Condensed azines and their applications for the regulation of EP300 or CBP

Abstract

A compound of Formula I, or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or deuterated analog thereof, wherein A 1 , A 2 , A 3 , A 4 , R 4 , X 1 , X 2 , and X 3 as described in any of the embodiments described in this disclosure), compositions thereof, and uses thereof are disclosed. TIFF2022527562000250.tif3954

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit under 35 U.S.C. § 119(e) of U.S. Provisional Patent Application No. 62 / 831,622, filed April 9, 2019, which is incorporated by reference in its entirety herein.

[0002] The present invention relates to organic compounds useful for therapy in mammals, and in particular for the modulation of EP300 or CBP for various diseases associated with overexpression of EP300 or CBP. [Background technology]

[0003] Adenovirus E1A-associated 300 kDa protein (EP300, also called P300 or KAT3B) and CREB-binding protein (CBP, also called CREBBP or KAT3A) have transcriptional coactivators that contain homologous bromodomains and assemble with other proteins to initiate the expression of specific genes. More specifically, EP300 and CBP are histone acetyltransferases (HATs) that acetylate both histone and nonhistone proteins that play roles in gene expression regulation, transcription, and cell cycle regulation. The acetylation status of lysine residues in histone tails is one of many epigenetic post-translational modifications that alter DNA-templated processes such as transcription to promote malignant transformation. Protein acetylation also serves to block polyubiquitination, thereby preventing proteasomal degradation and cell death. (Giotopoulos et al. The epigenetic regulators CBP and p300 facilitate leukemogenesis and represent therapeutic targets in acute myeloid leukemia, Oncogene, 2016 January 21;35(3):279-289). Bromodomain containing BDR4 is the reader of acetyl marks in histone tails written by EP300 / CBP, therefore, bromodomain, EP300, and CBP all share the same pathway in regulating gene transcription (Perez-Salvia et al., Bromodomain inhibitors and cancer therapy: From structures to applications, Epigenetics&Chromatin, 2018,11:30). These proteins interact with many other proteins involved in transcription and cell cycle regulation, as well as with the products of oncogenes and fusion genes (Giotopoulos et al., 2016).

[0004] Inhibition of CBP or EP300 has been shown to be effective in inhibiting the proliferation of acute myeloid leukemia cells, and EP300 and CPB are promising therapeutic targets across multiple subtypes of acute myeloid leukemia (AML) (Giotopoulos et al., 2016). Furthermore, inactivating mutations of acetyltransferase genes have been reported in B-cell lymphomas (Mullighan et al.,CREBBP mutations in relapsed acute lymphoblastic leukemia,Nature,2011;471(7337):235-9).

[0005] It has also been reported that CBP or EP300 inhibition abolishes the survival of multiple myeloma cell lines as a result of direct transcriptional repression of the lymphocyte-specific transcription factor IRF4, which is required for myeloma cell survival, and that CBP / EP300 inhibition is a viable therapeutic strategy to target multiple myeloma and other lymphoid malignancies that depend on the IRF4 network (Conery et al,Bromodomain inhibition of the transcriptional coactivators CBP / EP300 as a therapeutic strategy to target the IRF4 network in multiple myeloma.https: / / doi.org / 10.7554 / eLife.10483.001).

[0006] EP300 inhibition can also stimulate autophagy to provide anti-aging effects. For example, spermidine is a polyamine drug that delays age-related diseases and death by acting as an EP300 inhibitor that stimulates autophagy to provide anti-aging effects (Madeo et al., Spermidine delays ageing in humans, Aging, 2018, Vol. 10, No. 8).

[0007] Inhibition of CBP or EP300 has also been shown to be able to downregulate expression in AR (androgen receptor)-dependent cancer cells, as demonstrated in AR-dependent prostate cancer cell lines and AR-dependent breast cancer tumors (Garcia-Carpizo et al., CREBBP / EP300 bromodomain inhibitors in breast cancer, Mol. Cancer Res., 17(3) March 2019).

[0008] Thus, compounds that can inhibit EP300 or CBP represent a new class of potential therapeutics that can modulate histone acetyltransferases (HATs) that acetylate histone and non-histone proteins. As there are no EP300 or CBBP inhibitors currently approved for the treatment or prevention of disease in humans, there is an unmet need for new compounds that can modulate EP300 or CBP. Summary of the Invention

[0009] One embodiment of the present disclosure relates to novel compounds described in any of the embodiments herein, or pharma- ceutically acceptable salts, solvates, tautomers, stereoisomers, or deuterated analogs thereof, which novel compounds are capable of modulating EP300 or CBP.

[0010] Another embodiment of the present disclosure relates to a compound of formula I, [ka] In the formula, A 1 , A 2 , A 3 , A 4 , R 4 , X 1 , X 2 , or X 3 is as described in any of the embodiments described in this disclosure.

[0011] Other embodiments and subembodiments of Formula I are described further herein in this disclosure.

[0012] Another embodiment of the present disclosure relates to a pharmaceutical composition comprising a compound according to Formula I, or any of the embodiments and subembodiments of Formula I as described herein of the present disclosure, or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or deuterated analog of any of these compounds, and a pharma- ceutically acceptable carrier or excipient.

[0013] Another embodiment of the disclosure relates to a pharmaceutical composition comprising a compound according to Formula (I), or any embodiment of Formula (I), as described herein in this disclosure, or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or deuterated analog of any of these compounds, and another therapeutic agent.

[0014] Another embodiment of the present disclosure relates to a method for treating a subject having a disease or condition mediated by EP300 or CBP, the method comprising administering to the subject an effective amount of a compound according to formula I, or any embodiment of formula I, as described in this disclosure, or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or deuterated analog of any of these compounds, or a pharmaceutical composition of any of the compounds described in this disclosure, wherein the disease or condition aberrantly or otherwise expresses EP300 or CBP, or activates a mutation or translocation of any of the foregoing.

[0015] Additional embodiments are further described in the detailed description of the present disclosure. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] I. Definition As used herein, the following definitions apply unless expressly stated otherwise.

[0017] It should be noted that as used in this specification and the appended claims, the singular forms "a," "an," and "the" include plural references unless the context clearly dictates otherwise.

[0018] Unless the point of attachment is otherwise indicated, the chemical moieties listed in the variable definitions of formula (I) and all embodiments thereof in this disclosure are to be read from left to right, with the right hand side being directly attached to the parent structure as defined. However, when the point of attachment (e.g., a dash "-") is indicated on the left hand side of the chemical moiety (e.g., -alkyloxy-(C 1 ~C 25 ) alkyl), then the left side of this chemical moiety is directly attached to the parent moiety as defined.

[0019] For purposes of constructing compounds, when considering the general descriptions of compounds described herein, it is assumed that such construction will result in the creation of stable structures, i.e., one of ordinary skill in the art will theoretically recognize some constructions (i.e., sterically practical and / or synthetically feasible) that would not normally be considered stable compounds.

[0020] Unless otherwise stated, “alkyl” by itself or as part of another substituent means a straight or branched chain hydrocarbon having the specified number of carbon atoms (i.e., C 1 ~ 6means 1-6 carbons). Representative alkyl groups include straight and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 carbon atoms. Further representative alkyl groups include straight and branched chain alkyl groups having 1, 2, 3, 4, 5, 6, 7, or 8 carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. For each definition herein (e.g., alkyl, alkoxy, arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, heteroarylalkyl, and the like), when a prefix is ​​not included to indicate the number of carbon atoms in the alkyl portion, the alkyl moiety or portion thereof has 12 or fewer main chain carbon atoms, or 8 or fewer main chain carbon atoms, or 6 or fewer main chain carbon atoms. For example, C 1~6 Alkyl refers to a straight or branched chain hydrocarbon having 1, 2, 3, 4, 5, or 6 carbon atoms and is represented by the radical -CH 3 , C 2 Alkyl, C 3 Alkyl, C 4 Alkyl, C 5 Alkyl, C 6 Alkyl, C 1~2 Alkyl, C 2 Alkyl, C 3 Alkyl, C 1~3 Alkyl, C 1~4 Alkyl, C 1~5 Alkyl, C 1~6 Alkyl, C 2~3 Alkyl, C 2~4 Alkyl, C 2~5 Alkyl, C 2~6 Alkyl, C 3~4 Alkyl, C 3~5 Alkyl, C 3~6 Alkyl, C 4~5 Alkyl, C 4~6 Alkyl, C 5~6 Alkyl, and C 6Including, but not limited to, alkyl. Substituents may be attached to any available atom to produce a stable compound, but when an optionally substituted alkyl is an R group of a moiety such as -OR (e.g., alkoxy), -SR (e.g., thioalkyl), -NHR (e.g., alkylamino), -C(O)NHR, etc., the substituents on the alkyl R group are such that the substituents on the alkyl carbon bonded to any O, S, or N of the moiety (except when N is a heteroaryl ring atom) exclude any O, S, or N of the substituents bonded to the alkyl carbon bonded to any O, S, or N of the moiety (except when N is a heteroaryl ring atom).

[0021] "Alkylene" by itself or as part of another substituent means a linear or branched saturated divalent hydrocarbon moiety derived from an alkane having the number of carbon atoms indicated in the prefix. For example, (i.e., C 1~6 means 1 to 6 carbons, C 1~6 Alkylene is meant to include methylene, ethylene, propylene, 2-methylpropylene, pentylene, hexylene, etc.). 1~4 Alkylene is methylene-CH 2 -, ethylene-CH 2 CH 2 -, Propylene-CH 2 CH 2 CH 2 -, and isopropylene -CH(CH 3 )CH 2 -, -CH 2 CH(CH 3 )-, -CH 2 -(CH 2 ) 2 CH 2 -, -CH 2 -CH(CH 3 )CH 2 -, -CH 2 -C(CH 3 ) 2 -CH 2 -CH 2 CH(CH 3)-. Typically, alkyl (or alkylene) groups have from 1 to 24 carbon atoms, with those groups having 10 or fewer, 8 or fewer, or 6 or fewer carbon atoms. If no prefix is ​​included to indicate the number of carbon atoms in the alkylene moiety, the alkylene moiety or portion thereof will have 12 or fewer main chain carbon atoms, or 8 or fewer main chain carbon atoms, or 6 or fewer main chain carbon atoms, or 4 or fewer main chain carbon atoms, or 3 or fewer main chain carbon atoms, or 2 or fewer main chain carbon atoms, or 1 carbon atom.

[0022] "Alkenyl" refers to a linear or branched monovalent hydrocarbon radical having the number of carbon atoms indicated in the prefix and containing at least one double bond. For example, C 2 ~C 6 Alkenyl is meant to include ethenyl, propenyl, and the like. 2 ~C 6 Alkenyl C 1 ~C 6 "Alkylene" is a group -C 1 ~C 6 Alkylene-C 2 ~C 6 alkenyl, where alkenyl and alkylene are as defined herein.

[0023] The term "alkenylene" refers to a linear or branched divalent hydrocarbon radical containing at least one double bond and having the number of carbon atoms indicated in the prefix.

[0024] The term "alkynyl" refers, in some embodiments, to a monoradical of an unsaturated hydrocarbon having 2 to 20 carbon atoms (in some embodiments, 2 to 10 carbon atoms, e.g., 2 to 6 carbon atoms) and having 1 to 6 carbon-carbon triple bonds, e.g., 1, 2, or 3 carbon-carbon triple bonds. In some embodiments, an alkynyl group is an ethynyl (-C≡CH), propargyl (or propynyl, i.e., -C≡CCH 3), etc. If no prefix is ​​included to indicate the number of carbon atoms in the alkenyl or alkynyl moiety, the alkenyl or alkynyl substructure or portion thereof will have 12 or fewer main chain carbon atoms, or 8 or fewer main chain carbon atoms, 6 or fewer main chain carbon atoms, 4 or fewer main chain carbon atoms.

[0025] The term "alkynylene" refers to a straight-chain or branched divalent hydrocarbon radical containing at least one triple bond and having the number of carbon atoms indicated in the prefix. Examples of such unsaturated alkyl groups include vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers.

[0026] "Alkoxy" or "alkoxyl" refers to an -O-alkyl group, where alkyl is as defined herein. 1 ~C 6 "Alkoxy" is -OC 1 ~C 6 Refers to an alkyl group, where alkyl is as defined herein. The substituents of an alkoxy are such that they are attached to any available atom that will produce a stable compound, but that O, S, or N (except when N is a heteroaryl ring atom) are not attached to an alkyl carbon that is attached to the alkoxy O. Furthermore, when alkoxy is recited as a substituent of another moiety, the alkoxy oxygen is not attached to a carbon atom that is attached to an O, S, or N (when N is a heteroaryl ring atom) of the other moiety, or to an alkene or alkyne carbon of the other moiety.

[0027] The terms "alkoxyalkyl" and "alkoxyalkylene" refer to an alkyl group substituted with an alkoxy group. 1 ~C 6 Alkoxy C 1 ~C 6 Alkyl" is C1 ~C 6 Alkoxy-substituted C 1 ~C 6 Alkyl, where alkyl and alkoxy are as defined herein, but "C 1 ~C 3 Alkoxy C 1 ~C 3 Alkylene" is C 1 ~C 3 Alkoxy-substituted C 1 ~C 3 It refers to alkyl, alkylene, and alkoxy as defined herein.

[0028] "Alkylsulfonyl" refers to the group -S(O) 2 -alkyl, e.g., C 1 ~C 6 Alkylsulfonyl is the group -S(O) 2 -C 1 ~C 6 An "alkylsulfonylalkylene" is a radical alkylene-S(O) 2 -alkyl, e.g., C 1 ~C 6 Alkyl Sulfonyl C 1 ~C 6 Alkylene is -C 1 ~C 6 Alkylene-S(O) 2 -C 1 ~C 6 It is an alkyl.

[0029] "Amino" or "amine" refers to the group -NH 2 Represents.

[0030] "Alkylamino" refers to the group -NH-alkyl, where alkyl is as defined herein. Exemplary alkylamino groups include CH 3 NH-, ethylamino, etc. 1 ~C 6 Alkylamino is -N(H)C 1 ~C 6 Refers to alkyl.

[0031] The terms "aminoalkyl" and "aminoalkylene" refer to -alkylene-NH 2 For example, C 1 ~C 6 Aminoalkyl is -C 1 ~C 6 Alkyl-NH 2 "Alkylaminoalkylene" refers to an -alkylene-NH-alkyl group, such as, for example, C 1 ~C 6 Alkylamino C 1 ~C 6 Alkylene is the group -C 1 ~C 6 Alkylene-NH-C 1 ~C 6 It is an alkyl.

[0032] "Dialkylamino" refers to an -N(alkyl)(alkyl) group, where each alkyl is independently as defined herein. Exemplary dialkylamino groups include dimethylamino, diethylamino, ethylmethylamino, and the like. Di-C 1 ~C 6 Alkylamino is -N(C 1 ~C 6 Alkyl) 2 Refers to...

[0033] "Cycloalkyl" or "carbocycle" or "carbocyclic", by itself or as part of another substituent, refers to a saturated or partially unsaturated, non-aromatic monocyclic or fused ring (such as a bicyclic or tricyclic carbocyclic ring system), or cubane, having the number of carbon atoms indicated in the prefix, or, if not specified, 3-6, 4-6, or 5-6 ring members per ring (e.g., cyclopropyl, cyclopentyl, cyclohexyl), unless otherwise specified, in which one or two ring carbon atoms may be optionally replaced by carbonyl. Additionally, the term cycloalkyl is intended to encompass ring systems fused to an aromatic ring (e.g., aryl or heteroaryl), regardless of the point of attachment to the remainder of the molecule. Cycloalkyl refers to a hydrocarbon ring having the indicated number of ring atoms (e.g., C 3~6 (Cycloalkyl and 3-6 membered cycloalkyl both mean 3 to 6 ring carbon atoms.) The term "cycloalkenyl" refers to a cycloalkyl having at least one unit of unsaturation. A cycloalkyl or cycloalkenyl substituent may be at the point of attachment of the cycloalkyl or cycloalkenyl group, forming a quaternary center.

[0034] "Cycloalkylalkyl" and "cycloalkylalkylene" refer to the -(alkylene)-cycloalkyl group, where alkylene, as defined herein, has the indicated number of carbon atoms, or, unless specified, up to 6 carbon atoms, and cycloalkyl, as defined herein, has the indicated number of carbon atoms, or, unless specified, 3 to 10, or 3 to 8, or 3 to 6 ring members per ring. An example is a 4-6 membered cycloalkyl-C 1 ~C 6 Alkyl refers to a cycloalkyl having 4 to 6 carbon atoms attached to an alkylene chain having 1 to 6 carbon atoms, which is attached to the parent moiety. Other exemplary cycloalkylalkyls include, for example, cyclopropylmethylene, cyclobutylethylene, cyclobutylmethylene, and the like. "Cycloalkylalkynylene" refers to an -(alkynylene)-cycloalkyl group, for example, C3 ~C 6 Cycloalkyl C 2 ~C 6 Alkynylene is a radical -(C 2 ~C 6 Alkynylene)-C 3 -C 6 It is a cycloalkyl. 3 ~C 6 Cycloalkylethynylene is a group -C≡CC 3 ~C 6 It is cycloalkyl.

[0035] "Cycloalkylalkoxy" refers to the -(alkoxy)-cycloalkyl group, where alkoxy is as defined herein having the indicated number of carbon atoms, or, if not specified, up to 6 carbon atoms, and cycloalkyl is as defined herein having the indicated number of carbon atoms, or, if not specified, 3 to 10, or, alternatively, 3 to 8, or 3 to 6 ring members per ring. 3 ~C 6 Cycloalkylalkoxy refers to a cycloalkyl having 3 to 6 ring carbon atoms attached to an alkoxy having 1 to 6 carbon atoms, where the alkoxy chain is attached to a parent moiety. Other exemplary cycloalkylalkoxy include, for example, cyclopropylmethoxy, cyclobutylethoxy, cyclobutylmethoxy, and the like.

[0036] The term "cyano" refers to the group -CN. 1 ~C 6 The term "cyanoalkyl" refers to a C alkyl group, as defined herein, that is substituted with one, two, or three cyano groups. 1 ~C 6 Refers to alkyl. 1 ~C 6 "Cyanoalkylethynylene" is a group -C≡CC 1 ~C 6 It is a cyanoalkyl.

[0037] "Aryl," alone or as part of another substituent, refers to a monocyclic, bicyclic, or polycyclic polyunsaturated aromatic hydrocarbon radical containing 6 to 14 ring carbon atoms, which may be a single ring or multiple rings (up to three rings), fused together or covalently linked, unless otherwise specified. However, aryl does not encompass or in any way overlap with heteroaryl, as defined below. When one or more aryl groups are fused with a heteroaryl ring, the resulting ring system is a heteroaryl. Non-limiting examples of unsubstituted aryl groups include phenyl, 1-naphthyl, and 2-naphthyl. The term "arylene" refers to a divalent aryl, where aryl is as defined herein.

[0038] "Arylalkyl" or "aralkyl" refers to -(alkylene)-aryl, where the alkylene group is as defined herein and has the indicated number of carbon atoms, or up to 6 main chain carbon atoms, or up to 4 main chain carbon atoms, and aryl is as defined herein. Examples of arylalkyl include benzyl, phenethyl, 1-methylbenzyl, and the like. Another example is phenyl-C 1 ~C 6 Alkoxy is C 1 ~C 6 Refers to a phenyl group attached to an alkoxy group, C 1 ~C 6 The alkoxy is as defined herein and is attached to the parent moiety.

[0039] The term "haloalkyl" refers to an alkyl substituted with one to seven halogen atoms. Haloalkyl includes monohaloalkyl or polyhaloalkyl. For example, "C 1 ~C 6 The term "haloalkyl" is meant to include trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. Additionally, the term "haloalkylene" refers to an alkylene substituted with 1 to 7 halogen atoms.

[0040] "Halogen" or "halo" refers to all halogens, that is, chloro (Cl), fluoro (F), bromo (Br), or iodo (I).

[0041] The term "haloalkoxy" refers to an alkoxy substituted with one to seven halogen atoms. Haloalkoxy includes monohaloalkoxy or polyhaloalkoxy. For example, "C 1 ~C 6 The term "haloalkoxy" is meant to include trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy, 4-chlorobutoxy, 3-bromopropoxy, and the like.

[0042] "Heteroatom" is meant to include oxygen (O), nitrogen (N), and sulfur (S).

[0043] "Heteroaryl" refers to a monocyclic or bicyclic aromatic ring radical containing 5-9 ring atoms (also referred to in this disclosure as 5-9 membered heteroaryl), including a monocyclic aromatic ring radical containing 5 or 6 ring atoms (also referred to in this disclosure as 5-6 membered heteroaryl), containing one or more, 1-4, 1-3, or 1-2 heteroatoms independently selected from the group consisting of O, S, and N. Any aromatic ring or ring system containing at least one heteroatom is heteroaryl, regardless of the point of attachment (i.e., through any one of the fused rings). Heteroaryl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl, and N-oxide of a tertiary ring nitrogen. A carbon or nitrogen atom is the point of attachment of the heteroaryl ring structure such that a stable compound is produced. Examples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl, indolizinyl, benzo[b]thienyl, quinazolinyl, purinyl, indolyl, quinolinyl, pyrimidinyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl, triazolyl, furanyl, benzofuryl, indolyl, triazinyl, quinoxalinyl, cinnolinyl, furanyl, and the like. Examples of heteroaryls include, but are not limited to, thalazinyl, benzotriazinyl, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl, isoindolyl, indolizinyl, benzotriazinyl, thienopyridyl, thienopyrimidyl, pyrazolopyrimidinyl, imidazopyridine, benzothiaxolyl, benzothienyl, quinolyl, isoquinolyl, indazolyl, pteridinyl, and thiadiazolyl. "Nitrogen-containing heteroaryl" refers to a heteroaryl in which at least one of the ring heteroatoms is N.

[0044] "Heteroarylalkyl" refers to an -(alkylene)-heteroaryl where the alkylene group is as defined herein and has the indicated number of carbon atoms, or, if not specified, up to 6 main chain carbon atoms or up to 4 main chain carbon atoms, and heteroaryl is as defined herein.

[0045] "Heterocycloalkyl" refers to any of the following heterocyclic groups: N, O, S(O) and S(O) 2 (including aryl), or P (including phosphine oxide), where the nitrogen, sulfur, and phosphorus atoms are optionally oxidized, the nitrogen atom is optionally quaternized, and the remaining ring atoms are C, with one or two C atoms optionally present as carbonyl. Furthermore, the term heterocycloalkyl is intended to encompass any ring or ring system containing at least one heteroatom that is not heteroaryl, regardless of the point of attachment to the rest of the molecule. Heterocycloalkyl groups include those with rings that have formally charge-separated aromatic resonance structures, such as N-methylpyridonyl. Heterocycloalkyls may be substituted with one or two oxo groups and may include sulfone and sulfoxide derivatives. Heterocycloalkyl can be a monocyclic, fused bicyclic, or fused polycyclic ring system of 3 to 12, 4 to 10, 5 to 10, or 5 to 6 ring atoms, where 1 to 5 ring atoms are -N=, -N-, -O-, -S-, -S(O)-, or -S(O) 2 -, and further, one or two ring atoms are optionally replaced with a -C(O)- group. As an example, a 4-6 membered heterocycloalkyl is a heterocycloalkyl having 4-6 ring members with at least one heteroatom. A heterocycloalkyl can also be a heterocyclic alkyl ring fused with a cycloalkyl. Non-limiting examples of heterocycloalkyl groups include pyrrolidinyl, piperidinyl, morpholinyl, pyridonyl, and the like. A heterocycloalkyl group can be attached to the remainder of the molecule through a ring carbon or a heteroatom. "Heterocycloalkenyl" refers to a heterocycloalkyl having at least one unit of unsaturation. A heterocycloalkyl or heterocycloalkenyl substituent can be at the point of attachment of the heterocycloalkyl or heterocycloalkenyl group, forming a quaternary center.

[0046] "Heterocycloalkylalkyl" or "heterocyclylalkyl" refers to -(alkylene)-heterocycloalkyl, where the alkylene group is as defined herein and has the indicated number of carbon atoms, or, if not specified, up to 6 main chain carbon atoms, or up to 4 main chain carbon atoms, and heterocycloalkyl is as defined herein.

[0047] "Hydroxyl" or "hydroxy" refers to the group -OH. The terms "hydroxyalkyl" or "hydroxyalkylene" refer to an alkyl or alkylene group, respectively, as defined herein, that is substituted with one, two, three, or five hydroxy groups.

[0048] "C 1 ~C 6 The term "haloalkoxy" refers to a C alkyl group, as defined herein, substituted with one or more halogen atoms. 1 ~C 6 Refers to alkoxy.

[0049] The term "oxo" refers to C(=O) or (O). In some embodiments, the two possible attachment points on the carbon form an oxo group.

[0050] As used throughout this disclosure, "optional substituents" or "optionally substituted" means that substitution of a compound may or may not occur, and the description includes cases where substitution occurs and cases where substitution does not occur. For example, "optionally 1 to 4 J 1 The phrase "substituted with a J group" is intended to include 1 It is meant that the group may be present, but need not be present. Any substitution of compounds in this disclosure is contemplated to be made in a way that results in stable compounds.

[0051] As used herein in connection with the compounds of the present disclosure, the term "synthesize" and like terms refer to chemical synthesis from one or more precursor materials.

[0052] As used herein, the term "composition" refers to a formulation suitable for administration to an animal subject intended for therapeutic purposes, containing at least one pharma- ceutically active compound and at least one pharma- ceutically acceptable carrier or excipient.

[0053] The term "pharmaceutical acceptable" indicates that the indicated substance does not possess properties that would cause a reasonably prudent practitioner, having regard to the disease or condition to be treated and the respective route of administration, to avoid administering the substance to a patient. For example, such materials are generally required to be essentially sterile, e.g., for injectables.

[0054] "Pharmaceutically acceptable salt" refers to a salt that is acceptable for administration to a patient, such as a mammal (e.g., a salt that has acceptable mammalian safety for a given dosing regimen). Possible pharmaceutically acceptable salt forms include, but are not limited to, mono, bis, tris, tetrakis, and the like. Pharmaceutically acceptable salts are non-toxic in the amounts and concentrations at which they are administered. The preparation of such salts can facilitate pharmacological use by altering the physical characteristics of a compound without preventing the compound from exerting its physiological effect. Useful changes in physical properties include lowering the melting point to facilitate transmucosal administration and increasing solubility to facilitate administering higher concentrations of the drug. Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids, depending on the particular substituents found on the compounds described herein.

[0055] Pharmaceutically acceptable salts can be prepared by standard techniques.For example, the free base form of the compound can be dissolved in a suitable solvent, such as an aqueous or aqueous alcoholic solution containing a suitable acid, and then isolated by evaporating the solution.In another example, salts can be prepared by reacting a free base and an acid in an organic solvent.

[0056] When compounds of the present disclosure contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such a compound, either neat or in a suitable inert solvent, with a sufficient amount of the desired base (i.e., a primary, secondary, tertiary, quaternary, or cyclic amine, an alkali metal hydroxide, an alkaline earth metal hydroxide, etc.). The desired acid can be, for example, a pyranosidyl acid (such as glucuronic acid or galacturonic acid), an alpha-hydroxy acid (such as citric acid or tartaric acid), an amino acid (such as aspartic acid or glutamic acid), an aromatic acid (such as benzoic acid or cinnamic acid), a sulfonic acid (such as p-toluenesulfonic acid or ethanesulfonic acid), and the like. In some embodiments, the salt may be, for example, acetic acid, trifluoroacetic acid, propionic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glycolic acid, gluconic acid, glucoronic acid, glutamic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, malonic acid, mandelic acid, oxalic acid, methanesulfonic acid, mucic acid, naphthalenesulfonic acid, nicotinic acid, nitric acid, pamoic acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, sulfamine acid, or the like. The acid may be derived from pharma- ceutically acceptable acids such as hydroiodic acid, carboxylic acid, tartaric acid, p-toluenesulfonic acid, pyruvic acid, aspartic acid, benzoic acid, cinnamic acid, anthranilic acid, mesylic acid, salicylic acid, p-hydroxybenzoic acid, phenylacetic acid, embonic acid (pamoic acid), ethanesulfonic acid, benzenesulfonic acid, 2-hydroxyethanesulfonic acid, sulfanilic acid, stearic acid, cyclohexylsulfamic acid, cyclohexylaminosulfonic acid, quinic acid, alginic acid, hydroxybutyric acid, galactaric acid, and galacturonic acid.

[0057] Also included are salts of amino acids, such as arginates, and salts of organic acids, such as glucuronic acid or galacturonic acid (see, e.g., Berge, SM et al, "Pharmaceutical Salts," J. Pharmaceutical Science, 1977, 66:1-19). Certain compounds of the present disclosure contain both basic and acidic functionalities that allow the compounds to be converted into either base or acid addition salts.

[0058] The neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent forms of the compounds differ from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent forms of the compounds for the purposes of this disclosure.

[0059] Pharmaceutically acceptable salts of different compounds may exist as complexes. Examples of complexes include 8-chlorotheophylline complexes (e.g., dimenhydrinate, diphenhydramine 8-chlorotheophylline (1:1) complex, similar to dramamine) and various cyclodextrin inclusion complexes.

[0060] The term "deuterated" as used herein alone or as part of a group refers to a deuterium atom that is substituted. The term "deuterated analog" as used herein alone or as part of a group refers to a deuterium atom that is substituted in place of hydrogen. The deuterated analogs of the present disclosure can be fully or partially deuterium substituted derivatives. In some embodiments, the deuterium substituted derivatives of the present disclosure retain a fully or partially deuterium substituted alkyl, aryl, or heteroaryl group.

[0061] The present disclosure also encompasses the isotopically labeled compounds of the present disclosure, which are identical to those listed herein, but which have one or more atoms replaced by atoms with different atomic masses or mass numbers than those usually found in nature.All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure.Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, but 2 H (deuterium, D), 3 H (tritium), 11 C. 13 C. 14 C. 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl, and 125 Unless otherwise specified, when a position is specifically designated as "H" or "hydrogen," the position may also be designated as deuterium (D) or tritium ( 3 H) or its natural abundance isotopic composition or isotopes thereof. Certain isotopically labeled compounds of the present disclosure (e.g., 3 H and 14 C) are useful in compound and / or substrate tissue distribution assays. 3 H) and carbon-14 (i.e. 14 C) and fluorine-18( 18 F) isotopes are useful for their ease of preparation and detectability. Additionally, deuterium (i.e., 2 Substitution with heavier isotopes, such as H, may confer certain therapeutic advantages due to greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and therefore may be preferred in some circumstances. Isotopically labeled compounds of the present disclosure may generally be prepared following procedures similar to those described in the protocols and examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0062] "Prodrug" refers to any compound that releases an active parent drug according to formula I in vivo when such prodrug is administered to a subject. Prodrugs of compounds of formula I are prepared by modifying functional groups present in the compounds of formula I, either by routine manipulation or in vivo, which modifications can be cleaved in vivo to release the parent compound. Prodrugs can progress from the prodrug form to the active form in a single step, or can have one or more intermediate forms that themselves can be active or inactive. Some prodrugs are enzymatically activated to produce the active compound, or a compound that upon further chemical reaction produces the active compound. Prodrugs include compounds of formula I in which a hydroxyl, amino, carboxyl, or sulfhydryl group in the compound of formula I is bonded to any group that can be cleaved in vivo to regenerate a free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, esters (e.g., acetate, formate, and benzoate derivatives), amides, guanidines, carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups in the compounds of formula I. Other examples of prodrugs include, but are not limited to, carbonates, ureides, solvates, or hydrates of the active compound. The preparation, selection, and use of prodrugs are discussed in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14, of the ACS Symposium Series, "Design of Prodrugs," ed. H. Bundgaard, Elsevier, 1985, and Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, each of which is incorporated herein by reference in its entirety.

[0063] As described in The Practice of Medicinal Chemistry, Ch. 31-32 (Ed. Wermuth, Academic Press, San Diego, CA, 2001), prodrugs can be conceptually divided into two non-exclusive categories: bioprecursor prodrugs and carrier prodrugs. In general, bioprecursor prodrugs are compounds that are inactive or have low activity compared to the corresponding active drug compound, contain one or more protecting groups, and are converted to active forms by metabolism or solvolysis. Both the active drug form and any released metabolites should have acceptably low toxicity. Typically, the formation of an active drug compound involves a metabolic process or reaction that is one of the following types:

[0064] (1) Oxidation Reactions: Oxidation reactions are exemplified by reactions such as, but not limited to, the oxidation of alcohol, carbonyl, and acidic functional groups, hydroxylation of aliphatic carbons, hydroxylation of alicyclic carbon atoms, oxidation of aromatic carbon atoms, oxidation of carbon-carbon double bonds, oxidation of nitrogen-containing functional groups, oxidation of silicon, phosphorus, arsenic, and sulfur, oxidative N-dealkylation, oxidative O- and S-dealkylation, oxidative deamination, and other oxidation reactions.

[0065] (2) Reduction Reactions: Reduction reactions are exemplified, but are not limited to, reactions such as reduction of carbonyl functional groups, reduction of alcohol functional groups and carbon-carbon double bonds, reduction of nitrogen-containing functional groups, and other reduction reactions.

[0066] (3) Reactions that do not change the oxidation state: Reactions that do not change the oxidation state are exemplified, but not limited to, reactions such as hydrolysis of esters and ethers, hydrolytic cleavage of carbon-nitrogen single bonds, hydrolytic cleavage of non-aromatic heterocycles, hydration and dehydration at multiple bonds, dehydration reactions, hydrolytic dehalogenation, elimination of hydrogen halide molecules, and new atomic bonds resulting from other such reactions.

[0067] Carrier prodrugs are, for example, drug compounds that contain a transport moiety that improves uptake and / or localized delivery to the site of action. Desirably for such carrier prodrugs, the bond between the drug moiety and the transport moiety is a covalent bond, the prodrug is inactive or less active than the drug compound, and the prodrug and any release transport moiety are acceptably non-toxic. For prodrugs where the transport moiety is intended to promote uptake, typically the release of the transport moiety should be rapid. In other cases, it is desirable to utilize moieties that provide sustained release, such as certain polymers or other moieties, such as cyclodextrins. (See, for example, Cheng et al., U.S. Patent Application Publication No. 2004 / 0077595, incorporated herein by reference.) Such carrier prodrugs are often advantageous for orally administered drugs. Carrier prodrugs can be used, for example, to improve one or more of the following properties: increased lipophilicity, increased duration of pharmacological effect, increased site specificity, reduced toxicity and adverse reactions, and / or improved drug formulation (stability, water solubility, reduced undesirable organoleptic or physicochemical properties). For example, lipophilicity can be increased by esterifying hydroxyl groups with lipophilic carboxylic acids or carboxylic acid groups with alcohols, such as aliphatic alcohols.

[0068] The term "carrier" is also meant to include microspheres, liposomes, micelles, nanoparticles (naturally equipped nanocarriers, e.g., exosomes), etc. It is known that exosomes can be highly effective drug carriers, and there are various methods by which drugs can be loaded into exosomes, including the techniques described in J Control Release, 2015 December 10;219:396-405, the entire contents of which are incorporated herein by reference.

[0069] Metabolites, for example, active metabolites, overlap with the above-mentioned prodrugs, for example, bioprecursor prodrugs.Thus, such metabolites are compounds that are further metabolized into pharmacologically active compounds, or derivatives that result from metabolic processes in the subject's body.Of these, active metabolites are such pharmacologically active derivative compounds.For prodrugs, prodrug compounds are generally inactive or less active than metabolites.For active metabolites, parent compounds can be active compounds or inactive prodrugs.

[0070] Prodrugs and active metabolites can be identified using routine techniques known in the art.See, for example, Bertolini et al., 1997, J.Med.Chem., 40:2011-2016; Shan et al., 1997, J Pharm Sci 86(7):756-757; Bagshawe, 1995, Drug Dev.Res., 34:220-230; Wermuth.

[0071] "Tautomer" refers to a compound produced by the phenomenon of the transfer of a proton from one atom of a molecule to another atom. See Jerry March, Advanced Organic Chemistry: Reactions, Mechanisms and Structures, Fourth Edition, John Wiley & Sons, pp. 69-74 (1992). Tautomer also refers to one of two or more structural isomers that exist in equilibrium and are easily converted from one isomeric form to another. Examples include keto-enol tautomers such as acetone / propen-2-ol, imine-enamine tautomers, ring-chain tautomers such as glucose / 2,3,4,5,6-pentahydroxy-hexanal, and tautomeric forms of heteroaryl groups containing the -N=C(H)-NH- ring atom configuration such as pyrazole, imidazole, benzimidazole, triazole, and tetrazole. When a compound contains, for example, a keto or oxime group, or an aromatic moiety, tautomeric isomerism ("tautomerism") may occur. The compounds described herein may have one or more tautomers, and thus include various isomers. Those skilled in the art will recognize that other tautomeric ring atom arrangements are possible. All such isomeric forms of these compounds are expressly included in the present disclosure.

