Condensed azine for EP300 or CBP regulation and indications thereof

Abstract

The present invention discloses 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 embodiment described in the present disclosure; compositions thereof; and uses thereof.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit under 35 U.S.C. §119(e) of U.S. Provisional Application Serial No. 62 / 831,622, filed on April 9, 2019, which is hereby incorporated by reference in its entirety. Technical Field

[0003] The present invention relates to organic compounds that can be used for treating mammals, particularly for regulating EP300 or CBP in various diseases associated with overexpression of EP300 or CBP. Background Art

[0004] Adenovirus E1A related 300kDa protein (EP300, also referred to as P300 or KAT3B) and CREB binding protein (CBP, also referred to as CREBBP or KAT3A) have homologous transcriptional coactivators containing bromodomains, which are assembled with other proteins to cause the start of specific gene expression. More specifically, EP300 and CBP are histone acetyltransferases (HATs), which acetylate both histones and non-histones that play a role in gene expression regulation, transcription and cell cycle regulation. The acetylation state of lysine residues in histone tails is one of many epigenetic post-translational modifications that change DNA templated processes, such as transcription, to promote malignant transformation. Protein acetylation also helps to block polyubiquitination, thereby preventing protein body 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 Jan 21; 35(3): 279–289). Bromodomains (including BDR4) are readers of acetyl marks in histone tails written by EP300 / CBP, and therefore, bromodomains, EP300, and CBP all share the same pathway in the regulation of 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 transcriptional and cell cycle regulation, as well as the products of oncogenes and fusion genes (Giotopoulos et al., 2016).

[0005] It has been found that inhibition of CBP or EP300 has an inhibitory effect on the growth 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). Inactivating mutations of acetyltransferase genes in B-cell lymphomas have been further reported. (Mullighan et al., CREBBP mutations in relapsed acute lymphoblastic leukemia, Nature, 2011; 471(7337): 235-9.)

[0006] It has also been reported that CBP or EP300 inhibition abolishes the viability of multiple myeloma cell lines due to direct transcriptional inhibition of the lymphocyte-specific transcription factor IRF4, which is essential for myeloma cell viability, and that CBP / EP300 inhibition is a viable therapeutic strategy to target the IRF4 network in multiple myeloma and other lymphoid malignancies that rely on the IRF4 network (Conery et al., Bromodomain inhibition of the transcriptional coactivators CBP / EP300 as atherapeutic strategy to target the IRF4 network in multiple myeloma. https: / / doi.org / 10.7554 / eLife.10483.001).

[0007] EP300 inhibition can also stimulate autophagy to produce anti-aging effects. For example, spermidine is a polyamine agent that delays age-related diseases and death by acting as an EP300 inhibitor that stimulates autophagy to produce anti-aging effects (Madeo et al., Spermidine delays ageing in humans, Aging, 2018, Vol. 10 No. 8).

[0008] It has also been shown that inhibition of CBP or EP300 can downregulate the expression of AR (androgen receptor)-dependent cancer cells, which has been confirmed 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).

[0009] Therefore, compounds that can inhibit EP300 or CBP represent a new class of potential therapeutic agents that can modulate histone acetyltransferases (HATs) that acetylate histones and non-histone proteins. Since there are currently no approved EP300 or CBBP inhibitors for the treatment or prevention of human disease, there is an unmet need for new compounds that can modulate EP300 or CBP. Summary of the invention

[0010] One embodiment of the present disclosure relates to novel compounds as described in any of the embodiments herein, or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer or deuterated analog thereof, wherein these novel compounds can modulate EP300 or CBP.

[0011] Another embodiment of the present disclosure relates to a compound of formula I:

[0012]

[0013] Among them A 1 , A 2 , A 3 , A 4 , R 4 , X 1 , X 2 or X 3 As described in any of the embodiments described in the present disclosure.

[0014] Other embodiments and subembodiments of Formula I are further described in this disclosure.

[0015] Another embodiment of the present disclosure is directed to a pharmaceutical composition comprising a compound according to Formula I or any embodiment and sub-embodiment of Formula I described in the present disclosure, or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer or deuterated analog of any of these compounds, and a pharmaceutically acceptable carrier or excipient.

[0016] Another embodiment of the present disclosure is directed to a pharmaceutical composition comprising a compound according to Formula I, or any embodiment of Formula I described in the present disclosure, or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or deuterated analog of any of these compounds, and another therapeutic agent.

[0017] Another embodiment of the present disclosure is directed 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 described in the present disclosure, or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer, or deuterated analog of any of these compounds, or a pharmaceutical composition of any of the compounds as described in the present disclosure, wherein the disease or condition comprises abnormal or other expression of EP300 or CBP, or an activating mutation or translocation of any of the foregoing.

[0018] Additional embodiments are further described in the detailed description of the disclosure. DETAILED DESCRIPTION

[0019] I. Definitions

[0020] As used herein, unless expressly stated otherwise, the following definitions apply:

[0021] It is noted herein that as used herein and the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise.

[0022] Unless the point of attachment is otherwise indicated, the chemical moieties listed in the definitions of the variables of Formula I of the present disclosure and all embodiments thereof should be read from left to right, with the right-hand side directly attached to the parent structure being defined. However, if the point of attachment (e.g., a dash "-") is shown on the left side of the chemical moiety (e.g., -alkoxy-(C 1 -C 25 )alkyl), the left side of the chemical moiety is directly attached to the defined parent moiety.

