen to give a pale yellow suspension which was heated in a microwave reactor at 140 ° C for 60 min. The reaction mixture was then concentrated to give the title compound mjjjjjj

Step C: (5-Methyl-1-((3-methylisoxazol-5-yl)methyl)-4-(6-(trifluoromethyl)-1 H -indazol-4-yl) -1 H -pyrazol-3-yl)methanol and (3-methyl-1-((3-methylisoxazol-5-yl)methyl)-4-(6-(trifluoromethyl) )-1 H -carbazol-4-yl)-1 H -pyrazole-5-yl)methanol

3-methyl-1-((3-methylisoxazol-5-yl)methyl)-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1 Ethyl H -pyrazole-5-carboxylate and 5-methyl-1-((3-methylisoxazol-5-yl)methyl)-4-(6-(trifluoromethyl)-1 H - indazol-4-yl) -1 H - pyrazole-3-carboxylate (0.210 g) in a mixture of charged 40mL vial (6mL) in the THF. The mixture was cooled to 0 °C. A 1M lithium aluminum hydride solution (1.454 mL, 1.454 mmol) in diethyl ether was added and the mixture was stirred at room temperature for 30 min. The reaction was quenched with 1N EtOAc (2 mL). The mixture was allowed to warm to rt and the product was extracted EtOAc. The organic phase was washed with brine, and dried over Na ₂ SO _4. The volatiles were evaporated, and the crude residue was purified by the 35% ACN containing H ₂ O (containing 10mM NH ₄ HCO ₃₎ was purified over a period of 10 minutes eluting LCMS. The solution containing the product were combined and used parts from GeneVac ^TM volatiles were evaporated to give the title compound. The late elution peak was designated as the regioisomer of Example 411 (3.3 mg). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 2.19 (s, 3 H), 2.30 (s, 3 H), 4.59 (s, 2 H), 5.63 (s, 2 H), 6.26 (s, 1 H) ), 7.31 (d, J = 1.26 Hz, 1 H), 7.92 (s, 1 H), 8.04 (d, J = 0.76 Hz, 1 H); ESI-MS m/z [M+H] ⁺ for C _{18 16} F ₃ N ₅ O ₂ calculated values of H: 392.13; Found: 392.21. The earlier dissolving peak was designated as the regioisomer of Example 412 (2.8 mg). ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 2.30 (s, 3 H), 2.31 (s, 3 H), 4.50 (s, 2 H), 5.55 (s, 2 H), 6.28 (s, 1 H) ), 7.34-7.43 (m, 1 H), 7.90 (s, 1 H), 7.96-8.05 (m, 1 H); ESI-MS m/z [M+H] ⁺ for C ₁₈ H ₁₆ F ₃ N Calculated for ₅ O ₂ : 392.13; found: 392.21.

Example 413: ( R )-1-(4-Methyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyrimidin-2-yl)pyrrolidin-3-ol

Step A: ( R )-1-(5-Bromo-4-methylpyrimidin-2-yl)pyrrolidin-3-ol

( R )-pyrrolidin-3-ol hydrochloride (8.94 g, 72.3 mmol), 5-bromo-2-chloro-4-methylpyrimidine (15 g, 72.3 mmol), DIPEA (31.6 mL, 181 mmol) EtOH (150 mL) was mixed in a 500 mL pear-shaped flask equipped with a magnetic stir bar. The resulting yellow suspension was heated to 70 ° C in a sand bath for 18 hours. At this point, about half of the solvent was evaporated. Water (250 mL) was added to the flask while the solution was stirred rapidly. The title compound (16.7 g, 89.5%) was obtained.

Step B: ( R )-1-(4-Methyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyrimidin-2-yl)pyrrolidin-3-ol

Dioxane (150 mL) and saturated aqueous NaHCO ₃ (60 mL) of the 4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -6 -(trifluoromethyl)-1 H -carbazole (15 g, 48.1 mmol), ( R )-1-(5-bromo-4-methylpyrimidin-2-yl)pyrrolidin-3-ol (10.34 g , 40.1 mmol) and PdCl ₂ (dppf) (1.465 g, 2.003 mmol) were charged with a 350 mL glass high pressure bottle. The resulting pale yellow suspension was washed with N ₂ and the glass autoclave was sealed. The mixture was heated at 110 ° C for 24 hours in an oil bath. The reaction mixture was cooled with EtOAc EtOAc m. The organic layers were washed with brine (100mL), dried over Na ₂ SO _4, and filtered. The solvent was evaporated to give a crystal crystal crystal crystal crystal crystal crystal crystal crystal crystals The pure fractions were combined and concentrated to give the product as a rust solid. The solid was dissolved in THF (250 mL) and treated with Si-Thiol (20 g, 1.28 mmol/g, Silicycle® Lot 22477). The mixture was stirred overnight at RT and then filtered through a pad of Celite. The filtrate was concentrated and the product by using 20% to 45% ACN gradient of H ₂ O was purified by preparative HPLC from the solution (containing 0.1% formic acid). The pure dissolved fraction is concentrated to about 1 L of solvent. , And extracted with EtOAc (3 × 800mL) washed with saturated aqueous NaHCO ₃ solution and the resulting white slurry. The organic layers were washed with water (800 mL), dried over Na ₂ SO _4, filtered, and concentrated. When the volume of EtOAc was about 300 mL, MeOH (300 mL) was evaporated and evaporated. The solid was dried in a vacuum oven for 2 days at 50 ° C to give the title compound (5.85 g, 40.2%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.88-1.95 (m, 1 H), 2.03 (dt, J = 12.95, 4.14 Hz, 1 H), 2.22 (s, 3 H), 3.33 (s, 2 H), 3.50-3.70 (m, 4 H), 4.41 (br s, 1 H), 4.98 (br s, 1 H), 7.28 (d, J = 1.26 Hz, 1 H), 7.92 (s, 1 H), 8.04 (s, 1 H), 8.29 (s, 1 H), 13.67 (s, 1 H); ESI-MS m/z [M+H] ⁺ for C ₁₇ H ₁₆ F ₃ N ₅ O Calculated: 364.1; found: 364.4.

Example 414: ( R )-4-(2-Methyl-6-(3-methylpiperazin-1-yl)pyridin-3-yl)-6-(trifluoromethyl)-1 H -indazole

Step A: ( R )-1-(5-Bromo-6-methylpyridin-2-yl)-3-methylpiperazine

The medium of DMF (4mL) 3- bromo-6-chloro-2-methylpyridine (515mg, 2.496mmol), (R ) -2- methylpiperazine (250mg, 2.496mmol) and Et ₃ N (1.044mL , 7.49 mmol) was mixed in a 10 mL microwave vial equipped with a magnetic stir bar. The resulting yellow suspension was heated to 165 ° C for 4 hours in a microwave reactor. The reaction mixture was then partitioned between EtOAc (40 mL)EtOAc The phases were separated and the aqueous extracted with EtOAc EtOAc The organic layers were combined, washed with brine (20 mL), dried over Na ₂ SO _4, filtered, and concentrated. The residue was purified using flash chromatography (12 g column) eluting with EtOAc EtOAc EtOAc The pure fractions were combined and concentrated to give crystall

Step B: ( R )-4-(2-Methyl-6-(3-methylpiperazin-1-yl)pyridin-3-yl)-6-(trifluoromethyl)-1 H -carbazole

( R )-1-(5-Bromo-6-methylpyridin-2-yl)-3-methylpiperazine (120 mg, 0.444 mmol) in dioxane (10 mL), (6-(trifluoro) Methyl)-1 H -indazol-4-yl)boronic acid (133 mg, 0.577 mmol), PdCl ₂ (dppf) (32.5 mg, 0.044 mmol) and aqueous NaHCO ₃ (0.950 mL, 1.77 mmol) in a 10 mL microwave vial Mix to give an orange suspension. The vial was sealed and heated to 145 ° C in a microwave reactor for 45 minutes. The reaction mixture was then filtered and the product was purified by preparative HPLC eluting with &_lt;RTIID=0.0&gt_;0&gt_; The pure fractions were lyophilized to give the title compound (31.6 mg, 14. ^{1 H NMR (400MHz, DMSO- d} 6) δ ppm 1.31 (d, J = 6.57Hz, 3 H), 2.27 (s, 3 H), 2.95 (dd, J = 14.02,10.48Hz, 1 H), 3.05 -3.21 (m, 2 H), 3.36 (d, J = 7.33 Hz, 1 H), 3.44 (d, J = 11.62 Hz, 1 H), 4.44 (d, J = 13.14 Hz, 2 H), 6.94 ( d, J = 8.59 Hz, 1 H), 7.24 (d, J = 1.52 Hz, 1 H), 7.64 (d, J = 8.59 Hz, 1 H), 7.92 - 7.94 (m, 1 H), 7.95 (d , J = 1.01 Hz, 1 H), 8.77 (d, J = 8.59 Hz, 1 H), 9.10 (d, J = 8.34 Hz, 1 H); ESI-MS m/z [M+H] ⁺ for C calculation ₁₉ H ₂₀ F ₃ N ₅ the Found: 376.2; Found: 376.4.

Example 415: (1 R , 5 S )-3-(4-Methyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyrimidin-2-yl)-3- Azabicyclo[3.1.0]hexane-2-carboxamide

Step A: (1 R , 5 S )-3-(5-Bromo-4-methylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid

5-Bromo-2-chloro-4-methylpyrimidine (438 mg, 2.109 mmol), (1 R , 5 S )-3-azabicyclo[3.1.0]hexane-2- in EtOH (90 mL) acid (295mg, 2.320mmol) and Et ₃ N (0.882mL, 6.33mmol) were mixed in 40mL vial. The resulting yellow solution was stirred at 75 ° C for 3 days. The reaction mixture was partitioned between 1N EtOAc (40 mL The phases were separated and the aqueous extracted with EtOAc (EtOAc) The organic layers were combined, washed with brine (40 mL), dried over Na ₂ SO _4, filtered and concentrated to give a white solid of the title compound (660 mg of), which was used without further purification of the.