[0072] "Isomers" refer to compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or in the spatial arrangement of their atoms. Isomers that differ in the spatial arrangement of their atoms are termed "stereoisomers". "Stereoisomer" and "stereoisomers" refer to compounds that exist in different stereoisomeric forms when they possess one or more asymmetric centers or double bonds with asymmetric substitutions and thus can be produced as individual stereoisomers or mixtures. Stereoisomers include enantiomers and diastereomers. Stereoisomers that are not mirror images of each other are termed "diastereomers" and stereoisomers that are non-superimposable mirror images of each other are termed "enantiomers". When a compound has an asymmetric center, for example an atom such as a carbon that is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric centers, described by the R- and S-sequence rules of Cahn and Prelog, or by the way the molecule rotates the plane of polarized light, and are called dextrorotatory or levorotatory (i.e., as (+) or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is called a "racemic mixture." As another example, stereoisomers include geometric isomers, such as cis or trans orientation of substituents on adjacent carbons of a double bond. Unless otherwise indicated, the present description is intended to include individual stereoisomers as well as mixtures. Methods for the determination of stereochemistry and separation of stereoisomers are well known in the art (see discussion in Chapter 4 of ADVANCED ORGANIC CHEMISTRY, 6th edition J. March, John Wiley and Sons, New York, 2007), and differ in the chirality of one or more stereocenters.

[0073] "Hydrate" refers to a complex formed by the combination of water molecules with molecules or ions of a solute. "Solvate" refers to a complex formed by the combination of solvent molecules with molecules or ions of a solute. The solvent can be an organic compound, an inorganic compound, or a mixture of both. Solvate is meant to include hydrates. Some examples of solvents include, but are not limited to, methanol, N,N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, and water. In general, solvated forms are equivalent to unsolvated forms and are included within the scope of the present disclosure.

[0074] In the context of using, testing, or screening compounds that are or may be modulators, the term "contacting" means that the compound is brought into sufficient proximity with a particular molecule, complex, cell, tissue, organism, or other particular substance that a potential binding interaction and / or chemical reaction between the compound and the other particular substance can occur.

[0075] "Assaying" refers to the creation of experimental conditions and the collection of data regarding a particular outcome of exposure to a particular experimental condition. For example, enzymes can be assayed based on their ability to act on a detectable substrate. Compounds can be assayed based on their ability to bind to a particular target molecule or molecules.

[0076] As used herein, the terms "ligand" and "modulator" are used equivalently to refer to a compound that alters (i.e., increases or decreases) the activity of a target biomolecule, e.g., an enzyme, such as those described herein. Generally, a ligand or modulator is a small molecule, "small molecule" refers to a compound having a molecular weight of 1500 daltons or less, 1000 daltons or less, 800 daltons or less, or 600 daltons or less. Thus, an "improved ligand" possesses pharmacological and / or pharmacokinetic properties that are superior to a reference compound, where "superior" can be defined by one of skill in the art with respect to a particular biological system or therapeutic application.

[0077] The term "bind" in reference to the interaction between a target and a potential binding compound indicates that the potential binding compound associates with the target to a statistically significant extent compared to association with proteins in general (i.e., non-specific binding). Thus, the term "binding compound" refers to a compound that has a statistically significant association with a target molecule. In some embodiments, a binding compound has a dissociation constant (K D In the context of a compound that binds to a target, the terms "higher affinity" and "selective" indicate that the compound binds more strongly, i.e., with a lower dissociation constant, than a reference compound or the same compound under reference conditions. In some embodiments, the greater affinity is at least 2, 3, 4, 5, 8, 10, 50, 100, 200, 400, 500, 1000, or 10,000 times higher affinity.

[0078] The terms "modulate", "modulation" and the like refer to the ability of a compound to increase or decrease the function and / or expression of a target such as EP300 or CBP, and such functions may include transcriptional regulatory activity and / or binding. Modulation may occur in vitro or in vivo. Modulation as described herein includes inhibition, antagonism, partial antagonism, activation, agonism or partial agonism of a function or characteristic associated with EP300 or CBP, either directly or indirectly, and / or upregulation or downregulation of expression of EP300 or CBP, either directly or indirectly. In other embodiments, the modulation is direct. An inhibitor or antagonist is, for example, a compound that binds to a stimulus, partially or fully blocks the stimulus, reduces, prevents, inhibits, delays, delays activation, inactivates, desensitizes, or downregulates signal transduction. An activator or agonist is, for example, a compound that binds to an activation, stimulates, increases, opens, activates, promotes, enhances it, activates, sensitizes, or upregulates signal transduction.

[0079] As used herein, the terms "treat," "treating," "therapy," "therapies," and similar terms refer to the administration of a substance, e.g., an effective amount of any one or more of the compounds described herein, to prevent, alleviate, or relieve one or more symptoms (i.e., signs) of a disease or condition and / or prolong the survival of the subject being treated.

[0080] As used herein, the terms "prevent", "preventing", "prevention" and grammatical variations thereof refer to a method of partially or completely delaying or preventing the recurrence of a disease, disorder or condition and / or one or more of its attendant symptoms, or preventing a subject from acquiring or re-acquiring a disorder or condition, or reducing the risk of a subject in need of acquiring or in need of a disorder or condition, or one or more of its attendant symptoms.

[0081] As used herein, the terms "subject," "animal subject," and similar terms refer to living organisms, including, but not limited to, humans and non-human vertebrates, e.g., any mammal, such as humans, other primates, sport animals, and commercial animals, such as cows, horses, ovoviviparous animals, pigs, or rodents, or pets, such as dogs and cats.

[0082] "Unit dosage form" refers to a composition intended for single administration to treat a subject suffering from a disease or condition. Each unit dosage form typically contains, in addition to each of the active ingredients of the present disclosure, pharma- ceutically acceptable excipients. Examples of unit dosage forms are individual tablets, individual capsules, bulk powders, liquids, ointments, creams, eye drops, suppositories, emulsions, or suspensions. Treatment of a disease or condition may require periodic administration of a unit dosage form, e.g., one unit dosage form, more than once a day, once with each meal, once every four hours, or at other intervals, or only once a day. The term "oral unit dosage form" refers to a unit dosage form designed to be taken orally.

[0083] The term "administering" refers to oral administration, administration as a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, or implantation of a sustained release device, such as a mini-osmotic pump, into a subject. Administration is by any route, including parenteral and transmucosal (e.g., buccal, sublingual, palatal, gingival, nasal, vaginal, rectal, or transdermal). Parenteral administration includes, for example, intravenous, intramuscular, intraarteriolar, intradermal, subcutaneous, intraperitoneal, intraventricular, and intracranial. Other modes of delivery include, but are not limited to, the use of liposomal formulations, intravenous infusion, transdermal patches, and the like.

[0084] In this context, the term "therapeutically effective" or "effective amount" indicates that the compound or material, or the amount of the compound or material, when administered, is sufficient or effective to prevent, alleviate, or ameliorate one or more symptoms of the disease, disorder, or medical condition being treated, and / or to prolong the survival of the subject being treated. The therapeutically effective amount will vary depending on the compound, the disease, disorder, or condition, and its severity, as well as the age, weight, etc., of the mammal being treated. In general, satisfactory results in a subject are indicated to be obtained with a daily dose of about 0.1 to about 10 g per kg of subject body weight. In some embodiments, the daily dose is in the range of about 0.10 to 10.0 mg / kg of body weight, about 1.0 to 3.0 mg / kg of body weight, about 3 to 10 mg / kg of body weight, about 3 to 150 mg / kg of body weight, about 3 to 100 mg / kg of body weight, about 10 to 100 mg / kg of body weight, about 10 to 150 mg / kg of body weight, or about 150 to 1000 mg / kg of body weight. Dosage may be conveniently administered in divided doses, for example up to four times a day, or in sustained release form.

[0085] The ability of a compound to inhibit the function of EP300 or CBP can be demonstrated in a biochemical assay, for example a binding assay, or a cell-based assay.

[0086] As used herein, the term "EP300- or CBP-mediated disease or condition" refers to a disease or condition in which the biological function of EP300, CBP, or both EP300 and CBP influences the onset and / or course of the disease or condition, and / or modulation of EP300, CBP, or both EP300 and CBP alters the onset, course, and / or symptoms. EP300- or CBP-mediated disease or condition includes diseases or conditions in which EP300 inhibition, CBP inhibition, or both EP300 inhibition and CBP inhibition provide a therapeutic benefit, e.g., treatment with an EP300 or CBP inhibitor, including the compounds described herein, provides a therapeutic benefit to a subject suffering from or at risk for the disease or condition. EP300- or CBP-mediated disease or condition is intended to include cancers harboring loss-of-function mutations of CBP or EP300, or cancers in which there is activation of EP300 or CBP. An EP300- or CBP-mediated disease or condition is also intended to include cancers that express the androgen receptor.

[0087] The term "EP300-mediated disease or disorder" includes diseases associated with or involving EP300 activity, such as EP300 hyperactivity and conditions associated with these diseases. The term "EP300 hyperactivity" refers to either 1) EP300 expression in cells that do not normally express EP300, 2) increased EP300 expression resulting in undesirable cell proliferation, or 3) a mutation resulting in constitutive activation of EP300. EP300-mediated diseases or disorders include tumors with CBP inactivating mutations, also known as synthetic lethality. Examples of EP300-mediated diseases or disorders include disorders resulting from abnormally high amounts of EP300 activity. EP300-mediated diseases or conditions are intended to include cancers that harbor loss-of-function mutations in CBP or cancers in which there is activation of EP300. EP300-mediated diseases or conditions are also intended to include cancers that express the androgen receptor. Hyperactivity of EP300 is known to be involved in the pathogenesis of many diseases, including proliferative and non-proliferative disorders, including neoplastic disorders and cancer, inflammatory disorders, cognitive disorders, and neurodegenerative diseases.

[0088] The term "CBP-mediated disease or disorder" includes diseases associated with or involving CBP activity, such as overactivity of CBP, and conditions associated with these diseases. The term "overactivity of CBP" refers to either 1) CBP expression in cells that do not normally express CBP, 2) increased CBP expression resulting in undesirable cell proliferation, or 3) a mutation resulting in constitutive activation of CBP. Examples of CBP-mediated diseases or disorders include disorders resulting from abnormally high amounts of CBP activity. CBP-mediated diseases or conditions are intended to include cancers that harbor loss-of-function mutations of EP300 or cancers in which there is activation of CBP. CBP-mediated diseases or conditions are also intended to include cancers that express the androgen receptor. Overactivity of CBP is known to be involved in the pathogenesis of many diseases, including proliferative and non-proliferative disorders, including neoplastic disorders and cancers, inflammatory disorders, cognitive disorders, and neurodegenerative diseases.

[0089] Also, in the context of a compound that binds to a biomolecular target, the term "higher specificity" indicates that the compound binds to a particular target to a greater extent than another biomolecule or biomolecules that may be present under the relevant binding conditions, and that binding to such other biomolecules results in a biological activity that is different from binding to the particular target. Typically, the specificity is relative to a limited set of other biomolecules, for example, in the case of EP300, CBP, or other epigenetic targets. In certain embodiments, the greater specificity is at least 2, 3, 4, 5, 8, 10, 50, 100, 200, 400, 500, or 1000 times more specific.

[0090] When used herein in relation to a binding compound or ligand, the term "specific for EP300" and terms of similar meaning mean that a particular compound binds to EP300 to a statistically greater extent than to other epigenetic targets that may be present in a particular sample. Also, when biological activities other than binding are indicated, the term "specific for EP300" indicates a greater biological effect, such as enzyme activity inhibition, associated with the binding of a particular compound to EP300 than to other enzymes. Specificity is also with respect to other biomolecules (not limited to EP300 enzyme) that may be present in a particular sample.

[0091] When used herein in connection with a binding compound or ligand, the term "specific for CBP" and terms of similar meaning mean that a particular compound binds to CBP to a statistically greater extent than to other epigenetic targets that may be present in a particular sample. In addition, when biological activities other than binding are indicated, the term "specific for CBP" indicates a superior biological effect, such as enzyme activity inhibition, associated with the binding of a particular compound to CBP, compared to other enzymes. Specificity is also with respect to other biomolecules (not limited to CBP) that may be present in a particular sample.

[0092] The term "first-line cancer therapy" refers to a therapy administered to a subject as an initial regimen to reduce the number of cancer cells. First-line therapy is also called induction therapy, primary therapy, and primary treatment. First-line therapy can be administered in combination with one or more drugs. A summary of the currently accepted approach to first-line treatment for a particular disease can be found in the NCI guidelines for such disease.

[0093] The term "second-line cancer therapy" refers to a cancer treatment administered to subjects who do not respond to first-line therapy, i.e., who often undergo first-line therapy or who experience a recurrence of cancer after going into remission. In certain embodiments, the second-line therapy that can be administered includes a repeat of the initial successful cancer therapy, which can be any of the treatments described in "first-line cancer therapy". A summary of currently accepted approaches to second-line therapy for a particular disease is described in the NCI guidelines for such disease.

[0094] The term "refractory" refers to a subject that does not respond to or is otherwise resistant to a cancer therapy or treatment. The cancer therapy can be a first-line, second-line, or any subsequent treatment. In certain embodiments, refractory refers to a state in which a subject cannot achieve complete remission after two induction attempts. A subject can be refractory due to the inherent resistance of cancer cells to a particular therapy, or a subject can be refractory due to acquired resistance that occurs during or following the course of a particular therapy.

[0095] In addition, the abbreviations used herein have the following respective meanings: [Table 1]

[0096] II. Compounds Embodiment 1 of the present disclosure relates to a compound of formula I: 1. A compound of formula I, [ka] During the ceremony, A 1 But R 6 And A 2 But R 7 And A 3 But -LR 1 And A 4 But R 5 and X 1 is CH and X 2 But C and X 3 is N, or A 1 But R 6 And A 2 But R 7 And A 3 But -LR 1 And A 4 But R 5 and X 1 is CH and X 2 But C and X 3 is CH, or A 1 But R 6 And A 2 However, A is absent. 3 But -LR 1 And A 4 But R 5 and X 1 is CH and X 2 is N and X 3 is CH, or A 1 But R 7 And A 2 But R 6 And A 3 But -LR 1 And A 4 But R 5 and X 1 is N and X 2 But C and X 3 is CH, or A 1 But R 7 And A 2 But R 6 And A 3 But R 5 And A4 But -LR 1 and X 1 is N and X 2 But C and X 3 is CH, L is a bond, -CH 2 -CH 2 -, -(CH 2 ) 1~2 -CH=CH-(CH 2 ) 0~1 -, -CR 2 R 3 -, -C(O)-, or -S(O) 2 - and L 2 is a bond or -C(R 13 ) 2 - and R 1 phenyl, 5-9 membered heteroaryl, C 3 ~C 6 Cycloalkyl, C 5 ~C 6 Cycloalkenyl, 4-9 membered heterocycloalkyl or 5-6 membered heterocycloalkenyl; R 1 But optionally, one G 1 Group and 1 to 3 G 2 is substituted with a group, R 2 But, H, C 1 ~C 6 alkyl, or OH; R 3 But, H, C 1 ~C 6 Alkyl, C 1 ~C 6 Cyanoalkyl, C 1 ~C 6 Haloalkyl, C 3 ~C 6 cycloalkyl, or 5-6 membered heteroaryl; R 4 But H, OH, C 1 ~C 6 Alkyl, or C 1 ~C 6 is haloalkyl, R5 is attached to a carbon, it is a 4- to 6-membered cycloalkyl, a 5- to 6-membered cycloalkenyl, a phenyl, a 5- to 9-membered heteroaryl, a 5- to 6-membered heterocycloalkyl, a 4- to 6-membered cycloalkyl-C 1 ~C 6 Alkyl, [ka] or [ka] and is a 4- to 6-membered cycloalkyl, a 5- to 6-membered cycloalkenyl, a phenyl, a 5- to 9-membered heteroaryl, or a 4- to 6-membered cycloalkyl-C 1 ~C 6 Each alkyl may optionally be one -L 2 -J 1 Group and 0 to 4 J 2 It is substituted with a J group. 1 is directly attached to a carbon atom, or Or R 5 is attached to a nitrogen atom, a 4- to 6-membered cycloalkyl, a 5- to 6-membered cycloalkenyl, a phenyl, a 5- to 9-membered heteroaryl, or a 4- to 6-membered cycloalkyl-C 1 ~C 6 alkyl, 4- to 6-membered cycloalkyl, 5- to 6-membered cycloalkenyl, phenyl, 5- to 9-membered heteroaryl, or 4- to 6-membered cycloalkyl-C 1 ~C 6 Each alkyl may optionally be one -L 2 -J 1 Group and 1 to 4 J 2 It is substituted with a J group. 1 is directly attached to a carbon atom, R 6 is a 5-membered heteroaryl containing at least one nitrogen atom, and the 5-membered heteroaryl is optionally selected from 0 to 2 R 8 is substituted with a group, R 7 H, halo, or C 1 ~C 6is alkyl, R 8 But, C 1 ~C 6 Alkyl or C 1 ~C 3 Alkoxy C 1 ~C 3 is alkylene, Each R 10 However, independently, H, C 1 ~C 6 Alkyl, C 1 ~C 6 haloalkyl, or cyclopropyl; Each R 11 However, independently, H, C 1 ~C 6 Alkyl or C 1 ~C 6 haloalkyl or two R 11 The groups are both R 11 joins together with the carbon atom to which the group is attached to form a cyclopropyl group, Each R 12 However, independently, H, C 1 ~C 6 Alkyl, C 1 ~C 6 Hydroxyalkyl, or C 1 ~C 6 is haloalkyl, Each R 13 However, independently, H, CH 3 , or F, or each R 13 But they both bond together with the carbon atom to which they are attached, forming C 3 ~C 6 Forming a cycloalkyl group, R 14 But, H, C 1 ~C 6 Alkyl or C 1 ~C 3 Alkoxy C 1 ~C 3 is alkylene, G 1 But, Cyano, C 2 ~C 6 Alkenyl, C 1 ~C 6Cyanoalkyl, C 1 ~C 6 Cyanoalkylethynylene, C 2 ~C 6 Alkenyl C 1 ~C 6 Alkylene, C 1 ~C 6 Alkylsulfonyl, C 1 ~C 6 Alkyl Sulfonyl C 1 ~C 6 Alkylene, -N(R 10 ) 2 , Ji-C 1 ~C 6 Alkylamino C 1 ~C 6 Alkylene, C 1 ~C 6 Alkylamino C 1 ~C 6 Alkylene, Amino C 1 ~C 6 Alkylene, -C(O)-C 1 ~C 6 Alkyl, -C(O)-C 1 ~C 6 Hydroxyalkyl, -C(O)-C 1 ~C 6 Haloalkyl, -C(O)OR 12 , -C 1 ~C 3 Alkylene-C(O)OR 12 , -C(O)-N(H)-C 3 ~C 6 Cycloalkyl, C 3 ~C 6 Cycloalkyl, C 3 ~C 6 Cycloalkyl C 1 ~C 6 Alkylene, C 3 ~C 6 Cycloalkyl C 2 ~C 6 Alkynylene, 4-6 membered heterocycloalkyl, -C(O)-N(R 10 ) 2 , -C 1 ~C 6 Alkylene-C(O)-N(R 10 ) 2, or phenyl-C 1 ~C 6 Alkoxy, but G 1 is attached to a nitrogen atom, G 1 However, provided that it is not CN, each G 2 But independently, Halo, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Alkoxy, C 1 ~C 6 Haloalkoxy, OH, oxo, C 1 ~C 6 Hydroxyalkyl, but G 2 is attached to a nitrogen atom, G 2 But, Halo, C 1 ~C 6 Alkoxy, C 1 ~C 6 provided that it is not haloalkoxy or OH; J 1 But -C(R 11 ) 2 -C(O)OH, -C(O)OH, -C(O)OC 1 ~C 6 Alkyl, -CH 2 -C(O)OC 1 ~C 6 Alkyl, -C(O)N(R 10 ) 2 , -C(O)N(H)-CN, -C(O)N(H)OH, -C(O)N(H)-SO 2 -C 1 ~C 6 Alkyl, -N(H)-SO 2 -C 1 ~C 6 Alkyl, C 1 ~C 6 Alkylsulfonyl, tetrazolyl, or -S(O) 2 -N(R 10 ) 2 and each J 2are independently 4- to 6-membered heterocycloalkyl, -O-(4- to 6-membered heterocycloalkyl), -OC 3 ~C 6 Cycloalkyl, C 3 ~C 6 Cycloalkylalkoxy, Phenyl-C 1 ~C 6 Alkoxy, C 1 ~C 6 Alkyl, C 1 ~C 6 Alkoxy, Halo, C 1 ~C 6 Haloalkyl, C 1 ~C 6 Haloalkoxy, OH, C 1 ~C 6 Hydroxyalkyl, CN, C 1 ~C 6 Cyanoalkyl, C 2 ~C 6 Alkynyl, C 3 ~C 6 Cycloalkylethynylene, C 3 ~C 6 Cycloalkyl, 4-6 membered heterocycloalkyl, NO 2 , or -N(R 10 ) 2 However, J 2 If is attached to nitrogen, J 2 is -O-(4-6 membered heterocycloalkyl), -OC 3 ~C 6 Cycloalkyl, C 3 ~C 6 Cycloalkylalkoxy, Phenyl-C 1 ~C 6 Alkoxy, C 1 ~C 6 Alkoxy, Halo, C 1 ~C 6 Haloalkoxy, OH, CN, C 2 ~C 6 Alkynyl, C 3 ~C 6 Cycloalkylethynylene, or -N(R 10 ) 2or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or deuterated analogue thereof, provided that:

[0097] "R 1 But optionally, one G 1 Group and 1 to 3 G 2 The phrase "substituted with an R group" includes 1 But optionally, one G 1 substituted with R 1 Optionally, 1 to 3 G 2 substituted with R 1 But optionally, one G 1 Group and 1 to 3 G 2 This interpretation is intended to include cases where both the R 1 , and R 5 About J 1 and J. 2 ) which may optionally be joined by multiple additional variables (G 1 and G 2 or J 1 and J. 2 ) may be substituted.

[0098] Subembodiments of embodiment 1 Embodiment 1(a1) of the present disclosure relates to embodiment 1, wherein L is a bond, -CH 2 -CH 2 -, -(CH 2 ) 1~2 -CH=CH-(CH 2 ) 0~1 -, -CR 2 R 3 -, -C(O)-, or -S(O) 2 However, A 1 But R 7 And A 2 But R 6 And A 3 But -LR 1 And A 4 But R 5 and X 1 is N and X 2But C and X 3 is C, provided that L is a bond.

[0099] Embodiment 1(a2) of the present disclosure relates to embodiment 1, 5 when attached to a carbon, is a 4- to 6-membered cycloalkyl, a 5- to 6-membered cycloalkenyl, a phenyl, a 5- to 9-membered heteroaryl, a 5- to 6-membered heterocycloalkyl, [ka] or [ka] and each of the 4- to 6-membered cycloalkyl, 5- to 6-membered cycloalkenyl, phenyl, or 5- to 9-membered heteroaryl is optionally selected from one -L 2 -J 1 Group and 0 to 4 J 2 It is substituted with a J group. 1 is directly attached to a carbon atom, or or R 5 when attached to a nitrogen, is a 4-6 membered cycloalkyl, a 5-6 membered cycloalkenyl, a phenyl, or a 5-9 membered heteroaryl, each of which is optionally followed by one -L 2 -J 1 Group and 1 to 4 J 2 It is substituted with a J group. 1 is directly attached to a carbon atom.

[0100] Embodiment 1(a) of the present disclosure relates to embodiment 1, A 1 But R 6 And A 2 But R 7 And A 3 But -LR 1 And A 4 But R 5 and X 1 But C and X2 But C and X 3 is N, or A 1 But R 7 And A 2 But R 6 And A 3 But -LR 1 And A 4 But R 5 and X 1 is N and X 2 But C and X 3 is C, or A 1 But R 7 And A 2 But R 6 And A 3 But R 5 And A 4 But -LR 1 and X 1 is N and X 2 But C and X 3 But the answer is C.

[0101] Embodiment 1(b) of the present disclosure relates to embodiment 1, A 1 But R 7 And A 2 But R 6 And A 3 But -LR 1 And A 4 But R 5 and X 1 is N and X 2 But C and X 3 is C, or A 1 But R 7 And A 2 But R 6 And A 3 But R 5 And A 4 But -LR 1 and X 1 is N and X 2 But C and X 3 But the answer is C.

[0102] Embodiment 1(c) of the present disclosure relates to embodiment 1, A 1 But R 6 And A 2 But R 7 And A 3 But -LR 1 And A 4 But R 5 and X 1 But C and X 2 But C and X 3 But it is N.

[0103] Embodiment 1(d) of the present disclosure relates to embodiment 1, A 1 But R 6 And A 2 But R 7 And A 3 But -LR 1 And A 4 But R 5 and X 1 But C and X 2 But C and X 3 But the answer is C.

[0104] Embodiment 1(e) of the present disclosure relates to embodiment 1, A 1 But R 6 And A 2 However, A is absent. 3 But -LR 1 And A 4 But R 5 and X 1 But C and X 2 is N and X 3 But the answer is C.

[0105] Embodiment 1(f) of the present disclosure relates to embodiment 1, A 1 But R 7 And A 2 But R 6 And A 3 But -LR 1 And A 4 But R 5and X 1 is N and X 2 But C and X 3 But the answer is C.

[0106] Embodiment 1(g) of the present disclosure relates to embodiment 1, A 1 But R 7 And A 2 But R 6 And A 3 But R 5 And A 4 But -LR 1 and X 1 is N and X 2 But C and X 3 But the answer is C.

[0107] Embodiment 1(h) of the present disclosure relates to embodiment 1, 1(a1), 1(a2), 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), or 1(g), wherein L is a bond.

[0108] Embodiment 1(i) of the present disclosure relates to embodiment 1, 1(a1), 1(a2), 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), or 1(g), wherein L is a bond, or -CR 2 R 3 -It is.

[0109] Embodiment 1(i) of the present disclosure relates to embodiment 1, 1(a1), 1(a2), 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), or 1(g), wherein L is -CR 2 R 3 -It is.

[0110] Embodiment 1(j) of the present disclosure relates to embodiment 1, 1(a1), 1(a2), 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), or 1(g), wherein L-(CH 2 ) 1~2 -CH=CH-(CH 2 ) 0~1 -.

[0111] Embodiment 1(k) of the present disclosure relates to embodiment 1, 1(a1), 1(a2), 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), or 1(g), wherein L is -C(O)-.

[0112] Embodiment 1(l) of the present disclosure relates to embodiment 1, 1(a1), 1(a2), 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), or 1(g), wherein L is -S(O). 2 -It is.

[0113] Embodiment 1(m) of the present disclosure relates to embodiment 1, 1(a1), 1(a2), 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), 1(j), 1(k), or 1(l), further comprising: R 1 is phenyl or 5-9 membered heteroaryl, R 1 Optionally, one G 1 Group and 1 to 3 G 2 is substituted with a group.

[0114] Embodiment 1(o) of the present disclosure relates to embodiment 1, 1(a1), 1(a2), 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), 1(j), 1(k), or 1(l), further comprising: R 1 Optionally, one G 1 Group and 1 to 3 G 2 It is a phenyl substituted with a group.

[0115] Embodiment 1(p) of the present disclosure relates to embodiment 1, 1(a1), 1(a2), 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), 1(j), 1(k), or 1(l), further comprising: R 1 Optionally, one G 1 Group and 1 to 3 G 2 It is a 5-9 membered heteroaryl substituted with a group.

[0116] Embodiment 1(q) of the present disclosure relates to embodiment 1, 1(a1), 1(a2), 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), 1(j), 1(k), or 1(l), further comprising: R 1 is C 3 ~C 6 Cycloalkyl or C 5 ~C 6 cycloalkenyl, R 1 Optionally, one G 1 Group and 1 to 3 G 2 is substituted with a group.

[0117] Embodiment 1(r) of the present disclosure relates to embodiment 1, 1(a1), 1(a2), 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), 1(j), 1(k), or 1(l), and 1 is a 4- to 9-membered heterocycloalkyl or a 5- to 6-membered heterocycloalkenyl; R 1 Optionally, one G 1 Group and 1 to 3 G 2 is substituted with a group.

[0118] Embodiment 1(s) of the present disclosure relates to embodiment 1, 1(a1), 1(a2), 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), 1(j), 1(k), 1(l), 1(m), 1(n), 1(o), 1(p), 1(q), or 1(r), and 5 teeth, attached to carbon, 4-6 membered cycloalkyl, 5-6 membered cycloalkenyl, phenyl, 5-9 membered heteroaryl, 5-6 membered heterocycloalkyl, [ka] or [ka] and each of the 4- to 6-membered cycloalkyl, 5- to 6-membered cycloalkenyl, phenyl, or 5- to 9-membered heteroaryl is optionally selected from one -L2 -J 1 Group and 0 to 4 J 2 It is substituted with a J group. 1 is directly attached to a carbon atom.

[0119] Embodiment 1(t) of the present disclosure relates to embodiment 1, 1(a1), 1(a2), 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), 1(j), 1(k), 1(l), 1(m), 1(n), 1(o), 1(p), 1(q), or 1(r), or R 5 is attached to the nitrogen and is a 4-6 membered cycloalkyl, a 5-6 membered cycloalkenyl, a phenyl, or a 5-9 membered heteroaryl, each of which is optionally followed by one -L 2 -J 1 Group and 1 to 4 J 2 It is substituted with a J group. 1 is directly attached to a carbon atom.

[0120] Embodiment 1(u) of the present disclosure relates to embodiment 1, 1(a1), 1(a2), 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), 1(j), 1(k), 1(l), 1(m), 1(n), 1(o), 1(p), 1(q), 1(r), 1(s), or 1(t), and 1 is -C(O)OH or -C(O)OC 1 ~C 6 It is an alkyl.

[0121] Embodiment 1(v) of the present disclosure relates to embodiment 1, 1(a1), 1(a2), 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), 1(j), 1(k), 1(l), 1(m), 1(n), 1(o), 1(p), 1(q), 1(r), 1(s), or 1(t), and 1 is -C(O)OH.

[0122] Embodiment 1(w) of the present disclosure relates to embodiment 1, 1(a1), 1(a2), 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), 1(j), 1(k), 1(l), 1(m), 1(n), 1(o), 1(p), 1(q), 1(r), 1(s), or 1(t), and 1 is -C(O)OC 1 ~C 6 Alkyl or CH 2 -C(O)OC 1 ~C 6 It is an alkyl.

[0123] Embodiment 1(x) of the present disclosure relates to embodiment 1, 1(a1), 1(a2), 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), 1(j), 1(k), 1(l), 1(m), 1(n), 1(o), 1(p), 1(q), 1(r), 1(s), or 1(t), and 1 is -C(O)N(R 10 ) 2 , -C(O)N(H)-CN, or -C(O)N(H)OH.

[0124] Embodiment 1(y) of the present disclosure relates to embodiment 1, 1(a1), 1(a2), 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), 1(j), 1(k), 1(l), 1(m), 1(n), 1(o), 1(p), 1(q), 1(r), 1(s), or 1(t), and 1 is -C(O)N(H)-SO 2 -C 1 ~C 6 Alkyl, -N(H)-SO 2 -C 1 ~C 6 Alkyl, C 1 ~C 6 Alkylsulfonyl, or -S(O) 2 -N(R 10 ) 2 It is.

[0125] Embodiment 1(z) of the present disclosure relates to embodiment 1, 1(a1), 1(a2), 1(a), 1(b), 1(c), 1(d), 1(e), 1(f), 1(g), 1(h), 1(i), 1(j), 1(k), 1(l), 1(m), 1(n), 1(o), 1(p), 1(q), 1(r), 1(s), or 1(t), and 1 is tetrazolyl.

[0126] J 1 The tetrazolyl in the definition is a carboxylic acid isostere, and other carboxylic acid isosteres can be used instead, such as those set forth in FIG. 25 in Meanwell, Synopsis of Some Recent Tactical Application of Bioisosteres in Drug Design, Journal of Medicinal Chemistry, dx.doi.org / 10.1021 / jm1013693, which is incorporated by reference in its entirety.

[0127] In another embodiment of embodiment 1, J 1 may be a carboxylic acid isostere as described in Meanwell.

[0128] Embodiment 2 of the present disclosure relates to a compound according to embodiment 1 or embodiment 1(a1), R 1 phenyl, 5-6 membered heteroaryl, C 3 ~C 6 Cycloalkyl, C 5 ~C 6 Cycloalkenyl, 4-6 membered heterocycloalkyl or 5-6 membered heterocycloalkenyl, R 1 But optionally, one G 1 Group and 1 to 3 G 2 is substituted with a group, R 3 But, H, C 1 ~C 6 Alkyl, C 1 ~C 6 Cyanoalkyl, C 1 ~C6 Haloalkyl, C 3 ~C 6 cycloalkyl, or 5-6 membered heteroaryl; R 4 But H, OH, C 1 ~C 2 Alkyl, or C 1 ~C 2 is haloalkyl, R 5 when attached to a carbon, it is a 4- to 6-membered cycloalkyl, cyclohexenyl, phenyl, 5- to 6-membered heteroaryl, 5- to 6-membered heterocycloalkyl, [ka] or [ka] and each of the 4- to 6-membered cycloalkyl, cyclohexenyl, phenyl, 5- to 6-membered heteroaryl, and 5- to 6-membered heterocycloalkyl is optionally selected from one -L 2 -J group and 0 to 4 J 2 It is substituted with a J group. 1 is directly attached to a carbon atom, or or R 5 when attached to a nitrogen, is a 4-6 membered cycloalkyl, cyclohexenyl, phenyl, or 5-6 membered heteroaryl, each of which is optionally followed by one -L 2 -J 1 Group and 1 to 4 J 2 It is substituted with a J group. 1 is directly attached to a carbon atom, R 6 is a 5-membered heteroaryl containing at least one nitrogen atom, the heteroaryl optionally being selected from 1 to 2 R 8 is substituted with a group, R 7 H, halo, or C 1 ~C 5is alkyl, R 8 But, C 1 ~C 4 Alkyl or C 1 ~C 2 Alkoxy C 1 ~C 2 is alkylene, Each R 10 However, independently, H, C 1 ~C 5 Alkyl, C 1 ~C 5 haloalkyl, or cyclopropyl; Each R 11 However, independently, H, C 1 ~C 5 Alkyl or C 1 ~C 5 haloalkyl or two R 11 The groups are both R 11 joins together with the carbon atom to which the group is attached to form a cyclopropyl group, Each R 12 But H, G 1 But, CN, C 1 ~C 6 Cyanoalkyl, C 1 ~C 5 Cyanoalkylethynylene, C 2 ~C 5 Alkenyl C 1 ~C 5 Alkylene, C 1 ~C 5 Alkylsulfonyl, C 1 ~C 5 Alkyl Sulfonyl C 1 ~C 5 Alkylene, -N(R 10 ) 2 , Ji-C 1 ~C 5 Alkylamino-C 1 ~C 5 Alkylene, C 1 ~C 5 Alkylamino-C 1 ~C 5 Alkylene, Amino C 1 ~C 5Alkylene, -C(O)-C 1 ~C 5 Alkyl, -C(O)-C 1 ~C 5 Hydroxyalkyl, -C(O)-C 1 ~C 5 Haloalkyl, -C(O)OR 12 , -C 1 ~C 3 Alkylene-C(O)OR 12 , -C(O)-N(H)-C 3 ~C 6 Cycloalkyl, C 3 ~C 6 Cycloalkyl, C 3 ~C 6 Cycloalkyl C 1 ~C 5 Alkylene, C 3 ~C 6 Cycloalkyl C 2 ~C 5 Alkynylene, 4-6 membered heterocycloalkyl, -C(O)-N(R 10 ) 2 , -C 1 ~C 5 Alkylene-C(O)-N(R 10 ) 2 , or phenyl-C 1 ~C 5 Alkoxy, but G 1 is attached to a nitrogen atom, G 1 However, provided that it is not CN, each G 2 However, independently, CN, Halo, C 1 ~C 5 Alkyl, C 1 ~C 5 Haloalkyl, C 1 ~C 5 Alkoxy, C 1 ~C 5 Haloalkoxy, OH, oxo, C 1 ~C 5 Hydroxyalkyl, but G 2 is attached to a nitrogen atom, G 2 But CN, Halo, C 1 ~C 5 Alkoxy, C1 ~C 5 provided that it is not haloalkoxy or OH; J 1 But -C(R 11 ) 2 -C(O)OH, -C(O)OH, -C(O)OC 1 ~C 5 Alkyl, -CH 2 -C(O)OC 1 ~C 5 Alkyl, -C(O)N(R 10 ) 2 , -C(O)N(H)-CN, -C(O)N(H)OH, -C(O)N(H)-SO 2 -C 1 ~C 5 Alkyl, -N(H)-SO 2 -C 1 ~C 5 Alkyl, C 1 ~C 5 Alkylsulfonyl, tetrazolyl, or -S(O) 2 -N(R 10 ) 2 and each J 2 are independently 4- to 6-membered heterocycloalkyl, -O-(4- to 6-membered heterocycloalkyl), -OC 3 ~C 6 Cycloalkyl, C 3 ~C 6 Cycloalkylalkoxy, Phenyl-C 1 ~C 5 Alkoxy, C 1 ~C 5 Alkyl, C 1 ~C 5 Alkoxy, Halo, C 1 ~C 5 Haloalkyl, C 1 ~C 5 Haloalkoxy, OH, C 1 ~C 5 Hydroxyalkyl, CN, C 1 ~C 5 Cyanoalkyl, C 2 ~C 5 Alkynyl, C 3 ~C 6Cycloalkylethynylene, C 3 ~C 6 Cycloalkyl, 4-6 membered heterocycloalkyl, or -N(R 10 ) 2 However, J 2 If is attached to nitrogen, J 2 -O-(4-6 membered heterocycloalkyl), -OC 3 ~C 6 Cycloalkyl, C 3 ~C 6 Cycloalkylalkoxy, Phenyl-C 1 ~C 5 Alkoxy, C 1 ~C 5 Alkoxy, Halo, C 1 ~C 5 Haloalkoxy, OH, CN, C 2 ~C 6 Alkynyl, C 3 ~C 6 Cycloalkylethynylene, or -N(R 10 ) 2 Provided that:

[0129] Subembodiment of embodiment 2 Embodiment 2(a) of the present disclosure relates to embodiment 2, A 1 But R 6 And A 2 But R 7 And A 3 But -LR 1 And A 4 But R 5 and X 1 But C and X 2 But C and X 3 is N, or A 1 But R 7 And A 2 But R 6 And A 3 But -LR 1 And A 4 But R 5 and X 1 is N and X 2 But C and X3 is C, or A 1 But R 7 And A 2 But R 6 And A 3 But R 5 And A 4 But -LR 1 and X 1 is N and X 2 But C and X 3 But the answer is C.