[0023] It is assumed that when the general description of the compounds described herein is considered for the purpose of constructing compounds, such construction results in the generation of stable structures. That is, one of ordinary skill in the art will recognize that, in theory, some constructs are not generally considered to be stable compounds (that is, sterically practical and / or synthetically feasible).

[0024] Unless otherwise indicated, "alkyl" by itself or as part of another substituent means a straight or branched chain hydrocarbon (i.e., C 1-6Meaning one to six carbons). Representative alkyl groups include straight and branched chain alkyl groups with 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. Other representative alkyl groups include straight and branched chain alkyl groups with 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, etc. For each of the definitions herein (e.g., alkyl, alkoxy, arylalkyl, cycloalkylalkyl, heterocycloalkylalkyl, heteroarylalkyl, etc.), when the prefix indicating the number of carbon atoms in the alkyl portion is not included, the alkyl portion or a portion thereof will have 12 or less main chain carbon atoms, or 8 or less main chain carbon atoms, or 6 or less 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 includes but is not limited to -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 6 Alkyl. While it is understood that when optionally substituted alkyl is the R group of a moiety such as -OR (e.g., alkoxy), -SR (e.g., thioalkyl), -NHR (e.g., alkylamino), -C(O)NHR, etc., the substitution is attached at any atom that is available to produce a stable compound, substitution of the alkyl R group is such that substitution of an alkyl carbon bound to any O, S, or N (except where N is a heteroaryl ring atom) of the moiety excludes substituents that would result in any O, S, or N (except where N is a heteroaryl ring atom) of the substituent being bound to an alkyl carbon bound to any O, S, or N of the moiety.

[0025] "Alkylene" by itself or as part of another substituent means a straight or branched chain saturated divalent hydrocarbon moiety derived from an alkane having the number of carbon atoms indicated in the prefix. 1-6 Refers to one to six carbons; C 1-6 Alkylene refers to methylene, ethylene, propylene, 2-methylpropylene, pentylene, hexylene, etc.). 1-4 Alkylene includes methylene -CH 2 -, ethylene-CH 2 CH 2 -、propylene-CH 2 CH 2 CH 2 - and isopropylidene-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, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer, 8 or fewer, or 6 or fewer carbon atoms. When a prefix indicating the number of carbon atoms in the alkylene portion is not included, the alkylene portion or a 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, 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.

[0026] "Alkenyl" refers to a straight or branched monovalent hydrocarbon radical having the number of carbon atoms indicated in the prefix and containing at least one double bond. 2 -C 6 Alkenyl means ethenyl, propenyl, etc. 2 -C 6 Alkenyl C 1 -C 6 "Alkylene" is a group -C 1 -C 6 Alkylene-C 2 -C 6Alkenyl, wherein alkenyl and alkylene are as defined herein.

[0027] The term "alkenylene" refers to a straight or branched chain divalent hydrocarbon radical containing at least one double bond and having the number of carbon atoms indicated in the prefix.

[0028] The term "alkynyl" refers to a monovalent radical of an unsaturated hydrocarbon having, in some embodiments, 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, alkynyl groups include ethynyl (-C≡CH), propargyl (or propynyl, e.g., -C≡CCH 3 ) etc. When a prefix indicating the number of carbon atoms in the alkenyl or alkynyl moiety is not included, the alkenyl or alkynyl moiety or a 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, or 4 or fewer main chain carbon atoms.

[0029] The term "alkynylene" refers to a straight or branched chain 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 ethenyl, 2-propenyl, crotyl, 2-isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1-propynyl and 3-propynyl, 3-butynyl, and higher carbon homologs and isomers.

[0030] "Alkoxy" refers to an -O-alkyl group, where alkyl is as defined herein. For example, "C 1 -C 6 "Alkoxy" refers to -OC 1 -C 6 Alkyl groups, wherein alkyl is as defined herein. While it is understood that substitutions on alkoxy groups are attached at any atom that is available to produce a stable compound, substitutions on alkoxy groups are such that O, S, or N (except where N is a heteroaryl ring atom) are not bound to an alkyl carbon bound to the alkoxy O. Furthermore, in cases where alkoxy is described as a substituent of another moiety, the alkoxy oxygen is not bound to a carbon atom bound to O, S, or N (except where N is a heteroaryl ring atom) of the other moiety, or to an alkene or alkyne carbon of the other moiety.

[0031] The terms "alkoxyalkyl" and "alkoxyalkylene" refer to an alkyl group substituted with an alkoxy group. For example, "C 1 -C 6 Alkoxy C 1 -C 6 "Alkyl" refers to a C 1 -C6 Alkoxy substituted C 1 -C 6 alkyl, wherein alkyl and alkoxy are as defined herein, and “C 1 -C 3 Alkoxy C 1 -C 3 "Alkylene" refers to a C 1 -C 3 Alkoxy substituted C 1 -C 3 Alkyl, wherein alkylene and alkoxy are as defined herein.

[0032] "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 "Alkylsulfonylalkylene" refers to the group alkylene-S(O) 2 -alkyl, e.g., C 1 -C 6 Alkylsulfonyl C 1 -C 6 Alkylene is -C 1 -C 6 Alkylene-S(O) 2 -C 1 -C 6 alkyl.

[0033] "Amino" or "amine" refers to the group -NH 2 .