Step B: (1 R , 5 S )-3-(4-methyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyrimidin-2-yl)-3- Azabicyclo[3.1.0]hexane-2-carboxylic acid

(1 R , 5 S )-3-(5-bromo-4-methylpyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane-2- in dioxane (10 mL) Formic acid (200 mg, 0.671 mmol), (6-(trifluoromethyl)-1 H -indazol-4-yl)boronic acid (201 mg, 0.872 mmol), PdCl ₂ (dppf) (49.1 mg, 0.067 mmol) and NaHCO ₃ aqueous solution (1.435 mL, 2.68 mmol) was mixed in a 10 mL microwave vial to give an orange suspension. The vial was sealed and heated to 140 ° C in a microwave reactor for 40 minutes. Additional (6-(Trifluoromethyl)-1 H -indazol-4-yl)boronic acid (201 mg, 0.872 mmol) and PdCl ₂ (dppf) (49.1 mg, 0.067 mmol) were added and heating was continued for 45 min. The reaction mixture was then partitioned between water (50 mL)EtOAcEtOAc Separate the phases. The organic layer was taken and EtOAc (EtOAc)EtOAc. The organic layers were combined, washed with brine (50 mL), dried over Na ₂ SO _4, filtered and concentrated to give the title compound as a tan glass (170mg, 62.8%), which was used without further purification of the.

Step C: (1 R , 5 S )-3-(4-methyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyrimidin-2-yl)-3- Azabicyclo[3.1.0]hexane-2-carboxamide

(1 R , 5 S )-3-(4-methyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyrimidin-2-yl in DMF (2 mL) --3-Azabicyclo[3.1.0]hexane-2-carboxylic acid (80 mg, 0.198 mmol), NH ₄ Cl (21.22 mg, 0.397 mmol), HATU (90 mg, 0.238 mmol) and Et ₃ N (0.083 mL) , 0.595 mmol) was mixed in a 4 mL vial equipped with a magnetic stir bar. The resulting brown solution was stirred overnight. The product by using 25% to 50% ACN (containing 0.035% TFA) gradient of H ₂ O (containing 0.05% TFA) and purified by preparative HPLC eluting in. The pure fractions were lyophilized to give the title compound <RTI ID=0.0> ¹ H NMR (400 MHz, CD ₃ OD) δ ppm 0.78-0.86 (m, 2 H), 1.88 (ddd, J = 12.06, 7.26, 4.67 Hz, 1 H), 2.09-2.15 (m, 1 H), 2.25 -2.29 (m, 3 H), 3.82 (dd, J = 10.61, 5.05 Hz, 1 H), 3.92-3.96 (m, 1 H), 4.61 (d, J = 5.31 Hz, 1 H), 7.28 (d) , J = 1.01 Hz, 1 H), 7.93-7.95 (m, 2 H), 8.27 (s, 1 H); ESI-MS m/z [M+H] ⁺ for C ₁₉ H ₁₇ F ₃ N ₆ O Calculated value: 403.2; found: 403.4.

Table 1 lists a number of examples of the compound of MetAP2 inhibition data which pIC ₅₀ values indicate higher potency. Compounds were tested according to the enzyme assay described on page 32 of the specification, wherein the MetAP2 enzyme is complexed with cobalt or manganese ions.

The singular articles such as "a", "the", "the", "the" Multiple objects. Thus, for example, a composition containing "a compound" may include a single compound or two or more compounds. The above description is intended to be illustrative, and not restrictive. Many embodiments will be apparent to those skilled in the art after reading this description. The scope of the invention should be determined by the scope of the appended claims. The disclosures of all cited articles and references (including patents, patent applications, and publications) are hereby incorporated by reference in their entirety in their entirety herein

Claims (21)