[0130] Embodiment 2(b) of the present disclosure relates to embodiment 2, A 1 But R 7 And A 2 But R 6 And A 3 But -LR 1 And A 4 But R 5 and X 1 is N and X 2 But C and X 3 is C, or A 1 But R 7 And A 2 But R 6 And A 3 But R 5 And A 4 But -LR 1 and X 1 is N and X 2 But C and X 3 But the answer is C.

[0131] Embodiment 2(c) of the present disclosure relates to embodiment 2, A 1 But R 6 And A 2 But R 7 And A 3 But -LR 1 And A 4 But R 5 and X 1 But C and X 2 But C and X 3But it is N.

[0132] Embodiment 2(d) of the present disclosure relates to embodiment 2, A 1 But R 6 And A 2 But R 7 And A 3 But -LR 1 And A 4 But R 5 and X 1 But C and X 2 But C and X 3 But the answer is C.

[0133] Embodiment 2(e) of the present disclosure relates to embodiment 2, A 1 But R 6 And A 2 However, A is absent. 3 But -LR 1 And A 4 But R 5 and X 1 But C and X 2 is N and X 3 But the answer is C.

[0134] Embodiment 2(f) of the present disclosure relates to embodiment 2, A 1 But R 7 And A 2 But R 6 And A 3 But -LR 1 And A 4 But R 5 and X 1 is N and X 2 But C and X 3 But the answer is C.

[0135] Embodiment 2(g) of the present disclosure relates to embodiment 2, A 1 But R 7 And A 2 But R 6 And A 3 But R 5And A 4 But -LR 1 and X 1 is N and X 2 But C and X 3 But the answer is C.

[0136] Embodiment 2(h) of the present disclosure relates to embodiment 2, 2(a), 2(b), 2(c), 2(d), 2(e), 2(f), or 2(g), wherein L is a bond.

[0137] Embodiment 2(i) of the present disclosure relates to embodiment 2, 2(a), 2(b), 2(c), 2(d), 2(e), 2(f), or 2(g), wherein L is a bond or -CR 2 R 3 -It is.

[0138] Embodiment 2(j) of the present disclosure relates to embodiment 2, 2(a), 2(b), 2(c), 2(d), 2(e), 2(f), or 2(g), wherein L is -CR 2 R 3 -It is.

[0139] Embodiment 2(j) of the present disclosure relates to embodiment 2, 2(a), 2(b), 2(c), 2(d), 2(e), 2(f), or 2(g), wherein L-(CH 2 ) 1~2 -CH=CH-(CH 2 ) 0~1 -.

[0140] Embodiment 2(k) of the present disclosure relates to embodiment 2, 2(a), 2(b), 2(c), 2(d), 2(e), 2(f), or 2(g), wherein L is -C(O)-.

[0141] Embodiment 2(l) of the present disclosure relates to embodiment 2, 2(a), 2(b), 2(c), 2(d), 2(e), 2(f), or 2(g), wherein L is -S(O). 2 -It is.

[0142] Embodiment 2(m) of the present disclosure relates to embodiment 2, 2(a), 2(b), 2(c), 2(d), 2(e), 2(f), 2(g), 2(h), 2(i), 2(j), 2(k), or 2(l), further comprising: R 1 is phenyl or 5-6 membered heteroaryl, R 1 Optionally, one G 1 Group and 1 to 3 G 2 is substituted with a group.

[0143] Embodiment 2(o) of the present disclosure relates to embodiment 2, 2(a), 2(b), 2(c), 2(d), 2(e), 2(f), 2(g), 2(h), 2(i), 2(j), 2(k), or 2(l), further comprising: R 1 Optionally, one G 1 Group and 1 to 3 G 2 It is a phenyl substituted with a group.

[0144] Embodiment 2(p) of the present disclosure relates to embodiment 2, 2(a), 2(b), 2(c), 2(d), 2(e), 2(f), 2(g), 2(h), 2(i), 2(j), 2(k), or 2(l), further comprising: R 1 Optionally, one G 1 Group and 1 to 3 G 2 It is a 5-6 membered heteroaryl substituted with a group.

[0145] Embodiment 2(q) of the present disclosure relates to embodiment 2, 2(a), 2(b), 2(c), 2(d), 2(e), 2(f), 2(g), 2(h), 2(i), 2(j), 2(k), or 2(l), further comprising: R 1 is C 3 ~C 6 Cycloalkyl or C 5 ~C 6 cycloalkenyl, R 1 Optionally, one G 1 Group and 1 to 3 G 2 is substituted with a group.

[0146] Embodiment 2(r) of the present disclosure relates to embodiment 2, 2(a), 2(b), 2(c), 2(d), 2(e), 2(f), 2(g), 2(h), 2(i), 2(j), 2(k), or 2(l), further comprising: R 1 is a 4- to 9-membered heterocycloalkyl or a 5- to 6-membered heterocycloalkenyl; R 1 Optionally, one G 1 Group and 1 to 3 G 2 is substituted with a group.

[0147] Embodiment 2(s) of the present disclosure relates to embodiment 2, 2(a), 2(b), 2(c), 2(d), 2(e), 2(f), 2(g), 2(h), 2(i), 2(j), 2(k), 2(l), 2(m), 2(n), 2(o), 2(p), 2(q), or 2(r), wherein R 5 teeth, attached to carbon, 4-6 membered cycloalkyl, cyclohexenyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, [ka] or [ka] wherein each of the 4- to 6-membered cycloalkyl, cyclohexenyl, phenyl, 5- to 6-membered heteroaryl, or 5- to 6-membered heterocycloalkyl is optionally selected from one -L 2 -J 1 Group and 0 to 4 J 2 It is substituted with a J group. 1 is directly attached to a carbon atom.

[0148] Embodiment 2(t) of the present disclosure relates to embodiment 2, 2(a), 2(b), 2(c), 2(d), 2(e), 2(f), 2(g), 2(h), 2(i), 2(j), 2(k), 2(l), 2(m), 2(n), 2(o), 2(p), 2(q), or 2(r), or R 5is attached to the nitrogen and is a 4-6 membered cycloalkyl, cyclohexenyl, phenyl, or 5-6 membered heteroaryl, each of which is optionally followed by one -L 2 -J 1 Group and 1 to 4 J 2 It is substituted with a J group. 1 is directly attached to a carbon atom.

[0149] Embodiment 2(u) of the present disclosure relates to embodiment 2, 2(a), 2(b), 2(c), 2(d), 2(e), 2(f), 2(g), 2(h), 2(i), 2(j), 2(k), 2(l), 2(m), 2(n), 2(o), 2(p), 2(q), 2(r), 2(s), or 2(t), and 1 is -C(O)OH or -C(O)OC 1 ~C 5 It is an alkyl.

[0150] Embodiment 2(v) of the present disclosure relates to embodiment 2, 2(a), 2(b), 2(c), 2(d), 2(e), 2(f), 2(g), 2(h), 2(i), 2(j), 2(k), 2(l), 2(m), 2(n), 2(o), 2(p), 2(q), 2(r), 2(s), or 2(t), further comprising: 1 is -C(O)OH.

[0151] Embodiment 2(w) of the present disclosure relates to embodiment 2, 2(a), 2(b), 2(c), 2(d), 2(e), 2(f), 2(g), 2(h), 2(i), 2(j), 2(k), 2(l), 2(m), 2(n), 2(o), 2(p), 2(q), 2(r), 2(s), or 2(t), and 1 is -C(O)OC 1 ~C 5 Alkyl or CH 2 -C(O)OC 1 ~C 5 It is an alkyl.

[0152] Embodiment 2(x) of the present disclosure relates to embodiment 2, 2(a), 2(b), 2(c), 2(d), 2(e), 2(f), 2(g), 2(h), 2(i), 2(j), 2(k), 2(l), 2(m), 2(n), 2(o), 2(p), 2(q), 2(r), 2(s), or 2(t), 1 is -C(O)N(R 10 ) 2 , -C(O)N(H)-CN, or -C(O)N(H)OH.

[0153] Embodiment 2(y) of the present disclosure relates to embodiment 2, 2(a), 2(b), 2(c), 2(d), 2(e), 2(f), 2(g), 2(h), 2(i), 2(j), 2(k), 2(l), 2(m), 2(n), 2(o), 2(p), 2(q), 2(r), 2(s), or 2(t), further comprising: 1 is -C(O)N(H)-SO 2 -C 1 ~C 5 Alkyl, -N(H)-SO 2 -C 1 ~C 5 Alkyl, C 1 ~C 5 Alkylsulfonyl, or -S(O) 2 -N(R 10 ) 2 It is.

[0154] Embodiment 2(z) of the present disclosure relates to embodiment 2, 2(a), 2(b), 2(c), 2(d), 2(e), 2(f), 2(g), 2(h), 2(i), 2(j), 2(k), 2(l), 2(m), 2(n), 2(o), 2(p), 2(q), 2(r), 2(s), or 2(t), further comprising: 1 is tetrazolyl.

[0155] Embodiment 3 of the present disclosure relates to a compound according to embodiment 1 or 2 having formula II(a), II(b), or II(c): [ka] or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or deuterated analog thereof.

[0156] Subembodiment of embodiment 3 Embodiment 3(a1) of the present disclosure relates to embodiment 3 having formula II(a) or II(b).

[0157] Embodiment 3(a) of the present disclosure relates to embodiment 3 having formula II(a).

[0158] Embodiment 3(b) of the present disclosure relates to embodiment 3 having formula II(b).

[0159] Embodiment 3(c) of the present disclosure relates to embodiment 3 having formula II(c).

[0160] Embodiment 3(d) of the present disclosure relates to embodiment 3, 3(a1), 3(a), 3(b), or 3(c), wherein L is a bond.

[0161] Embodiment 3(e) of the present disclosure relates to embodiment 3, 3(a1), 3(a), 3(b), or 3(c), wherein L is a bond, or -CR 2 R 3 -It is.

[0162] Embodiment 3(f) of the present disclosure relates to embodiment 3, 3(a1), 3(a), 3(b), or 3(c), wherein L is -CR 2 R 3 -It is.

[0163] Embodiment 3(g) of the present disclosure relates to embodiment 3, 3(a1), 3(a), 3(b), 3(c), 3(d), 3(e), or 3(f), further comprising: R 1 is phenyl or 5-6 membered heteroaryl, R 1 Optionally, one G 1 Group and 1 to 3 G 2 is substituted with a group.

[0164] Embodiment 3(h) of the present disclosure relates to embodiment 3, 3(a1), 3(a), 3(b), 3(c), 3(d), 3(e), or 3(f), further comprising: R 1 Optionally, one G 1 Group and 1 to 3 G 2 It is a phenyl substituted with a group.

[0165] Embodiment 3(i) of the present disclosure relates to embodiment 3, 3(a1), 3(a), 3(b), 3(c), 3(d), 3(e), or 3(f), wherein R 1 Optionally, one G 1 Group and 1 to 3 G 2 It is a 5-6 membered heteroaryl substituted with a group.

[0166] Embodiment 3(j) of the present disclosure relates to embodiment 3, 3(a1), 3(a), 3(b), 3(c), 3(d), 3(e), or 3(f), further comprising: R 1 is C 3 ~C 6 Cycloalkyl or C 5 ~C 6 cycloalkenyl, R 1 Optionally, one G 1 Group and 1 to 3 G 2 is substituted with a group.

[0167] Embodiment 3(k) of the present disclosure relates to embodiment 3, 3(a1), 3(a), 3(b), 3(c), 3(d), 3(e), or 3(f), further comprising: R 1 is a 4- to 9-membered heterocycloalkyl or a 5- to 6-membered heterocycloalkenyl; R 1 Optionally, one G 1 Group and 1 to 3 G 2 is substituted with a group.

[0168] Embodiment 3(l) of the present disclosure relates to embodiment 3, 3(a1), 3(a), 3(b), 3(c), 3(d), 3(e), 3(f), 3(g), 3(h), 3(i), 3(j), or 3(k), further comprising: R 5is attached to a carbon and is a 4- to 6-membered cycloalkyl, cyclohexenyl, phenyl, 5- to 6-membered heteroaryl, 5- to 6-membered heterocycloalkyl, [ka] or [ka] and each of the 4-6 membered cycloalkyl, cyclohexenyl, phenyl, 5-6 membered heteroaryl, or heterocycloalkyl is optionally selected from one -L 2 -J 1 Group and 0 to 4 J 2 It is substituted with a J group. 1 is directly attached to a carbon atom.

[0169] Embodiment 3(m) of the present disclosure relates to embodiment 3, 3(a1), 3(a), 3(b), 3(c), 3(d), 3(e), 3(f), 3(g), 3(h), 3(i), 3(j), or 3(k), further comprising: R 5 is attached to the nitrogen and is a 4-6 membered cycloalkyl, cyclohexenyl, phenyl, or 5-6 membered heteroaryl, each of which is optionally followed by one -L 2 -J 1 Group and 1 to 4 J 2 It is substituted with a J group. 1 is directly attached to a carbon atom.

[0170] Embodiment 3(n) of the present disclosure relates to 3, 3(a1), 3(a), 3(b), 3(c), 3(d), 3(e), 3(f), 3(g), 3(h), 3(i), 3(j), 3(k), 3(l), or 3(m), and 1 is -C(O)OH or -C(O)OC 1 ~C 5 It is an alkyl.

[0171] Embodiment 3(o) of the present disclosure relates to embodiment 3, 3(a1), 3(a), 3(b), 3(c), 3(d), 3(e), 3(f), 3(g), 3(h), 3(i), 3(j), 3(k), 3(l), or 3(m), further comprising: 1 is -C(O)OH.

[0172] Embodiment 3(p) of the present disclosure relates to embodiment 3, 3(a1), 3(a), 3(b), 3(c), 3(d), 3(e), 3(f), 3(g), 3(h), 3(i), 3(j), 3(k), 3(l), or 3(m), 1 is -C(O)OC 1 ~C 5 Alkyl or -CH 2 -C(O)OC 1 ~C 5 It is an alkyl.

[0173] Embodiment 3(q) of the present disclosure relates to embodiment 3, 3(a1), 3(a), 3(b), 3(c), 3(d), 3(e), 3(f), 3(g), 3(h), 3(i), 3(j), 3(k), 3(l), or 3(m), further comprising: 1 is -C(O)N(R 10 ) 2 , -C(O)N(H)-CN, or -C(O)N(H)OH.

[0174] Embodiment 3(r) of the present disclosure relates to embodiment 3, 3(a1), 3(a), 3(b), 3(c), 3(d), 3(e), 3(f), 3(g), 3(h), 3(i), 3(j), 3(k), 3(l), or 3(m), further comprising: 1 is -C(O)N(H)-SO 2 -C 1 ~C 5 Alkyl, -N(H)-SO 2 -C 1 ~C 5 Alkyl, C 1 ~C 5 Alkylsulfonyl, or -S(O) 2 -N(R 10 ) 2 It is.

[0175] Embodiment 3(s) of the present disclosure relates to embodiment 3, 3(a1), 3(a), 3(b), 3(c), 3(d), 3(e), 3(f), 3(g), 3(h), 3(i), 3(j), 3(k), 3(l), or 3(m), further comprising: 1 is tetrazolyl.

[0176] Embodiment 4 of the present disclosure relates to a compound according to any one of embodiments 1 to 3, including any subembodiments thereof, having any one of formulas III(a) to III(f): [ka] or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or deuterated analog thereof.

[0177] Subembodiment of embodiment 4 Embodiment 4(a1) of the present disclosure relates to embodiment 4 having any one of formulas III(a), III(c), III(d), III(e), or III(f).

[0178] Embodiment 4(a2) of the present disclosure relates to embodiment 4 having any one of formulas III(a), III(c), or III(d).

[0179] Embodiment 4(a) of the present disclosure relates to embodiment 4 having any one of formulas III(a), III(b), III(c), or III(d).

[0180] Embodiment 4(b) of the present disclosure relates to embodiment 4 having formula III(e) or III(f).

[0181] Embodiment 4(c) of the present disclosure relates to embodiment 4 having formula III(a).

[0182] Embodiment 4(d) of the present disclosure relates to embodiment 4 having formula III(b).

[0183] Embodiment 4(e) of the present disclosure relates to embodiment 4 having formula III(c).

[0184] Embodiment 4(f) of the present disclosure relates to embodiment 4 having formula III(d).

[0185] Embodiment 4(g) of the present disclosure relates to embodiment 4 having formula III(e).

[0186] Embodiment 4(h) of the present disclosure relates to embodiment 4 having formula III(f).

[0187] Embodiment 4(i) of the present disclosure relates to embodiment 4, 4(a1), 4(a2), 4(a), 4(b), 4(c), 4(d), 4(e), 4(f), 4(g), or 4(h), further comprising: R 1 is phenyl or 5-6 membered heteroaryl, R 1 Optionally, one G 1 Group and 1 to 3 G 2 is substituted with a group.

[0188] Embodiment 4(j) of the present disclosure relates to embodiment 4, 4(a1), 4(a), 4(b), 4(c), 4(d), 4(e), 4(f), 4(g), or 4(h), further comprising: R 1 Optionally, one G 1 Group and 1 to 3 G 2 It is a phenyl substituted with a group.

[0189] Embodiment 4(k) of the present disclosure relates to embodiment 4, 4(a1), 4(a2), 4(a), 4(b), 4(c), 4(d), 4(e), 4(f), 4(g), or 4(h), further comprising: R 1 Optionally, one G 1 Group and 1 to 3 G 2 It is a 5-6 membered heteroaryl substituted with a group.

[0190] Embodiment 4(l) of the present disclosure relates to embodiment 4, 4(a1), 4(a2), 4(a), 4(b), 4(c), 4(d), 4(e), 4(f), 4(g), or 4(h), further comprising: R 1is C 3 ~C 6 Cycloalkyl or C 5 ~C 6 cycloalkenyl, R 1 Optionally, one G 1 Group and 1 to 3 G 2 is substituted with a group.

[0191] Embodiment 4(m) of the present disclosure relates to embodiment 4, 4(a1), 4(a2), 4(a), 4(b), 4(c), 4(d), 4(e), 4(f), 4(g), or 4(h), further comprising: R 1 is a 4- to 9-membered heterocycloalkyl or a 5- to 6-membered heterocycloalkenyl; R 1 Optionally, one G 1 Group and 1 to 3 G 2 is substituted with a group.

[0192] Embodiment 4(n) of the present disclosure relates to embodiment 4, 4(a1), 4(a2), 4(a), 4(b), 4(c), 4(d), 4(e), 4(f), 4(g), 4(h), 4(i), 4(j), 4(k), 4(l), or 4(m), further comprising: R 5 is attached to a carbon and is a 4- to 6-membered cycloalkyl, cyclohexenyl, phenyl, 5- to 6-membered heteroaryl, 5- to 6-membered heterocycloalkyl, [ka] or [ka] and each of the 4-6 membered cycloalkyl, cyclohexenyl, phenyl, 5-6 membered heteroaryl, or heterocycloalkyl is optionally selected from one -L 2 -J 1 Group and 0 to 4 J 2 It is substituted with a J group. 1 is directly attached to a carbon atom.

[0193] Embodiment 4(o) of the present disclosure relates to embodiment 4, 4(a1), 4(a2), 4(a), 4(b), 4(c), 4(d), 4(e), 4(f), 4(g), 4(h), 4(i), 4(j), 4(k), 4(l), or 4(m), or R 5 is attached to the nitrogen and is a 4-6 membered cycloalkyl, cyclohexenyl, phenyl, or 5-6 membered heteroaryl, each of which is optionally followed by one -L 2 -J 1 Group and 1 to 4 J 2 It is substituted with a J group. 1 is directly attached to a carbon atom.

[0194] Embodiment 4(p) of the present disclosure relates to embodiment 4, 4(a1), 4(a2), 4(a), 4(b), 4(c), 4(d), 4(e), 4(f), 4(g), 4(h), 4(i), 4(j), 4(k), 4(l), 4(m), 4(n), or 4(o), and 1 is -C(O)OH or -C(O)OC 1 ~C 5 It is an alkyl.

[0195] Embodiment 4(q) of the present disclosure relates to embodiment 4, 4(a1), 4(a2), 4(a), 4(b), 4(c), 4(d), 4(e), 4(f), 4(g), 4(h), 4(i), 4(j), 4(k), 4(l), 4(m), 4(n), or 4(o), further comprising: 1 is -C(O)OH.

[0196] Embodiment 4(r) of the present disclosure relates to embodiment 4, 4(a1), 4(a), 4(b), 4(c), 4(d), 4(e), 4(f), 4(g), 4(h), 4(i), 4(j), 4(k), 4(l), 4(m), 4(n), or 4(o), further comprising: 1 is -C(O)OC 1 ~C 5 Alkyl or -CH 2 -C(O)OC 1 ~C 5It is an alkyl.

[0197] Embodiment 4(s) of the present disclosure relates to embodiment 4, 4(a1), 4(a2), 4(a), 4(b), 4(c), 4(d), 4(e), 4(f), 4(g), 4(h), 4(i), 4(j), 4(k), 4(l), 4(m), 4(n), or 4(o), and 1 is -C(O)N(R 10 ) 2 , -C(O)N(H)-CN, or -C(O)N(H)OH.

[0198] Embodiment 4(t) of the present disclosure relates to embodiment 4, 4(a1), 4(a2), 4(a), 4(b), 4(c), 4(d), 4(e), 4(f), 4(g), 4(h), 4(i), 4(j), 4(k), 4(l), 4(m), 4(n), or 4(o), further comprising: 1 is -C(O)N(H)-SO 2 -C 1 ~C 5 Alkyl, -N(H)-SO 2 -C 1 ~C 5 Alkyl, C 1 ~C 5 Alkylsulfonyl, or -S(O) 2 -N(R 10 ) 2 It is.

[0199] Embodiment 4(u) of the present disclosure relates to embodiment 4, 4(a1), 4(a2), 4(a), 4(b), 4(c), 4(d), 4(e), 4(f), 4(g), 4(h), 4(i), 4(j), 4(k), 4(l), 4(m), 4(n), or 4(o), and further includes any of the following: 1 is tetrazolyl.

[0200] Embodiment 5 of the present disclosure relates to a compound according to any one of embodiments 1 to 4 (including any subembodiments thereof), wherein R 6 teeth, [ka] It is.

[0201] Embodiment 6 of the present disclosure relates to a compound according to any one of embodiments 1 to 5 (including any subembodiments thereof), wherein R 6 teeth, [ka] It is.

[0202] Subembodiment of embodiment 6 Embodiment 6(a) of the present disclosure relates to embodiment 6, 6 teeth, [ka] It is.

[0203] Embodiment 6(b) of the present disclosure relates to embodiment 6, 6 teeth, [ka] It is.

[0204] Embodiment 6(c) of the present disclosure relates to embodiment 6, 6 teeth, [ka] It is.

[0205] Embodiment 7 of the present disclosure relates to a compound according to any one of embodiments 1 to 6 (including any subembodiments thereof), wherein R 4 are H, OH, and CF 3 , or C.H. 3 It is.

[0206] Subembodiment of embodiment 7 Embodiment 7(a) of the present disclosure relates to embodiment 7, 4 , H, CF 3 , or C.H. 3 It is.

[0207] Embodiment 7(b) of the present disclosure relates to embodiment 7, 4 is H.

[0208] Embodiment 7(c) of the present disclosure relates to embodiment 7, 4 CF 3 or CH 3 It is.

[0209] Embodiment 7(d) of the present disclosure relates to embodiment 7, 4 is CH 3 It is.

[0210] Embodiment 8 of the present disclosure relates to a compound according to any one of embodiments 1, 2, 3, 5, 6 or 7 (including any subembodiments thereof), wherein L is a bond, -CH 2 -, -(CH 2 ) 2 -, CH(CH 3 )-, CH(CH 2 CH 3 )-, -C(O)-, -CH(C 3 ~C 6 Cycloalkyl)-, -CH(pyridyl)-, -C(CH 3 )(pyridyl)-, -S(O) 2 - or -C(H)(CH 2 CN)-. The term "where applicable" used in the embodiments and subembodiments of the present disclosure means excluding cases where the earlier subembodiment is narrower in scope than the later embodiment. For example, embodiment 8 is broader in scope than embodiments 2(h)-2(l), so embodiment 8 cannot be applied to subembodiments 2(h)-2(l). This interpretation of the embodiments and subembodiments of the present disclosure applies in all cases, regardless of whether the term "where applicable" is used.

[0211] Subembodiment of embodiment 8 Embodiment 8(a) of the present disclosure relates to embodiment 8, wherein L is a bond.

[0212] Embodiment 8(b) of the present disclosure relates to embodiment 8, wherein L is -CH 2 -, -(CH 2 ) 2 -, CH(CH 3 )-, or CH(CH 2 CH 3 )-.

[0213] Embodiment 8(c) of the present disclosure relates to embodiment 8, wherein L is -C(O)- or -S(O) 2 -It is.

[0214] Embodiment 8(d) of the present disclosure relates to embodiment 8, wherein L is -CH(C 3 ~C 6 cycloalkyl)-.

[0215] Embodiment 8(e) of the present disclosure relates to embodiment 8, wherein L is -CH(pyridyl)- or -C(CH 3 )(pyridyl)-.

[0216] Embodiment 8(f) of the present disclosure relates to embodiment 8, wherein L is -C(H)(CH 2 CN)-.

[0217] Embodiment 9 of the present disclosure relates to a compound according to any one of embodiments 1 to 8 (including any subembodiments thereof, if applicable), wherein R 1 is phenyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazolyl, C 3 ~C 6 cycloalkyl, cyclohexenyl, morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydro-2H-furanyl, oxetanyl, azetidine, tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl 1,1-dioxide, tetrahydro-2H-thiopyranyl 1-oxide, tetrahydro-2H-thiopyranyl, tetrahydrothienyl, or thienyl; R 1 Optionally, one G 1 Group and 1 to 3 G 2 is substituted with a group.

[0218] Subembodiment of embodiment 9 Embodiment 9(a) of the present disclosure relates to embodiment 9, 1 is phenyl, pyridyl, or pyrimidinyl; R 1 Optionally, one G 1 Group and 1 to 3 G 2 is substituted with a group.

[0219] Embodiment 9(b) of the present disclosure relates to embodiment 9, 1 is C 3 ~C 6 cycloalkyl, or cyclohexynyl; R 1 Optionally, one G 1 Group and 1 to 3 G 2 is substituted with a group.

[0220] Embodiment 9(c) of the present disclosure relates to embodiment 9, 1 is morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydro-2H-furanyl, tetrahydro-2H-pyranyl, tetrahydro-2H-thiopyranyl 1,1-dioxide, tetrahydro-2H-thiopyranyl 1-oxide, tetrahydro-2H-thiopyranyl, or tetrahydrothiophenyl; R 1 Optionally, one G 1 Group and 1 to 3 G 2 is substituted with a group.

[0221] Embodiment 9(d) of the present disclosure relates to embodiment 9, 1 Optionally, one G 1 Group and 1 to 3 G 2 It is a phenyl substituted with a group.

[0222] Embodiment 9(f) of the present disclosure relates to embodiment 9, 1 Optionally, one G 1 Group and 1 to 3 G 2 and pyridyl substituted with a group.

[0223] Embodiment 9(g) of the present disclosure relates to embodiment 9,1 Optionally, one G 1 Group and 1 to 3 G 2 and pyrimidinyl substituted with a group.

[0224] Embodiment 9(h) of the present disclosure relates to embodiment 9, 1 Optionally, one G 1 Group and 1 to 3 G 2 C substituted with a group 3 ~C 6 It is cycloalkyl.

[0225] Embodiment 9(j) of the present disclosure relates to embodiment 9, 1 Optionally, one G 1 Group and 1 to 3 G 2 and morpholinyl substituted with a group.

[0226] Embodiment 9(k) of the present disclosure relates to embodiment 9, 1 Optionally, one G 1 Group and 1 to 3 G 2 The piperazinyl is substituted with a group.

[0227] Embodiment 9(l) of the present disclosure relates to embodiment 9, 1 Optionally, one G 1 Group and 1 to 3 G 2 The piperidinyl is substituted with a group.

[0228] Embodiment 9(m) of the present disclosure relates to embodiment 9, 1 Optionally, one G 1 Group and 1 to 3 G 2 and pyrrolidinyl substituted with a group.

[0229] Embodiment 9(n) of the present disclosure relates to embodiment 9, 1 Optionally, one G 1 Group and 1 to 3 G 2 The tetrahydro-2H-furanyl is substituted with a group.

[0230] Embodiment 9(o) of the present disclosure relates to embodiment 9, 1 Optionally, one G 1 Group and 1 to 3 G 2 and tetrahydro-2H-pyranyl substituted with a group.

[0231] Embodiment 9(p) of the present disclosure relates to embodiment 9, 1 Optionally, one G 1 Group and 1 to 3 G 2 and tetrahydro-2H-thiopyranyl substituted with a group.

[0232] Embodiment 10 of the present disclosure relates to a compound according to any one of embodiments 1 to 9 (including any subembodiments thereof, where applicable), R 1 is one of (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l), or (m). (a) optionally, 1 to 3 G 2 C substituted with a group 3 ~C 6 Cycloalkyl(G 2 is F, cyano, or -CH 2 CN), (b) One G 1 Group and 1 to 3 G 2 Phenyl optionally substituted with a group (G 1 is benzyloxy, -C(=CH 2 )CH 3 , -C(O)OH, -C(O)NH 2 , -C(O)N(H)-cyclopropyl, cyclopropyl, cyano, or -SO 2 CH 3 And each G 2 are independently -OCHF 2 , Cl, F, -OCH 3 , -OCF 3 , C.H. 3 , C.F. 3 , and -C(CH 3 ) 2 -OH), (c) One G 1Group and 1-2 G 2 Pyridyl optionally substituted with a group (G 1 -C(O)OH, -C(O)NH 2 , cyclopropyl, or cyclopropylalkynylene, and each G 2 are independently F, CN, and OCH 3 , C.F. 3 , C.H. 3 , OH, -CH(CH 3 ) 2 , and Cl), (d) One G 1 Group and 1-2 G 2 Pyrazolyl optionally substituted with a group (R 1 is pyrazolyl, provided that L is a bond, and a hydrogen atom of -NH- or =CH- can be replaced by G 1 is -CH 2 -SO 2 -CH 3 , -(CH 2 ) 2 -N(CH 3 ) 2 , cyclopropyl, -CH 2 -Cyclopropyl, -(CH 2 ) 2 -CN, or -CH 2 C(O)N(CH 3 ) 2 Each G can replace a hydrogen atom of -NH- or =CH-. 2 is independently 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, and hydroxyC 1 ~C 6 alkyl), (e)-NH 2 , -N(CH 3 ) 2 , O.C.H. 3 , n-azetidinyl, or pyrimidinyl optionally substituted with cyclopropyl; (f) pyridazinyl, (g) each independently, C 1 ~C 6 Alkyl, C1 ~C 6 Haloalkyl, Hydroxy C 1 ~C 6 tetrahydro-2H-pyranyl optionally substituted with 1-2 groups, which are alkyl, Cl, and F; (h) each independently, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, Hydroxy C 1 ~C 6 tetrahydro-2H-furanyl optionally substituted with 1-2 groups, which are alkyl, Cl, and F; (i) each independently, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, and hydroxyC 1 ~C 6 morpholinyl optionally substituted with 1 to 2 groups, which is alkyl; (j) oxetanyl, (k) each independently: C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, and hydroxyC 1 ~C 6 piperidinyl optionally substituted with 1 to 2 groups, which is alkyl; (l) each independently, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, Hydroxy C 1 ~C 6 cyclohexenyl optionally substituted with 1-2 groups, which are alkyl, Cl, and F; or (m) Thienyl.

[0233] Subembodiment of embodiment 10 An eleventh embodiment of the present disclosure relates to a compound according to any one of the first to seventh embodiments (including any subembodiments thereof, where applicable), comprising -LR 1 teeth, [ka] [ka] [ka] During the ceremony, G 3 But, H, OCH 3 , N-azetidinyl, NH 2 , -N(CH 3 ) 2 , cyclopropyl; G 4 But, H, CH 3 , -CH 2 CH 3 , -(CH 2 )N(CH 3 ) 2 , -CH 2 -SO 2 -CH 3 , -CH(CH 3 ) 2 , -CH 2 C(CH 3 ) 2 (OH), cyclopropyl, -CH 2 -Cyclopropyl, -(CH 2 ) 2 -CN, or -CH 2 C(O)N(CH 3 ) 2 and G 5 is H or OH, G 6 is H or CH 3 and G 7 But, H, CH 3 , -(CH 2 )N(CH 3 ) 2 , -SO 2 -CH 3 , -CH 2 -SO 2 -CH 3 , -CH(CH 3 ) 2 , -CH 2 C(CH3 ) 2 (OH), cyclopropyl, -CH 2 -Cyclopropyl, -(CH 2 ) 2 -CN, -CH 2 C(O)N(CH 3 ) 2 , -C(O)OC(CH 3 ) 3 , -C(O)CH 3 , or -C(O)C(CH 3 ) 3 It is.

[0234] Subembodiment of embodiment 11 Embodiment 11(a) of the present disclosure relates to embodiment 11, 1 teeth, [ka] It is.

[0235] Embodiment 11(b) of the present disclosure relates to embodiment 11, 1 teeth, [ka] It is.

[0236] Embodiment 11(c) of the present disclosure relates to embodiment 11, 1 teeth, [ka] It is.

[0237] Embodiment 11(d) of the present disclosure relates to embodiment 11, 1 teeth, [ka] It is.

[0238] Embodiment 12 of the present disclosure relates to a compound according to embodiment 11 (including any subembodiments thereof, where applicable), G 1 Benzyloxy, -C(=CH 2 )CH 3 , -C(O)OH, -C(O)NH 2 , -C(O)N(H)-cyclopropyl, cyclopropyl, -CH 2 -Cyclopropyl, cyclopropylalkynylene, -CH 2 -SO 2 -CH 3 , -SO 2 -CH 3 , -(CH 2 )N(CH 3 ) 2 , -(CH 2 ) 2 -N(CH 3 ) 2 , -CH 2 -Cyclopropyl, -(CH 2 ) 2 -CN, -C(O)OC(CH 3 ) 3 , -C(O)CH 3 , and -C(O)C(CH 3 ) 3 , -CH 2 C(O)N(CH 3 ) 2 , cyano, or -SO 2 CH 3 and each G 2 But independently, -OCHF 2 , -OCH 2 F, Cl, F, -OCH 3 , OH, -OCF 3 , C.H. 3 , -CH(CH 3 ) 2 , C.F. 3 , -CH 2 CN, CH 2 C(CH 3 ) 2 (OH), and -C(CH 3 ) 2 -OH.

[0239] Embodiment 13 of the present disclosure relates to a compound according to embodiment 11, 1 teeth, [ka] It is.

[0240] Embodiment 14 of the present disclosure relates to a compound according to embodiment 13, 1 Benzyloxy, -C(=CH 2 )CH 3 , -C(O)OH, -C(O)NH 2 , -C(O)N(H)-cyclopropyl, cyclopropyl, -CH 2 -Cyclopropyl, cyclopropylalkynylene, -CH 2 -SO 2 -CH 3 , -SO 2 -CH 3 , -(CH 2 )N(CH 3 ) 2 , -(CH 2 ) 2 -N(CH 3 ) 2 , -CH 2 -Cyclopropyl, -(CH 2 ) 2 -CN, -C(O)OC(CH 3 ) 3 , -C(O)CH 3 , -C(O)C(CH 3 ) 3 , -CH 2 C(O)N(CH 3 ) 2 , cyano, or -SO 2 CH 3 and each G 2 But independently, -OCHF 2 , -OCH 2 F, Cl, F, -OCH 3 , OH, -OCF 3 , C.H. 3 , -CH(CH 3 ) 2 , C.F. 3 , -CH 2 CN, CH 2 C(CH 3 ) 2 (OH), and -C(CH 3 )2 -OH.