[0034] "Alkylamino" refers to a -NH-alkyl group, wherein alkyl is as defined herein. Exemplary alkylamino groups include CH 3 NH-, ethylamino, etc. For example, C 1 -C 6 Alkylamino refers to -N(H)C 1 -C 6 alkyl.

[0035] The terms "aminoalkyl" and "aminoalkylene" refer to -alkylene-NH 2 For example, C 1 -C 6 Aminoalkyl refers to -C 1 -C 6 Alkyl-NH 2 "Alkylaminoalkylene" refers to an -alkylene-NH-alkyl group, for example, C 1 -C 6 Alkylamino C1 -C 6 Alkylene is a group -C 1 -C 6 Alkylene-NH-C 1 -C 6 alkyl.

[0036] "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. 1 -C 6 Alkylamino refers to -N(C 1 -C 6 alkyl) 2 .

[0037] Unless otherwise indicated, "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, each ring has 3-6, 4-6 and 5-6 ring members, such as cyclopropyl, cyclopentyl, cyclohexyl, wherein one or two of the ring carbon atoms may be optionally substituted with a carbonyl group. In addition, the term cycloalkyl is intended to include ring systems fused to an aromatic ring (e.g., aryl or heteroaryl), regardless of the point of attachment to the rest of the molecule. Cycloalkyl refers to a hydrocarbon ring (e.g., C 2-14-16) having the specified number of ring atoms. 3-6 Cycloalkyl and 3-6 membered cycloalkyl both mean three to six ring carbon atoms). The term "cycloalkenyl" refers to a cycloalkyl group having at least one unsaturated unit. Substituents of the cycloalkyl or cycloalkenyl group may be located at the point of attachment of the cycloalkyl or cycloalkenyl group, thereby forming a quaternary center.

[0038] "Cycloalkylalkyl" and "cycloalkylalkylene" refer to -(alkylene)-cycloalkyl groups, where alkylene, as defined herein, has the indicated number of carbon atoms, or, if not specified, has six or fewer carbon atoms; and cycloalkyl, as defined herein, has the indicated number of carbon atoms, or, if not specified, has 3-10, 3-8, and 3-6 ring members per ring. For example, 4-6 membered cycloalkyl-C 1 -C 6 Alkyl refers to a cycloalkyl group having 4 to 6 carbon atoms attached to an alkylene chain having 1 to 6 carbon atoms, wherein the alkylene chain is attached to the parent moiety. Other exemplary cycloalkylalkyl groups include, for example, cyclopropylmethylene, cyclobutylethylene, cyclobutylmethylene, and the like. "Cycloalkylalkynylene" refers to an -(alkynylene)-cycloalkyl group, for example, C 3 -C 6 Cycloalkyl C 2 -C 6Alkyne is a group -(C 2 -C 6 Alkynylidene)-C 3 -C 6 Cycloalkyl. 3 -C 6 Cycloalkylethynylene" is the group -C≡CC 3 -C 6 Cycloalkyl.

[0039] "Cycloalkylalkoxy" refers to a -(alkoxy)-cycloalkyl radical where alkoxy is as defined herein and has the indicated number of carbon atoms, or, if not specified, has six or fewer carbon atoms; and cycloalkyl is as defined herein and has the indicated number of carbon atoms, or, if not specified, has 3-10, 3-8, or 3-6 ring members per ring. For example, C 3 -C 6 Cycloalkylalkoxy refers to a cycloalkyl group having 3-6 ring carbon atoms attached to an alkoxy group having one to six carbon atoms, wherein the alkoxy chain is attached to the parent moiety. Other exemplary cycloalkylalkoxy groups include, for example, cyclopropylmethoxy, cyclobutylethoxy, cyclobutylmethoxy, and the like.

[0040] The term "cyano" refers to the group -CN. 1 -C 6 "Cyanoalkyl" refers to a C alkyl group as defined herein substituted with 1, 2 or 3 cyano groups. 1 -C 6 Alkyl. "C 1 -C 6 "Cyanoalkylethynylene" is the group -C≡CC 1 -C 6 Cyanoalkyl.

[0041] Unless otherwise indicated, "aryl" by itself or as part of another substituent refers to a monocyclic, bicyclic or polycyclic polyunsaturated aromatic hydrocarbon group containing 6 to 14 ring carbon atoms, which can be a single ring or multiple rings (up to three rings) fused together or covalently linked. However, aryl does not include heteroaryl as defined below or does not overlap with heteroaryl in any way. If one or more aromatic rings are fused to a heteroaromatic ring, the resulting ring system is a heteroaryl. Non-limiting examples of unsubstituted aryl include phenyl, 1-naphthyl and 2-naphthyl. The term "arylene" refers to a divalent aromatic group, wherein aryl is as defined herein.

[0042] "Arylalkyl" or "aralkyl" refers to -(alkylene)-aryl, where the alkylene group is as defined herein and has the indicated number of carbon atoms, or, if unspecified, has six or fewer main chain carbon atoms, or four or fewer main chain carbon atoms; and aryl is as defined herein. Examples of arylalkyl include benzyl, phenethyl, 1-methylbenzyl, and the like. In another example, phenyl-C 1 -C 6 Alkoxy refers to 1 -C 6 A phenyl group attached to an alkoxy group, wherein C 1 -C 6 The alkoxy group is as defined herein and is attached to the parent moiety.