a compound of formula 1, Or a pharmaceutically acceptable salt thereof, wherein: R ¹ is hydrogen; R ^{2 is} selected from the group consisting of hydrogen, -OH, chlorine, fluorine, -CN, methyl and hydroxymethyl; and R ^{3 is} selected from C _6-14 aryl a C _1-9 heteroaryl group and a C _2-6 heterocyclic group, each of which is optionally substituted with one to five substituents independently selected from the group consisting of halo, pendant oxy, -CN, R ⁷ And R ⁸ ; R ⁴ is hydrogen; R ⁵ is C _1-3 haloalkyl; R ^{6 is} selected from the group consisting of hydrogen, -OH, -NH ₂ , chlorine, fluorine, and methyl; each R ^{7 is} independently selected from -OR ⁹ , -N(R ⁹ )R ¹⁰ , -NR ⁹ C(O)R ¹⁰ , -NHC(O)NR ⁹ R ¹⁰ , -NR ⁹ C(O)NHR ¹⁰ , -C(O)R ⁹ , -C (O)OR ⁹ , -C(O)N(R ⁹ )R ¹⁰ , -C(O)N(R ⁹ )OR ¹⁰ , -C(O)N(R ⁹ )S(O) ₂ R ⁸ , -N(R ⁹ )S(O) ₂ R ⁸ , -SR ⁹ , -S(O)R ⁸ , -S(O) ₂ R ⁸ and -S(O) ₂ N(R ⁹ )R ¹⁰ ; R ^{8 is} independently selected from the group consisting of: (a) a C _1-6 alkyl group, a C _2-6 alkenyl group, and a C _2-6 alkynyl group, each of which is optionally one to five substituents independently selected from the group consisting of Substituted: halo, pendant oxy, -CN and R ¹¹ ; and (b) C _3-8 cycloalkyl-(CH ₂ ) _m -, C _2-6 heterocyclyl-(CH ₂ ) _m -, C _6-14 aryl - (CH _{2) m} - and a C _1-9 heteroaryl group - (CH _{2) m} -, each of these groups, as appropriate, By one to five substituents independently selected from the substituents: halo, oxo, -CN, R ¹¹ and C _1-6 alkyl, which C _1-6 alkyl is independently selected from optionally by one to five Substituted from the following substituents: halo, pendant oxy, -CN and R ¹¹ ; each R ⁹ and R ^{10 are} independently selected from: (a) hydrogen; (b) C _1-6 alkyl, C _2-6 Alkenyl and C _2-6 alkynyl, each of which is optionally substituted with one to five substituents independently selected from the group consisting of halo, pendant, -CN and R ¹¹ ; and (c)C _{3 -8} cycloalkyl-(CH ₂ ) _m -, C _2-6 heterocyclyl-(CH ₂ ) _m -, C _6-14 aryl-(CH ₂ ) _m - and C _1-9 heteroaryl - (CH ₂ ) _m -, each of these groups being optionally substituted with one to five substituents independently selected from the group consisting of halo, pendant oxy, -CN, R ¹¹ and C _1-6 alkyl, C _{The 1-6} alkyl group is optionally substituted with one to five substituents independently selected from the group consisting of halo, pendant oxy, -CN and R ¹¹ ; each R ^{11 is} independently selected from -OR ¹² , -N (R ¹² R ¹³ , -N(R ¹² )C(O)R ¹³ , -NHC(O)NR ¹² R ¹³ , -NR ¹² C(O)NHR ¹³ , -C(O)R ¹² , -C(O) OR ¹² , -C(O)N(R ¹² )R ¹³ , -C(O)N(R ¹² )OR ¹³ , -C(O)N(R ¹² )S(O) ₂ R ¹⁴ , -NR ¹² S(O) ₂ R ¹⁴ , -SR ¹² , -S(O)R ¹⁴ , -S(O) ₂ R ¹⁴ and -S(O) ₂ N(R ¹² )R ¹³ ; ¹² and R ^{13 are} independently selected from: (a) hydrogen; and (b) C _1-6 alkyl and C _3-8 cycloalkyl-(CH ₂ ) _m -, each of which may be one to five, as appropriate Substituents independently selected from the group consisting of halo, pendant, -CN, -OH, and -NH ₂ ; each R ^{14 is} independently selected from C _1-6 alkyl and C _3-8 cycloalkyl- (CH ₂ ) _m -, each of these groups being optionally substituted with one to five substituents independently selected from the group consisting of halo, pendant oxy, -CN, -OH and -NH ₂ ; and each m independently It is selected from the group consisting of 0, 1, 2, 3 and 4; wherein each heteroaryl and heterocyclic moiety has from one to four heteroatoms independently selected from N, O and S. A compound or a pharmaceutically acceptable salt according to the first aspect of the invention, wherein R ^{3 is} selected from the group consisting of phenyl, naphthyl, anthracenyl, pyrrolyl, furyl, thienyl, pyrazolyl, imidazolyl, isomer Azyl, oxazolyl, isothiazolyl, thiazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl, 1-oxa-2,3-oxadiazole, 1-oxo Hetero-2,4-oxadiazolyl, 1-oxa-2,5-oxadiazolyl, 1-oxa-3,4-oxadiazole, 1-thia-2,3-diazolyl, 1 -thia-2,4-diazolyl, 1-thia-2,5-oxadiazolyl, 1-thia-3,4-oxadiazole, tetrazolyl, pyridyl, pyridazinyl, pyrimidine , pyrazinyl, benzofuranyl, isobenzofuranyl, benzothienyl, benzo[ c ]thienyl, 1 H -indolyl, 3 H -indolyl, isodecyl, 1 H -isoindenyl, porphyrinyl, isoindolyl, benzimidazolyl, oxazolyl, benzotriazolyl, 1 H -pyrrolo[2,3- b ]pyridinyl, 1 H -pyrrolo[2,3- c ]pyridinyl, 1 H -pyrrolo[3,2- c ]pyridyl, 1 H -pyrrolo[3,2- b ]pyridyl, 3 H -imidazo[4 , 5- b ]pyridyl, 3 H -imidazo[4,5- c ]pyridinyl, 1 H -pyrazolo[4,3- b ]pyridinyl, 1 H -pyrazolo[4,3- c ]pyridinyl, 1 H -pyrazolo[3,4- c ]pyridinyl, 1 H -pyrazolo[3,4- b ]pyridinyl, 7 H - mercapto, pyridazinyl, imidazo[1,2- a ]pyridyl, imidazo[1,5- a ]pyridyl, pyrazolo[1,5- a ]pyridyl, pyrrolo[1 ,2- b ]pyridazinyl, imidazo[1,2- c ]pyrimidinyl, quinolyl, isoquinolinyl, Lolinyl, quinazolinyl, quinoxalinyl, pyridazinyl, 1,6-naphthyridinyl, 1,7-naphthyridinyl, 1,8-naphthyridinyl, 1,5-naphthyridinyl, 2 , 6-naphthyridinyl, 2,7-naphthyridinyl, pyrido[3,2- d ]pyrimidinyl, pyrido[4,3- d ]pyrimidinyl, pyrido[3,4- d ]pyrimidinyl , pyrido[2,3- d ]pyrimidinyl, pyrido[2,3- b ]pyrazinyl, pyrido[3,4- b ]pyrazinyl,pyrimido[5,4- d ]pyrimidinyl , pyrazino[2,3- b ]pyrazinyl, pyrimido[4,5- d ]pyrimidinyl, 1,2,3,4-tetrahydropyrido[2,3- b ]pyrazinyl, 2,3-Dihydrobenzo[ b ][1,4]dioxin, 3,4-dihydro- 2H -pyrido[3,2- b ][1,4]oxazinyl, 2 , 3-dihydro-1 H -benzo[ d ]imidazolyl, benzo[ d ]thiazolyl, 2,3-dihydro-1 H -pyrrolo[2,3- b ]pyridinyl, [1, 2,4]triazolo[1,5- a ]pyridyl, 2,3-dihydro-1 H -imidazo[4,5- b ]pyridyl, tetrazolo[1,5- a ]pyridine , 7 H -pyrrolo[2,3- d ]pyrimidinyl, pyrazolo[1,5- a ]pyrimidinyl, imidazo[1,2- a ]pyrimidinyl, 4,5-dihydro-1 H -pyrazolo[3,4- d ]pyrimidinyl, 2,3,6,7-tetrahydro-1 H -indenyl, 5 H -pyrrolo[2,3- b ]pyrazinyl, imidazo [1,2- a ] Pyrazinyl, imidazo[1,2- b ]pyridazinyl, oxiranyl, thiocyclopropane, aziridine, oxetanyl, thiocyclobutane, azetidin Alkyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, 1,4-dioxyl, 1,4-oxathiane , morpholinyl, 1,4-dithiazyl, piperazinyl, 1,4-azetidinyl, oxetanyl, thiaheptanyl, azepane Base, 1,4-dioxanyl, 1,4-oxathialenyl, 1,4-oxazepanyl, 1,4-dithiaheptanyl, 1,4-thiazepine, 1,4-diazepanyl, 3,4-dihydro- 2H -pyranyl, 3,6-dihydro- 2H -pyran , 2 H -pyranyl, 1,2-dihydropyridyl, 1,2,3,4-tetrahydropyridyl, 1,2,5,6-tetrahydropyridyl, 1,6-dihydro Pyrimidinyl, 1,2,3,4-tetrahydropyrimidinyl and 1,2-dihydropyrazolo[1,5- d ][1,2,4]triazinyl, each of which is optionally the case by one to five substituents independently selected from the substituents: halo, oxo, -CN, R ⁷ and R ^8. A compound or a pharmaceutically acceptable salt according to claim 1, wherein R ^{3 is} selected from the group consisting of phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2-dihydropyridyl, ,6-dihydropyrimidinyl, 1,2,3,4-tetrahydropyrimidinyl, imidazolyl, pyrazolyl, tetrazolyl, thiazolyl, isoxazolyl, quinolyl, isoquinolinyl, 1 , 7-naphthyridinyl, 1,2,3,4-tetrahydropyrido[2,3- b ]pyrazinyl, 2,3-dihydrobenzo[ b ][1,4]dioxyl , 3,4-dihydro-2 H -pyrido[3,2- b ][1,4]oxazinyl, 1 H -indolyl, porphyrinyl, isoindolyl, benzimidazole , 2,3-dihydro-1 H -benzo[ d ]imidazolyl, benzo[ d ]thiazolyl, 1 H -pyrrolo[2,3- b ]pyridinyl, 1 H -pyrrolo[2 ,3- c ]pyridyl, imidazo[1,2- a ]pyridyl, pyrazolo[1,5- a ]pyridyl, 2,3-dihydro-1 H -pyrrolo[2,3- b ] pyridyl, 3 H -imidazo[4,5- b ]pyridinyl, [1,2,4]triazolo[1,5- a ]pyridyl, 2,3-dihydro-1 H - Imidazo[4,5- b ]pyridinyl, tetrazolo[1,5- a ]pyridinyl, 7 H -pyrrolo[2,3- d ]pyrimidinyl, pyrazolo[1,5- a ] Pyrimidinyl, imidazo[1,2- a ]pyrimidine , 4,5-dihydro-1 H -pyrazolo[3,4- d ]pyrimidinyl, 2,3,6,7-tetrahydro-1 H -indenyl, 5 H -pyrrolo[2, 3- b ] pyrazinyl, imidazo[1,2- a ]pyrazinyl, imidazo[1,2- b ]pyridazinyl and 1,2-dihydropyrazolo[1,5- d ] [1, 2,4] triazinyl, these groups are each optionally substituted with one to five substituents independently selected from the following group of substituents: halo, oxo, -CN, R ⁷ and R ^8. A compound or a pharmaceutically