[0241] Embodiment 15 of the present disclosure relates to a compound according to any one of embodiments 1 to 14 (including any subembodiments thereof, where applicable), wherein R 5 If attached to carbon, [ka] It is.

[0242] Subembodiment of embodiment 15 Embodiment 15(a) of the present disclosure relates to embodiment 15, 5 teeth, [ka] It is.

[0243] Embodiment 15(b) of the present disclosure relates to embodiment 15, 5 teeth, [ka] It is.

[0244] Embodiment 15(c) of the present disclosure relates to embodiment 15, 5 teeth, [ka] It is.

[0245] Embodiment 15(d) of the present disclosure relates to embodiment 15, 5 teeth, [ka] It is.

[0246] Embodiment 15(d) of the present disclosure relates to embodiment 15, 5 teeth, [ka] It is.

[0247] Embodiment 15(e) of the present disclosure relates to embodiment 15, 5 teeth, [ka] It is.

[0248] Embodiment 16 of the present disclosure relates to a compound according to any one of embodiments 1 to 14 (including any subembodiments thereof, where applicable), wherein R 5 teeth, [ka] It is.

[0249] Subembodiment of embodiment 16 Embodiment 16(a) of the present disclosure relates to embodiment 16, 5 teeth, [ka] It is.

[0250] Embodiment 16(b) of the present disclosure relates to embodiment 16, 5 teeth, [ka] It is.

[0251] Embodiment 16(c) of the present disclosure relates to embodiment 16, 5 teeth, [ka] It is.

[0252] Embodiment 16(d) of the present disclosure relates to embodiment 16, 5 teeth, [ka] It is.

[0253] Embodiment 16(e) of the present disclosure relates to embodiment 16, 5 teeth, [ka] It is.

[0254] Embodiment 16(f) of the present disclosure relates to embodiment 16, 5 teeth, [ka] It is.

[0255] Embodiment 16(g) of the present disclosure relates to embodiment 16, 5 teeth, [ka] It is.

[0256] Embodiment 16(h) of the present disclosure relates to embodiment 16, 5 teeth, [ka] It is.

[0257] Embodiment 17 of the present disclosure relates to a compound according to any one of embodiments 1 to 14 (including any subembodiments thereof, where applicable), wherein R 5 teeth, [ka] It is.

[0258] An eighteenth embodiment of the present disclosure relates to a compound according to any one of the first to fourth embodiments (including any subembodiments thereof, where applicable), wherein R 5 teeth, [ka] It is.

[0259] Subembodiment of embodiment 18 Embodiment 18(a) of the present disclosure relates to embodiment 18, 5 teeth, [ka] It is.

[0260] Embodiment 18(b) of the present disclosure relates to embodiment 18, 5 teeth, [ka] It is.

[0261] Embodiment 18(c) of the present disclosure relates to embodiment 18, 5 teeth, [ka] It is.

[0262] Embodiment 18(d) of the present disclosure relates to embodiment 18, 5 teeth, [ka] It is.

[0263] Embodiment 18(e) of the present disclosure relates to embodiment 18, 5 teeth, [ka] It is.

[0264] Embodiment 19 of the present disclosure relates to a compound according to any one of embodiments 15 to 18 (including any subembodiments thereof, where applicable), wherein R 5 teeth, J 1 -C(O)OH, -C(O)OCH 3 , -CH 2 C(O)OH, -C(O)N(H)CH 3, -C(O)NH 2 , Tetrazolyl, -SO 2 CH 3 , -C(O)N(H)CN, C(O)N(H)OH, -SO 2 NH 2 , -SO 2 NH-Cyclopropyl, -C(O)N(H)SO 2 CH 3 and each J 2 are independently -O-cyclobutyl, -OCH 2 -phenyl, -O-cyclopropyl, -O-CH 2 -Cyclopropyl, Cyclopropylethynylene, CN, OH, Cyclopropyl, F, Cl, -OCH 3 , -OCHF 2 , OCF 3 , -OCH 2 CF 3 , -OCH 2 CHF 2 , -OCH(CH 3 ) 2 , -CH 2 CH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , and C.H. 3 It is.

[0265] Embodiment 20 of the present disclosure relates to a compound according to embodiment 19, J 1 is -C(O)OH or -C(O)OCH 3 and each J 2 are independently F, Cl, -OCH 3 , -OCHF 2 , OCF 3 , -OCH 2 CF 3 , -OCH 2 CHF 2 , -OCH(CH 3 ) 2 , -CH 2 CH 3 , -OCH 2 CH3 , -OCH 2 CH 2 CH 3 , and C.H. 3 It is.

[0266] Embodiment 21 of the present disclosure is a compound according to embodiment 1 having any one of formulas IV(a)-IV(c): [ka] During the ceremony, R 5 but, [ka] and J 1 -C(O)OH or -C(O)OCH 3 and each J 2 are independently F, Cl, -OCH 3 , -OCHF 2 , OCF 3 , -OCH 2 CF 3 , -OCH 2 CHF 2 , -OCH(CH 3 ) 2 , -CH 2 CH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , and C.H. 3 and -LR 1 but, [ka] and G 1 Benzyloxy, -C(=CH 2 )CH 3 , -C(O)OH, -C(O)NH 2 , -C(O)N(H)-cyclopropyl, cyclopropyl, -CH 2-Cyclopropyl, cyclopropylalkynylene, -CH 2 -SO 2 -CH 3 , -SO 2 -CH 3 , -(CH 2 )N(CH 3 ) 2 , -(CH 2 ) 2 -N(CH 3 ) 2 , -CH 2 -Cyclopropyl, -(CH 2 ) 2 -CN, -C(O)OC(CH 3 ) 3 , -C(O)CH 3 , -C(O)C(CH 3 ) 3 , -CH 2 C(O)N(CH 3 ) 2 , CN, or -SO 2 CH 3 and each G 2 But independently, -OCHF 2 , -OCH 2 F, Cl, F, -OCH 3 , OH, -OCF 3 , C.H. 3 , -CH(CH 3 ) 2 , C.F. 3 , CN, -CH 2 CN, CH 2 C(CH 3 ) 2 (OH), and -C(CH 3 ) 2 or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or deuterated analogue thereof, wherein

[0267] Subembodiment of embodiment 21 Embodiment 21(a1) of the present disclosure relates to embodiment 21 having formula IV(a) or formula IV(c).

[0268] Embodiment 21(a) of the present disclosure relates to embodiment 21 having formula IV(a).

[0269] Embodiment 21(b) of the present disclosure relates to embodiment 21 having formula IV(b).

[0270] Embodiment 21(c) of the present disclosure relates to embodiment 21 having formula IV(c).

[0271] Example 21(d) of the present disclosure relates to any one of embodiments 21, 21(a1), 21(a), 21(b), or 21(c), wherein R 5 teeth, [ka] It is.

[0272] Example 21(e) of the present disclosure relates to any one of embodiments 21, 21(a1), 21(a), 21(b), or 21(c), wherein R 5 teeth, [ka] It is.

[0273] Embodiment 21(f) of the present disclosure relates to any one of embodiments 21, 21(a1), 21(a), 21(b), or 21(c), further comprising: R 5 teeth, [ka] It is.

[0274] Example 21(g) of the present disclosure relates to any one of embodiments 21, 21(a1), 21(a), 21(b), or 21(c), wherein R 5 teeth, [ka] It is.

[0275] Example 21(g) of the present disclosure relates to any one of embodiments 21, 21(a1), 21(a), 21(b), or 21(c), wherein R 5 teeth, [ka] It is.

[0276] Embodiment 21(h) of the present disclosure relates to any one of embodiments 21, 21(a1), 21(a), 21(b), or 21(c), further comprising: R 5 teeth, [ka] It is.

[0277] Example 21(i) of the present disclosure relates to any one of embodiments 21, 21(a1), 21(a), 21(b), or 21(c), wherein R 5 teeth, [ka] It is.

[0278] Example 21(j) of the present disclosure relates to any one of embodiments 21, 21(a1), 21(a), 21(b), or 21(c), wherein R 5 teeth, [ka] It is.

[0279] Embodiment 21(k) of the present disclosure relates to any one of embodiments 21, 21(a1), 21(a), 21(b), or 21(c), further comprising: R 5 teeth, [ka] It is.

[0280] Example 21(l) of the present disclosure relates to any one of embodiments 21, 21(a1), 21(a), 21(b), or 21(c), wherein R 5 teeth, [ka] It is.

[0281] Embodiment 21(m) of the present disclosure relates to any one of embodiments 21, 21(a1), 21(a), 21(b), 21(c), 21(d), 21(e), 21(f), 21(g), 21(h), 21(i), 21(j), 21(k), or 21(l), further comprising: -LR 1 teeth, [ka] It is.

[0282] Embodiment 21(n) of the present disclosure relates to any one of embodiments 21, 21(a1), 21(a), 21(b), 21(c), 21(d), 21(e), 21(f), 21(g), 21(h), 21(i), 21(j), 21(k), or 21(l), further comprising: -LR 1 teeth, [ka] It is.

[0283] Embodiment 21(o) of the present disclosure relates to any one of embodiments 21, 21(a1), 21(a), 21(b), 21(c), 21(d), 21(e), 21(f), 21(g), 21(h), 21(i), 21(j), 21(k), or 21(l), further comprising: -LR 1 teeth, [ka] It is.

[0284] Embodiment 21(p) of the present disclosure relates to any one of embodiments 21, 21(a1), 21(a), 21(b), 21(c), 21(d), 21(e), 21(f), 21(g), 21(h), 21(i), 21(j), 21(k), or 21(l), comprising: -LR 1 teeth, [ka] It is.

[0285] Embodiment 21(q) of the present disclosure relates to any one of embodiments 21, 21(a1), 21(a), 21(b), 21(c), 21(d), 21(e), 21(f), 21(g), 21(h), 21(i), 21(j), 21(k), or 21(l), further comprising: -LR 1 teeth, [ka] It is.

[0286] Embodiment 21(r) of the present disclosure relates to any one of embodiments 21, 21(a1), 21(a), 21(b), 21(c), 21(d), 21(e), 21(f), 21(g), 21(h), 21(i), 21(j), 21(k), or 21(l), further comprising: -LR 1 teeth, [ka] It is.

[0287] Embodiment 21(s) of the present disclosure relates to any one of embodiments 21, 21(a1), 21(a), 21(b), 21(c), 21(d), 21(e), 21(f), 21(g), 21(h), 21(i), 21(j), 21(k), or 21(l), 1 teeth, [ka] It is.

[0288] Embodiment 21(t) of the present disclosure relates to any one of embodiments 21, 21(a1), 21(a), 21(b), 21(c), 21(d), 21(e), 21(f), 21(g), 21(h), 21(i), 21(j), 21(k), or 21(l), further comprising: -LR 1 teeth, [ka] It is.

[0289] Embodiment 21(u) of the present disclosure relates to any one of embodiments 21, 21(a1), 21(a), 21(b), 21(c), 21(d), 21(e), 21(f), 21(g), 21(h), 21(i), 21(j), 21(k), or 21(l), further comprising: -LR 1 teeth, [ka] It is.

[0290] Embodiment 21(v) of the present disclosure relates to any one of embodiments 21, 21(a1), 21(a), 21(b), 21(c), 21(d), 21(e), 21(f), 21(g), 21(h), 21(i), 21(j), 21(k), or 21(l), further comprising: -LR 1 teeth, [ka] It is.

[0291] Embodiment 21(w) of the present disclosure relates to any one of embodiments 21, 21(a1), 21(a), 21(b), 21(c), 21(d), 21(e), 21(f), 21(g), 21(h), 21(i), 21(j), 21(k), or 21(l), further comprising: -LR 1 teeth, [ka] It is.

[0292] Embodiment 21(x) of the present disclosure relates to any one of embodiments 21, 21(a1), 21(a), 21(b), 21(c), 21(d), 21(e), 21(f), 21(g), 21(h), 21(i), 21(j), 21(k), or 21(l), further comprising: -LR 1 teeth, [ka] It is.

[0293] Embodiment 22 relates to a compound according to embodiment 1 of the present disclosure selected from Table 1 of the present disclosure, or a pharma- ceutically acceptable salt thereof.

[0294] The compounds contemplated herein are described with reference to both general formulas and specific compounds.In addition, all compounds described herein may exist in several different forms or derivatives within the scope of this disclosure.These include, for example, tautomers, stereoisomers, racemic mixtures, positional isomers, salts, prodrugs (e.g., carboxylic acid esters), solvated forms, and active metabolites.

[0295] It is understood that some compounds may exhibit tautomerism.In such cases, the formula provided herein expressly shows only one of possible tautomeric forms.Therefore, it should be understood that the formula provided herein is intended to represent any tautomeric form of the compound shown, and should not be limited to the specific tautomeric form shown by the drawing of the formula.

[0296] Likewise, some of the compounds described in this disclosure may exist as stereoisomers as defined herein.All such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of this disclosure.Unless otherwise specified, all such stereoisomeric forms are included within the formula provided herein.

[0297] In some embodiments, the chiral compounds of the present disclosure are in a form that contains at least 80% (60% enantiomeric excess ("ee") or diastereomeric excess ("de")) of a single isomer, or at least 85% (70% ee or de), 90% (80% ee or de), 95% (90% ee or de), 97.5% (95% ee or de), or 99% (98% ee or de). As will generally be understood by those of skill in the art, an optically pure compound having one chiral center is one that consists essentially of one of the two possible enantiomers (i.e., is enantiomerically pure), and an optically pure compound having multiple chiral centers is both diastereomerically pure and enantiomerically pure. In some embodiments, the compound is present in an optically pure form.

[0298] For compounds whose synthesis involves the addition of a single group at a double bond, particularly a carbon-carbon double bond, the addition can occur at either of the double bond-bonding atoms. With respect to such compounds, the present disclosure includes both such positional isomers.

[0299] In addition to the present formulas and compounds described herein, the present disclosure also includes prodrugs (generally pharma- ceutically acceptable prodrugs), active metabolic derivatives (active metabolites), and pharma- ceutically acceptable salts thereof.

[0300] Unless specified to the contrary, references to compounds herein include pharma- ceutically acceptable salts of such compounds.

[0301] In some embodiments, the compounds of the present disclosure form complexes with acids or bases, including base addition salts such as ammonium, diethylamine, ethanolamine, ethylenediamine, diethanolamine, t-butylamine, piperazine, meglumine; acid addition salts such as acetate, acetylsalicylate, besylate, camsylate, citrate, formate, fumarate, glutarate, hydrochloride, maleate, mesylate, nitrate, oxalate, phosphate, succinate, sulfate, tartrate, thiocyanate, and tosylate; and amino acids such as alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine. In some cases, the amorphous complex is facilitated by further processing, such as mechanochemical methods such as spray drying, roller compaction, or microwave irradiation of the parent compound mixed with acid or base. Such methods may also include the addition of ionic and / or non-ionic polymeric systems, including but not limited to hydroxypropyl methylcellulose acetate succinate (HPMCAS) and methacrylic acid copolymers (e.g., Eudragit® L100-55), which further stabilize the amorphous nature of the complex. Such amorphous complexes offer several advantages. For example, the reduced melting temperature compared to the free base facilitates additional processing, such as hot melt extrusion, to further improve the biopharmaceutical properties of the compound. Also, amorphous complexes are easily friable, improving compression for filling the solid into capsule or tablet forms.

[0302] In addition, the formula is intended to encompass hydrated or solvated forms as well as non-hydrated or unsolvated forms of the identified structures. For example, the compounds shown include both hydrated and non-hydrated forms. Other examples of solvates include the structures in combination with a suitable solvent, such as isopropanol, ethanol, methanol, dimethylsulfoxide, ethyl acetate, acetic acid, or ethanolamine.

[0303] III. Formulation and Administration Embodiment 23 of the present disclosure relates to a pharmaceutical composition comprising a compound according to one of the embodiments of the present disclosure (a compound according to any one of embodiments 1 to 22, including any subembodiments thereof), and a pharma- ceutically acceptable carrier.

[0304] Embodiment 24 of the present disclosure relates to the pharmaceutical composition of embodiment 23, further comprising a second pharmaceutical agent.

[0305] The appropriate dosage form depends, in part, on the use or route of administration, e.g., oral, transdermal, transmucosal, inhalation, or injection (parenteral). Such a dosage form should enable the compound to reach the target cells. Other factors are well known in the art and include considerations such as toxicity and dosage forms that delay the compound or composition from exerting its effect. Techniques and formulations are generally described in The Science and Practice of Pharmacy, 21 st edition, Lippincott, Williams and Wilkins, Philadelphia, PA, 2005, which is incorporated herein by reference.

[0306] The compounds of the present disclosure (i.e., any of the compounds described in embodiments 1-22, including any of their subembodiments) can be formulated as a pharma- ceutically acceptable salt.

[0307] Carrier or excipient can be used to produce the composition. Carrier or excipient can be selected to facilitate administration of compound. Examples of carrier include calcium carbonate, calcium phosphate, various sugars such as lactose, glucose or sucrose, or types of starch, cellulose derivatives, gelatin, vegetable oil, polyethylene glycol, and physiologically compatible solvent. Examples of physiologically compatible solvent include sterile water for injection (WFI), saline, and dextrose.

[0308] The compound can be administered by different routes, including intravenous, intraperitoneal, subcutaneous, intramuscular, oral, transmucosal, rectal, transdermal, or inhalant.In some embodiments, the compound can be administered by oral administration.For example, when administered orally, the compound can be formulated into conventional oral dosage forms, such as capsules, tablets, and liquid preparations, such as syrups, elixirs, and concentrated drops.

[0309] For inhalation, the compounds of the present disclosure can be prepared as dry powder or suitable solution, suspension or aerosol.Powder and solution can be formulated with suitable additives known in the art.For example, powder can contain suitable powder base such as lactose or starch, and solution can contain propylene glycol, sterilized water, ethanol, sodium chloride, and other additives such as acid, alkali, and buffer salt.Such solution or suspension can be administered by inhalation through spray, pump, atomizer, or nebulizer. The compounds of the present disclosure may also be used in combination with other inhalation therapies, for example, corticosteroids such as fluticasone propionate, beclomethasone dipropionate, triamcinolone acetonide, budesonide, and mometasone furoate; beta agonists such as albuterol, salmeterol, and formoterol; anticholinergics such as ipratropium bromide or tiotropium bromide; vasodilators such as treprotin and iloprost; enzymes such as DNAase; therapeutic proteins; immunoglobulin antibodies; oligonucleotides such as single- or double-stranded DNA or RNA, siRNA; antibiotics such as tobramycin; muscarinic receptor antagonists; leukotriene antagonists; cytokine antagonists; protease inhibitors; cromolyn sodium; nedocryl sodium; and sodium cromoglycate.

[0310] Pharmaceutical preparations for oral use can be obtained, for example, by mixing active compound with solid excipient, optionally grinding the resulting mixture, optionally adding suitable auxiliary, and then processing the granulated mixture to obtain tablets or dragee cores, if necessary.Suitable excipients are fillers, such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations, such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose (CMC), and / or polyvinylpyrrolidone (PVP: povidone).If necessary, disintegrants, such as cross-linked polyvinylpyrrolidone, agar, or alginic acid, or its salts, such as sodium alginate, can be added.

[0311] The dragee core is provided with a suitable coating.For this purpose, for example, gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol (PEG) and / or titanium dioxide, lacquer solution and concentrated sugar solution, which may optionally contain suitable organic solvent or solvent mixture, can be used.Dyes or pigments can be added to the tablet or dragee coating for identification or to characterize different combinations of active compound doses.

[0312] Pharmaceutical preparations that can be used orally include push-fit capsules ("gelcaps") made of gelatin, as well as soft sealed capsules made of gelatin and plasticizers such as glycerol or sorbitol. Push-fit capsules can contain active ingredients mixed with fillers such as lactose, binders such as starch, and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, active compounds can be dissolved or suspended in suitable liquids such as fatty oils, liquid paraffin, or liquid polyethylene glycol (PEG). In addition, stabilizers can be added.

[0313] Alternatively, injection (parenteral administration), for example, intramuscular, intravenous, intraperitoneal, and / or subcutaneous injection, can be used.For injection, the compound of the present disclosure is formulated in a physiologically compatible buffer solution or a sterile liquid such as a solution such as physiological saline, Hank's solution, or Ringer's solution.In addition, the compound can be formulated in solid form and redissolved or suspended immediately before use.Lyophilized forms can also be produced.

[0314] Administration can also be transmucosal, topical, transdermal, or by inhalation.For transmucosal, topical, or transdermal administration, a penetrant suitable for the barrier to be permeated is used in the formulation.Such penetrants are generally known in the art, and include, for example, for transmucosal administration, bile salts and fusidic acid derivatives.In addition, detergents can be used to facilitate penetration.Transmucosal administration can be, for example, via nasal spray or suppository (rectal or vaginal).

[0315] The topical compositions of the present disclosure are formulated as oils, creams, lotions, ointments, etc., by selection of an appropriate carrier known in the art. Suitable carriers include vegetable or mineral oils, white petrolatum (white soft paraffin), branched chain fats or oils, animal fats, and high molecular weight alcohols (C 12 In another embodiment, the carrier is one in which the active ingredient is soluble. If desired, emulsifiers, stabilizers, humectants and antioxidants, as well as agents that impart color or fragrance, may also be included. Creams for topical application are formulated from a mixture of mineral oil, self-emulsifying beeswax, and water, into which the active ingredient dissolved in a small amount of solvent (e.g., oil) is mixed. In addition, administration by transdermal means may include a transdermal patch or dressing, such as a bandage impregnated with the active ingredient and, optionally, one or more carriers or diluents known in the art. To be administered in the form of a transdermal delivery system, dosage administration will of course be continuous rather than intermittent throughout the administration regime.

[0316] The amounts of various compounds administered are determined based on compound IC 50The dosage can be determined by standard procedures taking into account factors such as the biological half-life of the compound, the age, size, and weight of the subject, and the indication being treated. The importance of these and other factors is well known to those of skill in the art. In general, the dosage will be about 0.01 to 50 mg / kg, or 0.1 to 20 mg / kg, of the subject being treated. Multiple doses can be used.

[0317] The compounds of the present disclosure can also be used in combination with other therapies to treat the same disease.The use of such combinations includes the administration of the compound and one or more other therapeutic agents at different times, or the simultaneous administration of the compound and one or more other therapies.In some embodiments, the dosage of one or more of the compounds of the present disclosure or other therapeutic agents used in combination can be changed by methods well known to those skilled in the art, for example, the dosage of the compound can be reduced or the therapy can be used alone.

[0318] Combination uses include use with other therapies, drugs, medical procedures, and the like, where the other therapy or treatment may be administered at a different time than the compounds of the present disclosure (e.g., within a short time, such as within a few hours (e.g., 1, 2, 3, 4-24 hours), or within a longer time, such as 1-2 days, 2-4 days, 4-7 days, 1-4 weeks), or at the same time as the compounds of the present disclosure. Combination uses also include use with therapies or medical procedures that are administered once or infrequently, such as surgery, with the compounds of the present disclosure administered within a short or longer time period before or after the other therapy or procedure. In some embodiments, the present disclosure provides for the delivery of a compound of the present disclosure and one or more other drug therapies delivered by different or the same route of administration. Combination uses for any route of administration include the delivery of a compound of the present disclosure and one or more other drug therapies delivered together by the same route of administration in any formulation, including formulations in which the two compounds are chemically linked in a manner that maintains their therapeutic activity when administered. In one embodiment, other drug therapies can be co-administered with one or more compounds of the present disclosure. The use of combinations by co-administration includes co-formulation or administration of a formulation of chemically linked compounds, or administration of two or more compounds in separate formulations (administered by the same or different routes) within a short time of each other (e.g., 1 hour, 2 hours, 3 hours, up to 24 hours). Co-administration of separate formulations includes co-administration by delivery via one device, such as the same inhalation device, the same syringe, etc., or administration from separate devices within a short time of each other. Co-formulation of a compound of the present disclosure with one or more additional drug therapies delivered by the same route includes preparation together in a single formulation of separate compounds, or materials that can be administered by one device, including modified compounds that are chemically linked but still maintain their biological activity. Such chemically linked compounds may have bonds that are substantially maintained in vivo, or the bonds may degrade in vivo to separate the two active ingredients.

[0319] IV.How to use The methods and compounds will typically be used in therapy for human subjects, however, they may also be used to treat similar or identical indications in other animal subjects.

[0320] In certain embodiments, the patient is 60 years or older and relapses after first-line cancer therapy. In certain embodiments, the patient is 18 years or older and relapses or is refractory to second-line cancer therapy. In certain embodiments, the patient is 60 years or older and is primarily refractory to first-line cancer therapy. In certain embodiments, the patient is 70 years or older and has not been previously treated. In certain embodiments, the patient is 70 years or older and is ineligible and / or unlikely to benefit from cancer therapy.

[0321] In certain embodiments, the therapeutically effective amount used in the methods provided herein is at least 10 mg per day.In certain embodiments, the therapeutically effective amount is 10, 50, 90, 100, 135, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2200, 2500 mg per day. In other embodiments, the therapeutically effective amount is 10, 50, 90, 100, 135, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2200, 2500, 3000, 3500, 4000, 4500, 5000 mg or more per day. In certain embodiments, the compound is administered continuously.

[0322] In certain embodiments, provided herein is a method for treating a disease or condition mediated by EP300 or CBP by administering at least 10, 50, 90, 100, 135, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2200, 2500, 3000, 3500, 4000, 4500, 5000 mg / day of any of the compounds described in any of the compounds in any of the embodiments 1-22, or a pharma- ceutically acceptable salt, deuterated analog, tautomer, or stereoisomer thereof, to a mammal having the disease or condition, wherein the compound is administered on an empty stomach.

[0323] Embodiment 25 of the present disclosure relates to a method for treating a subject having a disease or condition mediated by EP300 or CBP, comprising administering to the subject an effective amount of a compound described in one of embodiments 1 to 22, or a pharma- ceutically acceptable salt, deuterated analog, tautomer, or stereoisomer thereof, or a pharmaceutical composition described in embodiment 23 or 24.

[0324] Embodiment 26 of the present disclosure relates to a method for treating a subject having a disease or condition according to embodiment 25, wherein the disease or condition is a cancer with an inactivating mutation in CBP or EP300, or a cancer with activation of EP300 or CBP.

[0325] Embodiment 27 of the present disclosure relates to a method for treating a subject having a disease or condition according to embodiment 25, wherein the disease or condition is an androgen receptor-expressing cancer.

[0326] Embodiment 28 of the present disclosure relates to a method for treating a subject having a disease or condition according to embodiment 25, wherein the disease or condition is a neoplastic disorder, a cancer, an inflammatory disorder, an aging disease, a cognitive disorder, and / or a neurodegenerative disease.

[0327] Embodiment 29 of the present disclosure relates to a method for treating a subject having a disease or condition according to embodiment 25, wherein the disease or condition is selected from the group consisting of acral lentiginous melanoma, acute eosinophilic leukemia, acute erythroblastic leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, bladder cancer, adenocarcinoma, adult T-cell leukemia / lymphoma, aggressive NK-cell leukemia, AIDS-related lymphoma, anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, B-cell chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, B-cell lymphoma, bone cancer, Burkitt's lymphoma, cutaneous T-cell lymphoma, colorectal cancer, diffuse large B-cell lymphoma, enteropathy-associated T-cell lymphoma, follicular lymphoma, pleomorphic lymphoma, leukemia, leukemia, and / or leukemia. glioblastoma, glioma, gastric cancer, hepatosplenic T-cell lymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, leukemia, lymphoma, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, small cell lung cancer, non-small cell lung cancer, MALT lymphoma, malignant peripheral nerve sheath tumor, mantle cell lymphoma, marginal zone B-cell lymphoma, mast cell leukemia, breast cancer, medulloblastoma, melanoma, Merkel cell carcinoma, mesothelioma, multiple myeloma, neuroblastoma, neurofibroma, nodular melanoma, osteosarcoma, ovarian cancer, precursor T-lymphoblastic lymphoma, primary central nervous system lymphoma, primary effusion lymphoma, prostate cancer, pancreatic cancer, skin cancer, T-cell lymphoma, uveal melanoma, Alzheimer's disease, Parkinson's disease, or colorectal cancer.

[0328] Embodiment 29(a) of the present disclosure relates to a method for treating a subject having a disease or condition according to embodiment 29, wherein the disease or condition is acute myeloid leukemia.

[0329] Embodiment 29(b) of the present disclosure relates to a method for treating a subject having a disease or condition according to embodiment 29, wherein the disease or condition is multiple myeloma.

[0330] Embodiment 29(c) of the present disclosure relates to a method for treating a subject having a disease or condition according to embodiment 29, wherein the disease or condition is prostate cancer.

[0331] Embodiment 29(d) of the present disclosure relates to a method for treating a subject having a disease or condition according to embodiment 29, wherein the disease or condition is prostate cancer.

[0332] Embodiment 30 of the present disclosure relates to a method for treating a subject having a disease or condition according to embodiment 29, wherein the disease or condition is small cell lung cancer, non-small cell lung cancer, bladder cancer, non-Hodgkin's lymphoma, acute myeloid leukemia, multiple myeloma, diffuse large B-cell lymphoma, breast cancer, or prostate cancer.

[0333] Embodiment 31 of the present disclosure relates to a method for treating a subject having a disease or condition according to embodiment 29, wherein the disease or condition is Alzheimer's disease or Parkinson's disease.

[0334] V. Combination Therapy EP300 and CBP modulators can be usefully combined with other pharmacologically active compounds, or with two or more other pharmacologically active compounds, particularly in the treatment of cancer. In one embodiment, the composition comprises any one or more compounds described herein with one or more compounds that are therapeutically effective against the same disease indication, and the compounds have a synergistic effect against the disease indication. In one embodiment, the composition comprises any one or more compounds described herein that are effective in the treatment of cancer, and one or more other compounds that are effective in the treatment of the same cancer, and the compounds are synergistically effective in the treatment of cancer.

[0335] In another embodiment, the present disclosure provides a method for treating a disease or condition mediated by EP300 or CBP by administering to a subject a composition comprising an effective amount of any one or more compounds described herein in combination with one or more other suitable therapies for treating the disease.

[0336] Embodiment 32 of the present disclosure relates to a method according to any one of embodiments 25-31, or any subembodiment thereof, further comprising administering one or more additional therapeutic agents.

[0337] Embodiment 33 of the present disclosure relates to a method according to embodiment 32, wherein the one or more additional therapeutic agents are selected from i) an alkylating agent selected from adozerecin, altretamine, bizerecin, busulfan, carboplatin, carboquone, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, estramustine, fotemustine, hepsulfam, ifosfamide, improsulfan, irofulven, lomustine, mechlorethamine, melphalan, oxaliplatin, piposulfan, semustine, streptozocin, temozolomide, thiotepa, and threosulfan; ii) bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, menogaril, myosulfan, iii) an alkylating agent selected from iodine, ... iii) an antimetabolite selected from the group consisting of azacitidine, capecitabine, cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, 5-fluorouracil, ftorafur, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, nelarabine, pemetrexed, raltitrexed, thioguanine, and trimetrexate; iv) an antimetabolite selected from the group consisting of alemtuzumab, bevacizumab, cetuximab, galiximab, gemtuzumab, nivolumab, panitumumab, pembrolizumab, pertuzumab, rituximab, tositumomab, trastuzumab, and 90 i) an immunotherapeutic agent (including a PD-1 or PD-L1 inhibitor) selected from ibritumomab tiuxetan; v) a hormone or hormone antagonist selected from the group consisting of enzalutamide, abiraterone, anastrozole, androgens, buserelin, diethylstilbestrol, exemestane, flutamide, fulvestrant, goserelin, idoxifene, letrozole, leuprolide, mazestrol, raloxifene, tamoxifen, and toremifene; vi) a taxane selected from DJ-927, docetaxel, TPI 287, paclitaxel, and DHA-paclitaxel; vii) a retinoid selected from alitretinoin, bexarotene, fenretinide, isotretinoin, and tretinoin; viii) etoposide, homoharringtonine;ix) an alkaloid selected from teniposide, vinblastine, vincristine, vindesine, and vinorelbine; ix) an antiangiogenic agent selected from AE-941 (GW786034, Neovastat), ABT-510, 2-methoxyestradiol, lenalidomide, and thalidomide; x) a topoisomer selected from amsacrine, edotecarin, exatecan, irinotecan, SN-38 (7-ethyl-10-hydroxy-camptothecin), rubitecan, topotecan, and 9-aminocamptothecin. xi) kinase inhibitors selected from erlotinib, gefitinib, flavopiridol, imatinib mesylate, lapatinib, sorafenib, sunitinib malate, AEE-788, AG-013736, AMG706, AMN107, BMS-354825, BMS-599626, UCN-01 (7-hydroxystearosporine), vemurafenib, dabrafenib, trametinib, cobimetinib, selumetinib, and vatalanib; xii) bortezomib, geldanamycin, and rapamycin. xiii) a biological response modifier selected from imiquimod, interferon-α, and interleukin-2; xiv) an IDO inhibitor; and xv) 3-AP (3-amino-2-carboxaldehyde thiosemicarbazone), altrasentan, aminoglutethimide, anagrelide, asparaginase, bryostatin-1, cilengitide, elesclomol, eribulin mesylate (E7389), ixabepilone, lonidamine, masoprocol, mitoguanazone, obsolete, serotin ... a chemotherapeutic agent selected from rimersen, sulindac, testolactone, tiazofurin, an mTOR inhibitor, a PI3K inhibitor, a Cdk4 inhibitor, an Akt inhibitor, an Hsp90 inhibitor, a farnesyltransferase inhibitor, or an aromatase inhibitor (anastrozole, letrozole, exemestane); xvi) a Mek inhibitor; xvii) a tyrosine kinase inhibitor; xviii) a c-Kit mutant inhibitor; xix) an EGFR inhibitor; a PD-1 inhibitor; or xx) an epigenetic modulator.

[0338] Embodiment 33(a) of the present disclosure relates to a method according to embodiment 32, wherein the one or more additional therapeutic agents are i) an alkylating agent selected from adozelesin, altretamine, bizelesin, busulfan, carboplatin, carboquone, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, estramustine, fotemustine, hepsulfam, ifosfamide, improsulfan, irofulven, lomustine, mechlorethamine, melphalan, oxaliplatin, piposulfan, semustine, streptozocin, temozolomide, thiotepa, and threosulfan; ii) an antibiotic selected from bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, menogaril, mitomycin, mitoxantrone, neocarzinostatin, pentostatin, and plicamycin; iii) antimetabolites selected from the group consisting of azacitidine, capecitabine, cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, 5-fluorouracil, ftorafur, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, nelarabine, pemetrexed, raltitrexed, thioguanine, and trimetrexate; iv) immunotherapeutics selected from PD-1 or PD-L1 inhibitors; v) hormones or hormone antagonists selected from the group consisting of enzalutamide, abiraterone, anastrozole, androgens, buserelin, diethylstilbestrol, exemestane, flutamide, fulvestrant, goserelin, idoxifene, letrozole, leuprolide, mazestrol, raloxifene, tamoxifen, and toremifene; vi) DJ-927, docetaxel, TPI 287, paclitaxel, and DHA-paclitaxel; vii) a retinoid selected from alitretinoin, bexarotene, fenretinide, isotretinoin, and tretinoin; viii) an alkaloid selected from etoposide, homoharringtonine, teniposide, vinblastine, vincristine, vindesine, and vinorelbine; ix) AE-941 (GW786034, Neovastat), ABT-510, 2-methoxyestradiol;x) an antiangiogenic agent selected from amsacrine, edotecan, exatecan, irinotecan, SN-38 (7-ethyl-10-hydroxy-camptothecin), rubitecan, topotecan, and 9-aminocamptothecin; xi) an antiangiogenic agent selected from erlotinib, gefitinib, flavopiridol, imatinib mesylate, lapatinib, sorafenib, sunitinib malate, AEE-788, AG- xii) kinase inhibitors selected from 013736, AMG706, AMN107, BMS-354825, BMS-599626, UCN-01 (7-hydroxystearosporine), vemurafenib, dabrafenib, trametinib, cobimetinib, selumetinib, and vatalanib; xiii) targeted signal transduction inhibitors selected from bortezomib, geldanamycin, and rapamycin; xiii) imiquimod, interferon-α, and interleukin-11. -2, xiv) IDO inhibitors, and xv) 3-AP (3-amino-2-carboxaldehyde thiosemicarbazone), altrasentan, aminoglutethimide, anagrelide, asparaginase, bryostatin-1, cilengitide, elesclomol, eribulin mesylate (E7389), ixabepilone, lonidamine, masoprocol, mitoganazone, oblimersen, sulindac, testolactone, tiazofurin, a chemotherapeutic agent selected from an mTOR inhibitor, a PI3K inhibitor, a Cdk4 inhibitor, an Akt inhibitor, an Hsp90 inhibitor, a farnesyltransferase inhibitor, or an aromatase inhibitor (anastrozole, letrozole, exemestane); xvi) a Mek inhibitor; xvii) a tyrosine kinase inhibitor; xviii) a c-Kit mutant inhibitor; xix) an EGFR inhibitor; a PD-1 inhibitor; or xx) an epigenetic modulator.