[0043] The term "haloalkyl" refers to an alkyl group substituted with one to seven halogen atoms. The haloalkyl group includes a monohaloalkyl group or a polyhaloalkyl group. For example, the term "C 1 -C 6 The term "haloalkyl" refers to an alkene substituted with one to seven halogen atoms, including trifluoromethyl, difluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like. In addition, the term "haloalkene" refers to an alkene substituted with one to seven halogen atoms.

[0044] "Halogen" or "halo" refers to all halogens, that is, chlorine (Cl), fluorine (F), bromine (Br) or iodine (I).

[0045] The term "haloalkoxy" refers to an alkoxy group substituted with one to seven halogen atoms. Halogenated alkoxy includes monohalogenated alkoxy or polyhalogenated alkoxy. For example, the term "C 1 -C 6 The term "haloalkoxy" refers to trifluoromethoxy, difluoromethoxy, 2,2,2-trifluoroethoxy, 4-chlorobutoxy, 3-bromopropoxy, and the like.

[0046] "Heteroatom" is meant to include oxygen (O), nitrogen (N) and sulfur (S).

[0047] "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 monocyclic aromatic ring radicals 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 a heteroaryl, regardless of the point of attachment (i.e., through either fused ring). Heteroaryl is also intended to include oxidized S or N, such as sulfinyl, sulfonyl, and N-oxides of tertiary ring nitrogens. A carbon or nitrogen atom is the point of attachment of the heteroaryl ring structure such that a stable compound results. Examples of heteroaryl groups include, but are not limited to, pyridyl, pyridazinyl, pyrazinyl, indolizinyl, benzo[b]thiophenyl, quinazolinyl, purinyl, indolyl, quinolinyl, pyrimidinyl, pyrrolyl, pyrazolyl, oxazolyl, thiazolyl, thienyl, isoxazolyl, oxathiadiazolyl, isothiazolyl, tetrazolyl, imidazolyl, triazolyl, furanyl, benzofuranyl, indolyl, triazinyl, The term "nitrogen-containing heteroaryl" refers to a heteroaryl group in which at least one of the heteroatoms is N.

[0048] "Heteroarylalkyl" refers to an -(alkylene)-heteroaryl group in which the alkylene group is as defined herein and has the indicated number of carbon atoms, or, if unspecified, six or fewer backbone carbon atoms, or four or fewer backbone carbon atoms; and heteroaryl is as defined herein.

[0049] "Heterocycloalkyl" refers to a group containing one to five radicals selected from N, O, S (including S(O) and S(O) 2) or P (including phosphine oxide) of the heteroatom saturated or partially unsaturated non-aromatic cycloalkyl group, wherein the nitrogen, sulfur and phosphorus atoms are optionally oxidized, and the nitrogen atom is optionally quaternized, and the remaining ring atoms are C, wherein one or two C atoms may optionally exist as carbonyl. In addition, the term heterocycloalkyl is intended to cover any ring or ring system containing at least one heteroatom that is not a heteroaryl, regardless of the point of attachment to the rest of the molecule. Heterocycloalkyl groups include those having a ring of a formally charge-separated aromatic resonance structure, such as N-methylpyridone. Heterocycloalkyl may be substituted by one or two oxy groups, and may include sulfone and sulfoxide derivatives. Heterocycloalkyl may be a monocyclic, fused bicyclic or fused polycyclic system of 3 to 12, 4 to 10, 5 to 10 or 5 to 6 ring atoms, wherein one to five ring atoms are selected from -N=, -N-, -O-, -S-, -S(O)- or -S(O) 2 -heteroatom, and further one or two of the ring atoms are optionally substituted by -C (O) -groups. For example, 4-6 membered heterocycloalkyl is a heterocycloalkyl having 4-6 ring members with at least one heteroatom. Heterocycloalkyl can also be a heterocycloalkyl ring fused to a cycloalkyl. Non-limiting examples of heterocycloalkyl groups include pyrrolidinyl, piperidinyl, morpholinyl, pyridone groups, etc. The heterocycloalkyl group can be connected to the remainder of the molecule through a ring carbon or a heteroatom. "Heterocycloalkenyl" refers to a heterocycloalkyl having at least one unsaturated unit. The substituent of a heterocycloalkyl or heterocycloalkenyl group can be located at the point of attachment of a heterocycloalkyl or heterocycloalkenyl group, thereby forming a quaternary center.

[0050] "Heterocycloalkylalkyl" or "heterocycloalkyl" refers to an -(alkylene)-heterocycloalkyl group in which the alkylene group is as defined herein and has the indicated number of carbon atoms, or, if unspecified, has six or fewer main chain carbon atoms, or four or fewer main chain carbon atoms; and heterocycloalkyl is as defined herein.

[0051] "Hydroxy" refers to the group -OH. The term "hydroxyalkyl" or "hydroxyalkylene" refers to an alkyl group or alkylene group, respectively, as defined herein, substituted with 1 to 5 hydroxy groups.

[0052] The term "C 1 -C 6 "Haloalkoxy" refers to a C 1 -C 6 Alkoxy.

[0053] The term "oxy" refers to C(=O) or (O). In some embodiments, the two possible points of attachment on the carbon form an oxy group.

[0054] As used throughout this disclosure, "optional substituents" or "optionally substituted" means that substitution on a compound may or may not occur, and the description includes instances where substitution occurs and instances where substitution does not occur. For example, the phrase "optionally substituted with 1-4 J 1 "Group substitution" means J 1 The group may, but need not, be present. It is assumed in this disclosure that optional substitutions on compounds occur in a manner that will result in stable compounds.