acceptable salt according to claim 1, wherein R ^{3 is} selected from the group consisting of phenyl, pyridyl, 1,2-dihydropyridyl, pyrimidinyl, 1,2,3,4-tetra Hydropyrimidinyl, pyrazolyl and 3H -imidazo[4,5- b ]pyridinyl, each of which is optionally substituted with a substituent selected from the group consisting of halo, pendant oxy, -CN , R ⁷ and R ⁸ . A compound or a pharmaceutically acceptable salt according to claim 1, wherein R ³ is a phenyl group, and the phenyl group is optionally substituted with one to five substituents independently selected from the group consisting of halo and pendant oxy groups. , -CN, R ⁷ and R ⁸ . A compound or a pharmaceutically acceptable salt according to the first aspect of the invention, wherein R ³ is pyridyl, which is optionally substituted with one to four substituents independently selected from the group consisting of halo and pendant oxy groups. , -CN, R ⁷ and R ⁸ . A compound or a pharmaceutically acceptable salt according to claim 1, wherein R ³ is 1,2-dihydropyridinyl, and the 1,2-dihydropyridyl group is independently selected from one to five, optionally The following substituents are substituted: halo, pendant oxy, -CN, R ⁷ and R ⁸ . A compound or a pharmaceutically acceptable salt according to claim 1, wherein R ³ is a pyrimidinyl group, which is optionally substituted with one to three substituents independently selected from the group consisting of halo and pendant oxy groups. , -CN, R ⁷ and R ⁸ . A compound or a pharmaceutically acceptable salt according to the first aspect of the invention, wherein R ³ is pyrazolyl, the pyrazole group being optionally substituted by one to three substituents independently selected from the group consisting of halo, side Oxyl, -CN, R ⁷ and R ⁸ . A compound or a pharmaceutically acceptable salt according to the first aspect of the invention, wherein R ³ is 3 H -imidazo[4,5- b ]pyridinyl, the 3 H -imidazo[4,5- b ] pyridyl optionally substituted with one to four substituents independently selected from the substituents: halo, oxo, -CN, R ⁷ and R ^8. The compound or pharmaceutically acceptable salt of any one of claims 1 to 10 wherein R ² is hydrogen. The compound or pharmaceutically acceptable salt of any one of claims 1 to 10 wherein R ⁵ is a trifluoromethyl group. The compound or pharmaceutically acceptable salt of any one of claims 1 to 10 wherein R ⁶ is hydrogen. A compound according to claim 1 which is selected from the group consisting of 4-phenyl-6-(trifluoromethyl)-1 H -carbazole; 4-(3-methylpyridin-4-yl)- 6-(trifluoromethyl)-1 H -carbazole; 4-(imidazo[1,2-a]pyridin-6-yl)-6-(trifluoromethyl)-1 H -indazole; -(6-(trifluoromethyl)-1 H -indazol-4-yl)-3,4-dihydro- 2H -pyrido[3,2- b ][1,4]oxazine; -(6-(trifluoromethyl)-1 H -indazol-4-yl)nicotinonitrile; 4-(pyrimidin-5-yl)-6-(trifluoromethyl)-1 H -carbazole 4-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzamide; (3-(6-(trifluoromethyl)-1 H -indazol-4-yl) Phenyl)methanol; 5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyrimidin-2-amine; 2-(6-(trifluoromethyl)-1 H -indole (4-(6-(trifluoromethyl)-1 H -indazol-4-yl)phenyl)methanol; (2-(6-(trifluoromethyl)) ) -1 H - indazol-4-yl) phenyl) methanol; 4- (1 H - pyrazol-3-yl) -6- (trifluoromethyl) -1 H - indazole; 4- (pyridin- 4-yl)-6-(trifluoromethyl)-1 H -carbazole; 2'-methyl-6-(trifluoromethyl)-1 H , 2' H -4,4'-di Azole; 5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridin-2-amine; 4-(1 H -benzo[ d ]imidazol-5-yl)-6- (trifluoromethyl) -1 H -carbazole; 3-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzamide; 4-(pyridin-3-yl)-6-(trifluoromethyl) -1 H -carbazole; 4-(1-methyl-1 H -pyrazol-5-yl)-6-(trifluoromethyl)-1 H -carbazole; 4-(3-methyl -1 H -pyrazol-4-yl)-6-(trifluoromethyl)-1 H -carbazole; 4-(1 H -pyrazol-4-yl)-6-(trifluoromethyl)- 1 H -carbazole; 1'-methyl-6-(trifluoromethyl)-1 H , 1' H -4,6'-dicarbazole; 4-(6-(trifluoromethyl)-1 H -carbazol-4-yl)benzenesulfonamide; 7-(6-(trifluoromethyl)-1 H -indazol-4-yl)isoquinoline; 4-(benzo[ d ][1 , 3]dioxol-4-yl)-6-(trifluoromethyl)-1 H -carbazole; N -isobutyl-3-(6-(trifluoromethyl)-1 H -oxazol-4-yl)benzamide; (5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridin-3-yl)methanol; 4-(4-A Oxypyridin-3-yl)-6-(trifluoromethyl)-1 H -carbazole; 8-(6-(trifluoromethyl)-1 H -indazol-4-yl)quinoline; N , N -diethyl-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzamide; 3-(6-(trifluoromethyl)-1 H -吲Zyridin-4-yl)benzonitrile; N -benzyl-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzamide; N -cyclopropyl-4-( 6- (trifluoromethyl) -1 H - indazol-4-yl) benzene Amides; 1'-methyl-6- (trifluoromethyl) -1 H, 1 'H -4,5'- two indazole; methyl-5- (3- (6- (trifluoromethyl Methyl)-1 H -indazol-4-yl)phenyl)-1,3,4-oxadiazole; 2-(3-(6-(trifluoromethyl)-1 H -indazole-4 -yl)phenyl)acetamide; 4-(1,3-dimethyl-1 H -pyrazol-4-yl)-6-(trifluoromethyl)-1 H -carbazole; 2,4 -Dimethyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)thiazole; 4-(pyrazolo[1,5- a ]pyridin-3-yl)-6 -(trifluoromethyl)-1 H -carbazole; 4-(5-methoxypyridin-3-yl)-6-(trifluoromethyl)-1 H -carbazole; 4-(1-( Pyridin-4-ylmethyl)-1 H -pyrazol-4-yl)-6-(trifluoromethyl)-1 H -carbazole; N- (2-(6-(trifluoromethyl)-) 1 H -carbazol-4-yl)phenyl)methanesulfonamide; 4-(3-methoxypyridin-4-yl)-6-(trifluoromethyl)-1 H -carbazole; 4- (3-fluoropyridin-4-yl)-6-(trifluoromethyl)-1 H -carbazole; N , N -dimethyl-2-(6-(trifluoromethyl)-1 H -indole Zin-4-yl)benzamide; 4-(4-(methoxymethyl)phenyl)-6-(trifluoromethyl)-1 H -carbazole; 4-(3-chloropyridine- 4-yl)-6-(trifluoromethyl)-1 H -carbazole; 4-(2-methylpyridin-3-yl)-6-(trifluoromethyl)-1 H -carbazole; 4 -(1-methyl-1 H -indol-2-yl)-6-(trifluoromethyl) -1 H -carbazole; 2-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzonitrile; 4-(2-methoxypyridin-3-yl)-6-( Trifluoromethyl)-1 H -carbazole; 5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyrimidine-2,4(1 H ,3 H )-dione; 4-(2,6-dimethoxypyridin-3-yl)-6-(trifluoromethyl)-1 H -indazole; N- (4-(6-(trifluoromethyl)-1 H -oxazol-4-yl)phenyl)methanesulfonamide; 4-(3-(6-(trifluoromethyl)-1 H -indazol-4-yl)phenyl)morpholine; 4-( 6-(cyclopropylmethoxy)pyridin-3-yl)-6-(trifluoromethyl)-1 H -carbazole; 4-(1 H -pyrrolo[2,3-b]pyridine-5 -yl)-6-(trifluoromethyl)-1 H -carbazole; 4-(4-(6-(trifluoromethyl)-1 H -indazol-4-yl)thiazol-2-yl) Morpholine; 4-(3-(1 H -pyrazol-3-yl)phenyl)-6-(trifluoromethyl)-1 H -carbazole; 4-(4-(1 H -pyrazole- 5-yl)phenyl)-6-(trifluoromethyl)-1 H -carbazole; 2-chloro-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzene Methionine; 4-(1-methyl-1 H -benzo[ d ]imidazol-6-yl)-6-(trifluoromethyl)-1 H -carbazole; 4-(3-fluoro-4 -(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridin-2-yl)morpholine; 4-(5-fluoro-1 H -pyrrolo[2,3- b ]pyridine 4-yl)-6-(trifluoromethyl)-1 H -carbazole; 1',3'-dimethyl -6-(trifluoromethyl)-1 H ,1' H -4,6'-dicarbazole; 4-(3-(1 H -pyrazol-1-yl)phenyl)-6-(three Fluoromethyl)-1 H -carbazole; 4-(5-methyl-1-phenyl-1 H -pyrazol-4-yl)-6-(trifluoromethyl)-1 H -carbazole; 4-(1-(pyridin-2-ylmethyl)-1 H -pyrazol-4-yl)-6-(trifluoromethyl)-1 H -carbazole; N -(3-(6-( Trifluoromethyl)-1 H -indazol-4-yl)pyridin-2-yl)trimethylacetamide; 4-(2-(4-(6-(trifluoromethyl)-1 H - Oxazol-4-yl)-1 H -pyrazol-1-yl)ethyl)morpholine; 5-fluoro-2-(6-(trifluoromethyl)-1 H -indazol-4-yl) Benzonitrile; 4-(1 H -吲哚-7-yl)-6-(trifluoromethyl)-1 H -carbazole; 4-(1-methyl-1 H -indol-4-yl) -6-(trifluoromethyl)-1 H -carbazole; 3-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridin-2-amine; 4-(1,5 -Dimethyl-1 H -pyrazol-4-yl)-6-(trifluoromethyl)-1 H -carbazole; 3,5-dimethyl-4-(6-(trifluoromethyl) -1 H -carbazol-4-yl)isoxazole; 4-(1 H -indol-4-yl)-6-(trifluoromethyl)-1 H -carbazole; 1,3-dimethyl 5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyrimidine-2,4(1 H ,3 H )-dione; 4-(3,5-dimethyl -1 H -pyrazol-4-yl)-6-(trifluoromethyl)-1 H -carbazole; (4-methylpiperazin-1-yl)(3-(6-(three) Fluoromethyl)-1 