[0339] Embodiment 34 of the present disclosure relates to a method according to embodiment 33, wherein the one or more additional therapeutic agents are (a) DNA methyltransferase, (b) histone or protein methyltransferases; (c) histone demethylase, (d) histone deacetylase inhibitors, (f) other chromatin remodelers, and (g) an epigenetic modulator selected from the group consisting of BRD4 inhibitors.

[0340] Embodiment 35 of the present disclosure relates to a method according to embodiment 34, wherein the epigenetic modulator is a histone deacetylase inhibitor selected from the group consisting of vorinostat, romidepsin, chidamide, panobinostat, belinostat, valproic acid, mocetinostat, abexinostat, entinostat, resminostat, gibinostat, and xinostat.

[0341] Embodiment 36 of the present disclosure relates to a method according to embodiment 34, wherein the epigenetic modulator is a BRD4 inhibitor.

[0342] Embodiment 37 of the present disclosure relates to a method according to embodiment 33, wherein the one or more additional therapeutic agents is a PD-1 inhibitor, quizartinib, enzalutamide, abiraterone, or a BRD4 inhibitor.

[0343] Embodiment 38 of the present disclosure relates to a method according to embodiment 33, wherein the one or more additional therapeutic agents is enzalutamide, and the disease is prostate cancer, including but not limited to castration-resistant prostate cancer.

[0344] Embodiment 39 of the present disclosure relates to a method according to embodiment 33, wherein the one or more additional therapeutic agents is abiraterone, and the disease is prostate cancer, including but not limited to castration-resistant prostate cancer.

[0345] Bromodomains (e.g., BET proteins such as BRD2, BRD3, BRD4, and / or BRDT) and diseases associated with, for example, aberrant expression of bromodomains include, among others, cell proliferation disorders, cancer, chronic autoimmune, and inflammatory conditions. Non-limiting examples of BET inhibitors include PLX1107, GSK1210151A, and GSK525762.

[0346] Histone deacetylase inhibitors (HDAC inhibitors) are cytostatic agents that inhibit the growth of tumor cells in culture and in vivo by inducing cell cycle arrest, differentiation, and / or apoptosis. HDAC inhibitors exert their antitumor effects through the induction of altered expression of oncogenes or tumor suppressors by regulating the acetylation / deacetylation of histones and / or non-histone proteins such as transcription factors. Histone acetylation and deacetylation play an important role in regulating chromatin topology and controlling gene transcription. Non-limiting examples of HDAC inhibitors include vorinostat, romidepsin, chidamide, panobinostat, belinostat, valproic acid, mocetinostat, abexinostat, entinostat, resminostat, divinostat, and xinostat. HDAC inhibitors have been widely used in psychiatry and neurology as mood stabilizers and antiepileptic agents. One example of this is valproic acid, marketed as a drug under the trade names Depakene, Depakote, and Divalproex. HDAC inhibitors are also used as mitigating agents for neurodegenerative diseases such as Alzheimer's and Huntington's disease.

[0347] In another embodiment, the present disclosure provides a method for treating cancer in a subject in need thereof by administering to the subject an effective amount of a composition comprising any one or more compounds described herein in combination with one or more other therapies or medical procedures that are effective in treating cancer.Other therapies or medical procedures include suitable anti-cancer therapies (e.g., drug therapy, vaccine therapy, gene therapy, photodynamic therapy), or medical procedures (e.g., surgery, radiation therapy, hyperthermia, bone marrow or stem cell transplantation). In one embodiment, the one or more suitable anti-cancer therapies or medical procedures are selected from treatment with chemotherapeutic agents (e.g., chemotherapy drugs), radiation therapy (e.g., x-rays, gamma rays, or electron, proton, neutron, or alpha, particle beams), hyperthermia (e.g., microwave, ultrasound, radiofrequency ablation), vaccine therapy (e.g., AFP gene hepatocellular carcinoma vaccine, AFP adenovirus vector vaccine, AG-858, allogeneic GM-CSF-secreting breast cancer vaccine, dendritic cell peptide vaccine), gene therapy (e.g., Ad5CMV-p53 vector, adenovector encoding MDA7, adenovirus 5-tumor necrosis factor alpha), photodynamic therapy (e.g., aminolevulinic acid, motexatin luteinium), surgery, or bone marrow and stem cell transplantation.

[0348] VI. Kit In another aspect, the disclosure provides a kit comprising one or more compounds described in any one of the compounds in one of the embodiments 1-22, or a pharma- ceutically acceptable salt, deuterated analog, tautomer, or stereoisomer thereof, or a pharmaceutical composition in embodiment 23 or 24. In some embodiments, the compound or composition is packaged, for example, in a vial, bottle, flask, which may be further packaged, for example, in a box, envelope, or bag. The compound or composition may be approved by the U.S. Food and Drug Administration or a similar regulatory agency for administration to a mammal, for example, a human. The compound or composition may be approved for administration to a mammal, for example, a human, for an EP300- or CBP-mediated disease or condition. The kits described herein may include instructions for use and / or other indications that the compound or composition is suitable or approved for administration to a mammal, for example, a human, for an EP300- or CBP-mediated disease or condition. The compound or composition may be packaged in a unit dose or single dose form, for example, a single dose pill, capsule, or the like.

[0349] VII. Binding Assays The method of the present disclosure may include an assay that can detect the binding of a compound to a target molecule. Such binding is at a statistically significant level, with at least a 90% confidence level, or at least a 95, 97, 98, 99% or higher confidence level, that the assay signal represents the binding to the target molecule, i.e., is distinguished from background. In some embodiments, a control is used to distinguish target binding from non-specific binding. A wide variety of assays that show binding are known for different target types and can be used in the present disclosure.

[0350] Binding compounds can be characterized by their effect on the activity of the target molecule. Thus, a "low activity" compound is one that has an inhibitory concentration (IC) of greater than 1 μM under standard conditions. 50 ) or effective concentration (EC 50 "Very low activity" is defined as an IC of more than 100 μM under standard conditions. 50 or EC50 "Very low activity" means an IC50 activity of more than 1 mM under standard conditions. 50 or EC 50 "Moderate activity" means an IC of 200 nM to 1 μM under standard conditions. 50 or EC 50 "Slightly high activity" means an IC of 1 nM to 200 nM. 50 or EC 50 "High activity" means an IC of less than 1 nM under standard conditions. 50 or EC 50 It stands for IC 50 or EC 50 is defined as the concentration of a compound at which 50% of the target molecule (e.g., an enzyme or other protein) activity being measured is lost or gained, relative to the range of activity observed in the absence of the compound. Methods known to those of skill in the art can be used to measure activity, for example, by measuring any detectable product or signal produced by the occurrence of an enzymatic reaction, or other activity by the protein being measured.

[0351] "Background signal" in the context of binding assays means the signal recorded under standard conditions for a particular assay in the absence of a test compound, molecular scaffold, or ligand that binds to the target molecule. Those skilled in the art will appreciate that accepted methods exist and are widely available for determining background signal.

[0352] "Standard deviation" means the square root of the variance. Variance is a measure of how spread out a distribution is. It is calculated as the average squared deviation of each number from the mean. For example, for the numbers 1, 2, and 3, the mean is 2 and the variance is:

number

[0353] Surface plasmon resonance Binding parameters can be measured using surface plasmon resonance, for example, using a BIAcore® chip (BIAcore, Japan) coated with immobilized binding moieties. Surface plasmon resonance is used to characterize the microscopic association and dissociation constants of the reaction between sFv or other ligands to target molecules. Such methods are generally described in the following references, which are incorporated herein by reference: Vely F. et al., (2000) BIAcore® analysis to test phosphopeptide-SH2 domain interactions, Methods in Molecular Biology.121:313-21, Lipschultz et al., (1999) Biosensor analysis of the interleukin-2 receptor complex, Journal of Molecular Recognition.12:316-21, Lipschultz et al. al.,(2000)Experimental design for analysis of complex kinetics using surface plasmon resonance,Methods.20(3):310-8,Malmqvist.,(1999)BIACORE: an affinity biosensor system for characterization of biomolecular interactions,Biochemical Society Transactions 27:335-40,Alfthan,(1998)Surface plasmon resonance biosensors as a tool in antibody engineering,Biosensors&Bioelectronics.13:653-63, Fivash et al.,(1998)BIAcore for macromolecular interaction, Current Opinion in Biotechnology.9:97-101, Price et al.;(1998)Summary report on the ISOBM TD-4 Workshop:analysis of 56 monoclonal antibodies against the MUC1 mucin.Tumour Biology 19 Suppl 1:1-20、Malmqvist et al,(1997)Biomolecular interaction analysis:affinity biosensor technologies for functional analysis of proteins,Current Opinion in Chemical Biology.1:378-83、O’Shannessy et al.,(1996)Interpretation of deviations from pseudo-first-order kinetic behavior in the characterization of ligand binding by biosensor technology,Analytical Biochemistry.236:275-83、Malmborg et al.,(1995)BIAcore as a tool in antibody engineering,Journal of Immunological Methods.183:7-13、Van Regenmortel,(1994)Use of biosensors to characterize recombinant proteins,Developments in Biological Standardization.83:143-51、およびO’Shannessy,(1994)Determination of kinetic rate and equilibrium binding constants for macromolecular interactions:a critique of the surface plasmon resonance literature,Current Opinions in Biotechnology.5:65-71。.

[0354] BIAcore® uses the optical properties of surface plasmon resonance (SPR) to detect changes in the concentration of proteins bound to a dextran matrix (dextran biosensor matrix) on the surface of a gold / glass sensor chip interface. Briefly, proteins are covalently bound to the dextran matrix at known concentrations, and ligands for the proteins are injected through the dextran matrix. Near-infrared light directed to the opposite side of the sensor chip surface is reflected and induces an evanescent wave in the gold film, which in turn causes an intensity drop in the reflected light at a specific angle, known as the resonance angle. When the refractive index of the sensor chip surface changes (e.g., by binding of a ligand to the binding protein), a shift in the resonance angle occurs. This angle shift can be measured, and 1000 RU corresponds to 1 ng / mm 2 These changes are expressed as resonance units (RU) to correspond to changes in surface protein concentration. These changes are displayed with respect to time along the y-axis of the sensorgram, and represent the association and dissociation of any biological response.

[0355] High Throughput Screening (HTS) Assays HTS typically uses automated assays to search large numbers of compounds for a desired activity. Typically, HTS assays are used to find new drugs by screening chemicals that act on a specific enzyme or molecule. For example, if a chemical inactivates an enzyme, it may prove effective in preventing a process within a cell that causes disease. High-throughput methods allow researchers to very rapidly analyze thousands of different chemicals against each target molecule, using robotic handling systems and automated analysis of the results.

[0356] As used herein, "high throughput screening" or "HTS" refers to the rapid in vitro screening of large numbers of compounds (libraries) (typically tens to hundreds of thousands of compounds) using robotic screening assays. Ultra high throughput screening (uHTS) generally refers to high throughput screening accelerated to 100,000 tests per day.

[0357] To achieve high throughput screening, it is advantageous to accommodate samples on a multi-container carrier or platform. Multi-container carriers facilitate the simultaneous measurement of the response of multiple candidate compounds. Multi-well microplates can be used as carriers. Such multi-well microplates and methods for their use in multiple assays are known in the art and commercially available.

[0358] Screening assays may include controls for the purpose of calibration and confirmation of proper operation of the components of the assay. Empty wells containing all reactants but no members of the chemical library are usually included. As another example, a known inhibitor (or activator) of the enzyme for which a modulator is sought can be incubated with one sample of the assay, and the resulting decrease (or increase) in enzyme activity is used as a comparator or control. It will also be understood that modulators can be combined with enzyme activators or inhibitors to find modulators that inhibit enzyme activation or inhibition otherwise caused by the presence of a known enzyme modulator.

[0359] Measurement of enzymatic and binding reactions during screening assays Techniques for measuring the progress of enzymatic and binding reactions, for example in multicontainer carriers, are known in the art and include, but are not limited to, the following.

[0360] Spectrophotometric and spectrofluorometric assays are well known in the art. Examples of such assays include the use of colorimetric assays for the detection of peroxide, as described in Gordon, AJ and Ford, RA, (1972) The Chemist's Companion: A Handbook Of Practical Data, Techniques, And References, John Wiley and Sons, NY, Page 437.

[0361] Fluorescence spectroscopy can be used to monitor the formation of reaction products. Fluorescence methods are generally more sensitive than absorption methods. The use of fluorescent probes is well known to those skilled in the art. For reviews, see Bashford et al., (1987) Spectrophotometry and Spectrofluorometry: A Practical Approach, pp. 91-114, IRL Press Ltd., and Bell, (1981) Spectroscopy In Biochemistry, Vol. I, pp. 155-194, CRC Press.

[0362] In spectrofluorometry, enzymes are exposed to substrates that change their intrinsic fluorescence when processed by the target enzyme. Typically, the substrates are non-fluorescent and are converted to fluorophores through one or more reactions. As a non-limiting example, SMase activity can be detected using Amplex® Red reagent (Molecular Probes, Eugene, OR). To measure sphingomyelinase activity using Amplex® Red, the following reactions occur: First, SMase hydrolyzes sphingomyelin to produce ceramide and phosphorylcholine. Second, alkaline phosphatase hydrolyzes phosphorylcholine to produce choline. Third, choline is oxidized to betaine by choline oxidase. Finally, H in the presence of horseradish peroxidase is converted to fluorophore oxidized to ceramide and phosphorylcholine. 2 O 2reacts with Amplex® Red to produce a fluorescent product, resorufin, from which signal is detected using spectroscopy.

[0363] Fluorescence polarization (FP) is based on the reduction in the molecular rotation rate of a fluorophore that occurs upon binding to a larger molecule, such as a receptor protein, allowing polarized fluorescence emission by the bound ligand. FP is determined empirically by measuring the vertical and horizontal components of the fluorophore emission after excitation with plane polarized light. Polarized emission increases when the molecular rotation of the fluorophore decreases. A fluorophore produces a larger polarized signal when it binds to a larger molecule (i.e., a receptor), slowing the molecular rotation of the fluorophore. The magnitude of the polarized signal is quantitatively related to the degree of fluorescent ligand binding. Thus, polarization of the "bound" signal is dependent on the maintenance of high affinity binding.

[0364] FP is a homogeneous technique and the reaction is very fast, taking seconds to minutes to reach equilibrium. The reagents are stable and large batches can be prepared, resulting in high reproducibility. Because of these properties, FP has proven highly automatable and is often performed in a single incubation with a single premixed tracer-receptor reagent. For a review, see Owicki et al., (1997), Application of Fluorescence Polarization Assays in High-Throughput Screening, Genetic Engineering News, 17:27.

[0365] FPs are particularly desirable because the readout is independent of emission intensity (Checovich, WJ, et al., (1995) Nature 375:254-256; Dandliker, WB, et al., (1981) Methods in Enzymology 74:3-28), and therefore insensitive to the presence of colored compounds that quench the fluorescence emission. FPs and FRET (see below) are well suited to identifying compounds that block the interaction between sphingolipid receptors and their ligands. See, for example, Parker et al., (2000) Development of high throughput screening assays using fluorescence polarization: nuclear receptor-ligand-binding and kinase / phosphatase assays, J Biomol Screen 5:77-88.

[0366] Sphingolipid-derived fluorophores that can be used in FP assays are commercially available, for example, Molecular Probes (Eugene, OR) currently sells sphingomyelin and one ceramide fluorophore. These are N-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-pentanoyl)sphingosylphosphocholine (BODIPY® FL C5-sphingomyelin), N-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-dodecanoyl)sphingosylphosphocholine (BODIPY® FL C12-sphingomyelin), and N-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a-diaza-s-indacene-3-pentanoyl)sphingosine (BODIPY® FL C5-ceramide), respectively. No. 4,150,949 (Immunoassay for Gentamicin) discloses fluorescein-labeled gentamicin, including fluoresceinthiocarbanyl gentamicin. Additional fluorophores can be prepared using methods well known to those skilled in the art.

[0367] Exemplary vertical polarization fluorescence readers include the POLARION® Fluorescence Polarization System (Tecan AG, Hombrechtikon, Switzerland). General multi-well plate readers for other assays are available, such as the VERSAMAX® reader and the SPECTRAMAX® multi-well plate spectrophotometer (both from Molecular Devices).

[0368] Fluorescence resonance energy transfer (FRET) is another useful assay for detecting interactions and has been described. See, for example, Heim et al., (1996) Curr. Biol. 6:178-182, Mitra et al., (1996) Gene 173:13-17, and Selvin et al., (1995) Meth. Enzymol. 246:300-345. FRET detects the energy transfer between two fluorophores in close proximity with known excitation and emission wavelengths. As an example, a protein can be expressed as a fusion protein with green fluorescent protein (GFP). When two fluorescent proteins are in close proximity, such as when a protein specifically interacts with a target molecule, resonance energy can be transferred from one excited molecule to the other excited molecule. As a result, the emission spectrum of the sample shifts, which can be measured by a fluorometer such as an fMAX multiwell fluorometer (Molecular Devices, Sunnyvale Calif.).

[0369] Scintillation proximity assay (SPA) is a particularly useful assay for detecting interaction with target molecules.SPA has been widely used and described in the pharmaceutical industry (Hanselman et al., (1997) J. Lipid Res. 38: 2365-2373; Kahl et al., (1996) Anal. Biochem. 243: 282-283; Undenfriend et al., (1987) Anal. Biochem. 161: 494-500).See also U.S. Patent Nos. 4,626,513 and 4,568,649, and European Patent No. 0,154,734.One commercially available system uses FLASHPLATE® scintillant-coated plates (NEN Life Science Products, Boston, MA).

[0370] The target molecule can be bound to the scintillator plate by various well-known means. Scintillant plates are available that are derivatized to bind fusion proteins, such as GST, His6, or Flag fusion proteins. If the target molecule is a protein complex or multimer, one protein or subunit can be attached to the plate first, and then the other components of the complex can be added later under binding conditions to obtain a bound complex.

[0371] In a typical SPA assay, gene products in the expression pool are radioactively labeled, added to the wells, and allowed to interact with the solid phase (immobilized target molecules in the wells and the scintillant coating). The assay can be measured immediately or allowed to reach equilibrium. Either way, if the radioactive label gets close enough to the scintillant coating, it will generate a signal that is detectable by an instrument such as a TOPCOUNT NXT® Microplate Scintillation Counter (Packard BioScience Co., Meriden Conn.). If the radioactively labeled expression product binds to the target molecule, the radioactive label will remain in close proximity to the scintillant long enough to produce a detectable signal.

[0372] In contrast, labeled proteins that do not bind to the target molecule or bind only briefly will not remain near the scintillant long enough to generate a signal above background. Any time spent near the scintillant caused by random Brownian motion will not result in a significant amount of signal. Similarly, there may be residual unincorporated radiolabel used during the expression step, but it will not generate a significant signal because it is in solution rather than interacting with the target molecule. Thus, these non-binding interactions will cause a certain level of background signal that can be mathematically removed. If too much signal is obtained, salts or other modifiers can be added directly to the assay plate until the desired specificity is obtained (Nichols et al., (1998) Anal. Biochem. 257:112-119).

[0373] General Synthesis Compounds can be prepared using the methods disclosed herein and their routine modifications that are obvious in light of the disclosure herein, as well as methods well known in the art.In addition to the teachings herein, conventional well-known synthetic methods can be used.The synthesis of typical compounds described herein can be achieved as described in the following examples.When available, reagents can be purchased commercially, for example, from Sigma Aldrich or other chemical suppliers.

[0374] The compounds of the present disclosure can be prepared, for example, from readily available starting materials using the following general methods and procedures. Where typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given, it will be understood that other process conditions can also be used unless otherwise stated. Optimum reaction conditions may vary with the particular reactants or solvents used, but such conditions can be determined by one skilled in the art by routine optimization procedures.

[0375] In addition, as will be apparent to those skilled in the art, conventional protective groups may be required to prevent certain functional groups from undergoing undesired reactions.Protective groups suitable for various functional groups, as well as suitable conditions for protecting and deprotecting certain functional groups, are well known in the art.For example, many protective groups are described in Wuts, PGM, Greene, TW, & Greene, TW (2006).Greene's protective groups in organic synthesis.Hoboken, NJ, Wiley-Interscience, and references cited therein.

[0376] The compounds of the present disclosure may contain one or more asymmetric or chiral centers. Thus, if desired, such compounds can be prepared or isolated as pure stereoisomers, i.e., as individual enantiomers or diastereomers, or as stereoisomer-enriched mixtures. Unless otherwise specified, all such stereoisomers (and enriched mixtures) are within the scope of the present disclosure. Pure stereoisomers (or enriched mixtures) can be prepared, for example, using optically active starting materials or stereoselective reagents well known in the art. Alternatively, racemic mixtures of such compounds can be separated, for example, using chiral column chromatography, supercritical fluid chromatography, chiral seed crystals, chiral resolving agents, and the like.

[0377] The starting materials for the following reactions are generally known compounds or can be prepared by known procedures or obvious modifications thereof. For example, many of the starting materials are available from commercial suppliers such as Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA). Others can be prepared by procedures described in standard reference texts such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-15 (John Wiley, and Sons, 1991), Rodd's Chemistry of Carbon Compounds, Volumes 1-5, and Supplementals (Elsevier Science Publishers, 1989) organic Reactions, Volumes 1-40 (John Wiley, and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley, and Sons, 5th Edition, 2001), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989), or obvious modifications thereof.

[0378] It will also be understood that in each scheme, the addition of any substituent may result in the production of several isomeric products (including, but not limited to, enantiomers or one or more diastereomers), any or all of which may be separated and purified using conventional techniques. Where enantiomerically pure or enriched compounds are desired, chiral chromatography and / or enantiomerically pure or enriched starting materials may be employed as conventionally used in the art or as described in the examples.

[0379] The compounds of the present disclosure can be synthesized according to the general reaction schemes and / or examples described below. The general schemes can be modified by replacing the starting materials with other materials having similar structures to produce the corresponding products. The structure of the desired product will generally reveal the necessary starting materials to those skilled in the art.

[0380] Schemes 1 and 2 show exemplary synthetic routes for the synthesis of compounds provided herein (e.g., compounds of formula I). ​​Compounds of formula I, or other formulas or compounds disclosed herein, are typically prepared by first providing a core formula X(a) or X(d) and then attaching the desired substituents using suitable conditions (e.g., coupling).

[0381] In some embodiments, the synthesis of compounds of formula I proceeds according to Scheme 1. [ka]

[0382] In Scheme 1, A 1 , A 2 , L, R 1 , R 4 , R 5 , X 1 , X 2 , and X 3 is as defined in formula I. In scheme 1, a compound of formula X(a) is converted to a compound of formula X(b) or formula X(c). Compounds of formula X(b) or formula X(c), respectively, can then be converted to a compound of formula I.

[0383] In Scheme 1, Z 1 , Z 2 , Z 3 , and Z 4Each of is independently a suitable leaving group, such as a halide or hydroxide (e.g., in the presence of triphenylphosphine and a dialkylazodicarboxylate), a suitable coupling partner, such as a halide, boronic acid, boronate, or hydrogen (e.g., of a terminal alkyne), or a suitable electrophile, such as an aldehyde or ketone.

[0384] In Scheme 1, R 51 is R 5a , hydrogen or a suitable leaving group, such as a halide or hydroxide (e.g., in the presence of triphenylphosphine and a dialkylazodicarboxylate), or a suitable coupling partner, such as a halide, boronic acid, boronate. 5a is R 5 or a suitable precursor, e.g., R 5 If contains a carboxylic acid, R 5a R may include esters. 5 When R contains a carboxylic acid, the conversion of formula X(b) to formula I, or formula X(a) to formula X(c), may include a step of hydrolyzing the ester. 18 -LR 1 , hydrogen, or a suitable leaving group such as a halide or hydroxide (e.g., in the presence of triphenylphosphine and a dialkylazodicarboxylate), a suitable coupling partner such as a halide, a boronic acid, a boronate, or a suitable electrophile such as an aldehyde or ketone. 41 is R 4 A 11 , A 12 , and A 13 Each of the following is A 1 A 21 , A 22 , and A 23 A 2 Or A 2 is any suitable moiety for attaching, for example, a suitable coupling partner such as a halide, a boronic acid, a boronate, or hydrogen.

[0385] One of skill in the art will appreciate that any of the compounds of formula X(a), X(b), or X(c) may be available from a commercial supplier for certain embodiments. Alternative syntheses of compounds of formula X(a), X(b), or X(c) may be as described herein or known to one of skill in the art.

[0386] In some embodiments, the synthesis of compounds of Formula I proceeds according to Scheme 2. [ka]

[0387] In Scheme 2, A 1 , A 2 , L, R 1 , R 4 , R 5 , X 1 , X 2 , and X 3 is as defined in formula I. In scheme 1, a compound of formula X(d) is converted to a compound of formula X(e) or formula X(f). Compounds of formula X(e) or formula X(f), respectively, can then be converted to a compound of formula I.

[0388] In Scheme 2, Z 5 , Z 6 , Z 7 , and Z 8 Each of is independently a suitable leaving group, such as a halide or hydroxide (e.g., in the presence of triphenylphosphine and a dialkylazodicarboxylate), a suitable coupling partner, such as a halide, boronic acid, boronate, or hydrogen (e.g., of a terminal alkyne), or a suitable electrophile, such as an aldehyde or ketone.

[0389] In Scheme 2, R 52 is R 5b, hydrogen, or a suitable leaving group such as a halide or hydroxide (e.g., in the presence of triphenylphosphine and a dialkylazodicarboxylate), or a suitable coupling partner such as a halide, boronic acid, boronate. 5b is R 5 or a suitable precursor, e.g., R 5 If contains a carboxylic acid, R 5b R may include esters. 5 When R contains a carboxylic acid, the conversion of formula X(e) to formula I, or formula X(d) to formula X(f), may include a step of hydrolyzing the ester. 19 -LR 1 , hydrogen, or a suitable leaving group such as a halide or hydroxide (e.g. in the presence of triphenylphosphine and a dialkyl azodicarboxylate), a suitable coupling partner such as a halide, a boronic acid, a boronate, or a suitable electrophile such as an aldehyde, a ketone, or a nitrile, or an α-, β-unsaturated derivative thereof, or an N-protecting group such as p-toluenesulfonyl or tert-butoxycarbonyl. 42 is R 4 , or R 4 A is any suitable moiety for attaching A, e.g., hydrogen. 14 , A 15 , and A 16 A 1 Or A 1 is any suitable moiety for attaching A, such as a halide, a boronic acid, a boronate, or a suitable coupling partner such as hydrogen. 24 , A 25 , and A 26 Each of the following is A 2 It is.

[0390] One of skill in the art will appreciate that any of the compounds of formula X(d), X(e), or X(f) may be available from a commercial supplier for certain embodiments. Alternative syntheses of compounds of formula X(d), X(e), or X(f) may be as described herein or known to one of skill in the art.

[0391] Palladium Coupling Conditions Where applicable, formula X(a), X(b), X(c), X(d), X(e), or X(f) is coupled to compound 501, 502, 503, 504, 505, 506, 507, or 508, where a (hetero)aryl carbon-(hetero)aryl carbon bond is formed, Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , or Z 8 is a suitable coupling partner, such as a halide (e.g., bromide or iodide) or boronic acid, or an ester thereof, under standard metal-catalyzed cross-coupling conditions (e.g., using a palladium catalyst) in a suitable solvent (e.g., dioxane, acetonitrile, water, etc.), optionally under an inert atmosphere. The cross-coupling reaction is carried out in an inert solvent, such as aqueous 1,4-dioxane or aqueous N,N-dimethylformamide, in the presence of a mild base, such as potassium acetate, potassium carbonate, sodium carbonate, or sodium bicarbonate. The reaction is typically carried out in the presence of a metal catalyst with a suitable ligand, such as dichlorobis(triphenylphosphine)palladium(II) or dichloro1,1'-bis(diphenylphosphino)ferrocenepalladium(II), at a temperature of about 60-150°C for about 10 minutes to about 12 hours. When the reaction is substantially complete, the product is isolated by conventional means.

[0392] Copper ("Buchwald") coupling conditions Where applicable, for example where a (hetero)aryl carbon-nitrogen bond is formed, formula X(a), X(b), X(c), X(d), X(e), or X(f) is coupled to compound 501, 502, 503, 504, 505, 506, 507, or 508 to form Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , or Z 8 is a suitable coupling partner, such as a halide (e.g., bromide or iodide), under copper catalyzed coupling conditions (e.g., using a copper catalyst) in a suitable solvent (e.g., toluene, DMF, etc.), optionally under an inert atmosphere. The coupling reaction is carried out in an inert solvent, such as toluene or N,N-dimethylformamide, in the presence of a mild base, such as potassium carbonate or potassium phosphate tribasic. The reaction is typically carried out in the presence of a metal catalyst, such as copper(I) iodide, copper(I) bromide, or copper(II) acetate monohydrate, with a suitable ligand, such as trans-N,N'-dimethylcyclohexane-1,2-diamine, at a temperature of about 60-150°C for about 10 minutes to about 7 days. When the reaction is substantially complete, the product is isolated by conventional means.

[0393] Aryl Nucleophilic Substitution Conditions Where applicable, for example where a (hetero)aryl carbon-nitrogen bond is formed, formula X(a), X(b), X(c), X(d), X(e), or X(f) is coupled to compound 501, 502, 503, 504, 505, 506, 507, or 508 to form Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , or Z 8 is a nucleophilic aromatic group ("SN Ar") conditions, optionally under an inert atmosphere, with a suitable leaving group, such as fluoride. The reaction is carried out in an inert solvent, such as DMSO, in the presence of a mild base, such as potassium carbonate or cesium carbonate. The reaction is typically carried out at a temperature of about 60-150°C for about 1 hour to about 7 days. When the reaction is substantially complete, the product is isolated by conventional means.

[0394] Alkyne coupling conditions Where applicable, for example where an alkynyl carbon-nitrogen bond is formed, formula X(a), X(b), X(c), X(d), X(e), or X(f) is coupled to compound 501, 502, 503, 504, 505, 506, 507, or 508 to form Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 , or Z 8 is hydrogen or trialkylsilane under copper catalyzed coupling conditions (e.g., using palladium and / or copper catalysts) in a suitable solvent (e.g., toluene, DMF, etc.), optionally under an inert atmosphere. The coupling reaction is carried out in an inert solvent, e.g., toluene or N,N-dimethylformamide, in the presence of a mild base, e.g., triethylamine. The reaction is typically carried out in the presence of a metal catalyst, e.g., bis(triphenylphosphine)palladium(II) dichloride, copper(I) iodide, or copper(I) bromide, optionally with a suitable ligand, e.g., trans-N,N'-dimethylcyclohexane-1,2-diamine, at a temperature of about 60-150°C for about 10 minutes to about 1 day. When the reaction is substantially complete, the product is isolated by conventional means.

[0395] Ester hydrolysis conditions Where applicable, for example, the carboxylic acid ester may be R 1a or R 5a are cut at R 1 or R 5When a carboxylic acid is formed in the carboxylic acid of formula X(a), X(b), X(c), X(d), X(e), or X(f), the compound of formula X(a), X(b), X(c), X(d), X(e), or X(f) is subjected to ester hydrolysis conditions. Ester hydrolysis conditions can include, for example, the use of a base such as an alkali metal alkoxide (e.g., sodium methoxide or sodium ethoxide) or an alkali metal hydroxide (e.g., sodium hydroxide or lithium hydroxide) in a suitable solvent (e.g., water, dioxane, alcohol, and / or THF) at a temperature of about 0 to 100° C. for about 10 minutes to about 24 hours. When the reaction is substantially complete, the product is isolated by conventional means. EXAMPLES

[0396] The following examples show general synthetic procedures for the compounds described herein. The synthesis of the compounds described herein is not limited by these examples and schemes. Those skilled in the art will understand that other procedures can be used to synthesize the compounds described herein, and the procedures described in the examples and schemes are only one such procedure. In the following description, those skilled in the art will recognize that certain reaction conditions, added reagents, solvents, and reaction temperatures can be modified for the synthesis of specific compounds that fall within the scope of this disclosure. Unless otherwise specified, intermediate compounds in the following examples that do not include descriptions of their preparation methods are either commercially available to those skilled in the art or can be synthesized by those skilled in the art using commercially available precursor molecules and synthetic methods known in the art.

[0397] The following schemes and synthetic examples are intended to be illustrative, and not limiting or restrictive of the scope of the disclosure.

[0398] Example 1 [ka] Step 1: Preparation of methyl 4-(5-(3,5-dimethylisoxazol-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)picolinate 2: To a microwave pressure vial charged with 4-[1-(benzenesulfonyl)-3-iodo-pyrrolo[2,3-b]pyridin-5-yl]-3,5-dimethyl-isoxazole (1, 150 mg, 0.313 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-carboxylate (167 mg, 0.635 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (26.6 mg, 0.033 mmol), 1,4-dioxane (3 ml) was added. The flask was flushed with argon and then 2.5 M aqueous potassium carbonate (0.376 ml) was added. The vial was sealed and stirred in a 120° C. oil bath for 2 h. The reaction was allowed to cool to room temperature and the biphasic mixture was filtered through Celite, washing with THF and ethyl acetate. The filtrate was concentrated under reduced pressure and the material was purified by silica gel flash column chromatography eluting with a gradient of 0-100% ethyl acetate in hexanes. This gave 4-(5-(3,5-dimethylisoxazol-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl picolinate (2). MS(ESI)[M+H + ] + =489.0.

[0399] Step 2: Preparation of 4-(5-(3,5-dimethylisoxazol-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)picolinic acid P-0055: A solution of methyl 4-(5-(3,5-dimethylisoxazol-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)picolinate (2, 78.5 mg, 0.16 mmol) dissolved in dioxane (6 ml) was cooled in an ice bath. 3 ml of 1 M LiOH(aq) was then added. After 30 min, the reaction was quenched with 1 M HCl(aq) to pH 1 and then extracted with ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. Volatiles were removed by rotary evaporation and the resulting residue was purified by reverse-phase HPLC (C18; 0–100% B; A: 5% CH 3 CN, 95%H 2 O, 0.1% HCO 2 H;B:95%CH 3 CN, 5%H 2 O, 0.1% HCO 2 H) to give 4-(5-(3,5-dimethylisoxazol-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)picolinic acid (P-0055). MS (ESI) [M+H + ] + =474.9.

[0400] Example 2 [ka] Step 1: Preparation of 4-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,5-dimethylisoxazole 4: To a round bottom flask charged with 4-(3-iodo-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,5-dimethyl-isoxazole (3, 10 g, 29.5 mmol) and anhydrous THF (150 ml) was added sodium hydride (60%, 1.65 g, 41.3 mmol). The reaction was stirred at room temperature for 1 h followed by the addition of 4-methylbenzenesulfonyl chloride (6.80 g, 35.7 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with brine (160 ml) and diluted with ethyl acetate (160 ml). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was dry loaded onto silica gel and purified by silica gel flash column chromatography eluting with 0-20% ethyl acetate in hexane to give 4-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,5-dimethylisoxazole (4). MS(ESI)[M+H + ] + =493.9.

[0401] Step 2: Preparation of methyl 4-(5-(3,5-dimethylisoxazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-dimethylbut-3-ynoate 5: A mixture of 4-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,5-dimethylisoxazole (4, 104 mg, 0.21 mmol), bis(triphenylphosphine)palladium(II) dichloride (4.42 mg, 6.3 umol), and copper(I) iodide (1.2 mg, 6.3 umol) in (1:3) triethylamine in acetonitrile (2.0 ml) was purged with nitrogen gas and then methyl 2,2-dimethylbut-3-ynoate (53 mg, 0.42 mmol) was added. The mixture was heated at 90° C. for 2 h. The mixture was concentrated under reduced pressure and purified by flash chromatography eluting with 20% ethyl acetate in hexane to give methyl 4-(5-(3,5-dimethylisoxazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-dimethylbut-3-ynoate (5). MS (ESI) [M+H + ] + =492.2.

[0402] Step 3: Preparation of methyl 4-(5-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-dimethylbut-3-ynoate 6: To a mixture of methyl 4-(5-(3,5-dimethylisoxazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-dimethylbut-3-ynoate (5, 88 mg, 0.18 mmol) in THF (2 ml) was added 1M TBAF in THF (0.400 ml). The mixture was stirred at 70° C. for 15 h. The reaction was diluted with ethyl acetate, which was washed with saturated sodium bicarbonate (aq), water, then brine. The layers were separated and the organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and triturated with 5% ethyl acetate in hexanes to give methyl 4-(5-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-dimethylbut-3-ynoate (6). MS (ESI) [M+H +] + =338.6.