[0055] As used herein with respect to compounds of the present disclosure, the term "synthesized" and like terms mean chemically synthesized from one or more precursor materials.

[0056] As used herein, the term "composition" refers to a formulation suitable for administration to an intended animal subject for therapeutic purposes, which contains at least one pharmaceutically active compound and at least one pharmaceutically acceptable carrier or excipient.

[0057] The term "pharmaceutically acceptable" indicates that the indicated substance does not have such properties that, taking into account the disease or condition to be treated and the respective route of administration, the properties would cause a reasonably cautious practitioner to avoid administering the substance to a patient. For example, it is usually required that such a substance be substantially sterile, such as for injectables.

[0058] "Pharmaceutically acceptable salt" refers to a salt that is acceptable for administration to a patient (such as a mammal) (e.g., a salt with acceptable mammalian safety for a given dosage regimen). The form of the expected pharmaceutically acceptable salt includes, but is not limited to, mono-, di-, tri-, tetra-, and the like. Pharmaceutically acceptable salts are non-toxic in the amount and concentration in which they are administered. The preparation of such salts can facilitate pharmacological use by changing the physical characteristics of the compound without preventing it from exerting its physiological effects. Useful changes in physical properties include lowering the melting point to facilitate transmucosal administration and increasing solubility to facilitate administration of higher concentrations of drugs. Depending on the specific substituents found on the compounds described herein, such salts can be derived from pharmaceutically acceptable inorganic or organic bases and derived from pharmaceutically acceptable inorganic or organic acids.

[0059] 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 water-alcohol solution containing an appropriate acid) and then isolated by evaporating the solution. In another example, the salt can be prepared by reacting the free base and the acid in an organic solvent.

[0060] When the compounds of the present disclosure contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds 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.), either neat or in a suitable inert solvent. The desired acid can be, for example, a pyranosidic acid (e.g., glucuronic acid or galacturonic acid), an α-hydroxy acid (e.g., citric acid or tartaric acid), an amino acid (e.g., aspartic acid or glutamic acid), an aromatic acid (e.g., benzoic acid or cinnamic acid), a sulfonic acid (e.g., p-toluenesulfonic acid or ethanesulfonic acid), and the like. In some embodiments, the salts can be derived from pharmaceutically acceptable acids such as acetic acid, trifluoroacetic acid, propionic acid, ascorbic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glycolic acid, gluconic acid, glucuronic 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, aminosulfonic acid, hydroiodic acid, carbonic acid, , tartaric acid, p-toluenesulfonic acid, pyruvic acid, aspartic acid, benzoic acid, cinnamic acid, anthranilic acid, methanesulfonic acid, salicylic acid, p-hydroxybenzoic acid, phenylacetic acid, methylene dihydroxy pamoic acid (pamoic acid), ethanesulfonic acid, benzenesulfonic acid, 2-hydroxyethanesulfonic acid, p-aminobenzenesulfonic acid, stearic acid, cyclohexylsulfamic acid, cyclohexylaminosulfonic acid, quinic acid, alginic acid, hydroxybutyric acid, galactaric acid and galacturonic acid, etc.

[0061] Also included are salts of amino acids such as arginine, and salts of organic acids such as glucuronic acid or galacturonic acid, etc. (see, e.g., Berge, SM et al., "Pharmaceutical Salts," J. Pharmaceutical Science, 1977, 66: 1-19). Certain specific compounds of the present disclosure contain basic and acidic functionalities that allow the compounds to be converted into base or acid addition salts.

[0062] The neutral form of the compound can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. The parent form of the compound differs from the various salt forms in certain physical properties (such as solubility in polar solvents), but for the purposes of this disclosure, these salts are equivalent to the parent form of the compound in other respects.

[0063] Pharmaceutically acceptable salts of different compounds may exist in the form of complexes. Examples of complexes include 8-chlorotheophylline complexes (similar to, for example, dimenhydrinate: diphenhydramine 8-chlorotheophylline (1:1) complex; dimenhydrinate) and various cyclodextrin inclusion compounds.

[0064] The term "deuterated" as used herein alone or as part of a group means a substituted deuterium atom. As used herein alone or as part of a group, the term "deuterated analog" means a substituted deuterium atom in place of hydrogen. Deuterated analogs of the present disclosure can be derivatives that are fully or partially substituted with deuterium. In some embodiments, the deuterated derivatives of the present disclosure include alkyl, aryl or heteroaryl groups that are fully or partially substituted with deuterium.

[0065] The present disclosure also encompasses isotopically labeled compounds of the present disclosure, which are identical to those listed herein, except that one or more atoms are replaced by atoms with an atomic mass or mass number different from the atomic mass or mass number normally 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 may be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, but not limited to, 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 I. Unless otherwise stated, when a position is specifically designated as "H" or "hydrogen", the position is understood to have hydrogen or its isotope, such as deuterium (D) or tritium ( 3 H). Certain isotopically labeled compounds of the present disclosure (e.g., 3 H and 14 C-labeled) 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 because of their ease of preparation and their detectability. In addition, heavier isotopes such as deuterium (i.e., 2 H) may offer certain therapeutic advantages resulting from greater metabolic stability (e.g., prolonged in vivo half-life or reduced dosage requirements) and therefore may be preferred in some circumstances. Isotopically labeled compounds of the present disclosure can generally be prepared by following procedures analogous to those described in the Schemes and Examples herein below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