H -indazol-4-yl)phenyl)methanone; pyrrolidin-1-yl (3-(6-(trifluoromethyl)-1 H -indazol-4-yl) Phenyl)methanone; 4-(2,5-dimethoxyphenyl)-6-(trifluoromethyl)-1 H -carbazole; 4-(2,3-dimethoxyphenyl) -6-(trifluoromethyl)-1 H -carbazole; N -ethyl-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzamide; 4- (5-(6-(Trifluoromethyl)-1 H -indazol-4-yl)pyridin-2-yl)morpholine; 2-(3-(6-(trifluoromethyl)-1 H - Oxazol-4-yl)phenyl)acetonitrile; 4-(6-methoxypyridin-2-yl)-6-(trifluoromethyl)-1 H -carbazole; 2-fluoro- N -methyl 4-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzamide; 2-(2-(6-(trifluoromethyl)-1 H -indazole-4 -yl)phenoxy)acetonitrile; 4-(5-(6-(trifluoromethyl)-1 H -oxazol-4-yl)pyrazin-2-yl)morpholine; N- (4-( 6-(trifluoromethyl)-1 H -indazol-4-yl)benzyl)methanesulfonamide; 4-(1-(pyridin-3-ylmethyl)-1 H -pyrazole-4- 6-(trifluoromethyl)-1 H -carbazole; N -methyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridinium; 4 -(2-(cyclopentyloxy)pyridin-3-yl)-6-(trifluoromethyl)-1 H -indazole; 4-(2-(benzyloxy)pyridin-3-yl)-6 -(trifluoromethyl)-1 H -carbazole; 4-(2-(2,2,2-trifluoroethoxy)pyridin-3-yl)-6-(trifluoromethyl)-1 H -indazole; 5-(6-(trifluoromethyl) -1 H -carbazol-4-yl)quinoline; 4-fluoro- N -methyl-2-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzamide 4-(3-(methylsulfonyl)phenyl)-6-(trifluoromethyl)-1 H -carbazole; N -methyl-3-(6-(trifluoromethyl)-1 H -carbazol-4-yl)benzenesulfonamide; 4-(5-(methylsulfonyl)pyridin-3-yl)-6-(trifluoromethyl)-1 H -carbazole; 2- (3-(6-(Trifluoromethyl)-1 H -indazol-4-yl)phenyl)ethanol; 5-(6-(trifluoromethyl)-1 H -indazol-4-yl) Benzo[ d ]thiazole; N , N -dimethyl-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzenesulfonamide; 2-fluoro- N- (2 -hydroxyethyl)-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzamide; 2-fluoro-5-(6-(trifluoromethyl)-1 H -carbazol-4-yl)benzamide; 4-(6-(trifluoromethyl)-1 H -indazol-4-yl)isoquinoline; 4-(6-(trifluoromethyl) -1 H -carbazol-4-yl)quinoline; 8-methoxy-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)quinoline; 4-fluoro- N -methyl-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzamide; 3-fluoro- N , N -dimethyl-5-(6-( trifluoromethyl) -1 H - indazol-4-yl) benzene Amides; 4- (2- (pyrrolidin-1-yl) pyrimidin-5-yl) -6- (trifluoromethyl) -1 H - indazole; N - methyl-4- (6- (three Fluoromethyl)-1 H -indazol-4-yl)benzamide; 4-(5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyrimidin-2-yl Morpholine; N , N -dimethyl-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzamide; 2-methyl-5-(4-( 6-(trifluoromethyl)-1 H -indazol-4-yl)phenyl)-1,3,4-oxadiazole; N , N -dimethyl-3-(6-(trifluoromethyl) -1 H -indazol-4-yl)benzamide; 4-methyl-7-(6-(trifluoromethyl)-1 H -indazol-4-yl)-3,4- Dihydro-2 H -pyrido[3,2- b ][1,4]oxazine; 4-(2-methoxy-4-methylpyridin-3-yl)-6-(trifluoromethyl -1 H -carbazole; 4-(3-chloro-2-methoxypyridin-4-yl)-6-(trifluoromethyl)-1 H -carbazole; N , N , 3-trimethyl 4-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzenesulfonamide; 4-(1,3-dimethyl-1 H -pyrazole-5-yl) -6-(trifluoromethyl)-1 H -carbazole; N , N ,4-trimethyl-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzenesulfonate Indoleamine; (4-chloro-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)phenyl)methanol; 4-(6-(trifluoromethyl)-1 H - indazol-4-yl) indol-2-one; N - (2- hydroxyethanesulfonate ) -4- (6- (trifluoromethyl) -1 H - indazol-4-yl) benzoyl amine; 4- (2,4-dimethoxypyrimidin-5-yl) -6- ( Trifluoromethyl)-1 H -carbazole; 4-(2-ethoxypyridin-3-yl)-6-(trifluoromethyl)-1 H -carbazole; 4-(2-propoxy) Pyridin-3-yl)-6-(trifluoromethyl)-1 H -carbazole; 4-(3-methylpyridin-2-yl)-6-(trifluoromethyl)-1 H -carbazole 7-(6-(Trifluoromethyl)-1 H -indazol-4-yl)porphyrin-2-one; 5-chloro-3-(6-(trifluoromethyl)-1 H - Oxazol-4-yl)pyridin-2-amine; 4-methoxy-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyrimidin-2-amine; 8-( 6-(trifluoromethyl)-1 H -oxazol-4-yl)-2 H -benzo[ b ][1,4]oxazin-3( 4H )-one; 4-(hydroxymethyl) )-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzonitrile; 4-(6-(trifluoromethyl)-1 H -oxazol-4-yl) Porphyrin-1-one; 5-(6-(trifluoromethyl)-1 H -oxazol-4-yl)-1,7-naphthyridin-8-amine; 4-(2-isopropoxy Pyridin-3-yl)-6-(trifluoromethyl)-1 H -carbazole; 1-methyl-4-(6-(trifluoromethyl)-1 H -indazol-4-yl) -1 H -pyrazol-3-amine; 4-(1-(ethoxymethyl)-1 H -imidazol-2-yl)-6-(trifluoromethyl)-1 H -carbazole; 4 - (1,2-dimethyl -1 H - imidazol-5-yl) -6- (trifluoromethyl) -1 H - indazole ; 4- (1 -methyl -1 H - imidazol-2-yl) -6- (trifluoromethyl) -1 H - indazole; 4- (6- (trifluoromethyl) -1 H - indazole Zin-4-yl)-1 H -pyrazole-3-carbonitrile; 4-(imidazo[1,2- a ]pyridin-3-yl)-6-(trifluoromethyl)-1 H -indole Azole; 4-(2-methylimidazo[1,2- a ]pyridin-3-yl)-6-(trifluoromethyl)-1 H -carbazole; 3-(6-(trifluoromethyl) -1 H -carbazol-4-yl)imidazo[1,2- a ]pyrimidine; 3-(6-(trifluoromethyl)-1 H -indazol-4-yl)imidazo[1, 2- a ]pyrazine; 3-(6-(trifluoromethyl)-1 H -oxazol-4-yl)imidazo[1,2-a]pyridine-6-carbonitrile; 4-(imidazolium [1.5- a ]pyridin-1-yl)-6-(trifluoromethyl)-1 H -carbazole; 5-(6-(trifluoromethyl)-1 H -indazol-4-yl)- 7 H -pyrrolo[2,3- d ]pyrimidine; 3-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1 H -pyrazolo[3,4- d ] Pyrimidine-4(5 H )-one; 7-(6-(trifluoromethyl)-1 H -oxazol-4-yl)-5 H -pyrrolo[2,3- b ]pyrazine; 4- (6-(Trifluoromethyl)-1 H -carbazol-4-yl)-1 H -pyrazole-5-carbonitrile; 7-amino-3-(6-(trifluoromethyl)-1 H -carbazol-4-yl)pyrazolo[1,5- a ]pyrimidine-6-carbonitrile; 7-methoxy-3-(6-(trifluoromethyl)-1 H -carbazole- 4-yl)imidazo[1,2- a ]pyridine-8-carbonitrile; 4-(5-A Yl -1 H - imidazol-4-yl) -6- (trifluoromethyl) -1 H - indazole; 4- (1,5-dimethyl -1 H - imidazol-2-yl) -6- (trifluoromethyl)-1 H -carbazole; 4-(1,4-dimethyl-1 H -imidazol-2-yl)-6-(trifluoromethyl)-1 H -carbazole; -(trifluoromethyl)-4-(1,3,5-trimethyl-1 H -pyrazol-4-yl)-1 H -carbazole; 1-methyl-4-(6-(three Fluoromethyl)-1 H -indazol-4-yl)-1 H -pyrazole-5-amine; 5-methyl-4-(6-(trifluoromethyl)-1 H -indazole-4 -yl)isoxazol-3-amine;3,7-dimethyl-8-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1 H -嘌呤-2,6 (3 H ,7 H )-dione; 4-(1-ethyl-3,5-dimethyl-1 H -pyrazol-4-yl)-6-(trifluoromethyl)-1 H - Carbazole; 4-(3,5-dimethyl-1-(1 H -tetrazol-5-yl)-1 H -pyrazol-4-yl)-6-(trifluoromethyl)-1 H -carbazole; 2-(3,5-dimethyl-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1 H -pyrazol-1-yl)acetonitrile; 4-(1-ethyl-3-methyl-1 H -pyrazol-4-yl)-6-(trifluoromethyl)-1 H -carbazole; 3-(3,5-dimethyl- 4-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1 H -pyrazol-1-yl)propanamine; 2-(3,5-dimethyl-4- (6-(Trifluoromethyl)-1 H -oxazol-4-yl)-1 H -pyrazol-1-yl)acetamidamine; 3-(3,5-dimethyl-4-(6) -(trifluoro Methyl)-1 H -carbazol-4-yl)-1 H -pyrazol-1-yl)propanenitrile; 4-(1-ethyl-5-methyl-1 H -pyrazol-4-yl - 6-(trifluoromethyl)-1 H -carbazole; 2-(3,5-dimethyl-4-(6-(trifluoromethyl)-1 H -indazol-4-yl) -1 H -pyrazol-1-yl)ethylamine; 4-methyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)thiazole; N- (6-methyl -5-(6-(trifluoromethyl)-1 H -oxazol-4-yl)pyridin-2-yl)acetamide; N- (4-methyl-5-(6-(trifluoromethyl) -1 H -indazol-4-yl)pyridin-2-yl)acetamide; 1-(N-morpholinyl)-3-(2-(6-(trifluoromethyl)-1 H ) -oxazol-4-yl)phenoxy)propan-2-ol; 4-methoxy- N -methyl-3-(6-(trifluoromethyl)-1 H -indazol-4-yl Benzoguanamine; 2-(2-(6-(trifluoromethyl)-1 H -indazol-4-yl)phenylsulfonyl)ethanol; N , N -dimethyl-2-( 6-(trifluoromethyl)-1 H -indazol-4-yl)benzenesulfonamide; 6-methoxy-2-(6-(trifluoromethyl)-1 H -carbazole-4- Pyridyl-3-amine; (4-methoxy-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)phenyl)methanol; 3-methyl-4-( 6-(trifluoromethyl)-1 H -indazol-4-yl)benzenesulfonamide; 6-methoxy-5-(6-(trifluoromethyl)-1 H -carbazole-4- Pyridin-3-amine; 6-methyl-2-(6-(trifluoromethyl)-1 H -carbazol-4-yl)pyridin-3-amine; (5-methoxy-2-(6-(trifluoromethyl)-1 H -indazol-4-yl)phenyl)methanol; ,6-Dimethyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyrimidin-2-amine; 