[0403] Step 4: Preparation of methyl 4-(1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-dimethylbut-3-ynoate 7: To a mixture of methyl 4-(5-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-dimethylbut-3-ynoate (6, 28.6 mg) in DMF (1 ml) was added 60% NaH in mineral oil (60%, 4.07 mg, 0.1 mmol). The mixture was stirred for 2 min, then bromomethylbenzene (21.75 mg, 0.13 mmol) was added. The resulting mixture was stirred at 60° C. for 2 h. The mixture was diluted with water, extracted with ethyl acetate, and the organic layer was washed with water followed by brine. The layers were separated and the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The material was purified by flash chromatography eluting with 50% ethyl acetate in hexane to give methyl 4-(1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-dimethylbut-3-ynoate (7). MS (ESI) [M+H + ] + =428.6.

[0404] Step 5: Preparation of 4-(1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-dimethylbut-3-ynoic acid P-0051: To a mixture of methyl 4-(1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-dimethylbut-3-ynoic acid (7, 22.6 mg, 0.05 mmol) in (1:1) THF / MeOH (0.5 ml) was added 4.18 M LiOH (0.030 ml). The mixture was stirred at 70 °C for 3 h. The reaction was acidified with 3N HCl in MeOH and concentrated under reduced pressure. The material was purified by reverse phase HPLC (C18; 0-100% B; A: 5% CH 3 CN, 95%H 2 O, 0.1% HCO2 H;B:95%CH 3 CN, 5%H 2 O), 0.1% HCO 2 H) to give 4-(1-benzyl-5-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-2,2-dimethylbut-3-ynoic acid (P-0051). MS (ESI) [M+H + ] + =414.5.

[0405] Example 3 [ka] Step 1: Preparation of (S)-4-(3-iodo-1-(1-(pyridin-2-yl)ethyl)-1H-pyrrolo[3,2-b]pyridin-6-yl)-3,5-dimethylisoxazole 9: To 4-(3-iodo-1H-pyrrolo[3,2-b]pyridin-6-yl)-3,5-dimethylisoxazole (8, 0.92 g, 2.71 mmol) in THF (20 ml) was added (1R)-1-(2-pyridyl)ethanol (0.38 g, 3.09 mmol) followed by triphenylphosphine (0.957 g, 3.65 mmol). The reaction was cooled to 0° C. in an ice-water bath followed by the dropwise addition of diisopropyl azodicarboxylate (0.738 g, 3.65 mmol). After 1 h the reaction was removed from the ice bath and allowed to warm to room temperature for 1 h. The reaction was concentrated under reduced pressure and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexanes to give (S)-4-(3-iodo-1-(1-(pyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-6-yl)-3,5-dimethylisoxazole (9).

[0406] Step 2: Preparation of (S)-4-(3-iodo-1-(1-(pyridin-2-yl)ethyl)-2-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-6-yl)-3,5-dimethylisoxazole 10: To (S)-4-(3-iodo-1-(1-(pyridin-2-yl)ethyl)-1H-pyrrolo[3,2-b]pyridin-6-yl)-3,5-dimethylisoxazole (9, 0.91 g, 2.05 mmol) and zinc trifluoromethanesulfinate (1.36 g, 4.10 mmol) was added DMSO (10 ml) followed by water (4 ml). The reaction was cooled in an ice bath and tert-butyl hydroperoxide (0.86 ml, 6.8 mmol) was added dropwise. The reaction was removed from the ice bath and allowed to warm to ambient temperature, then placed in a 50° C. oil bath and stirred overnight. After 22 hours, LCMS showed approximately 10% product formation. An additional 1.27 g of zinc trifluoromethanesulfinate was added, followed by 1 ml of tert-butyl hydroperoxide. The reaction was continued at 50° C. for an additional 17 hours. The reaction was extracted with saturated sodium bicarbonate and ethyl acetate. The organic layer was separated and the aqueous layer was extracted three more times with 5 mL portions of ethyl acetate. The organic layers were combined and the volatiles removed by rotary evaporation to give the crude product which was purified by silica gel column chromatography (10-60% ethyl acetate in hexanes). This gave (S)-4-(3-iodo-1-(1-(pyridin-2-yl)ethyl)-2-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-6-yl)-3,5-dimethylisoxazole (10). MS(ESI)[M+H + ] + =512.1.

[0407] Step 3: Preparation of (S)-3,5-dimethyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-(1-(pyridin-2-yl)ethyl)-2-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-6-yl)isoxazole P-160: (S)-4-(3-iodo-1-(1-(pyridin-2-yl)ethyl)-2-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-6-yl)isoxazole in dioxane (2 ml) 2.5MK2 was added to a reaction vial charged with 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (10, 61.47 mg, 0.12 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole (49.94 mg, 0.24 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (9.8 mg, 0.012 mmol) and purged with nitrogen gas. 2 CO 3 Aqueous solution (0.144 ml) was added. The mixture was heated at 110° C. for 15 hours. The sample was diluted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, concentrated, and purified by flash chromatography eluting with 100% ethyl acetate followed by reverse chromatography to give (S)-3,5-dimethyl-4-(3-(1-methyl-1H-pyrazol-4-yl)-1-(1-(pyridin-2-yl)ethyl)-2-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-6-yl)isoxazole (P-0160). MS(ESI)[M+H + ] + =467.6

[0408] Example 4 [ka] Step 1: Preparation of (3-(benzyloxy)phenyl)(6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methanol 12: To (3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-6-yl)isoxazole (11, 0.24 g, 1.11 mmol) in methanol (5 ml) was added potassium hydroxide (0.177 g, 3.15 mmol) and 3-benzyloxybenzaldehyde (0.26 g, 1.23 mmol). The mixture was stirred at room temperature for 4 hours. The reaction mixture was extracted with ethyl acetate and water containing 1N citric acid. The organic layer was washed with water and brine, then dried over magnesium sulfate and filtered. The volatiles were removed under reduced pressure and the material was purified by silica gel column chromatography (0-60% ethyl acetate in hexanes). This gave (3-(benzyloxy)phenyl)(6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methanol (12). MS (ESI) [M+H + ] + =426.5.

[0409] Step 2: Preparation of (3-(benzyloxy)phenyl)(6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methanone 13: To the obtained (3-(benzyloxy)phenyl)(6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methanol (12, 34 mg, 0.080 mmol) in tetrahydrofuran (10 ml) was added Dess-Martin periodinane (0.07 g, 0.16 mmol). The mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over magnesium sulfate and filtered. The volatiles were removed under reduced pressure and the material was purified by silica gel column chromatography (0-100% ethyl acetate in dichloromethane) to give (3-(benzyloxy)phenyl)(6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methanone (13). MS(ESI)[M+H + ] + =424.1.

[0410] Step 3: Preparation of 4-(3-(3-(benzyloxy)benzoyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-3,5-dichlorobenzoic acid P-0133: To a mixture of (3-(benzyloxy)phenyl)(6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methanone (13, 29 mg, 0.068 mmol), 3,5-dichloro-4-fluoro-benzoic acid (40 mg, 0.19 mmol), and cesium carbonate (120 mg, 0.37 mmol), DMSO (3 ml) was added. The reaction mixture was stirred at 90° C. for 3 days. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over magnesium sulfate and filtered. The volatiles were removed under reduced pressure and the crude material was purified by reverse-phase HPLC (C18; 0–100% B; A: 5% CH 3 CN, 95%H 2 O, 0.1% HCO 2 H;B:95%CH3 CN, 5%H 2 O, 0.1% HCO 2 H) to give 4-(3-(3-(benzyloxy)benzoyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-3,5-dichlorobenzoic acid (P-0133). MS (ESI) [M+H + ] + =612.0.

[0411] Example 5 [ka] Step 1: Preparation of ethyl 4-(6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-3,5-diethoxybenzoate 14: 3,5-Dimethyl-4-(1H-pyrrolo[3,2-b]pyridin-6-yl)isoxazole (11, 0.60 g, 2.81 mmol), ethyl 4-bromo-3,5-diethoxybenzoate (1.34 g, 4.21 mmol), potassium phosphate tribasic (1.25 g, 5.91 mmol), copper(I) iodide (0.11 g, 0.56 mmol), trans N,N'-dimethylcyclohexane-1,2-diamine (0.80 g, 5.6 mmol) were combined in toluene (6 ml) and flushed with argon. The reaction mixture was stirred at 110 °C overnight. The reaction mixture was cooled to ambient temperature, diluted with 2 mL of ethyl acetate, and filtered through a pad of Celite containing ethyl acetate. This material was purified by silica gel column chromatography (0-50% ethyl acetate in hexanes) to give ethyl 4-(6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-3,5-diethoxybenzoate (14).

[0412] Step 2: Preparation of ethyl 4-(3-bromo-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-3,5-diethoxybenzoate 15: In a 100 ml round bottom flask was added ethyl 4-(6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-3,5-diethoxybenzoate (14, 620 mg, 1.38 mmol) and acetonitrile (14 ml). The reaction flask was filled with N 2 The mixture was placed under reduced pressure and cooled to 0° C., followed by the slow addition of N-bromosuccinimide (246 mg, 1.38 mmol). The reaction mixture was stirred at 0° C. and allowed to warm to room temperature for 2 h. The reaction was diluted with ethyl acetate and partitioned between water and ethyl acetate. The extracted organic fraction was washed with brine, dried over magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (0-60% ethyl acetate in hexanes) to give ethyl 4-(3-bromo-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-3,5-diethoxybenzoate (15).

[0413] Step 3: Preparation of 4-(3-(4-(cyclopropylcarbamoyl)phenyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-3,5-diethoxybenzoic acid P-0218: Preparation of ethyl 4-(3-bromo-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-3,5-diethoxybenzoate (15, 40 mg, 0.08 mmol), (4-(cyclopropylcarbamoyl)phenyl)boronic acid (31 mg, 0.15 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (8.7 mg, 0.011 mmol), and 2.5 M K 2 CO 3The aqueous solutions (0.09 ml) were combined in dioxane / acetonitrile (0.5 ml each) and heated to 100° C. for 8 hours. The reaction was then cooled, filtered through Celite, and purified by silica gel column chromatography (0-10% methanol in dichloromethane) to give 4-(3-(4-(cyclopropylcarbamoyl)phenyl)-6-(3,5-dimethylisoxazol)-4-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-3,5-diethoxybenzoic acid (P-0218). MS(ESI)[M+H + ] + =581.2.

[0414] Example 6 [ka] Step 1: Preparation of (S)-5-bromo-1-(1-(pyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridine 17: To an ice-cold solution of 5-bromo-1H-pyrrolo[2,3-b]pyridine (16, 689 mg, 3.5 mmol), (1R)-1-(2-pyridyl)ethanol (646 mg, 5.25 mmol), and triphenylphosphine (1377 mg, 5.25 mmol) in THF (35 ml) was added diisopropyl azodicarboxylate (1.04 ml, 5.25 mmol) slowly under nitrogen gas. The mixture was stirred and allowed to reach room temperature over 15 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give (S)-5-bromo-1-(1-(pyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridine (17). MS(ESI)[M+H + ] + =303.9.

[0415] Step 2: Preparation of (S)-3,5-dimethyl-4-(1-(1-(pyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)isoxazole 18: A mixture of (S)-5-bromo-1-(1-(pyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridine (17, 618 mg, 2.05 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (502 mg, 2.25 mmol), and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (149 mg, 0.182 mmol) in dioxane (20 ml) was purged with nitrogen gas and then cooled to 20° C. for 1 hour. 2 CO 3 (2.5 ml) was added. The mixture was heated at 100° C. for 4 hours. The sample was diluted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The material was purified by silica gel column chromatography eluting with 40% ethyl acetate in hexane to give (S)-3,5-dimethyl-4-(1-(1-(pyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)isoxazole (18). MS(ESI)[M+H + ] + =319.5.

[0416] Step 3: Preparation of (S)-4-(3-iodo-1-(1-(pyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,5-dimethylisoxazole 19: To an ice-cold solution of (S)-3,5-dimethyl-4-(1-(1-(pyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)isoxazole (18, 620 mg, 1.56 mmol) in acetonitrile (20 ml) was added N-iodosuccinimide (420 mg, 1.87 mmol). The mixture was stirred and allowed to reach room temperature over 2 h. The mixture was diluted with saturated NaCl and cooled to 100° C. for 2 h. 2 S 2 O 3The mixture was diluted with aqueous solution and extracted with ethyl acetate, and the organic layer was washed with water followed by brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The material was purified by silica gel column chromatography eluting with 40% ethyl acetate in hexane to give (S)-4-(3-iodo-1-(1-(pyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,5-dimethylisoxazole (19). MS(ESI)[M+H + ] + =445.0.

[0417] Step 4: Preparation of methyl 4-bromo-3-(cyclopropylethynyl)benzoate 21: A mixture of methyl 4-bromo-3-iodo-benzoate (20, 1022 mg, 3 mmol), bis(triphenylphosphine)palladium(II) dichloride (63 mg, 0.09 mmol), and copper(I) iodide (17 mg, 0.09 mmol) in (1:3) triethylamine in acetonitrile (20.0 ml) was purged with nitrogen gas, and then ethynylcyclopropane (238 mg, 3.6 mmol) was added. The mixture was heated at 60° C. for 5 hours. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography eluting with 30% ethyl acetate in hexane to give methyl 4-bromo-3-(cyclopropylethynyl)benzoate (21). MS(ESI)[M+H + ] + =280.9.

[0418] Step 5: Preparation of methyl 3-(cyclopropylethynyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate 22: A mixture of methyl 4-bromo-3-(cyclopropylethynyl)benzoate (21, 307 mg, 1.1 mmol), bis(pinacolato)diboron (419 mg, 1.65 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (89.83 mg, 0.104 mmol), and potassium acetate (323 mg, 3.3 mmol) in dioxane (10 ml) was heated at 100° C. for 15 h. The mixture was diluted with ethyl acetate, which was washed with water, brine, and dried over anhydrous magnesium sulfate. The organic layer was filtered and concentrated under reduced pressure. The sample was purified by silica gel column chromatography eluting with 10% ethyl acetate in hexane to give methyl 3-(cyclopropylethynyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (22). MS (ESI) [M+H + ] + =327.1.

[0419] Step 6: Preparation of (S)-3-(cyclopropylethynyl)-4-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(pyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzoate methyl 23: (S)-4-(3-iodo-1-(1-(pyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,5-dimethylisoxazole (19, 62 mg, 0.14 mmol), 3-(2-cyclopropylethynyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate methyl (22,150 mg), in dioxane (2 ml). 0.46 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (11.43 mg, 0.013 mmol), 2 CO 3(0.170 ml) was added. The mixture was heated at 100° C. for 4 hours. The sample was diluted with ethyl acetate, which was washed with water, then brine, and dried over anhydrous magnesium sulfate. The organic layer was filtered and concentrated under reduced pressure. The material was purified by silica gel column chromatography eluting with 50% ethyl acetate in hexane to give (S)-3-(cyclopropylethynyl)-4-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(pyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl benzoate (23). MS(ESI)[M+H + ] + =517.2.

[0420] Step 7: Preparation of (S)-3-(cyclopropylethynyl)-4-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(pyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzoic acid P-0178: To a mixture of (S)-3-(cyclopropylethynyl)-4-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(pyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl benzoate (23, 12 mg, 0.02 mmol) in (1:1) THF / MeOH (1 ml) was added 4.18 M aqueous LiOH (0.020 ml). The mixture was stirred at 70° C. for 3 h. The mixture was acidified with 3M HCl / MeOH, diluted with ethyl acetate and concentrated under reduced pressure. The material was purified by reverse phase HPLC (C18; 0-100% B; A: 5% CH 3 CN, 95%H 2 O, 0.1% HCO 2 H;B:95%CH 3 CN, 5%H 2 O, 0.1% HCO 2 H) to give (S)-3-(cyclopropylethynyl)-4-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(pyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzoic acid (P-0178). MS (ESI) [M+H + ] + =503.2.

[0421] Example 7 [ka] Step 1: Preparation of methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethoxy)benzoate 25: A mixture of methyl 4-bromo-3-(trifluoromethoxy)benzoate (344 mg, 1.15 mmol), bis(pinacolato)diboron (24, 584 mg, 2.3 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (94 mg, 0.115 mmol), and potassium acetate (339 mg, 3.45 mmol) in dioxane (12 ml) was heated at 100° C. for 15 hours. The mixture was diluted with ethyl acetate, which was washed with water and brine, and then dried over anhydrous magnesium sulfate. The organic layer was filtered and concentrated under reduced pressure. The material was purified by silica gel column chromatography eluting with 10% ethyl acetate in hexane to give methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethoxy)benzoate (25). MS (ESI) [M+H + ] + =347.1.

[0422] Step 2: Preparation of methyl 4-(1-((1-cyanocyclobutyl)methyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-(trifluoromethoxy)benzoate 27: Prepare methyl 4-(1-((5-(3,5-dimethylisoxazol-4-yl)-3-iodo-1H-pyrrolo[2,3-b]pyridin-1-yl)methyl)cyclobutane-1-carbonitrile (26) in dioxane (2 ml) purged with nitrogen gas. To a mixture of 1,3,2-dioxaborolan-2-yl (25, 52 mg, 0.12 mmol, prepared in a similar manner to compound 19), methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethoxy)benzoate (25, 54 mg, 0.16 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (9.8 mg, 0.012 mmol) was added 2.5 M aqueous potassium carbonate (0.150 ml). The mixture was heated at 110° C. for 3 hours. The sample was diluted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The material was purified by silica gel column chromatography eluting with 40% ethyl acetate in hexane to give methyl 4-(1-((1-cyanocyclobutyl)methyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-(trifluoromethoxy)benzoate (27). MS (ESI) [M+H + ] + =525.1.

[0423] Step 3: Preparation of 4-(1-((1-cyanocyclobutyl)methyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-(trifluoromethoxy)benzoic acid P-0364: To methyl 4-(1-((1-cyanocyclobutyl)methyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-(trifluoromethoxy)benzoate (27, 31 mg, 0.06 mmol) in (1:1) THF / MeOH (2.0 ml) was added 4.18 M aqueous LiOH (0.050 ml). The mixture was stirred at 70° C. for 2 h. The mixture was diluted with ethyl acetate, acidified with 1N HCl in MeOH, and concentrated under reduced pressure. The material was purified by reversed-phase HPLC (C18; 0-100% B; A: 5% CH 3 CN, 95%H 2 O, 0.1% HCO 2 H;B:95%CH 3 CN, 5%H 2 O, 0.1% HCO 2 H) to give 4-(1-((1-cyanocyclobutyl)methyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-(trifluoromethoxy)benzoic acid (P-0364). MS (ESI) [M+H + ] + =511.2.

[0424] Example 8 [ka] Step 1: Preparation of methyl 4-ethoxypicolinate 29: A mixture of methyl 4-hydroxypyridine-2-carboxylate hydrochloride (28, 3.79 g, 20.00 mmol), iodoethane (2.41 ml, 30.00 mmol), potassium carbonate (8.29 g, 60.00 mmol), and N,N-dimethylformamide (60 mL) was stirred at room temperature overnight. The reaction mixture was poured into water (200 mL) and extracted with ethyl acetate / hexanes=1 / 1 (600 mL). The organic layer was isolated, washed with water (2×100 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered through a short pad of silica gel, and concentrated under reduced pressure. This afforded methyl 4-ethoxypicolinate (29).

[0425] Step 2: Preparation of 4-ethoxy-2-(methoxycarbonyl)pyridine 1-oxide 30: To a solution of methyl 4-ethoxypicolinate (29, 2.53 g, 13.96 mmol) in ethyl acetate (40.0 mL) was added mCPBA (77%, 3.755 g, 16.76 mmol) in portions at 0 °C and stirred at room temperature for 22 h. Additional mCPBA (77%, 1.876 g, 8.38 mmol) was added and the mixture was stirred for another 5 h. The reaction was diluted with ethyl acetate (200 mL) and washed with saturated aqueous sodium bicarbonate (50 mL). The separated aqueous phase was extracted with DCM / MeOH=9 / 1 (5 x 50 mL) and the combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting material was purified by silica gel column chromatography (0-10% methanol in dichloromethane) to give 4-ethoxy-2-(methoxycarbonyl)pyridine 1-oxide (30).

[0426] Step 3: Preparation of methyl 4-ethoxy-6-hydroxypicolinate 31: To a solution of 4-ethoxy-2-(methoxycarbonyl)pyridine-1-oxide (30, 740 mg, 3.75 mmol) and triethylamine (1.57 mL, 11.26 mmol) in THF (20.0 mL), trifluoroacetic anhydride (1.57 mL, 11.86 mmol) was added dropwise over 5 min at 0 °C. The mixture was stirred at 0 °C for an additional 4 h. The reaction was diluted with dichloromethane (200 mL) and extracted with a mixture of saturated aqueous sodium bicarbonate (10 mL) and brine (50 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude material was purified by silica gel column chromatography (0-10% methanol in dichloromethane) to give methyl 4-ethoxy-6-hydroxypicolinate (31). MS (ESI) [M+H + ] + =198.1.

[0427] Step 4: Preparation of methyl 4,6-diethoxypicolinate 32: To a mixture of methyl 4-ethoxy-6-hydroxypicolinate (31, 313 mg, 1.59 mmol), potassium carbonate (329 mg, 2.38 mmol) in DMF (8 mL), iodoethane (0.255 mL, 3.18 mmol) was added and the mixture was stirred at room temperature overnight. The reaction was diluted with ethyl acetate / hexane (1 / 1, 150 ml) and extracted with water (50 ml, 3×) and brine (30 ml). The organic layer was dried over anhydrous sodium sulfate, filtered through a short silica gel pad and concentrated under reduced pressure. The resulting material was purified by silica gel column chromatography (0–20% ethyl acetate in hexane) to give methyl 4,6-diethoxypicolinate (32).

[0428] Step 5: Preparation of methyl 5-bromo-4,6-diethoxypicolinate 33: To a solution of methyl 4,6-diethoxypicolinate (32, 95 mg, 0.42 mmol) in DMF (1.5 ml), N-bromosuccinimide (76 mg, 0.43 mmol) was added and the mixture was stirred at 50 °C overnight. Two more equivalents of N-bromosuccinimide (15 mg, 0.18 mmol) were added and stirred for an additional hour. LC / MS showed the reaction was incomplete, so two more equivalents of N-bromosuccinimide (15 mg, 0.18 mmol) were added and stirred for an additional hour. LC / MS showed all starting material had been consumed and the conversion was complete. The reaction was diluted with ethyl acetate / hexanes (1 / 1, 20 mL) and extracted with 5% aqueous sodium thiosulfate solution (3 mL), water (5 mL), and brine (5 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The material was purified by silica gel column chromatography (0-15% ethyl acetate in hexanes) to give methyl 5-bromo-4,6-diethoxypicolinate (33).

[0429] Step 6: Preparation of 4-(1-(2,4-difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,5-dimethylisoxazole 35: A mixture of 3,5-dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)isoxazole (34, 2.13 g, 10.00 mmol), 2,4-difluorobromobenzene (3.39 mL, 30.00 mmol), potassium carbonate (6.91 g, 50.00 mmol), CuI (571 mg, 3.00 mmol), trans N,N'-dimethylcyclohexane-1,2-diamine (0.473 mL, 3.00 mmol) in toluene (100 mL) was stirred at 110 °C for 7 h. Additional 2,4-difluorobromobenzene (2.26 mL, 20.00 mmol) was added and the reaction was continued overnight. The reaction mixture was filtered through Celite and washed with ethyl acetate. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (0-50% ethyl acetate in hexanes) to give 4-(1-(2,4-difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,5-dimethylisoxazole (35).

[0430] Step 7: Preparation of 4-(3-bromo-1-(2,4-difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,5-dimethylisoxazole 36: To a solution of 4-(1-(2,4-difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,5-dimethylisoxazole (35, 2.47 g, 7.59 mmol) in acetonitrile (75 ml) at 0° C. was added N-bromosuccinimide (1.49 g, 8.35 mmol). The reaction was stirred at 0° C. for 30 min and then at room temperature for 20 min, followed by the addition of 5% aqueous sodium thiosulfate solution (20 ml). The reaction was concentrated under reduced pressure to remove acetonitrile, then saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was washed with brine (50 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The material was purified by silica gel column chromatography (0-20% ethyl acetate in hexanes) to give 4-(3-bromo-1-(2,4-difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,5-dimethylisoxazole (36).

[0431] Step 8: Preparation of 4-(1-(2,4-difluorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,5-dimethylisoxazole 37: 4-(3-bromo-1-(2,4-difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,5-dimethyl A mixture of isoxazole (36, 1.68 g, 4.15 mmol), bis(pinacolato)diboron (2.11 g, 8.30 mmol), X-Phos (119 mg, 0.249 mmol), Pd2dba3 (114 mg, 0.125 mmol), potassium acetate (1631 mg, 16.62 mmol), and toluene (40 mL) was stirred under nitrogen atmosphere at 95° C. for 8 h. The reaction was filtered through Celite and concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (0-10% ethyl acetate in dichloromethane) to give 4-(1-(2,4-difluorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,5-dimethylisoxazole (37).

[0432] Step 9: Preparation of 5-(1-(2,4-difluorophenyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-4,6-diethoxypicolinic acid P-0329: 4-(1-(2,4-difluorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,5-dimethylisoxazole (37, 57 mg, 0.095 mmol), methyl 5-bromo-4,6-diethoxypicolinate (33, 29 mg, 0.095 mmol), Pd(OAc) 2(1.1 mg, 0.005 mmol), S-Phos (2.0 mg, 0.005 mmol), potassium phosphate (61 mg, 0.286 mmol), 1,4-dioxane (1 ml), and water (0.2 ml) were stirred at 95° C. for 4 h. 1N aqueous HCl (1 ml) was then added, and the mixture was diluted with dichloromethane / methanol (10 / 1, 20 ml) and filtered through Celite. The mother liquor was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude material was purified by silica gel column chromatography (0-10% methanol in dichloromethane) to give the methyl ester of P-0329 (85 mg). This material was dissolved in THF (0.75 ml) and methanol (0.25 ml), 2N aqueous LiOH (0.25 ml) was added to the solution, and the resulting mixture was stirred at room temperature for 2 h. After adding 1N HCl aqueous solution (0.25 ml), the mixture was concentrated under reduced pressure and purified by silica gel column chromatography (0-10% methanol in dichloromethane) to give 5-(1-(2,4-difluorophenyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-4,6-diethoxypicolinic acid (P-0329). MS(ESI)[M+H + ] + =535.2.

[0433] Example 9 [ka] Step 1: Preparation of methyl 4-amino-3-chloro-5-(trifluoromethoxy)benzoate 39: To a solution of methyl 4-amino-3-(trifluoromethoxy)benzoate (38, 1.06 g, 4.5 mmol) in acetonitrile (40 ml) was added N-chlorosuccinimide (631 mg, 4.73 mmol). The mixture was heated at 80° C. for 3 h. The reaction was diluted with saturated aqueous sodium thiosulfate and extracted with ethyl acetate, which was washed with water followed by brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give methyl 4-amino-3-chloro-5-(trifluoromethoxy)benzoate (39). MS (ESI) [M+H+ ] + =270.0.

[0434] Step 2: Preparation of methyl 4-bromo-3-chloro-5-(trifluoromethoxy)benzoate 40: To a mixture of methyl 4-amino-3-chloro-5-(trifluoromethoxy)benzoate (39, 502 mg, 1.86 mmol) in aqueous HBr (10 ml) was added sodium nitrite (193 mg, 2.79 mmol) slowly at 0° C. The mixture was stirred at 0° C. for 10 minutes and then copper(I) bromide (294 mg, 2.05 mmol) was added. The mixture was allowed to warm to room temperature for 3 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water followed by brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The material was purified by silica gel column chromatography (20% dichloromethane in hexanes) to give methyl 4-bromo-3-chloro-5-(trifluoromethoxy)benzoate (40).

[0435] Step 3: Preparation of 4-(3-iodo-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,5-dimethylisoxazole 41: 1 M diisopropyl azodicarboxylate in THF (19.46 mL, 19.46 mmol, 1.5 equiv) was added dropwise to a solution of 4-(3-iodo-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,5-dimethylisoxazole (3, 4.4 g, 12.97 mmol, 1 equiv), tetrahydro-2H-pyran-4-ol (1.99 g, 19.5 mmol, 1.5 equiv), and triphenylphosphine (5.10 g, 19.46 mmol, 1.5 equiv) in THF (65 mL) at -20 °C. The reaction was allowed to warm to room temperature and stirred overnight. The volatiles were removed under reduced pressure and the residue was triturated with toluene (approximately 100 mL) and filtered to give 4-(3-iodo-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,5-dimethylisoxazole (41).

[0436] Step 4: Preparation of 3,5-dimethyl-4-(1-(tetrahydro-2H-pyran-4-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)isoxazole 42: 2M i-propylmagnesium chloride in THF (9.1 mL, 18.15 mmol, 2.4 equiv) was added to a slurry of 4-(3-iodo-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,5-dimethylisoxazole (41, 3.2 g, 7.56 mmol, 1 equiv) in THF (76 mL) at 0 °C. The reaction was allowed to warm to room temperature and stirred for 30 minutes to allow dissolution, at which point the metal / halogen exchange was determined to be complete by 1H NMR. The solution was cooled to 0°C and pinacolborane (3.29 mL, 22.68 mmol, 3 equiv) was added. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was poured into saturated ammonium chloride (200 mL) and extracted with ethyl acetate (200 mL). The organic layer was washed with saturated brine (200 mL) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-100% ethyl acetate in heptane). This afforded 3,5-dimethyl-4-(1-(tetrahydro-2H-pyran-4-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)isoxazole (42).

[0437] Step 5: Preparation of 3-chloro-4-(5-(3,5-dimethylisoxazol-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethoxy)benzoic acid P-0355: 3,5-dimethyl-4-(1-(tetrahydro-2H-pyran-4-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) in dioxane (3 ml) To a mixture of 1H-pyrrolo[2,3-b]pyridin-5-yl)isoxazole (42, 0.1 g, 0.24 mmol), methyl 4-bromo-3-chloro-5-(trifluoromethoxy)benzoate (40, 0.12 g, 0.35 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (20 mg, 0.025 mmol) was added 1M aqueous potassium carbonate (0.47 ml). The reaction was stirred at 100 °C for 3 h. The reaction was allowed to cool, then diluted with ethyl acetate and evaporated onto silica. The methyl ester intermediate was purified by silica gel column chromatography (0-100% ethyl acetate in hexane). The resulting methyl ester of P-0355 was dissolved in methanol / THF (1:1, 4 ml) and 1M aqueous lithium hydroxide (1.18 ml) was added. The mixture was stirred at room temperature for 3 h. The reaction was quenched with solid extractant sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The material was purified by reverse phase HPLC (C18; 0-100% B; A: 5% CH 3 CN, 95%H 2 O, 0.1% HCO 2 H;B:95%CH 3 CN, 5%H 2 O, 0.1% HCO 2 H) to give 3-chloro-4-(5-(3,5-dimethylisoxazol-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-(trifluoromethoxy)benzoic acid (P-0355). MS (ESI) [M+H + ] + =536.0.

[0438] Example 10 [ka] Step 1: Preparation of 5-bromo-2-(methoxycarbonyl)-4-methylpyridine-1-oxide 44: To 5-bromo-4-methyl methyl picolinate (43, 1.00 g, 4.35 mmol) in 1,2-dichloroethane (10 ml) was added mCPBA (77%, 3.00 g, 13.39 mmol) in one portion. The reaction mixture was stirred at room temperature for 16 hours. The reaction was filtered and the filtrate was concentrated under reduced pressure. The material was purified by silica gel column chromatography (0-100% ethyl acetate in hexanes). This gave 5-bromo-2-(methoxycarbonyl)-4-methylpyridine-1-oxide (44). MS (ESI) [M+H + ] + =246.0.

[0439] Step 2: Preparation of methyl 5-bromo-6-hydroxy-4-methylpicolinate 45: To a solution of 5-bromo-2-(methoxycarbonyl)-4-methylpyridine 1-oxide (44, 480 mg, 1.95 mmol) in dichloromethane (5 ml) and triethylamine (0.8 ml, 5.74 mmol) cooled to 0° C. under argon gas, trifluoroacetic anhydride (0.7 ml, 5.04 mmol) was added. The reaction mixture was allowed to warm to room temperature and then quenched by adding water (5 ml). The reaction mixture was extracted with ethyl acetate and water. The organic layer was washed with water, then with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (0-75% ethyl acetate in hexane). This afforded methyl 5-bromo-6-hydroxy-4-methylpicolinate (45). MS(ESI)[M+H + ] + =246.0.

[0440] Step 3: Preparation of methyl 5-bromo-6-ethoxy-4-methylpicolinate 46: A mixture of methyl 5-bromo-6-hydroxy-4-methylpicolinate (45, 50 mg, 0.2 mmol) and cesium carbonate (150 mg, 0.46 mmol) in N,N-dimethylformamide (2 ml) was heated to 90 °C for 10 min. Iodoethane (0.5 ml, 5.18 mmol) was then added and the reaction was stirred at 90 °C for 4 h. The reaction mixture was diluted with THF (20 mL) and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (0-70% ethyl acetate in hexane). This afforded methyl 5-bromo-6-ethoxy-4-methylpicolinate (46). MS (ESI) [M+H + ] + =274.0 and 276.0.

[0441] Step 4: Preparation of 4-(1-(dicyclopropylmethyl)-3-iodo-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,5-dimethylisoxazole 47: Diisopropyl azodicarboxylate (26.1 ml, 133 mmol, 2.5 equiv) was added dropwise to a solution of 4-(3-iodo-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,5-dimethylisoxazole (3, 18 g, 53.1 mmol, 1 equiv), compound 10 (8.93 g, 80 mmol, 1.5 equiv), and triphenylphosphine (34.8 g, 133 mmol, 2.5 equiv) in THF (185 ml) at 0° C. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was poured into saturated sodium bicarbonate (500 ml) and extracted with ethyl acetate (300 ml). The organic layer was washed with saturated brine (500 ml) and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (0-50% ethyl acetate in heptane). The product was triturated with a approx. 1 to 1 mixture of MTBE and heptane (approx. 50 ml) to give 4-(1-(dicyclopropylmethyl)-3-iodo-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,5-dimethylisoxazole (47).

[0442] Step 5: Preparation of 4-(1-(dicyclopropylmethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,5-dimethylisoxazole 48: 2M i-propylmagnesium chloride in THF (11.1 ml, 22.16 mmol, 2.4 equiv.) was added to a solution of 4-(1-(dicyclopropylmethyl)-3-iodo-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,5-dimethylisoxazole (47, 4 g, 9.23 mmol, 1 equiv.) in THF (90 ml) at 0° C. After stirring for 30 min, the metal / halogen exchange was determined to be complete by 1H NMR. i-Propyl pinacorborate (11.3 ml, 55.4 mmol, 6 equiv) was added and the reaction was allowed to warm to room temperature and stirred overnight. The reaction was poured into water (200 ml) and the pH was adjusted to 6 with 10% aqueous acetic acid (ca. 40 ml). The mixture was extracted with ethyl acetate (200 ml). The organic layer was washed with saturated brine (200 ml) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-100% ethyl acetate in heptane) to give 4-(1-(dicyclopropylmethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,5-dimethylisoxazole (48).

[0443] Step 6: Preparation of methyl 5-(1-(dicyclopropylmethyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-ethoxy-4-methylpicolinate 49: 4-(1-(dicyclopropylmethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2 To a mixture of 1,3-b]pyridin-5-yl)-3,5-dimethylisoxazole (48, 55 mg, 0.127 mmol), methyl 5-bromo-6-ethoxy-4-methylpicolinate (46, 17 mg, 0 mol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (14 mg, 0.017 mmol) was added 1M aqueous potassium carbonate (1 ml). The reaction mixture was stirred at 90° C. for 15 minutes. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water followed by brine and then dried over anhydrous magnesium sulfate. The volatiles were removed under reduced pressure. The material was purified by silica gel column chromatography (0-75% ethyl acetate in hexanes). This gave methyl 5-(1-(dicyclopropylmethyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-ethoxy-4-methylpicolinate (49). MS (ESI) [M+H + ] + =501.2.

[0444] Step 7: Preparation of 5-(1-(dicyclopropylmethyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-ethoxy-4-methylpicolinic acid P-0417: To methyl 5-(1-(dicyclopropylmethyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-ethoxy-4-methylpicolinate (49, 27 mg, 0.05 mmol) in THF (10 ml) was added 1M aqueous lithium hydroxide solution (5 ml). The reaction mixture was stirred at room temperature for 5 hours. After addition of aqueous formic acid, the organic layer of the reaction mixture was separated and concentrated under reduced pressure. The material was purified by reverse phase HPLC (C18; 0-100% B; A: 5% CH 3 CN, 95%H 2 O, 0.1% HCO 2 H;B:95%CH 3 CN, 5%H 2 O), 0.1% HCO 2 H) to give 5-(1-dicyclopropylmethyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-6-ethoxy-4-methylpicolinic acid (P-0417). MS (ESI) [M+H + ] + =487.2.