[0066] "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 compounds of formula I in a manner that allows the modification to be cleaved in vivo to release the parent compound in conventional operations or in vivo. Prodrugs can be developed from prodrug forms to active forms in a single step, or can have one or more intermediate forms that can be active or inactive themselves. Some prodrugs are enzymatically activated to obtain active compounds, or compounds that obtain the active compounds after further chemical reactions. Prodrugs include compounds of formula I, wherein the hydroxyl, amino, carboxyl or sulfhydryl groups in the compounds of formula I are bonded to any group that can be cleaved in vivo to regenerate free hydroxyl, amino or sulfhydryl groups, respectively. Examples of prodrugs include, but are not limited to, esters (e.g., acetate, formate and benzoate derivatives) of hydroxyl functional groups in compounds of formula I, amides, guanidines, carbamates (e.g., N, N-dimethylaminocarbonyl), etc. Other examples of prodrugs include, but are not limited to, carbonates, ureides, solvates or hydrates of active compounds. The preparation, selection, and use of prodrugs are discussed in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems", the ACSSymposium Series Vol. 14; "Design of Prodrugs", H. Bundgaard, ed., Elsevier, 1985; and Bioreversible Carriers in Drug Design, Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, 1987, each of which is incorporated herein by reference in its entirety.

[0067] As described in "The Practice of Medicinal Chemistry" Chapters 31-32 (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 less active than the corresponding active drug compound, and contain one or more protecting groups and are converted to active forms by metabolism or solvent decomposition. 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 itself one of the following types:

[0068] (1) Oxidation reactions: Oxidation reactions are exemplified by, but not limited to, reactions such as: oxidation of alcohol, carbonyl and acid 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.

[0069] (2) Reduction reaction: The reduction reaction is exemplified by, but not limited to, reactions such as the reduction of a carbonyl functional group, the reduction of an alcohol functional group and a carbon-carbon double bond, the reduction of a nitrogen-containing functional group, and other reduction reactions.

[0070] (3) Reactions without Change in Oxidation State: Reactions without Change in Oxidation State are exemplified by, 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, generation of new atomic bonds by dehydration reactions, hydrolytic dehalogenation, removal of hydrogen halide molecules, and other such reactions.

[0071] Carrier prodrugs are drug compounds containing, for example, improved absorption of the site of action and / or the delivery part of the location delivery. For such carrier prodrugs, desirably, the linkage between the drug part and the delivery part is a covalent bond, the prodrug is inactive or less active than the drug compound, and the prodrug and any release delivery part are acceptably nontoxic. For the prodrug in which the delivery part is intended to enhance absorption, typically, the release of the delivery part should be fast. In other cases, it is desirable to utilize a part that provides slow release, such as some polymers or other parts, such as cyclodextrin. (See, for example, Cheng et al., U.S. Patent Publication No. 2004 / 0077595, which is incorporated herein by introduction.) Such carrier prodrugs are generally conducive to oral administration of drugs. For example, carrier prodrugs can be used to improve one or more of the following characteristics: lipophilicity increases, pharmacological effect duration increases, site-specificity increases, toxicity and adverse reactions decrease, and / or the improvement of drug formulations (such as improved stability, water solubility, inhibition of undesirable sensory or physicochemical properties). For example, lipophilicity can be increased by esterifying a hydroxyl group with a lipophilic carboxylic acid or esterifying a carboxylic acid group with an alcohol (eg, an aliphatic alcohol).

[0072] The term "carrier" is also intended to include microspheres, liposomes, micelles, nanoparticles (naturally equipped nanocarriers, such as exosomes), etc. Exosomes are known to be highly efficient drug carriers, and there are various ways in which drugs can be loaded into exosomes, including those techniques described in J Control Release. 2015 Dec 10;219:396-405, the contents of which are incorporated by reference in their entirety.

[0073] Metabolites (e.g., active metabolites) overlap with prodrugs (e.g., bioprecursor prodrugs) as described above. Therefore, such metabolites are pharmacologically active compounds or compounds that are further metabolized to pharmacologically active compounds, which are derivatives produced by metabolic processes in the subject. Among them, active metabolites are such pharmacologically active derivative compounds. For prodrugs, prodrug compounds are generally inactive or less active than metabolites. For active metabolites, the parent compound can be an active compound or can be an inactive prodrug.

[0074] 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.

[0075] "Tautomer" refers to a compound produced by the phenomenon that the proton of one atom of a molecule is transferred to another atom. See Jerry March, Advanced Organic Chemistry: Reactions, Mechanisms and Structures, Fourth Edition, John Wiley & Sons, pages 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 isomeric form. Examples include keto-enol tautomers, such as acetone / propene-2-ol; imine-enamine tautomers, etc.; ring-chain tautomers, such as glucose / 2,3,4,5,6-pentahydroxy-hexanal, etc.; tautomeric forms of heteroaryls containing -N=C(H)-NH-ring atom arrangements, such as pyrazole, imidazole, benzimidazole, triazole and tetrazole. In the case where a compound contains, for example, a keto or oxime group or an aromatic moiety, tautomerism ('tautomerism') may occur. The compounds described herein may have one or more tautomers and therefore include various isomers. One of ordinary skill in the art will recognize that other tautomeric ring atom arrangements are possible. All such isomeric forms of these compounds are explicitly included in the present disclosure.