2-chloro-5-(6-(trifluoromethyl) -1 H -indazol-4-yl)pyrimidine-4-amine; 5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyrimidine-4-carboxylic acid; 5-methyl- 3-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridin-2-amine; 5-fluoro-3-(6-(trifluoromethyl)-1 H -carbazole- 4-yl)pyridin-2-amine; 5-methyl-6-(6-(trifluoromethyl)-1 H -oxazol-4-yl)-3 H -imidazo[4,5- b ] Pyridine; N -methyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyrimidin-2-amine; N -cyclopropyl-5-(6-(trifluoromethyl) -1 H -indazol-4-yl)pyrimidine-2-amine; 5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyrimidine-2-carbonitrile; Ethyl-5-methyl-7-(6-(trifluoromethyl)-1 H -indazol-4-yl)porphyrin-2,3-dione; 4-(3-methoxy- 6-methylpyridin-2-yl)-6-(trifluoromethyl)-1 H -carbazole; 6-methoxy-3-(6-(trifluoromethyl)-1 H -carbazole- 4- yl) pyridin-acyl amine; 2- (1 H -1,2,4- triazol-1-yl) - N - (2- (6- ( trifluoromethyl) -1 H - indazole -4 -yl)benzyl)acetamide; 5-fluoro-2-(6-(trifluoromethyl)-1 H -oxazol-4-yl)benzamide;6-methyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyrimidine-2,4(1 H ,3 H )-dione; 2-amino-1-(2-(6-(trifluoromethyl)-1 H -indazol-4-yl)phenyl)ethanol; ( R )-2-(5- (6-(Trifluoromethyl)-1 H -oxazol-4-yl)pyrimidin-2-ylamino)propan-1-ol; ( R )-1-(5-(6-(trifluoromethyl) (1) H -carbazol-4-yl)pyrimidin-2-ylamino)propan-2-ol; ( S )-1-(5-(6-(trifluoromethyl)-1 H -indole Zin-4-yl)pyrimidin-2-ylamino)propan-2-ol; 2-(5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyrimidin-2-yl Amino)ethanol; 3-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridin-2-ol; 6-methyl-3-(6-(trifluoromethyl)- 1 H -carbazol-4-yl)pyridin-2-amine; 6-amino-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)nicotinonitrile; 4- (3-methoxypyridin-2-yl)-6-(trifluoromethyl)-1 H -carbazole; 2-(6-(trifluoromethyl)-1 H -indazol-4-yl) Pyridin-3-ol; 4-(2,6-dimethylpyridin-3-yl)-6-(trifluoromethyl)-1 H -carbazole; 5-chloro-2-(6-(trifluoro) Methyl)-1 H -indazol-4-yl)pyridin-3-amine; 4-(2-( 1H -imidazol-1-yl)pyrimidin-5-yl)-6-(trifluoromethyl) -1 H - indazole; N - (2- (6- (trifluoromethyl) -1 H - indazol-4-yl) 3-yl) acetyl amine; 2- (3,5-dimethyl-4- (6- (trifluoromethyl) -1 H - indazol-4-yl) -1 H - pyrazol - 1-yl) -N , N -dimethylethylamine; (1-methyl-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1 H -pyrazole- 3-yl)methanol; (6-amino-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridin-3-yl)(4-methylpiperazin-1- Methyl ketone; 2-methyl-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyrazolo[1,5- d ][1,2,4] Azin-7(6 H )-one; 4-(4-( 1H -pyrazol-1-ylsulfonyl)phenyl)-6-(trifluoromethyl)-1 H -carbazole; N - (2-hydroxyethyl)-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzenesulfonamide; 4-(4-(6-(trifluoromethyl)- 1 H -carbazol-4-yl)phenylsulfonyl)morpholine; 4-(3-methyl-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzene Methylsulfonyl)morpholine; 3-(4-methylpiperazine-1-carbonyl)-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridine-2 (1 H )-ketone; N- (2-hydroxyethyl)-2-oxo-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1,2-dihydro Pyridine-3-carboxamide; N- (2-hydroxyethyl)-2-methoxy-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)nicotinate ; 2-amino- N- (2-hydroxyethyl)-5-(6-(trifluoromethyl)-1 H -carbazol-4-yl)nicotinium amide; 2-sided oxy-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1,2-dihydropyridine 3-carbamamine; 2-methoxy-5-(6-(trifluoromethyl)-1 H -oxazol-4-yl)nicotinium amide; 2-amino-5-(6- (trifluoromethyl)-1 H -indazol-4-yl)nicotinium amide; 1-methyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)anthracene Porphyrin-2-one; 5-(6-(trifluoromethyl)-1 H -indazol-4-yl)porphyrin-2-one; 6-(trifluoromethyl)-1 H ,1 ' H- 4,5'-dicarbazole; 5-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1 H -benzo[ d ]imidazole-2(3 H ) -keto; 5-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1 H -pyrrolo[2,3- b ]pyridine-2(3 H )-one; 6- (6-(Trifluoromethyl)-1 H -indazol-4-yl)porphyrin-2-one; 2-(6-(trifluoromethyl)-1 H -indazol-4-yl) -5 H -pyrrolo[2,3- b ]pyrazine; 6-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1 H -imidazo[4,5- b Pyridine-2( 3H )-one; 2-(trifluoromethyl)-6-(6-(trifluoromethyl)-1 H -oxazol-4-yl)-3 H -imidazo[4 ,5- b ]pyridine; 5-(6-(trifluoromethyl)-1 H -oxazol-4-yl)-1 H -pyrazolo[3,4- b ]pyridine; 7-(6- (trifluoromethyl)-1 H -carbazol-4-yl)-3,4-dihydropyrido[2,3- b Pyrazin-2(1 H )-one; 6-amino-3-methyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyrimidine-4 (3 H -ketone; 4-(2-methoxypyrimidin-5-yl)-6-(trifluoromethyl)-1 H -carbazole; N , N -dimethyl-5-(6-(trifluoro) Methyl)-1 H -indazol-4-yl)pyrimidine-2-amine; 4-(3,6-dimethoxypyridazin-4-yl)-6-(trifluoromethyl)-1 H -carbazole; 4-(6-methoxy-2-methylpyridin-3-yl)-6-(trifluoromethyl)-1 H -carbazole; (1-methyl-4-(6- (trifluoromethyl)-1 H -indazol-4-yl)-1 H -pyrazol-5-yl)methanol; 5-(6-(trifluoromethyl)-1 H -indazole-4- Pyridylamine; 2-methyl-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridin-4-amine; 4-(6-methoxy-4- Methylpyridin-3-yl)-6-(trifluoromethyl)-1 H -indazole; N -methyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl Pyrimidine-4-carboamine; 6-methyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridin-2-amine; 2-methoxy-5- (6-(Trifluoromethyl)-1 H -indazol-4-yl)pyrimidine-4-amine; N- (6-methyl-5-(6-(trifluoromethyl)-1 H -吲Zin-4-yl)pyridin-2-yl)methanesulfonamide; 2-methoxy- N- (6-methyl-5-(6-(trifluoromethyl)-1 H -indazole-4 -yl)pyridin-2-yl)acetamide; 1-methyl- N- (6-methyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridin-2-yl)-1 H -pyrazole-4-sulfonamide; 2 -(4-(6-(Trifluoromethyl)-1 H -indazol-4-yl)-1 H -pyrazol-1-yl)acetate; 2-(4-(6-(trifluoro) Methyl)-1 H -carbazol-4-yl)-1 H -pyrazol-1-yl)acetic acid; (N-morpholinyl)(5-(6-(trifluoromethyl)-1 H - Oxazol-4-yl)pyridin-2-yl)methanone; methyl 4-methoxy-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzoate; -(4-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1 H -pyrazol-1-yl)acetamidamine; 6-sided oxy-5-(6- (trifluoromethyl)-1 H -indazol-4-yl)-1,6-dihydropyridine-3-carboxylic acid methyl ester; (4-methoxy-3-(6-(trifluoromethyl)) -1 H -indazol-4-yl)phenyl)(4-methylpiperazin-1-yl)methanone; (4-methoxy-3-(6-(trifluoromethyl)-1 H -oxazol-4-yl)phenyl)(N-morpholinyl)methanone; N- (2-hydroxyethyl)-4-methoxy-3-(6-(trifluoromethyl)-1 H -carbazol-4-yl)benzamide; methyl 5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridinecarboxylate; N- (2-hydroxyethyl) -5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridinium; (4-methylpiperazin-1-yl)(5-(6-(trifluoromethyl) ) -1 H - indazol-4-yl) pyridin-2-yl) methyl ; 4-methoxy - N, N - dimethyl-3- (6- (trifluoromethyl) -1 H - indazol-4-yl) benzoyl amine; 4-methoxy-3- (6-(Trifluoromethyl)-1 H -indazol-4-yl)benzamide; 2-(3-methyl-4-(6-(trifluoromethyl)-1 H -carbazole 4-yl)-1 H -pyrazol-1-yl)acetamidamine; 6-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyrazolo[1,5- a ] pyrimidine; 3-(6-(trifluoromethyl)-1 H -oxazol-4-yl)imidazo[1,2- b ]pyridazine-6-carboxamide; 2-(3-A 4-(6-(trifluoromethyl)-1 H -oxazol-4-yl)-1 H -pyrazol-1-yl)-1-(N-morpholinyl)ethanone; 1- Methyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyrimidine-2,4(1 H ,3 H )-dione; N -(2-hydroxyethyl) -2-(3-methyl-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1 H -pyrazol-1-yl)acetamide; N , N - Dimethyl-2-(4-(6-(trifluoromethyl)-1 H -indazol-4-yl)phenoxy)ethylamine; 4-(2-(4-(6-(trifluoro)) Methyl)-1 H -indazol-4-yl)phenoxy)ethyl)morpholine; (2-amino-5-(6-(trifluoromethyl)-1 H -indazole-4- Pyridin-3-yl)(4-methylpiperazin-1-yl)methanone; 4-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridiniumamine; 4-methylpiperazin-1-yl)(4-(6-(trifluoromethyl)-1 H -indazole-4- ()pyridin-2-yl)methanone; N- (2-hydroxyethyl)-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyrimidine-2-carboxamide (4-methylpiperazin-1-yl)(5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridin-3-yl)methanone; (2-methoxy 5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridin-3-yl)(4-methylpiperazin-1-yl)methanone; (2-fluoro- 5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridin-3-yl)(4-methylpiperazin-1-yl)methanone; N- (2-hydroxyethyl) 5-(6-(3-trifluoromethyl)-1 H -indazol-4-yl)nicotinium amide; 4-(7-methoxy-1 H -pyrrolo[2,3- c Pyridin-4-yl)-6-(trifluoromethyl)-1 H -carbazole; 4-(7-methyl-1 H -pyrrolo[2,3- c ]pyridin-4-yl)- 6-(trifluoromethyl)-1 H -carbazole; N- (2-methoxyethyl)-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyrimidine 2-amine; (N-morpholinyl)(5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyrimidin-2-yl)methanone; 5-(6-( Trifluoromethyl)-1 H -indazol-4-yl)pyrimidine-2-carboxamide; 4-methyl-6-(6-(trifluoromethyl)-1 H -indazol-4-yl ) -2 H - benzo [b] [1,4] oxazin -3 (4 H) - one; 5- (4-methylpiperazin-1-yl-carbonyl) -3- (6- (trifluoromethyl -1 H -indazol-4-yl)pyridine-2(1 H )-one; 5-( Morpholine-4-carbonyl)-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridine-2(1 H )-one; N -(2-hydroxyethyl)- 6-Sideoxy-5-(6-(trifluoromethyl)-1 H -oxazol-4-yl)-1,6-dihydropyridine-3-carboxamide; 2-(3-methyl -2,6-di-oxy-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)-2,3-dihydropyrimidin-1(6 H )-yl) Indoleamine; N -methyl-2-(3-methyl-2,6-di-oxo-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)-2, 3-dihydropyrimidin-1(6 H )-yl)acetamide; N -ethyl-2-(3-methyl-2,6-di-oxy-5-(6-(trifluoromethyl) -1 H -indazol-4-yl)-2,3-dihydropyrimidin-1(6 H )-yl)acetamidamine; 3-(2-hydroxyethyl)-1-methyl-5- (6-(Trifluoromethyl)-1 H -indazol-4-yl)pyrimidine-2,4(1 H ,3 H )-dione; 3-methoxy- N -methyl-4-( 6-(Trifluoromethyl)-1 H -indazol-4-yl)benzamide; N- (2-hydroxyethyl)-3-methoxy-4-(6-(trifluoromethyl) -1 H -indazol-4-yl)benzamide; 3-methoxy-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzamide; N- (2-hydroxyethyl)-4-methyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridiniumamine; N- (2-hydroxyethyl) -4-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridine Indoleamine; N , N -dimethyl-2-(3-methyl-2,6-di-oxy-5-(6-(trifluoromethyl)-1 H -indazol-4-yl) -2,3-dihydropyrimidin-1(6 H )-yl)acetamidamine; 1-methyl-3-(2-(N-morpholinyl)-2-oxoethyl)-5- (6-(Trifluoromethyl)-1 H -indazol-4-yl)pyrimidine-2,4(1 H ,3 H )-dione; 3-(4-fluorobenzyl)-1-methyl -5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyrimidine-2,4(1 H ,3 H )-dione; 2-(3-methyl-2,6 - Bis-oxy-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)-2,3-dihydropyrimidin-1(6 H )-yl)acetonitrile; 1-A 3-(2-(N-morpholinyl)ethyl)-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyrimidine-2,4(1 H ,3 H )-dione; 1-methyl-5-(morpholin-4-carbonyl)-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridine-2 (1 H )-ketone; N- (2-hydroxyethyl)-1-methyl-6-oxo-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1, 6-dihydropyridine-3-carboxamide; 2-(4-methoxy-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)phenyl)-1-( N-morpholinyl)ethanone; 2-(3,5-dimethyl-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1 H -pyrazole-1 -yl)-1-(N-morpholinyl)ethanone; (3-methoxy-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)phenyl)( N-morpholinyl)methanone; 3-(2-(dimethylamino)ethyl)-1-methyl-5-(6-(trifluoromethyl)-1 H -indazole-4- Pyrimidine-2,4(1 H ,3 H )-dione; N -(2-hydroxyethyl)-2-(4-methoxy-3-(6-(trifluoromethyl)-1 H -carbazol-4-yl)phenyl)acetamidamine; 3-fluoro-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzamide; 3-fluoro - N- (2-hydroxyethyl)-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzamide; 4-(5-(methoxymethyl) -3-methyl-1 H -pyrazol-4-yl)-6-(trifluoromethyl)-1 H -carbazole; 1-(3,5-dimethyl-4-(6-(three) Fluoromethyl)-1 H -indazol-4-yl)-1 H -pyrazol-1-yl)propan-2-one; 4-(4-methoxy-3-(6-(trifluoromethyl) -1 H -indazol-4-yl)benzylidene)-1-methylpiperazin-2-one; 4-fluoro-3-(6-(trifluoromethyl)-1 H -indole Zin-4-yl)benzamide; 1,3-dimethyl-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1 H -pyrazole-5- Methionamine; (3-hydroxyazetidin-1-yl)(4-methoxy-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)phenyl) Methyl ketone; 3-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzenesulfonamide; N- (2-hydroxyethyl)-3-methyl-4-(6- (trifluoromethyl)-1 H -indazol-4-yl)benzamide; 3-chloro- N -(2-hydroxyethyl)-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzamide; N -cyclopropyl-6-oxirane-5- (6-(Trifluoromethyl)-1 H -oxazol-4-yl)-1,6-dihydropyridine-3-carboxamide; N- (cyanomethyl)-6-sideoxy- 5-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1,6-dihydropyridine-3-carboxamide; N , N -dimethyl-6-sideoxy 5- (6- (trifluoromethyl) -1 H - indazol-4-yl) -1,6-dihydro-3-acyl-amine; (S) - N - ( 2- hydroxypropyl - 6-Phenoxy-5-(6-(trifluoromethyl)-1 H -oxazol-4-yl)-1,6-dihydropyridine-3-carboxamide; ( R ) -N -(2-hydroxypropyl)-6-oxo-5-(6-(trifluoromethyl)-1 H -oxazol-4-yl)-1,6-dihydropyridine-3-carboxamidine Amine; N- (2,3-dihydroxypropyl)-6-oxo-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1,6-dihydro Pyridine-3-carboxamide; N- (2,2-difluoroethyl)-6-oxo-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)- 1,6-dihydropyridine-3-carboxamide; 4-(3-fluoro-1 H -pyrrolo[2,3- b ]pyridin-5-yl)-6-(trifluoromethyl)-1 H -carbazole; 4-(3-methyl-1 H -pyrrolo[2,3- b ]pyridin-5-yl)-6-(trifluoromethyl)-1 H -indazole; 2-A -6-(6-(trifluoromethyl)-1 H -carbazole-4- Yl) -3 H - imidazo [4,5- b] pyridine; 3-fluoro-4- (6- (trifluoromethyl) -1 H - indazol-4-yl) benzenesulfonamide Amides; 2- Chloro-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzenesulfonamide; 2-fluoro-4-(6-(trifluoromethyl)-1 H -carbazole 4-yl)benzenesulfonamide; 5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridine-2-sulfonamide; 5-(6-(trifluoromethyl) -1 H -indazol-4-yl)pyridine-3-sulfonamide; 4-(4-(methylsulfonyl)phenyl)-6-(trifluoromethyl)-1 H -carbazole 4-(1-(Difluoromethyl)-3,5-dimethyl-1 H -pyrazol-4-yl)-6-(trifluoromethyl)-1 H -carbazole; 2-( 4-(6-(trifluoromethyl)-1 H -oxazol-4-yl)-1 H -pyrazol-1-yl)ethanol; 2-(4-methoxy-3-(6-( Trifluoromethyl)-1 H -indazol-4-yl)phenyl)acetamidamine; 3-chloro-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzene Sulfonamide; 2-(3,5-dimethyl-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1 H -pyrazol-1-yl) -N -isopropylacetamide; N , N , 1-trimethyl-6-oxo-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1,6 -dihydropyridine-3-carboxamide; N- (cyanomethyl)-1-methyl-6-oxo-5-(6-(trifluoromethyl)-1 H -indazole-4 - yl) -1,6-dihydro-3-acyl-amine; N - (2,2- Fluoroethyl) -1-methyl-6-oxo-5- (6- (trifluoromethyl) -1 H - indazol-4-yl) -1,6-dihydro-3- Indoleamine; N- (2,3-dihydroxypropyl)-1-methyl-6-oxo-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)- 1,6-dihydropyridine-3-carboxamide; N -cyclopropyl-1-methyl-6-oxo-5-(6-(trifluoromethyl)-1 H -indazole-4 - yl) -1,6-dihydro-3-acyl-amine; (R) - N - ( 2- hydroxypropyl) -1-methyl-6-oxo-5- (6- (three fluoromethyl) -1 H - indazol-4-yl) -1,6-dihydro-3-acyl-amine; (S) - N - ( 2- hydroxypropyl) -1-methyl-6 - pendant oxy-5-(6-(trifluoromethyl)-1 H -oxazol-4-yl)-1,6-dihydropyridine-3-carboxamide; 4-fluoro- N- (2 -hydroxyethyl)-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzamide; (3-hydroxyazetidin-1-yl)(3- Methyl-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)phenyl)methanone; 4-(6-(2-methoxyethoxy)-2-methyl Pyridin-3-yl)-6-(trifluoromethyl)-1 H -carbazole; 2-(3,5-dimethyl-4-(6-(trifluoromethyl)-1 H -吲(oxazol-4-yl)-1 H -pyrazol-1-yl) -N , N -dimethylacetamide; (5 S )-5-((3,5-dimethyl-4-(6) -(trifluoromethyl)-1 H -indazol-4-yl)-1 H -pyrazole-1- Methyl)pyrrolidin-2-one; 4-(2-(methylsulfonyl)phenyl)-6-(trifluoromethyl)-1 H -carbazole; 2-(3,5- Dimethyl-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1 H -pyrazol-1-yl)-1-(3-hydroxyazetidine- 1-yl)ethanone; 2-(3,5-dimethyl-4-(6-(trifluoromethyl)-1 H -oxazol-4-yl)-1 H -pyrazol-1-yl ) -N -methylacetamide; N- (2-hydroxyethyl)-4-methyl-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzimidazole (3-hydroxyazetidin-1-yl)(4-methyl-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)phenyl)methanone; (3-hydroxypyrrolidin-1-yl)(4-methyl-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)phenyl)methanone; (3-(hydroxy (methyl)pyrrolidin-1-yl)(4-methyl-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)phenyl)methanone; (4-hydroxypiperidine -1-yl)(4-methyl-3-(6-(trifluoromethyl)-1 H -indazol-4-yl)phenyl)methanone; 1-methyl-5-(6-( Trifluoromethyl)-1 H -indazol-4-yl)pyridine-2(1 H )-one; 2-(2-o-oxy-5-(6-(trifluoromethyl)-1 H - Oxazol-4-yl)pyridine-1( 2H )-yl)acetic acid; 1-methyl-5-(4-methylpiperazine-1-carbonyl)-3-(6-(trifluoromethyl) -1 H -carbazol-4-yl)pyridine-2(1 H )-one; 2,5 -difluoro-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)benzenesulfonamide; 6-methyl-5-(6-(trifluoromethyl)-1 H -oxazol-4-yl)2-cyanopyridine; N- (2-hydroxyethyl)-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridine-2- Sulfonamide; 6-methyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridinium; 4-(3,5-dimethyl-1-(( 3-methyloxetan-3-yl)methyl)-1 H -pyrazol-4-yl)-6-(trifluoromethyl)-1 H -carbazole; 1,5-dimethyl 4-(6-(trifluoromethyl)-1 H -oxazol-4-yl)-1 H -pyrazol-3-amine; 5-methyl-6-(6-(trifluoromethyl) ) -1 H - indazol-4-yl) -3 H - imidazo [4,5- b] pyridin-2-ol; 4- (2-methyl -6- (4 H -1,2,4 -Triazol-4-yl)pyridin-3-yl)-6-(trifluoromethyl)-1 H -indazole; 4-(2-methyl-6-(pyrrolidin-1-yl)pyridine- 3-yl)-6-(trifluoromethyl)-1 H -carbazole; (3-hydroxyazetidin-1-yl)(4-(6-(trifluoromethyl)-1 H - Oxazol-4-yl)pyridin-2-yl)methanone; 2-(3,5-dimethyl-4-(6-(trifluoromethyl)-1 H -indazol-4-yl)- 1 H - pyrazol-1-yl) - N - (2- hydroxyethyl) as acetamide; N - (2- hydroxyethyl) -6-methyl-5- (6- (trifluoromethyl) -1 H -indazol-4-yl)pyridinium; 4-(7-methylimidazo[1, 5- a ]pyridine-6-yl)-6-(trifluoromethyl)-1 H -carbazole; 6-methyl-5-(6-(trifluoromethyl)-1 H -indazole-4 -yl)pyridine-2(1 H )-one; 4-methyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridine-2(1 H )-one; 6-methoxy-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridiniumamine; 4-(6-chloro-2-methoxypyridin-3-yl) -6-(trifluoromethyl)-1 H -carbazole; 5-methyl-6-(6-(trifluoromethyl)-1 H -indazol-4-yl)-[1,2,4 Triazolo[1,5- a ]pyridine; N- (2-hydroxyethyl)-6-methoxy-5-(6-(trifluoromethyl)-1 H -indazol-4-yl Pyridylamine; (3-hydroxyazetidin-1-yl)(6-methoxy-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridine- 2-yl)methanone; 6-methoxy-5-(6-(trifluoromethyl)-1 H -indazol-4-yl) 2-cyanopyridine; (3-hydroxyazetidine -1-yl)(6-methyl-2-(methylamino)-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridin-3-yl)methanone 5-methyl-6-(6-(trifluoromethyl)-1 H -oxazol-4-yl)tetrazolo[1,5- a ]pyridine; 4-(6-methyl-5- (6-(Trifluoromethyl)-1 H -oxazol-4-yl)pyridin-2-yl)morpholine; 4-(2-methyl-6-(4-methylpiperazin-1-yl) ) pyridin-3-yl) -6- (trifluoromethyl) -1 H - indazole 1,6-dimethyl-5- (4-methylpiperazin-1-carbonyl) -3- (6- (trifluoromethyl) -1 H - indazol-4-yl) pyridin-2 (1 H )-keto; 1,6-dimethyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridine-2(1 H )-one; 1,4-two Methyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridine-2(1 H )-one; N -(2-hydroxyethyl)-1,2-di Methyl-6-o-oxy-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)-1,6-dihydropyridine-3-carboxamide; 2-(6 -methyl-2-oxo-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridine-1(2 H )-yl)acetonitrile; 4-methyl-1 -(pyridin-2-ylmethyl)-5-(6-(trifluoromethyl)-1 H -oxazol-4-yl)pyridine-2(1 H )-one; 6-methyl-1- (pyridin-2-ylmethyl)-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridine-2(1 H )-one; 2-(4-methyl- 2-sided oxy-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyridine-1(2 H )-yl)acetonitrile; 4-(2-methyl-6- (2-(methylsulfonyl)ethyl)pyridin-3-yl)-6-(trifluoromethyl)-1 H -carbazole; (3-methyl-1-((1-methyl-) 1 H -pyrazol-4-yl)methyl)-4-(6-(trifluoromethyl)-1 H -oxazol-4-yl)-1 H -pyrazol-5-yl)methanol; 5-methyl-1-((3-methylisoxazol-5-yl)methyl)-4-(6-(trifluoromethyl)-1 H - Oxazol-4-yl)-1 H -pyrazol-3-yl)methanol; (3-methyl-1-((3-methylisoxazol-5-yl)methyl)-4-(6) -(trifluoromethyl)-1 H -indazol-4-yl)-1 H -pyrazol-5-yl)methanol; ( R )-1-(4-methyl-5-(6-(three) Fluoromethyl)-1 H -indazol-4-yl)pyrimidin-2-yl)pyrrolidin-3-ol; ( R )-4-(2-methyl-6-(3-methylpiperazine- 1-yl)pyridin-3-yl)-6-(trifluoromethyl)-1 H -carbazole; (1 R , 5 S )-3-(4-methyl-5-(6-(trifluoro) Methyl)-1 H -indazol-4-yl)pyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane-2-carboxamide; stereoisomerism of any of the above compounds And a pharmaceutically acceptable salt of any of the above compounds or stereoisomers. A compound according to claim 1 which is selected from the group consisting of 4-(2-methyl-6-(2-(methylsulfonyl)ethyl)pyridin-3-yl)-6-(three Fluoromethyl)-1 H -carbazole; (3-methyl-1-((1-methyl-1 H -pyrazol-4-yl)methyl)-4-(6-(trifluoromethyl)) -1 H -carbazol-4-yl)-1 H -pyrazol-5-yl)methanol; (5-methyl-1-((3-methylisoxazol-5-yl)methyl) 4-(6-(trifluoromethyl)-1 H -oxazol-4-yl)-1 H -pyrazol-3-yl)methanol; (3-methyl-1-((3-methyl) Isoxazol-5-yl)methyl)-4-(6-(trifluoromethyl)-1 H -oxazol-4-yl)-1 H -pyrazol-5-yl)methanol; ( R ) 1-(4-methyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyrimidin-2-yl)pyrrolidin-3-ol; ( R )-4- (2-methyl-6-(3-methylpiperazin-1-yl)pyridin-3-yl)-6-(trifluoromethyl)-1 H -carbazole; (1 R , 5 S )- 3-(4-Methyl-5-(6-(trifluoromethyl)-1 H -indazol-4-yl)pyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane- 2-Proline; a stereoisomer of any of the above compounds; and a pharmaceutically acceptable salt of any of the above compounds or stereoisomers. A compound or a pharmaceutically acceptable salt of any one of claims 1 to 10, 14 and 15 which is used as a medicament. A compound or a pharmaceutically acceptable salt according to any one of claims 1 to 10, 14 and 15 for use in the treatment of a disease, disorder or condition selected from the group consisting of hyperglycemia, diabetes, Abnormal dyslipidemia, obesity, insulin resistance, metabolic syndrome X, impaired glucose tolerance, polycystic ovarian syndrome, cardiovascular disease, nonalcoholic hepatic steatosis, and atherosclerosis. A pharmaceutical composition comprising: a compound according to any one of claims 1 to 15 or a pharmaceutically acceptable Salt; and pharmaceutically acceptable excipients. A use of a compound or a pharmaceutically acceptable salt according to any one of claims 1 to 15 for the manufacture of a medicament, wherein the medicament is for treatment selected from the group consisting of obesity, overweight, cardiovascular disease, and high Blood pressure, diabetes, hyperglycemia, insulin resistance, metabolic syndrome X, impaired glucose tolerance, nonalcoholic hepatic steatosis, abnormal dyslipidemia, atherosclerosis, stroke, sleep apnea, osteoarthritis, infertility, and A disease, condition, or condition of the polycystic ovarian syndrome. An effective amount of a compound or a combination of a pharmaceutically acceptable salt of any one of claims 1 to 15 and at least one additional pharmacologically active agent. A combination of claim 20, wherein the additional pharmacologically active agent is selected from the group consisting of insulin, buformin, metformin, phenformin, pioglitazone, rosiglitazone, acesulfame, chlorosulfonate Propionil, tolazamide, tolbutamide, gliclazide, glimepiride, glipizide, glyburide, nag Nateglinide, repaglinide, acarbose, miglitol, exenatide, liraglutide, tsarushi Taspoglutide), alogliptin, linagliptin, saxagliptin, sitagliptin, vildagliptin, pramlinitide, Orlistat, atorvastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin , rosuvastatin, simvastatin, nicotinic acid Bezafibrate, ciprofibrate, clofibrate, fenofibrate, gemfibrozil, cholestyramine, Colesi Colesevelam, colestipol and ezetimibe.