[0445] Example 11 [ka] Step 1: Preparation of 4-(3-iodo-1-tosyl-1H-pyrrolo[3,2-b]pyridin-6-yl)-3,5-dimethylisoxazole 50: To 4-(3-iodo-1H-pyrrolo[3,2-b]pyridin-6-yl)-3,5-dimethylisoxazole (8, 1.2 g, 3.54 mmol) in THF (50 ml) was added sodium hydride (60%, 0.17 mg, 4.25 mmol). The mixture was stirred at room temperature for 30 minutes. Then 4-methylbenzenesulfonyl chloride (1.01 g, 5.31 mmol) was added and the reaction was stirred for 3 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water followed by brine, then dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The material was purified by silica gel column chromatography (0-45% ethyl acetate in hexanes). This gave 4-(3-iodo-1-tosyl-1H-pyrrolo[3,2-b]pyridin-6-yl)-3,5-dimethylisoxazole (50). MS (ESI) [M+H + ] + =494.1.

[0446] Step 2: Preparation of dicyclopropyl(6-(3,5-dimethylisoxazol-4-yl)-1-tosyl-1H-pyrrolo[3,2-b]pyridin-3-yl)methanol 51: To a solution of 4-(3-iodo-1-tosyl-1H-pyrrolo[3,2-b]pyridin-6-yl)-3,5-dimethylisoxazole (50, 866 mg, 1.76 mmol) in THF (5 ml) cooled to -55 °C was added a 2 M solution of isopropylmagnesium chloride (1.5 ml) in THF. The reaction mixture was allowed to warm slowly to 0 °C for about 1 h. The reaction mixture was cooled to -55 °C followed by the addition of dicyclopropylmethanone (0.35 ml, 3.05 mmol). The reaction mixture was allowed to warm slowly to room temperature for 1-2 h and maintained at room temperature for 90 min. The reaction was quenched with 1 N aqueous HCl (3 ml). The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water followed by brine, then dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The material was purified by silica gel column chromatography (0-80% ethyl acetate in hexanes). This afforded dicyclopropyl(6-(3,5-dimethylisoxazol-4-yl)-1-tosyl-1H-pyrrolo[3,2-b]pyridin-3-yl)methanol (51). MS(ESI)[M+H + ] + =478.1.

[0447] Step 3: Preparation of dicyclopropyl(6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methanol 52: To dicyclopropyl(6-(3,5-dimethylisoxazol-4-yl)-1-tosyl-1H-pyrrolo[3,2-b]pyridin-3-yl)methanol (51, 390 mg, 0.817 mmol) was added a solution of 1 M potassium hydroxide in methanol (10 ml). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water followed by brine, then dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give dicyclopropyl(6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methanol (52).

[0448] Step 4: Preparation of ethyl 4-(3-(dicyclopropyl(hydroxy)methyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-3,5-diethoxybenzoate 53: Dicyclopropyl(6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methanol (52, 100 To a mixture of 1,2-dichloro-3,5-dimethoxy-2,4-diphenylphosphine (100 mg, 0.309 mmol), potassium phosphate tribasic (140 mg, 0.660 mmol), copper(I) iodide (13 mg, 0.068 mmol), trans N,N'-dimethylcyclohexane-1,2-diamine (100 mg, 0.703 mmol), and ethyl 4-bromo-3,5-diethoxy-benzoate (160 mg, 0.504 mmol) was added toluene (2 ml). The reaction mixture was heated to 110° C. for 16 hours. The reaction mixture was filtered and the filtrate was concentrated to dryness under reduced pressure. The material was purified by silica gel column chromatography (0-8% methanol in dichloromethane). This gave ethyl 4-(3-(dicyclopropyl(hydroxy)methyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-3,5-diethoxybenzoate (53). MS (ESI) [M+H + ] + =560.6.

[0449] Step 5: Preparation of 4-(3-(dicyclopropyl(hydroxy)methyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-3,5-diethoxybenzoic acid P-0165: To ethyl 4-(3-(dicyclopropyl(hydroxy)methyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-3,5-diethoxybenzoate (53, 17 mg, 0.030 mmol) in THF (10 ml) was added 1M aqueous lithium hydroxide solution (5 ml). The reaction mixture was stirred at room temperature for 20 hours. The organic layer of the reaction mixture was collected and concentrated under reduced pressure. The material was purified by reverse phase HPLC (C18; 0-100% B; A: 5% CH 3 CN, 95%H 2 O, 0.1% HCO 2 H;B:95%CH 3 CN, 5%H 2 O, 0.1% HCO 2 H) to give 4-(3-(dicyclopropyl(hydroxy)methyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-3,5-diethoxybenzoic acid (P-0165). MS (ESI) [M+H + ] + =532.15.

[0450] Example 12 [ka] Step 1: Preparation of (6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl)(pyridin-2-yl)methanol 54: A mixture of 3,5-dimethyl-4-(1H-pyrrolo[3,2-b]pyridin-6-yl)isoxazole (11, 213 mg, 1.00 mmol), pyridine-2-carbaldehyde (161 mg, 1.50 mmol), and potassium hydroxide (281 mg, 5.00 mmol) in methanol (10 ml) was stirred at room temperature for 15 h. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water followed by brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by reverse phase HPLC (C18; 0-100% B; A: 5% CH). 3 CN, 95%H 2 O, 0.1% HCO 2 H;B:95%CH 3 CN, 5%H 2 O, 0.1% HCO 2 H) to give (6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl)(pyridin-2-yl)methanol (54). MS (ESI) [M+H + ] + =321.1.

[0451] Step 2: Preparation of 3,5-dimethyl-4-(3-(pyridin-2-ylmethyl)-1H-pyrrolo[3,2-b]pyridin-6-yl)isoxazole 55: To a mixture of (6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl)(pyridin-2-yl)methanol (54, 210 mg, 0.656 mmol) in dichloroethane (6 ml) was added triethylsilane (0.52 ml, 3.28 mmol) and trifluoroacetic acid (0.25 ml, 3.28 mmol). The mixture was stirred at 80° C. for 2 h. The reaction was quenched with saturated aqueous potassium carbonate solution and extracted with ethyl acetate. The organic layer was washed with water followed by brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 3,5-dimethyl-4-(3-(pyridin-2-ylmethyl)-1H-pyrrolo[3,2-b]pyridin-6-yl)isoxazole (55). MS (ESI) [M+H + ] + =305.1.

[0452] Step 3: Preparation of 4-(6-(3,5-dimethylisoxazol-4-yl)-3-(pyridin-2-ylmethyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-(trifluoromethoxy)benzoic acid P-0159: To 3,5-dimethyl-4-(3-(pyridin-2-ylmethyl)-1H-pyrrolo[3,2-b]pyridin-6-yl)isoxazole (55, 33 mg, 0.108 mmol) and copper(I) bromide (10 mg, 0.070 mmol) in N,N-dimethylformamide (2 ml) was added methyl 4-bromo-3-(trifluoromethoxy)benzoate (50 mg, 0.167 mmol) and potassium carbonate (50 mg, 0.362 mmol). The mixture was heated to 100 °C for 10 min. Sodium hydroxide (100 mg, 2.50 mmol) and copper(II) acetate monohydrate (10 mg, 0.050 mmol) were then added to the reaction mixture. The reaction mixture was heated to 110° C. for 6 days. The reaction was cooled to room temperature and filtered. The filtrate was concentrated to dryness under reduced pressure. The resulting residue was extracted with water (+1N citric acid) and ethyl acetate.

[0453] The organic layer was washed with water, then with brine, then dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by reverse phase HPLC (C18; 0-100% B; A: 5% CH 3 CN, 95%H 2 O, 0.1% HCO 2 H;B:95%CH 3 CN, 5%H 2 O, 0.1% HCO 2 H) to give 4-(6-(3,5-dimethylisoxazol-4-yl)-3-(pyridin-2-ylmethyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-(trifluoromethoxy)benzoic acid (P-0159). MS (ESI) [M+H + ] + =509.5.

[0454] Example 13 [ka] Step 1: Preparation of ethyl 4-bromo-3,5-diethoxy-2-fluorobenzoate 57: To ethyl 4-bromo-3,5-diethoxybenzoate (56, 1.02 g, 3.20 mmol) in acetonitrile (20 ml) was added 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane ditetrafluoroborate (2.08 g, 5.87 mmol). The reaction mixture was immediately heated at 60 °C. After 18 h, the reaction mixture was diluted with ethyl acetate and extracted with water (+HCl). The organic layer was washed with saturated aqueous sodium bicarbonate followed by brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The material was purified by silica gel flash column chromatography (0-20% ethyl acetate in hexanes / DCM 40 / 60). The front-running mixed fractions were combined and purified on a second column. The backrunning mixed fractions were combined and purified on a third column, which gave the mono-F product, ethyl 4-bromo-3,5-diethoxy-2-fluorobenzoate (57). MS (ESI) [M+H + ] + =334.9.

[0455] Step 2: Preparation of 4-(1-(2,4-difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,5-dimethylisoxazole 58: In a pressure vessel equipped with a magnetic stir bar was added 3,5-dimethyl-4-(1H-pyrrolo[2,3-b]pyridin-5-yl)isoxazole (3a, 1.91 g, 8.97 mmol), 1-bromo-2,4-difluorobenzene (4.71 g, 24.4 mmol), copper(I) iodide (521 mg, 2.74 mmol), potassium hydroxide (0.884 g, 15.8 mmol), and 1,4-dioxane (50 ml). (1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (0.524 g, 3.68 mmol) was then added and the reaction was purged with argon, sealed, and stirred in a 120 °C oil bath. After 17 h, the reaction was filtered through Celite and washed with ethyl acetate. The filtrate was extracted with 1M aqueous HCl (2x) and brine (1x). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated, and the resulting residue was purified by silica gel flash column chromatography eluting with a gradient of 20-50% ethyl acetate in hexane to give 4-(1-(2,4-difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,5-dimethylisoxazole (58). MS (ESI) [M+H + ] + =326.4.

[0456] Step 3: Preparation of 4-(1-(2,4-difluorophenyl)-3-iodo-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,5-dimethylisoxazole 59: To a solution of 4-(1-(2,4-difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,5-dimethylisoxazole (58, 825 mg, 2.54 mmol) in acetonitrile (20 ml) was added N-iodosuccinimide (857 mg, 3.81 mmol). The reaction was stirred at room temperature for 22 h. TLC showed that all starting material had been consumed. The reaction was poured into ethyl acetate and saturated aqueous sodium thiosulfate solution and the layers were separated. The organic layer was washed with additional saturated aqueous sodium thiosulfate solution, then with brine, dried over anhydrous magnesium sulfate and filtered. The volatiles were removed by rotary evaporation and the resulting residue was purified by silica gel flash column chromatography eluting with 0-20% ethyl acetate in hexanes. This gave 4-(1-(2,4-difluorophenyl)-3-iodo-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,5-dimethylisoxazole (59). MS(ESI)[M+H + ] + =451.9.

[0457] Step 4: Preparation of 4-(1-(2,4-difluorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaneborolan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,5-dimethylisoxazole 60: To a round bottom flask charged with 4-(1-(2,4-difluorophenyl)-3-iodo-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,5-dimethylisoxazole (59, 956 mg, 2.12 mmol), Pd X-Phos G1 (152 mg, 0.206 mmol), and pinacolborane (1.23 ml, 8.48 mmol), 1,4-dioxane (16 ml) was added. The stirred solution was purged with argon, then triethylamine (1.48 ml, 10.6 mmol) was added and the reaction was placed in a 60° C. oil bath under argon atmosphere for 1.5 hours. TLC indicated that the starting iodide had been consumed. The cooled reaction was diluted with ethyl acetate (25 ml) and brine (25 ml), stirred for 30 minutes, and filtered through a Celite wash with ethyl acetate. The layers were separated and the organic layer was dried over anhydrous sodium sulfate and filtered. The volatiles were removed by rotary evaporation and the resulting residue was purified by silica gel flash column chromatography eluting with 0-20% ethyl acetate in hexane to give 4-(1-(2,4-difluorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,5-dimethylisoxazole (60). MS(ESI)[M+H + ] + =452.0.

[0458] Step 5: Preparation of ethyl 4-(1-(2,4-difluorophenyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3,5-diethoxy-2-fluorobenzoate 61: In a pressure vessel equipped with a magnetic stir bar, add 4-(1-(2,4-difluorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaneborolan-2-yl)-1H-pyrrolo[2, 3-b]pyridin-5-yl)-3,5-dimethylisoxazole (60, 662 mg, 1.47 mmol), ethyl 4-bromo-3,5-diethoxy-2-fluoro-benzoate (57, 485 mg, 1.45 mmol), dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (239 mg, 0.293 mmol), and 1,4-dioxane (7 ml) were added. 2.5 M potassium carbonate in water (2.32 ml) was then added and the reaction was purged with argon, sealed, and immediately heated in an oil bath at 120° C. for 15 minutes. The reaction mixture was allowed to cool, poured into water (20 ml) and ethyl acetate (20 ml), and filtered through Celite. The organic layer was washed with 1 M aqueous HCl to give a dark solid material that was removed by filtration through Celite. The organic layer was washed with brine, then dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography eluting with a gradient of 20-50% ethyl acetate in hexane to give ethyl 4-(1-(2,4-difluorophenyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3,5-diethoxy-2-fluorobenzoate (61). MS(ESI)[M+H + ] + =580.4.

[0459] Step 6: Preparation of 4-(1-(2,4-difluorophenyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3,5-diethoxy-2-fluorobenzoic acid P-0297: To ethyl 4-(1-(2,4-difluorophenyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3,5-diethoxy-2-fluorobenzoate (61, 142 mg, 0.25 mmol) dissolved in THF (8.7 ml) was added 1 M aqueous lithium hydroxide solution (4.6 ml) and the biphasic mixture was stirred at room temperature for 5 hours. The reaction was quenched with 2N aqueous HCl (3 ml) and diluted with ethyl acetate (20 ml). The organic layer was washed with brine, then dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the material was purified by silica gel flash column chromatography (0-10% methanol in dichloromethane) to give 4-(1-(2,4-difluorophenyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3,5-diethoxy-2-fluorobenzoic acid (P-0297). MS(ESI)[M+H + ] + =552.1.

[0460] Example 14 [ka] Step 1: Preparation of 4-(6-chloropyridin-3-yl)-3,5-dimethylisoxazole 64: To 5-bromo-2-chloro-pyridine (63, 2.00 g, 10.4 mmol) was added 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (62, 2.55 g, 11.4 mol), 1M aqueous potassium carbonate (15.59 ml), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.76 g, 0.93 mmol), and dioxane (10 ml). The reaction was heated at 60° C. for 2 hours. The reaction was poured into brine and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered, and then evaporated onto silica. The product was isolated by silica gel flash column chromatography (0-100% ethyl acetate in hexanes) to give 4-(6-chloropyridin-3-yl)-3,5-dimethylisoxazole (64). MS (ESI) [M+H + ] + =209.1.

[0461] Step 2: Preparation of 5-(3,5-dimethylisoxazol-4-yl)-N-(3-methyltetrahydrofuran-3-yl)pyridin-2-amine 65: 4-(6-chloropyridin-3-yl)-3,5-dimethylisoxazole (64, 0.5 g, 2.4 mmol) was dissolved in DME (2 ml) in a 20 mL microwave vial. 3-Methyloxolan-3-amine (0.3 ml, 2.88 mmol), sodium tert-butoxide (345 mg, 3.59 mmol), and RuPhos (196 mg, 0.24 mmol) were then added and the vial was sealed and heated to 120 °C in an oil bath under nitrogen atmosphere for 18 h. The reaction mixture was filtered through Celite and then evaporated onto silica. The material was purified by reverse phase HPLC (C18; 0-100% B; A: 5% CH 3 CN, 95%H 2 O, 0.1% HCO 2 H;B:95%CH 3 CN, 5%H 2 O), 0.1% HCO 2H) to give 5-(3,5-dimethylisoxazol-4-yl)-N-(3-methyltetrahydrofuran-3-yl)pyridin-2-amine (65). MS (ESI) [M+H + ] + =274.2.

[0462] Step 3: Preparation of 5-(3,5-dimethylisoxazol-4-yl)-3-iodo-N-(3-methyltetrahydrofuran-3-yl)pyridin-2-amine 66: 5-(3,5-dimethylisoxazol-4-yl)-N-(3-methyltetrahydrofuran-3-yl)pyridin-2-amine (65, 515 mg, 1.88 mmol) was dissolved in DMF (8 ml) in a 20 ml microwave vial. Trifluoroacetic acid (0.42 ml, 5.65 mmol) and N-iodosuccinimide (636 mg, 2.83 mmol) were added, the vial was sealed and heated to 80° C. for 4 hours. The reaction mixture was poured into sodium thiosulfate, filtered and then evaporated onto silica gel. The product was isolated by silica gel flash column chromatography (0-100% ethyl acetate in hexanes) to give 5-(3,5-dimethylisoxazol-4-yl)-3-iodo-N-(3-methyltetrahydrofuran-3-yl)pyridin-2-amine (66). MS (ESI) [M+H + ] + =399.9.

[0463] Step 4: Preparation of 3,5-dimethyl-4-(1-(3-methyltetrahydrofuran-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)isoxazole 67: 5-(3,5-dimethylisoxazol-4-yl)-3-iodo-N-(3-methyltetrahydrofuran-3-yl)pyridin-2-amine (66, 0.5 g, 1.25 mmol) and (E)-1-ethoxyethene-2-boronic acid acid pinacol ester (0.413 ml, 1.88 mmol) were dissolved in DMF (3 ml) in a 5 ml microwave vial. 1,1'-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (92 mg, 0.11 mmol) and lithium hydroxide (90 mg, 3.76 mmol) were then added, the vial was sealed and heated to 80 °C in an oil bath under nitrogen atmosphere for 6 h. The reaction was then cooled to 50 °C, 25% aqueous HCl (0.37 ml, 2.5 mmol) was added via syringe and the reaction was stirred for 2 h. The reaction was poured into saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The organic layer was evaporated onto silica gel and purified by silica gel flash column chromatography (0-10% methanol in dichloromethane) to give 3,5-dimethyl-4-(1-(3-methyltetrahydrofuran-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)isoxazole (67). MS(ESI)[M+H + ] + =298.1.

[0464] Step 5: Preparation of 4-(3-iodo-1-(3-methyltetrahydrofuran-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,5-dimethylisoxazole 68: 3,5-Dimethyl-4-(1-(3-methyltetrahydrofuran-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)isoxazole (67, 340 mg, 1.14 mmol) was dissolved in DMF (3 ml) and cooled to 0° C. A solution of N-iodosuccinimide (309 mg, 1.37 mmol) in DMF (2 mL) was then added. The reaction was stirred for 2 h while warming to room temperature. The reaction was poured into saturated aqueous sodium thiosulfate solution and extracted with ethyl acetate. The organic layer was evaporated onto silica and purified by silica gel flash column chromatography (0 to 100% ethyl acetate in hexanes) to give 4-(3-iodo-1-(3-methyltetrahydrofuran-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,5-dimethylisoxazole (68).

[0465] Step 6: Preparation of 4-(5-(3,5-dimethylisoxazol-4-yl)-1-(3-methyltetrahydrofuran-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-(trifluoromethoxy)benzoic acid P-0383: 4-(3-iodo-1-(3-methyltetrahydrofuran-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,5-dimethylisoxazole (68, 50 mg, 0.12 A mixture of 25,4-diphenylphosphino-1,3,2-dioxaborolan-2-yl (25 mmol) and methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethoxy)benzoate (25, 61 mg, 0.18 mmol) was dissolved in dioxane (3 ml) followed by the addition of 1 M aqueous potassium carbonate (0.24 ml) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (9 mg, 0.01 mmol). The reaction was stirred at 110 °C for 4 h. The reaction was diluted with ethyl acetate and evaporated onto silica gel. The methyl ester intermediate was isolated by silica gel flash column chromatography (0-100% ethyl acetate in hexanes). The isolated product was dissolved in MeOH / THF (4 ml) and 1 M aqueous lithium hydroxide (0.59 ml) and stirred at room temperature for 4 h. The reaction was poured into saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was evaporated onto silica gel and purified by reversed-phase silica gel flash column chromatography (0–100% B; A: 5% CH 3 CN, 95%H 2 O, 0.1% HCO 2 H;B:95%CH 3 CN, 5%H 2 O, 0.1% HCO 2 H) to give 4-(5-(3,5-dimethylisoxazol-4-yl)-1-(3-methyltetrahydrofuran-3-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-(trifluoromethoxy)benzoic acid (P-0383). MS (ESI) [M+H + ] + =502.0.

[0466] Example 15 [ka] Step 1: Preparation of 3,5-dimethyl-4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isoxazole 70: To a mixture of 5-bromo-2-methyl-1H-pyrrolo[2,3-b]pyridine (69, 2.01 g, 9.5 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (4.24 g, 19 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (695 mg, 0.852 mmol) in nitrogen gas purged dioxane (60 ml) was added 2.5 M aqueous potassium carbonate solution (12 ml). The mixture was heated at 110° C. for 3 h. The reaction was cooled, diluted with water, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel flash column chromatography (40% ethyl acetate in hexanes) to give 3,5-dimethyl-4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isoxazole (70). MS (ESI) [M+H + ] + =228.1.

[0467] Step 2: Preparation of 4-(3-iodo-2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,5-dimethylisoxazole 71: To an ice-cold solution of 3,5-dimethyl-4-(2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)isoxazole (70, 1.00 g, 4.4 mmol) in acetonitrile (40 ml) was added N-iodosuccinimide (1.09 g, 4.84 mmol). The mixture was stirred at 0° C. for 2 h. The reaction was diluted with saturated aqueous sodium thiosulfate and extracted with ethyl acetate. The organic layer was washed with water followed by brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the material was purified by silica gel flash column chromatography (50% ethyl acetate in hexanes) to give 4-(3-iodo-2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,5-dimethylisoxazole (71). MS (ESI) [M+H + ] + =354.0.

[0468] Step 3: Preparation of 2-(5-(3,5-dimethylisoxazol-4-yl)-3-iodo-2-methyl-1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinonitrile 72: A mixture of 4-(3-iodo-2-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,5-dimethylisoxazole (71, 353 mg, 1.00 mmol), potassium carbonate (276 mg, 2.00 mmol), and 2-fluoropyridine-3-carbonitrile (244 mg, 2.00 mmol) in DMF (5 ml) was stirred at 100° C. for 3 h. The reaction was cooled, diluted with water, and extracted with ethyl acetate. The filtrate was washed with brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel flash column chromatography (70% ethyl acetate in hexanes) to give 2-(5-(3,5-dimethylisoxazol-4-yl)-3-iodo-2-methyl-1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinonitrile (72). MS (ESI) [M+H + ] + =456.0.

[0469] Step 4: Preparation of methyl 4-(1-(3-cyanopyridin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-(trifluoromethoxy)benzoate 73: 2-(5-(3,5-dimethylisoxazol-4-yl)-3-iodo-2-methyl-1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinonite in dioxane (2 ml) purged with nitrogen gas. To a mixture of 2,4-diphenylphosphino-1,3,2-dioxaborolan-2-yl (72, 100 mg, 0.22 mmol), methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethoxy)benzoate (25, 99 mg, 0.29 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (18 mg, 0.022 mmol) was added 2.5 M aqueous potassium carbonate (0.270 ml). The reaction was heated at 110° C. for 3 hours. The reaction was cooled to room temperature, diluted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated and purified by silica gel flash column chromatography (70% ethyl acetate in hexanes) to give methyl 4-(1-(3-cyanopyridin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-(trifluoromethoxy)benzoate (73). MS (ESI) [M+H + ] + =548.2.

[0470] Step 5: Preparation of 4-(1-(3-cyanopyridin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-(trifluoromethoxy)benzoic acid P-0345: To a mixture of methyl 4-(1-(3-cyanopyridin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-(trifluoromethoxy)benzoate (73, 116 mg, 0.21 mmol) in (1:1) THF / MeOH (2.0 ml) was added 4.18 M aqueous lithium hydroxide solution (0.150 ml). The mixture was stirred at 70° C. for 2 h. The reaction was diluted with ethyl acetate, acidified with 1N HCl in MeOH, and concentrated under reduced pressure. The material was purified by reverse-phase silica gel flash column chromatography (0-100% B; A: 5% CH 3 CN, 95%H 2 O, 0.1% HCO 2 H;B:95%CH 3 CN, 5%H 2 O, 0.1% HCO 2 H) to give 4-(1-(3-cyanopyridin-2-yl)-5-(3,5-dimethylisoxazol-4-yl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-(trifluoromethoxy)benzoic acid (P-0345). MS (ESI) [M+H + ] + =534.0.

[0471] Example 16 [ka] Step 1: Preparation of (3-methylisoxazol-5-yl)methanol 75: To a solution of 3-methylisoxazole-5-carboxylic acid (74, 6.36 g, 50 mmol) and TEA (8.36 ml, 60 mmol) in THF (150 ml) was added isobutyl carbonochloridate (7.13 mL, 55 mmol) dropwise over 5 min at 0° C. The mixture was then stirred at 0° C. for 5 min and at room temperature for 10 min. The precipitate was removed by filtration, and the mother liquor and the rinsed solution were then combined and cooled to 0° C. Water (5 ml) was added to the solution at 0° C., and then sodium borohydride (3.78 g, 100 mmol) was slowly added to the solution over 15 min at 0° C. Water (35 mL) was also carefully added. The resulting mixture was stirred at 0° C. for 1 h and then at room temperature for 30 min. After the reaction mixture was cooled to 0° C., 4N aqueous sulfuric acid (80 mL) was slowly added to the solution, and the mixture was extracted with ethyl acetate (400 mL). The extract was washed with water (50 ml) and brine (50 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give (3-methylisoxazol-5-yl)methanol (75).

[0472] Step 2: Preparation of 3-methylisoxazole-5-carbaldehyde 76: To a solution of (3-methylisoxazol-5-yl)methanol (75, 3.50 g, 27 mmol) in dichloromethane (140 mL) was added Dess-Martin periodinane (13.9 g, 32.7 mmol) at 0 °C, and the mixture was stirred at room temperature for 6.5 h. The mixture was diluted with dichloromethane (500 mL) and washed with 5% aqueous sodium thiosulfate (150 mL) and saturated aqueous sodium bicarbonate (150 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. This material was purified by silica gel flash column chromatography (0-40% ethyl acetate in hexanes) to give 3-methylisoxazole-5-carbaldehyde (76).

[0473] Step 3: Preparation of 3-methyl-5-vinylisoxazole 77: To a solution of 3-methylisoxazole-5-carbaldehyde (76, 1.91 g, 17.19 mmol) in THF (25 mL) was added ((trimethylsilyl)methyl)magnesium chloride solution (1.0 M in THF, 25.8 mL, 25.8 mmol) dropwise over 5 min at 0 °C. After stirring at 0 °C for 1 h, the solution was allowed to warm to room temperature and stirred for 6.5 h. At 0 °C, 1N aqueous sulfuric acid (25 mL) was added and the reaction was extracted with ethyl acetate (100 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (25 mL) and brine (25 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting TMS-CH2 adduct was dissolved in diethyl ether (60 mL) and concentrated sulfuric acid (3.41 mL) was added dropwise over 5 min at 0 °C. The mixture was then stirred at room temperature for 2 h. The mixture was poured into ice-cold saturated aqueous sodium bicarbonate (40 mL) and the resulting mixture was extracted with diethyl ether (160 mL). After the organic layer was washed with brine (30 mL), the solution was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 3-methyl-5-vinylisoxazole (77).

[0474] Step 4: Preparation of 5-ethyl-3-methylisoxazole 78: To a solution of crude 3-methyl-5-vinylisoxazole (77, 2.31 g, 17.2 mmol) in MeOH (120 mL) was added 10% Pd / C (50% wet, 730 mg) and stirred vigorously at room temperature under hydrogen for 1 h. After removing the catalyst by filtration through Celite, the mixture was concentrated under reduced pressure to give 5-ethyl-3-methylisoxazole (78).

[0475] Step 5: Preparation of 4-bromo-5-ethyl-3-methylisoxazole 79: To a solution of 5-ethyl-3-methylisoxazole (78, 1.63 g, 14.7 mmol) in DMF (30 mL), N-bromosuccinimide (3.13 g, 17.6 mmol) was added and the mixture was stirred at room temperature overnight. After additional N-bromosuccinimide (522 mg, 2.93 mmol) was added, the mixture was stirred at room temperature for an additional 5 h. The reaction was diluted with ethyl acetate and hexanes (1 / 1, 300 mL) and washed with 5% aqueous sodium thiosulfate (90 mL), 1 N aqueous NaOH (60 mL), water (60 mL), and brine (60 mL). The filtrate was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. This material was purified by silica gel flash column chromatography (0 to 10% ethyl acetate in hexanes) to give 4-bromo-5-ethyl-3-methylisoxazole (79).

[0476] Step 6: Preparation of 5-ethyl-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole 80: To a solution of 4-bromo-5-ethyl-3-methylisoxazole (79, 161 mg, 0.847 mmol) in THF (4.5 mL) was added dropwise n-BuLi solution (2.5 M in hexanes, 0.54 mL, 1.36 mmol) at -78 °C. After the mixture was stirred at -78 °C for 20 min, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.31 ml, 1.53 mmol) was added and the mixture was stirred at -78 °C for an additional 2 h. The reaction was quenched with saturated aqueous ammonium chloride solution (1 mL), diluted with ethyl acetate (50 mL) and washed with water (30 mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. This material was purified by silica gel flash column chromatography (0-10% ethyl acetate in hexanes) to give 5-ethyl-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (80).

[0477] Step 7: Preparation of 5-bromo-3-iodo-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine 82: To a solution of 5-bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine (81, 3.23 g, 10.0 mmol), tetrahydro-2H-pyran-4-ol (1.02 mg, 10.0 mmol), and triphenylphosphane (3.93 g, 15.0 mmol) in THF (50 mL) was added diisopropyl azodicarboxylate (2.95 mL, 15.0 mmol) dropwise over 5 min at 0 °C and the mixture was stirred at room temperature for 2 days. The reaction was concentrated under reduced pressure and the material was purified by silica gel flash column chromatography (0-35% ethyl acetate in hexanes). Impure fractions were further repurified by chromatography or suspension of the solid product in ethyl acetate / hexane (1 / 3 ratio) followed by filtration to give 5-bromo-3-iodo-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine (82).

[0478] Step 8: Preparation of methyl 4-(5-bromo-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-(trifluoromethoxy)benzoate 83: 5-bromo-3-iodo-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine (82, 330 mg, 0.811 mmol), methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaneborolan-2-yl)-3-(trifluoromethoxy)benzoate (25, 281 mg, 0.811 mmol), PdCl 2 (Ph 3 P) 2A mixture of 5-(28.5 mg, 0.041 mmol), sodium carbonate (258 mg, 2.432 mmol), 1,4-dioxane (6.4 mL), and water (1.6 mL) was stirred at 60° C. overnight. The reaction was concentrated under reduced pressure and then partitioned between ethyl acetate (50 mL) and water (10 mL). The organic layer was isolated, washed with brine (10 ml), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by silica gel flash column chromatography (0-30% ethyl acetate in hexanes) to give methyl 4-(5-bromo-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-(trifluoromethoxy)benzoate (83).

[0479] Step 9: Preparation of methyl 4-(5-(5-ethyl-3-methylisoxazol-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-(trifluoromethoxy)benzoate 84: 5-ethyl-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (80, 26 mg, 0.110 mmol), methyl 4-(5-bromo-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-(trifluoromethoxy)benzoate (83, 55 mg, 0.110 mmol), Pd(OAc) in dioxane (1.0 mL) and water (0.25 mL). 2 (1.2 mg, 0.006 mmol), S-Phos (2.3 mg, 0.006 mol), and K 3 PO 4 (58 mg, 0.275 mmol) was stirred at 105 °C for 15 h. The reaction was incomplete, so additional 5-ethyl-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (80, 26 mg, 0.110 mmol), Pd(OAc) 2 (1.2 mg, 0.006 mmol), S-Phos (2.3 mg, 0.006 mol), and K 3 PO 4(58 mg, 0.275 mmol) was added and the mixture was stirred at 105 °C for an additional 6 h. The reaction was cooled, filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting mixture of compound 84 and P-0401 was dissolved in DMF (0.5 mL), potassium carbonate (30 mg, 0.220 mmol) and methyl iodide (0.014 mL, 0.220 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction was diluted with ethyl acetate (50 mL), and the solution was washed with 0.2 N aqueous HCl (5 mL), water (2 x 5 mL), and brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. This material was purified by silica gel flash column chromatography (0-50% ethyl acetate in hexanes) to give methyl 4-(5-(5-ethyl-3-methylisoxazol-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-(trifluoromethoxy)benzoate (84). MS(ESI)[M+H + ] + =530.2.

[0480] Step 10: Preparation of 4-(5-(5-ethyl-3-methylisoxazol-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-(trifluoromethoxy)benzoic acid P-0401: To methyl 4-(5-(5-ethyl-3-methylisoxazol-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-(trifluoromethoxy)benzoate (84, 31 mg) dissolved in THF (0.75 mL) and MeOH (0.25 mL) was added 2N aqueous lithium hydroxide solution (0.25 mL, 0.500 mmol) and the reaction was stirred at room temperature for 3 h. The reaction was quenched by the addition of 1N aqueous HCl (0.5 mL) and the mixture was concentrated under reduced pressure. This material was purified by silica gel flash column chromatography (0-10% methanol in dichloromethane) to give 4-(5-(5-ethyl-3-methylisoxazol-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-(trifluoromethoxy)benzoic acid (P-0401). MS (ESI) [M+H + ] + =516.1.

[0481] Example 17 [ka] Step 1: Preparation of methyl 4-(5-(3-ethyl-5-methylisoxazol-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-(trifluoromethoxy)benzoate 85: 3-ethyl-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane) in dioxane (1.0 mL) and water (0.25 mL) -2-yl)isoxazole (84, 26 mg, 0.110 mmol, prepared in 6 steps from 5-methylisoxazole-3-carboxylic acid in a manner similar to compound 80 shown in Example 16), 4-(5-bromo-1-tetrahydropyran-4-yl-pyrrolo[2,3-b]pyridin-3-yl)-3-(trifluoromethoxy)benzoate methyl (83, 55 mg, 0.110 mmol), Pd(OAc) 2 A mixture of 3-ethyl-5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (84, 26 mg, 0.110 mmol), Pd(OAc) (1.2 mg, 0.006 mmol), S-Phos (2.3 mg, 0.006 mmol), and potassium phosphate (58 mg, 0.275 mmol) was stirred overnight at 105 °C. 2(1.2 mg, 0.006 mmol), S-Phos (2.3 mg, 0.006 mol), and potassium phosphate (58 mg, 0.275 mmol) were added and the reaction was continued at 105° C. for another 6 h. The reaction was then allowed to cool and filtered through Celite. The filtrate was concentrated under reduced pressure. The resulting mixture of compound 85 and P-0400 was dissolved in DMF (0.5 mL) and potassium carbonate (30 mg, 0.220 mmol) and methyl iodide (0.014 ml, 0.220 mmol) were added. The reaction was stirred at room temperature overnight. The reaction was diluted with ethyl acetate (50 mL) and the solution was washed with 0.2 N aqueous HCl (5 mL), water (2×5 mL), and brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. This material was purified by silica gel flash column chromatography (0-50% ethyl acetate in hexanes) to give methyl 4-(5-(3-ethyl-5-methylisoxazol-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-(trifluoromethoxy)benzoate (85). MS(ESI)[M+H + ] + =530.2.

[0482] Step 2: Preparation of 4-(5-(3-ethyl-3-methylisoxazol-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-(trifluoromethoxy)benzoic acid P-0400: To methyl 4-(5-(3-ethyl-5-methylisoxazol-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-(trifluoromethoxy)benzoate (85, 47 mg) dissolved in THF (0.75 mL) and MeOH (0.25 mL) was added 2N aqueous LiOH solution (0.25 mL, 0.500 mmol) and stirred at room temperature for 2.5 h. Then 1N aqueous HCl solution (0.5 mL) was added and the mixture was concentrated under reduced pressure. This material was purified by silica gel flash column chromatography (0-10% methanol in dichloromethane) to give 4-(5-(3-ethyl-5-methylisoxazol-4-yl)-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-(trifluoromethoxy)benzoic acid (P-0401). MS(ESI)[M+H + ] + =516.1.

[0483] Example 18 [ka] Step 1: Preparation of (S)-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-(1-(pyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridine 86: Mixture of (S)-5-bromo-1-(1-(pyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridine (17, 199 mg, 0.66 mmol), 1,4 in dioxane (6.0 ml). A mixture of 1,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)triazole (177 mg, 0.79 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (48 mg, 0.059 mmol) was purged with nitrogen gas and then 2.5 M aqueous potassium carbonate (0.80 ml) was added. The reaction vial was sealed and heated at 140° C. for 2 hours. The reaction was diluted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The material was purified by silica gel flash column chromatography (100% ethyl acetate) to give (S)-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-(1-(pyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridine (86). MS(ESI)[M+H + ] + =319.9.