[0076] "Isomers" refers to compounds with the same molecular formula but different bonding properties or order of their atoms or the arrangement of their atoms in space. Isomers with different atomic arrangements in space are called "stereoisomers". "Stereoisomers" refers to compounds that exist in different stereoisomeric forms, for example, if they have one or more asymmetric centers or have asymmetrically substituted double bonds, and can therefore be produced as individual stereoisomers or as a mixture. Stereoisomers include enantiomers and diastereomers. Stereoisomers that are not mirror images of each other are called "diastereomers", and stereoisomers that are non-superimposable mirror images are called "enantiomers". When a compound has an asymmetric center, for example, an atom (such as carbon) is bonded to four different groups, a pair of enantiomers is possible. Enantiomers can be characterized by the absolute configuration of their asymmetric centers and described by the R- and S- ordering rules of Cahn and Prelog, or described by the way in which the molecule rotates the plane of polarized light and designated as right-handed or left-handed (i.e., (+)-isomers or (-)-isomers, respectively). Chiral compounds can exist as individual enantiomers or as mixtures thereof. A mixture containing equal proportions of enantiomers is referred to as a "racemic mixture". As another example, stereoisomers include geometric isomers, such as the cis- or trans- orientation of substituents on adjacent carbons of a double bond. Unless otherwise indicated, descriptions are intended to include individual stereoisomers and mixtures. Methods for determining stereochemistry and separating 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), differing in the chirality of one or more stereocenters.

[0077] "Hydrate" refers to a complex formed by the combination of water molecules and molecules or ions of a solute. "Solvate" refers to a complex formed by the combination of solvent molecules and molecules or ions of a solute. The solvent can be an organic compound, an inorganic compound, or a mixture of the two. Solvate is meant to include hydrates. Some examples of solvents include, but are not limited to, methanol, N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide, and water. In general, the solvated form is equivalent to the unsolvated form and is encompassed within the scope of the present disclosure.

[0078] In the context of using, testing, or screening for compounds that are or may be modulators, the term "contacting" means bringing the compound into close enough proximity to a specific molecule, complex, cell, tissue, organism, or other specific substance so that a potential binding interaction and / or chemical reaction between the compound and the other specific substance may occur.

[0079] "Assay" refers to creating experimental conditions and collecting data about specific results of exposure to specific experimental conditions. For example, an enzyme can be assayed based on its ability to act on a detectable substrate. A compound can be assayed based on its ability to bind to one or more specific target molecules.

[0080] As used herein, the terms "ligand" and "modulator" are equivalently used to refer to a compound that alters (i.e., increases or decreases) the activity of a target biomolecule, such as an enzyme, such as those described herein. In general, a ligand or modulator will be a small molecule, where "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" is a ligand that has better pharmacological and / or pharmacokinetic properties than a reference compound, where "better" can be defined by one skilled in the relevant art with respect to a particular biological system or therapeutic use.

[0081] The term "binding" with respect to an interaction between a target and a potential binding compound means that the potential binding compound associates with the target to a statistically significant degree compared to its normal association with proteins (i.e., non-specific binding). Thus, the term "binding compound" refers to a compound that associates with a target molecule statistically significantly. In some embodiments, a binding compound has a dissociation constant (K) of 10 mM or less, 1,000 μM or less, 100 μM or less, 10 μM or less, 1 μM or less, 1,000 nM or less, 100 nM or less, 10 nM or less, or 1 nM or less. D ) interacts with a given target. In the context of compound binding to a target, the terms "greater affinity" and "selectivity" mean that the compound binds more tightly, i.e., has a smaller dissociation constant, than a reference compound or the same compound under reference conditions. In some embodiments, greater affinity is at least 2, 3, 4, 5, 8, 10, 50, 100, 200, 400, 500, 1000, or 10,000 times greater affinity.

[0082] The term "modulation" refers to the ability of a compound to increase or decrease the function and / or expression of a target (such as EP300 or CBP), wherein such function may include transcriptional regulatory activity and / or binding. Regulation can be performed in vitro or in vivo. As described herein, regulation includes direct or indirect inhibition, antagonism, partial antagonism, activation, excitement or partial excitement of a function or feature associated with EP300 or CBP, and / or direct or indirect upregulation or downregulation of expression of EP300 or CBP. In another embodiment, regulation is direct. An inhibitor or antagonist is a compound that (e.g., in combination with) partially or completely blocks stimulation, reduces, prevents, inhibits, delays activation, inactivates, passivates or downregulates signal transduction. An activator or agonist is a compound that (e.g., in combination with) stimulates, increases, opens, activates, promotes, enhances activation, activates, sensitizes or upregulates signal transduction.

[0083] As used herein, the terms "treat," "treatment," and similar terms refer to the administration of a substance, e.g., any one or more of the compounds described herein, in an amount effective to prevent, alleviate, lessen, or ameliorate one or more symptoms (i.e., indications) of a disease or condition and / or prolong the survival of the subject being treated.

[0084] As used herein, the term "prevent," "prevent," "prevent," and grammatical variations thereof refer to a method of partially or completely delaying or preventing the onset or recurrence of a disease, disorder or condition and / or one or more of its attendant symptoms, or preventing a subject from developing or reoccurring a disorder or condition, or reducing the risk of a subject developing or reoccurring a disorder or condition or one or more of its attendant symptoms.