[0484] Step 2: Preparation of (S)-3-bromo-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-(1-(pyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridine 87: A solution of (S)-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-(1-(pyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridine (86, 50 mg, 0.16 mmol) in acetonitrile (2 ml) was treated with N-bromosuccinimide. To the reaction mixture was added (29 mg, 0.16 mmol). The mixture was stirred and allowed to warm to room temperature for 2 h. The reaction was diluted with saturated aqueous sodium thiosulfate and extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give (S)-3-bromo-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-(1-(pyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridine (87). MS (ESI) [M+H] + ] + =399.0.

[0485] Step 3: Preparation of (S)-3-(5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-(1-(pyridin-2-yl)ethyl-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl benzoate 88: Mix (S)-3-bromo-5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-(1-(pyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridine (87, 39 mg, 0.10 mmol), 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl benzoate (39 mg, 0.15 mmol), and 1,1′-bis(diphenylphosphino)ferrocene-palladium in dioxane (1 ml). A mixture of 1,2-dichloromethane dichloride complex (8 mg, 0.009 mmol) was purged with nitrogen gas and then 2.5 M aqueous potassium carbonate (0.120 ml) was added. The reaction vial was sealed and heated at 130° C. for 2 days. The reaction was cooled, diluted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. This material was purified by silica gel flash column chromatography (30% ethyl acetate) to give (S)-3-(5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-(1-(pyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)methyl benzoate (88). MS (ESI) [M+H + ] + =453.2.

[0486] Step 4: (S)-3-(5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-(1-(pyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzoic acid P-0449: To a solution of methyl (S)-3-(5-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-1-(1-(pyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzoate (88, 20 mg, 0.04 mmol) in THF / MeOH (1:1, 1.0 ml) was added 4.18 M aqueous lithium hydroxide solution (0.020 ml). The reaction was stirred at 70° C. for 2 hours. The reaction was acidified with 1N aqueous HCl, concentrated under reduced pressure, and the material purified by reverse-phase silica gel flash column chromatography (0–100% B; A: 5% CH 3 CN, 95%H 2 O, 0.1% HCO 2 H;B:95%CH 3 CN, 5%H 2 O, 0.1% HCO 2 H) to give (S)-3-(5-(1,4-dimethyl-1H-1,2,3)-triazol-5-yl)-1-(1-(pyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzoic acid (P-0449). MS (ESI) [M+H + ] + =439.1.

[0487] Example 19 [ka] Step 1: Preparation of methyl 4-(5-(3,5-dimethylisoxazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-(trifluoromethoxy)benzoate 89: 4-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,5-dimethylisoxazole (4, 1.01 g, 2.05 mmHg) in dioxane (20 ml) purged with nitrogen gas. To a mixture of 2,4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethoxy)benzoate (25, 1.06 g, 3.08 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (167 mg, 0.205 mmol) was added 2.5 M aqueous potassium carbonate (2.5 ml). The reaction vial was sealed and heated at 110° C. for 3 hours. The reaction was cooled, diluted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered, and concentrated. This material was purified by silica gel flash column chromatography (30% ethyl acetate) to give methyl 4-(5-(3,5-dimethylisoxazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-(trifluoromethoxy)benzoate (89). MS (ESI) [M+H + ] + =586.5.

[0488] Step 2: Preparation of methyl 4-(5-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-(trifluoromethoxy)benzoate 90: To a solution of methyl 4-(5-(3,5-dimethylisoxazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-(trifluoromethoxy)benzoate (89, 865.8 mg, 1.48 mmol) dissolved in THF (15 ml) was added 1M tetra-n-butylammonium fluoride in THF (1.8 ml). The reaction was stirred at 70° C. for 15 hours. The reaction was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, water, and brine, and dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the resulting solid was triturated with dichloromethane / hexane to give methyl 4-(5-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-(trifluoromethoxy)benzoate (90). MS (ESI) [M+H + ] + =432.5.

[0489] Step 3: Preparation of methyl 4-(1-(1-(cyanomethyl)cyclobutyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-(trifluoromethoxy)benzoate 91: A mixture of methyl 4-(5-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-(trifluoromethoxy)benzoate (90, 52 mg, 0.12 mmol), DBU (0.06 ml, 0.48 mmol), and 2-cyclobutylideneacetonitrile (45 mg, 0.48 mmol) in acetonitrile (1 ml) was stirred at 80 °C for 15 h. The reaction was concentrated under reduced pressure and purified by silica gel flash column chromatography (50% ethyl acetate) to give methyl 4-(1-(1-(cyanomethyl)cyclobutyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-(trifluoromethoxy)benzoate (91). MS(ESI)[M+H + ]+ =525.1.

[0490] Step 4: Preparation of 4-(1-(1-(cyanomethyl)cyclobutyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-(trifluoromethoxy)benzoic acid P-0335: To a solution of methyl 4-(1-(1-(cyanomethyl)cyclobutyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-(trifluoromethoxy)benzoate (91, 55 mg, 0.1 mmol) in THF / MeOH (1:1, 1 ml) was added 4.18 M aqueous lithium hydroxide solution (0.050 ml). The reaction was stirred at 70° C. for 3 hours. The reaction was diluted with ethyl acetate, acidified with 1N HCl in MeOH, and concentrated under reduced pressure. The material was purified by reverse-phase silica gel flash column chromatography (0–100% B; A: 5% CH 3 CN, 95%H 2 O, 0.1% HCO 2 H;B:95%CH 3 CN, 5%H 2 O, 0.1% HCO 2 H) to give 4-(1-(1-cyanomethyl)cyclobutyl)-5-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-(trifluoromethoxy)benzoic acid (P-0335). MS (ESI) [M+H + ] + =511.0.

[0491] Example 20 [ka] Step 1: Preparation of 3-(cyclobutylmethyl)-6-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)-1H-pyrrolo[3,2-b]pyridine 93: Mix 3,5-dimethyl-4H-1,2,4-triazole (0.50 g, 5.2 mmol), 6-bromo-3-(cyclobutylmethyl)-1H-pyrrolo[3,2-b]pyridine (92) in toluene (5 mL) and DMF (5 ML). , 1.0 g, 3.8 mmol, prepared in two steps from 6-bromo-1H-pyrrolo[3,2-b]pyridine and cyclobutanecarbaldehyde in a similar manner to compound 55 shown in Example 12), trans N,N'-dimethylcyclohexane-1,2-diamine (1.1 mL, 7.0 mmol), and cesium carbonate (2.5 g, 7.67 mmol) were purged with nitrogen and stirred at 130 °C for 3 days. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was collected, washed with brine, and dried over anhydrous sodium sulfate. After removing the drying agent and solvent, the residue was purified by silica gel column chromatography to give 3-(cyclobutylmethyl)-6-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)-1H-pyrrolo[3,2-b]pyridine (93). MS (ESI) [M+H + ] + =282.1.

[0492] Step 2: Preparation of 4-(3-(cyclobutylmethyl)-6-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-3,5-diethoxybenzoic acid P-0270: 3-(cyclobutylmethyl)-6-(3,5-dimethyl-4H-1,2,4-triazol-4-yl) in toluene (5 ml) and DMF (5 ml) A mixture of 93-1H-pyrrolo[3,2-b]pyridine (93, 200 mg, 0.71 mmol), methyl 4-bromo-3,5-diethoxybenzoate (300 mg, 0.99 mmol), copper(I) iodide (30 mg, 1.58 mmol), and trans N,N'-dimethylcyclohexane-1,2-diamine (300 ul, 1.9 mmol) was purged with nitrogen and stirred overnight at 120 °C. The reaction mixture was filtered and the filtrate was analyzed by reverse phase HPLC (C18; 0-100% B; A: 5% CH3 CN, 95%H 2 O, 0.1% HCO 2 H;B:95%CH 3 CN), 5%H 2 O, 0.1% HCO 2 H) to give 4-(3-(cyclobutylmethyl)-6-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-3,5-diethoxybenzoic acid (P-0270). MS (ESI) [M+H + ] + =490.1.

[0493] Example 21 [ka] Step 1: Preparation of tert-butyl 6-bromo-3-(cyclobutylmethyl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylate 95: 6-Bromo-3-(cyclobutylmethyl)-1H-pyrrolo[3,2-c]pyridine (94, 300 mg, 1.13 mmol, prepared in two steps from 6-bromo-1H-pyrrolo[3,2-c]pyridine and cyclobutanecarbaldehyde in a similar manner to compound 55 shown in Example 12), di-tert-butyl dicarbonate (370 mg, 1.70 mmol), DMAP (14 mg, 0.11 mmol), and trimethylamine (0.79 ml, 5.66 mmol) were dissolved in THF and stirred at room temperature for 3 hours. The reaction was then partitioned between ethyl acetate and aqueous ammonium chloride. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered, and then loaded onto silica gel. The material was purified by silica gel flash column chromatography (0 to 50% ethyl acetate in hexanes) to give tert-butyl 6-bromo-3-(cyclobutylmethyl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (95).

[0494] Step 2: Preparation of 4-(3-(cyclobutylmethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-3,5-dimethylisoxazole 96: tert-Butyl 6-bromo-3-(cyclobutylmethyl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (95, 250 mg, 0.68 mmol), 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxazole Borolan-2-yl)isoxazole (343 mg, 1.54 mmol), 2.5 M aqueous potassium carbonate (0.55 ml), and 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (50 mg, 0.061 mmol) were combined in acetonitrile and dioxane, then flushed with argon and irradiated to 125°C in a microwave reactor for 1 hour. The reaction was then filtered through Celite and partitioned between ethyl acetate and aqueous ammonium chloride. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. This material was dissolved in DCM (3 ml) and trifluoroacetic acid (0.53 ml, 6.84 mmol). The reaction was stirred for 2 hours and then concentrated under reduced pressure. The resulting material was dissolved in ethyl acetate and washed with aqueous sodium bicarbonate. The organic layer was further washed with brine before being dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure and the material was purified by silica gel flash column chromatography (0-5% methanol in DCM) to give 4-(3-(cyclobutylmethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-3,5-dimethylisoxazole (96).

[0495] Step 3: Preparation of 3,5-dichloro-4-(3-(cyclobutylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-c]pyridin-1-yl)benzoic acid P-0149: 4-(3-(cyclobutylmethyl)-1H-pyrrolo[3,2-c]pyridin-6-yl)-3,5-dimethylisoxazole (96, 20 mg, 0.071 mmol), 3,5-dichloro-4-fluorobenzoic acid (22 mg, 0.107 mmol), and cesium carbonate (51 mg, 0.16 mmol) were combined in DMSO (0.8 ml) and stirred at 85° C. for 5 hours. The reaction was then filtered through cotton wool and partitioned between ethyl acetate and aqueous ammonium chloride. The organic layer was washed with water, then brine, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure and the material was purified by silica gel flash column chromatography (0-10% methanol in DCM) to give partially pure material which was purified by reverse phase HPLC (C18; 0-100% B; A: 5% CH 3 CN, 95%H 2 O, 0.1% HCO 2 H;B:95%CH 3 CN, 5%H 2 O, 0.1% HCO 2 Further purification by MS (ESI) [M+H] afforded 3,5-dichloro-4-(3-(cyclobutylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-c]pyridin-1-yl)benzoic acid (P-0149). + ] + =471.0.

[0496] All of the compounds in Table 1 below can be prepared by following the synthetic examples described in this disclosure and making any necessary substitutions of starting materials that can be obtained commercially or otherwise by one of ordinary skill in the art. [Table 2-1] [Table 2-2] [Table 2-3]

Table 2-4

Table 2-5

Table 2-6

Table 2-7

Table 2-8

Table 2-9

Table 2-10

Table 2-11

Table 2-12

Table 2-13

Table 2-14

Table 2-15

Table 2-16

Table 2-17

Table 2-18

Table 2-19

Table 2-20

Table 2-21

Table 2-22

Table 2-23

Table 2-24

Table 2-25

Table 2-26

Table 2-27

Table 2-28

Table 2-29

Table 2-30

Table 2-31

Table 2-32

Table 2-33

Table 2-34

Table 2-35

Table 2-36

Table 2-37

Table 2-38

Table 2-39

Table 2-40

Table 2-41

Table 2-42

Table 2-43

Table 2-44

Table 2-45

Table 2-46

Table 2-47

Table 2-48

Table 2-49

Table 2-50

Table 2-51

Table 2-52

Table 2-53

Table 2-54

Table 2-55

Table 2-56

Table 2-57

Table 2-58

Table 2-59

Table 2-60

Table 2-61

Table 2-62

Table 2-63

Table 2-64

Table 2-65

Table 2-66

Table 2-67

Table 2-68

Table 2-69

Table 2-70

Table 2-71

Table 2-72

Table 2-73

Table 2-74

Table 2-75

Table 2-76

Table 2-77

Table 2-78

Table 2-79

Table 2-80

Table 2-81

Table 2-82

Table 2-83

Table 2-84

Table 2-85

Table 2-86

Table 2-87

Table 2-88

Table 2-89

Table 2-90

Table 2-91

Table 2-92

Table 2-93

Table 2-94

Table 2-95

Table 2-96

Table 2-97

Table 2-98

Table 2-99

Table 2-100

Table 2-101

Table 2-102

Table 2-103

Table 2-104

[0497] Biological Examples Biological Test Methods The following assays were used to test the compounds of the present disclosure. EP300 Alphascreen binding assay Binding of compounds of formula (I) to EP300 was assessed using the Alphascreen™ binding assay. Inhibition of the interaction between EP300 bromodomain and its acetylated target protein was quantitatively measured using recombinant EP300 protein, acetylated histone 3 peptide, and AlphaScreen™ technology. In the absence of inhibition, EP300 protein bound to AlphaScreen™ nickel chelate acceptor beads may interact with acetylated histone 3 peptide immobilized by AlphaScreen™ streptavidin coated beads. This interaction brings the donor and acceptor beads into close proximity. Due to the close proximity, singlet oxygen generated by laser excitation of the donor beads can reach the acceptor beads and generate a luminescent signal. EP300 inhibitors result in a decrease in the proximity signal through inhibition of the EP300-acetylated peptide interaction.

[0498] Recombinant human EP300 containing the bromodomain (EP300-BD(1040-1161)) was prepared and purified as described in the Protein Expression and Purification session. The peptide was synthesized from human histone H3 45~64 K56 Ac -Biotin (Anaspec CA, USA).

[0499] EP300 assay protocol: All components were prepared in a buffer consisting of 50 mM HEPES pH 7.5, 50 mM NaCl, 0.01% BSA, 0.01% Triton X-100, 2 mM DTT. Test compounds and DMSO vehicle were diluted 1:50 in the buffer and a volume of 4 μL was transferred to an Alphaplate. 5.5 μL of EP300 protein and 5.5 μL of peptide were added to wells containing 4 μL of various concentrations of test compounds of formula (I) or DMSO vehicle in an Alphaplate (PerkinElmer GA, USA) and incubated for 1 hour at room temperature. Then, 5 μL of a mixture of donor and acceptor beads was added at a final concentration of 7.5 μg / ml. 60 minutes after the addition of the beads, the alpha signal is read on an Envision spectrometer (lambda Ex 680nm, λ Em The final concentrations of bromodomain proteins and peptides are as shown below. [Table 3]

[0500] All data were normalized to the average of 16 high and 16 low control wells on each plate. A four parameter curve fit of the following formula was then applied:

number

[0501] Protein expression and purification Recombinant human EP300 bromodomain (EP300-BD(1040–1161)) was expressed in E. coli cells (modified pET vector) with an N-terminal 6-His tag and purified using a combination of both IMAC (Ni-affinity) and size-exclusion chromatography steps.

[0502] Recombinant EP300 protein was expressed using E. coli strain BL21-CodonPlus(DE3) (Agilent Technologies CA, USA). Cells were grown in Terrific Broth (TB) medium at 37°C until OD600 reached 0.7, at which point the temperature was reduced to 18°C ​​and protein was harvested by induction with 1.0 mM isopropyl-β-D-thiogalactopyranoside ("IPTG") for 20 hours and centrifugation at 8500 x g for 20 minutes. Cells were cultured in 0.1 MK 1000 mL PBS containing 0.2 mg / ml lysozyme, 0.2 mM phenylmethanesulfonyl fluoride ("PMSF"), 25 μg / ml DNase I, and 0.5 mM phenylmethanesulfonyl fluoride ("PMSF"), ... 2 PO 4 The cells were resuspended in pH 8.0, 250 mM NaCl, 10% glycerol, 0.75% NP-40, 25 mM imidazole, incubated on ice for 30 min, and lysed with a cell disrupter (MicroFluidics MA, USA). The lysate was clarified by centrifugation at 20,000×g for 1 h. Proteins were captured with Ni-NTA resin (Life Technologies, USA). Contaminating proteins were washed off with 50 mM HEPES pH 7.5, 500 mM NaCl, and 5% glycerol. After three washing steps, proteins were stepwise eluted using 10, 25, 50, 100, 150, and 250 mM imidazole in 50 mM HEPES pH 7.5, 500 mM NaCl, and 5% glycerol. The protein was further purified using a size exclusion column (26 / 600 Superdex 200, GE Biosciences NJ, USA) in 10 mM HEPES pH 7.5, 500.

[0503] BRD4 Alphascreen binding assay Binding of compounds of formula (I) to BRD4 was assessed using the Alphascreen binding assay. Inhibition of the interaction between BRD4 and its acetylated target protein was quantitatively measured using recombinant BRD4 protein, acetylated histone 4 peptide, and AlphaScreen™ technology. In the absence of inhibition, BRD4 protein bound to AlphaScreen™ nickel-chelating acceptor beads may interact with acetylated histone 4 peptide immobilized by AlphaScreen™ streptavidin-coated beads. This interaction brings the donor and acceptor beads into close proximity. Due to the close proximity, singlet oxygen generated by laser excitation of the donor beads can reach the acceptor beads and generate a luminescence signal. BRD4 inhibitors result in a decrease in the proximity signal through inhibition of the BRD4-acetylated peptide interaction.

[0504] Recombinant human BRD4 containing the bromodomain (BRD4-BD12(1-477)) was prepared and purified as described in the Protein Expression and Purification session. The peptide was synthesized from human histone H4 1~21 K5 Ac K8 Ac K12 Ac K16 Ac -biotin (Anaspec CA, USA).

[0505] Protocol for the BRD4 assay: All components are prepared in a buffer consisting of 50 mM HEPES pH 7.5, 50 mM NaCl, 0.01% BSA, 0.01% Triton X-100, 2 mM DTT. Test compounds and DMSO vehicle were diluted 1:50 in the buffer and a volume of 4 μL was transferred to an Alphaplate. 5.5 μL of bromodomain protein and 5.5 μL of peptide were added to wells containing 4 μL of various concentrations of test compounds of formula (I) or DMSO vehicle in an Alphaplate (PerkinElmer GA, USA) and incubated for 1 hour at room temperature. Then, 5 μL of a mixture of donor and acceptor beads was added at a final concentration of 7.5 μg / ml. Thirty minutes after the addition of the beads, the alpha signal was read on an Envision spectrometer (λ Ex 680nm, λ Em The final concentrations of bromodomain proteins and peptides are as shown below. [Table 4]

[0506] All data were normalized to the average of 16 high and 16 low control wells on each plate. A four parameter curve fit of the following formula was then applied:

number

[0507] Protein expression and purification Recombinant human BRD4 containing dual bromodomains (BRD4-BD12(1–477)) was expressed in E. coli cells (modified pET vector) with an N-terminal 6-His tag and purified using a combination of both IMAC (Ni-affinity) and size-exclusion chromatography steps.

[0508] Recombinant BRD4 was expressed using E. coli strain BL21-CodonPlus(DE3) (Agilent Technologies CA, USA). Cells were grown in Terrific Broth (TB) medium at 37°C until an OD600 of 2.0 was reached, at which point the temperature was reduced to 18°C ​​and protein was harvested by induction with 0.1 mM isopropyl-β-D-thiogalactopyranoside ("IPTG") for 12-18 hours and centrifugation at 8000×g for 20 minutes. Cells were resuspended in 40 mM Tris-HCl pH 8.0, 0.5 M NaCl, 25 mM imidazole, 5% glycerol, 1 / 200 volume of protease inhibitor cocktail set III (Calbiochem), 5 mM β-mercaptoethanol ("BME"), 0.5 mg / mL lysozyme, and 0.5 mg / mL DNaseI, incubated on ice for 30 minutes, and lysed with a cell disrupter (MicroFluidics MA, USA). Lysates were clarified by centrifugation at 20,000×g for 2 hours. Proteins were captured with Ni-NTA resin (Life Technologies, USA). Contaminating proteins were washed away with 40 mM Tris-HCl pH 8.0, 0.5 M NaCl, 25 mM imidazole, 5% glycerol, and 5 mM BME. After three washing steps, the protein was stepwise eluted in wash buffer containing 50, 100, 150, and 500 mM imidazole. The protein was further purified using a Gel Filtration column 16 / 60 Superdex 200 (GE Biosciences NJ, USA) in 10 mM HEPES pH 8.0, 150 mM NaCl, and 5 mM DTT. Glycerol was added to a final concentration of 12%, and the protein was aliquoted and flash frozen in liquid nitrogen.

[0509] CBP Alphascreen binding assay Binding of compounds of formula (I) to CBP was assessed using the Alphascreen™ binding assay. Inhibition of the interaction between the CBP bromodomain and its acetylated target protein was quantitatively measured using recombinant CBP, acetylated histone 3 peptide, and AlphaScreen™ technology. In the absence of inhibition, CBP protein bound to AlphaScreen™ nickel-chelating acceptor beads may interact with acetylated histone 3 peptide immobilized by AlphaScreen™ streptavidin-coated beads. This interaction brings the donor and acceptor beads into close proximity. Due to the close proximity, singlet oxygen generated by laser excitation of the donor beads can reach the acceptor beads and generate a luminescence signal. CBP inhibitors result in a decrease in the proximity signal through inhibition of the CBP-acetylated peptide interaction.

[0510] Recombinant human CBP containing the bromodomain (CBP-BD(1043-1159)) was prepared and purified as described in the Protein Expression and Purification session. The peptide was human histone H345-64K56Ac-biotin (Anaspec CA, USA).

[0511] Protocol for CBP assay: All components are prepared in a buffer consisting of 50 mM HEPES pH 7.5, 50 mM NaCl, 0.01% BSA, 0.01% Triton X-100, 2 mM DTT. Test compounds and DMSO vehicle were diluted 1:50 in the buffer and a volume of 4 μL was transferred to an Alphaplate. 5.5 μL of CBP protein and 5.5 μL of peptide were added to wells containing 4 μL of various concentrations of test compounds of formula (I) or DMSO vehicle in an Alphaplate (PerkinElmer GA, USA) and incubated for 1 h at room temperature. Then, 5 μL of a mixture of donor and acceptor beads was added at a final concentration of 7.5 μg / ml. 60 min after adding the beads, the alpha signal was read on an Envision spectrometer (λE×680 nm, λEm520-620 nm). Final concentrations of bromodomain proteins and peptides are as indicated below. [Table 5]

[0512] All data were normalized to the average of 16 high and 16 low control wells on each plate. A four parameter curve fit of the following formula was then applied:

number

[0513] Protein expression and purification Recombinant human CBP bromodomain (CBP-BD(1043–1159)) was expressed in E. coli cells (modified pET vector) with an N-terminal 6-His tag and purified using a combination of both IMAC (Ni-affinity) and size-exclusion chromatography steps.

[0514] Recombinant CBP protein was expressed using E. coli strain BL21-CodonPlus(DE3) (Agilent Technologies CA, USA). Cells were grown in Terrific Broth (TB) medium at 37°C until OD600 reached 0.92, at which point the temperature was reduced to 20°C and protein was harvested by induction with 1.0 mM isopropyl-β-D-thiogalactopyranoside ("IPTG") for 20 hours and centrifugation at 8500×g for 20 minutes. Cells were resuspended in 0.1 M K2PO4 pH 8.0, 250 mM NaCl, 10% glycerol, 0.75% NP-40, 25 mM imidazole, containing 0.2 mg / ml lysozyme, 0.2 mM phenylmethanesulfonyl fluoride ("PMSF"), 0.5 β-mercaptoethanol ("BME"), 25 μg / ml DNase I, incubated on ice for 30 minutes, and lysed with a cell disrupter (MicroFluidics MA, USA). Lysates were clarified by centrifugation at 20,000×g for 1 hour. Proteins were captured with Ni-NTA resin (Life Technologies, USA). Contaminating proteins were washed away with 40 mM HEPES pH 7.5, 500 mM NaCl, 5% glycerol, 5 mM imidazole, and 5 mM BME. After three washing steps, the protein was eluted using 40 mM HEPES pH 7.5, 400 mM NaCl, and 400 mM imidazole in 5 mM BME. The protein was further purified using a size exclusion column (26 / 600 Superdex 200, GE Biosciences NJ, USA) in 40 mM HEPES pH 7.5, 250 mM NaCl, 5 mM BME. The protein was aliquoted and flash frozen in liquid nitrogen.

[0515] Table 2 below provides data showing biochemical and / or cellular inhibitory activity for exemplary compounds described herein in Table 1. In Table 2 below, activity is provided as follows: +++=0.0001 μM <IC 50 <1μM;++=1μM <IC 50 <8μM, +=8μM <IC 50 <1000μM. [Table 6-1] [Table 6-2] [Table 6-3] [Table 6-4] [Table 6-5] [Table 6-6] [Table 6-7] [Table 6-8] [Table 6-9] [Table 6-10] [Table 6-11] [Table 6-12] [Table 6-13] [Table 6-14]

[0516] All patents and other references cited in this specification are indicative of the level of skill of those skilled in the art to which this disclosure pertains, and are incorporated by reference in their entirety, including any tables and figures, to the same extent as if each reference was individually incorporated by reference in its entirety.

[0517] Those skilled in the art will readily recognize that the present disclosure is well adapted to obtain the objects and advantages mentioned, as well as those inherent therein. The methods, variations, and compositions described herein as the current representatives of the embodiments described herein are exemplary and are not intended as limitations on the scope of the disclosure. Modifications therein and other uses will occur to those skilled in the art, which are encompassed within the spirit of the disclosure and defined by the scope of the claims.

[0518] It will be readily apparent to those skilled in the art that various substitutions and modifications may be made to the disclosure described herein without departing from the scope and spirit of the disclosure. For example, modifications may be made to provide additional compounds of the disclosed compounds, and / or various administration methods may be used. Thus, such additional embodiments are within the scope of the disclosure and the appended claims.

[0519] The present disclosure illustratively described herein can be suitably implemented in the absence of any element or limitation not specifically described herein. The terms and expressions used are used as terms of description and not for limitation, and are not intended to exclude any equivalents of the features shown and described or any portion thereof, but it should be recognized that various modifications are possible within the scope of the claims. Thus, although the present disclosure has been specifically described by the embodiments and optional features, it should be understood that modifications and variations of the concepts described herein can be resorted to by those skilled in the art, and such modifications and variations are considered to be within the scope of the present disclosure as defined by the appended claims.

[0520] Additionally, when features or aspects of the disclosure have been described in terms of groupings of alternatives, those skilled in the art will recognize that the disclosure therefore also is described in terms of any individual members or subgroups of members of the group described herein.

[0521] Also, unless otherwise indicated, various numerical values ​​are provided in the embodiments, and additional embodiments are described by taking any two different values ​​as the endpoints of a range, such ranges are also within the scope of this disclosure.

[0522] Accordingly, additional embodiments are within the scope of this disclosure and the following claims.

Claims

1. having the formula IV(a) or IV(c): 【Chemistry 16】 During the ceremony, R ５ but, 【Chemistry 17】 and J １ is -C(O)OH or -C(O)OCH ３ and Each J ２ are independently F, Cl, -OCH ３ , -OCHF ２ , O.C.F. ３ , -OCH ２ CF ３ , -OCH ２ CHF ２ , -OCH(CH ３ ) ２ , -CH ２ CH ３ , -OCH ２ CH ３ , -OCH ２ CH ２ CH ３ , and C.H. ３ and -L-R １ but, 【Chemistry 18】 and G １ benzyloxy, -C(=CH ２ ) CH ３ , -C(O)OH, -C(O)NH ２ , —C(O)N(H)-cyclopropyl, cyclopropyl, —CH ２ -Cyclopropyl, cyclopropylalkynylene, -CH ２ -SO ２ -CH ３ , -SO ２ -CH ３ , -(CH ２ ) N(CH ３ ) ２ , -(CH ２ ) ２ -N(CH ３ ) ２ , -CH ２ -Cyclopropyl, -(CH ２ ) ２ -CN, -C(O)OC(CH ３ ) ３ , -C(O)CH ３ , -C(O)C(CH ３ ) ３ , -CH ２ C(O)N(CH ３ ) ２ , CN, or -SO ２ CH ３ and Each G ２ is independently -OCHF ２ , -OCH ２ F, Cl, F, -OCH ３ , OH, -OCF ３ , C.H. ３ , -CH(CH ３ ) ２ , C.F. ３ , CN, -CH ２ C.N., C.H. ２ C (CH ３ ) ２ (OH), and -C(CH ３ ) ２ -OH; 10. The compound of claim 1, or a pharma- ceutically acceptable salt, solvate, tautomer, stereoisomer, or deuterated analog thereof.

2. -L-R １ But, the following formula 2. The compound of claim 1, wherein:

3. A compound selected from Table 1 below, or a pharma- ceutically acceptable salt thereof. 【Table 1】

4. Below formula: The compound according to claim 3, represented by:

5. Below formula: The compound according to claim 3, represented by:

6. Below formula: The compound according to claim 3, represented by:

7. Below formula: The compound according to claim 3, represented by:

8. Below formula: The compound according to claim 3, represented by:

9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 8 or a pharma- ceutically acceptable salt thereof and a pharma- ceutically acceptable carrier.

10. 10. The pharmaceutical composition of claim 9, further comprising one or more additional therapeutic agents.

11. 11. The pharmaceutical composition of claim 9 or 10 for treating a disease or condition mediated by EP300 or CBP.

12. The pharmaceutical composition of claim 11, wherein the disease or condition is a cancer with an inactivating mutation in CBP or EP300, or a cancer with activation of EP300 or CBP.

13. 12. The pharmaceutical composition of claim 11, wherein the disease or condition is an androgen receptor expressing cancer.

14. The pharmaceutical composition of claim 11, wherein the disease or condition is a neoplastic disorder, a cancer, an age-related disease, an inflammatory disorder, a cognitive disorder, and / or a neurodegenerative disease.

15. The disease or condition is selected from the group consisting of acral lentiginous melanoma, acute eosinophilic leukemia, acute erythroblastic leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, bladder cancer, adenocarcinoma, adult T-cell leukemia / lymphoma, aggressive NK cell leukemia, AIDS-related lymphoma, anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, B-cell chronic lymphocytic leukemia, B-cell prolymphocytic leukemia, B-cell lymphoma, bone cancer, Burkitt's lymphoma, cutaneous T-cell lymphoma, colorectal cancer, diffuse large B-cell lymphoma, enteropathy-associated T-cell lymphoma, follicular lymphoma, glioblastoma multiforme, glioma, gastric cancer, hepatosplenic T-cell lymphoma, Hodgkin's lymphoma 12. The pharmaceutical composition of claim 11, wherein the cancer is selected from the group consisting of non-Hodgkin's lymphoma, leukemia, lymphoma, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, small cell lung cancer, non-small cell lung cancer, MALT lymphoma, malignant peripheral nerve sheath tumor, mantle cell lymphoma, marginal zone B-cell lymphoma, mast cell leukemia, breast cancer, medulloblastoma, melanoma, Merkel cell carcinoma, mesothelioma, multiple myeloma, neuroblastoma, neurofibroma, nodular melanoma, osteosarcoma, ovarian cancer, precursor T-lymphoblastic lymphoma, primary central nervous system lymphoma, primary effusion lymphoma, prostate cancer, pancreatic cancer, skin cancer, T-cell lymphoma, uveal melanoma, Alzheimer's disease, Parkinson's disease, and colorectal cancer.

16. 12. The pharmaceutical composition of claim 11, wherein the disease or condition is small cell lung cancer, non-small cell lung cancer, bladder cancer, non-Hodgkin's lymphoma, acute myeloid leukemia, multiple myeloma, diffuse large B-cell lymphoma, breast cancer, or prostate cancer.

17. 16. The pharmaceutical composition of claim 15, wherein the disease or condition is Alzheimer's disease or Parkinson's disease.

18. 18. The pharmaceutical composition of any of claims 11 to 17, further comprising one or more additional therapeutic agents.

19. 20. The pharmaceutical composition of claim 18, wherein the one or more additional therapeutic agents are one or more of i) alkylating agents, ii) antibiotics, iii) antimetabolites, iv) immunotherapeutics, v) hormones or hormone antagonists, vi) taxanes, vii) retinoids, viii) alkaloids, ix) anti-angiogenic agents, x) topoisomerase inhibitors, xi) kinase inhibitors, xii) target signal transduction inhibitors, xiii) biological response modifiers, xiv) IDO inhibitors, and xv) chemotherapeutic agents, xvi) Mek inhibitors, xvii) tyrosine kinase inhibitors, xviii) c-Kit mutant inhibitors, xix) EGFR inhibitors, XX) PD-1 inhibitors, or xxi) epigenetic modulators.

20. The additional therapeutic agent is: an alkylating agent selected from adozelin, altretamine, bizelin, busulfan, carboplatin, carboquone, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, estramustine, fotemustine, hepsulfam, ifosfamide, improsulfan, irofulven, lomustine, mechlorethamine, melphalan, oxaliplatin, piposulfan, semustine, streptozocin, temozolomide, thiotepa, and threosulfan; an antibiotic selected from bleomycin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, menogaril, mitomycin, mitoxantrone, neocarzinostatin, pentostatin, and plicamycin; an antimetabolite selected from the group consisting of azacitidine, capecitabine, cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, 5-fluorouracil, ftorafur, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, nelarabine, pemetrexed, raltitrexed, thioguanine, and trimetrexate; an immunotherapeutic agent selected from a PD-1 or PD-L1 inhibitor; a hormone or hormone antagonist selected from the group consisting of enzalutamide, abiraterone, anastrozole, androgens, buserelin, diethylstilbestrol, exemestane, flutamide, fulvestrant, goserelin, idoxifene, letrozole, leuprolide, mazestrol, raloxifene, tamoxifen, and toremifene; A taxane selected from DJ-927, docetaxel, TPI 287, paclitaxel, and DHA-paclitaxel. a retinoid selected from alitretinoin, bexarotene, fenretinide, isotretinoin, and tretinoin; an alkaloid selected from etoposide, homoharringtonine, teniposide, vinblastine, vincristine, vindesine, and vinorelbine; an antiangiogenic agent selected from AE-941 (GW786034, Neovastat), ABT-510, 2-methoxyestradiol, lenalidomide, and thalidomide; a topoisomerase inhibitor selected from amsacrine, edotecarin, exatecan, irinotecan, SN-38 (7-ethyl-10-hydroxy-camptothecin), rubitecan, topotecan, and 9-aminocamptothecin; a kinase inhibitor selected from erlotinib, gefitinib, flavopiridol, imatinib mesylate, lapatinib, sorafenib, sunitinib malate, AEE-788, AG-013736, AMG706, AMN107, BMS-354825, BMS-599626, UCN-01 (7-hydroxystearosporine), vemurafenib, dabrafenib, trametinib, cobimetinib, selumetinib, and vatalanib; a targeted signal transduction inhibitor selected from bortezomib, geldanamycin, and rapamycin; a biological response modifier selected from imiquimod, interferon-α and interleukin-2; a chemotherapeutic agent selected from 3-AP (3-amino-2-carboxaldehyde thiosemicarbazone), altrasentan, aminoglutethimide, anagrelide, asparaginase, bryostatin-1, cilengitide, elesclomol, eribulin mesylate (E7389), ixabepilone, lonidamine, masoprocol, mitoguanazone, oblimersen, sulindac, testolactone, tiazofurin, mTOR inhibitors, PI3K inhibitors, Cdk4 inhibitors, Akt inhibitors, Hsp90 inhibitors, farnesyltransferase inhibitors, or aromatase inhibitors (anastrozole letrozole exemestane); 20. The pharmaceutical composition of claim 19, wherein

21. the one or more additional therapeutic agents (a) DNA methyltransferase, (b) histone or protein methyltransferases; (c) histone demethylase, (d) histone deacetylase inhibitors, (e) histone acetyltransferase, (f) other chromatin remodelers, and (g) a BET inhibitor.

22. 22. The pharmaceutical composition of claim 21, wherein the epigenetic modulator is a histone deacetylase inhibitor selected from the group consisting of vorinostat, romidepsin, chidamide, panobinostat, belinostat, valproic acid, mocetinostat, abexinostat, entinostat, resminostat, gibinostat, and xinostat.

23. 22. The pharmaceutical composition of claim 21, wherein the epigenetic modulator is a BRD4 inhibitor.

24. 19. The pharmaceutical composition of claim 18, wherein the one or more additional therapeutic agents is a PD-1 inhibitor, quizartinib, enzalutamide, abiraterone, or a BRD4 inhibitor.

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