[0085] As used herein, the terms "subject," "animal subject," and the like refer to an organism, including, but not limited to, humans and non-human vertebrates, e.g., any mammal, such as humans, other primates, sport animals, and animals of commercial value, such as cattle, horses, sheep or pigs, rodents, or pets, such as dogs and cats.

[0086] "Unit dosage form" refers to a composition intended for a single administration to treat a subject with a disease or medical condition. Each unit dosage form typically contains each active ingredient of the present disclosure plus a pharmaceutically acceptable excipient. Examples of unit dosage forms are individual tablets, individual capsules, bulk powders, liquid solutions, ointments, creams, eye drops, suppositories, emulsions, or suspensions. Treatment of a disease or condition may require regular administration of a unit dosage form, for example: one unit dosage form twice or more a day, one unit dosage form with each meal, one unit dosage form every four hours or at other time intervals, or only one unit dosage form per day. The expression "oral unit dosage form" means a unit dosage form designed to be taken orally.

[0087] The term "administer" refers to oral administration to a subject, in the form of a suppository, topical contact, intravenous, intraperitoneal, intramuscular, intralesional, intranasal or subcutaneous administration, or implantation of a slow-release device such as a miniature osmotic pump. 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, intraarteriole, intradermal, subcutaneous, intraperitoneal, intraventricular and intracranial. Other delivery modes include, but are not limited to, use of liposome formulations, intravenous infusions, transdermal patches, etc.

[0088] In this context, the term "therapeutically effective" or "effective amount" means that the amount of a compound or substance or a compound or substance is sufficient or effective to prevent, alleviate or improve one or more symptoms of the disease, disorder or medical condition being treated when administered, and / or prolong the survival of the subject being treated."Therapeutically effective amount" will vary depending on the compound, disease, disorder or condition and its severity and the age, body weight, etc. of the mammal to be treated. In general, it is indicated to obtain satisfactory results in the subject with a daily dose of about 0.1 to about 10 g / kg of subject body weight. In some embodiments, the daily dose is about 0.10 to 10.0 mg per kilogram of body weight, about 1.0 to 3.0 mg per kilogram of body weight, about 3 to 10 mg per kilogram of body weight, about 3 to 150 mg per kilogram of body weight, about 3 to 100 mg per kilogram of body weight, about 10 to 100 mg per kilogram of body weight, about 10 to 150 mg per kilogram of body weight, or about 150 to 1000 mg per kilogram of body weight. The dose may conveniently be administered, for example, in divided doses up to four times a day or in sustained release form.

[0089] The ability of a compound to inhibit EP300 or CBP function can be demonstrated in a biochemical assay (eg, a binding assay or a cell-based assay).

[0090] 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 affects the development and / or course of the disease or condition, and / or in which the regulation of EP300, CBP, or both EP300 and CBP alters the development, course, and / or symptoms. Diseases or conditions mediated by EP300 or CBP include diseases or conditions in which EP300 inhibition, CBP inhibition, or both EP300 and CBP inhibition provide a therapeutic benefit, such as where treatment with an EP300 or CBP inhibitor (including a compound described herein) provides a therapeutic benefit to a subject suffering from the disease or condition or at risk of the disease or condition. Diseases or conditions mediated by EP300 or CBP are intended to include cancers with loss of function mutations of CBP or EP300, or cancers in which EP300 or CBP activation is present. Diseases or conditions mediated by EP300 or CBP are also intended to include cancers expressing androgen receptors.

[0091] The term "EP300-mediated disease or condition" includes diseases associated with or implicated in EP300 activity, such as overactivity of EP300, and conditions that accompany these diseases. The term "overactivity of EP300" refers to: 1) EP300 expression in cells that do not normally express EP300; 2) increased EP300 expression, resulting in unwanted cell proliferation; or 3) mutations, resulting in constitutive activation of EP300. EP300-mediated diseases or conditions would include tumors with CBP inactivating mutations, also known as synthetic lethality. Examples of EP300-mediated diseases or conditions include conditions caused by abnormally high amounts of EP300 activity. EP300-mediated diseases or conditions are intended to include cancers with loss of CBP function mutations, or cancers in which EP300 activation is present. EP300-mediated diseases or conditions are also intended to include cancers that express androgen receptors. It is well known that excessive activity of EP300 is implicated in the pathogenesis of a variety of diseases, including proliferative and non-proliferative disorders, including neoplastic disorders and cancer, inflammatory disorders, cognitive disorders and neurodegenerative diseases.

[0092] The term "CBP-mediated disease or condition" includes diseases associated with or involving CBP activity, such as excessive activity of CBP, and the pathologies associated with these diseases. The term "excessive activity of CBP" refers to: 1) CBP expression in cells that do not normally express CBP; 2) increased CBP expression, resulting in unwanted cell proliferation; or 3) mutation, resulting in constitutive activation of CBP. Examples of CBP-mediated diseases or conditions include disorders caused by abnormally high amounts of CBP activity. CBP-mediated diseases or conditions are intended to include cancers with loss of function mutations of EP300, or cancers in which CBP is activated. CBP-mediated diseases or conditions are also intended to include cancers expressing androgen receptors. It is well known that excessive activity of CBP is involved in the pathogenesis of a variety of diseases, including proliferative and non-proliferative disorders, including neoplastic disorders and cancers, inflammatory disorders, cognitive disorders, and neurodegenerative diseases.

[0093] Furthermore, in the context of compounds that bind to a biomolecular target, the term "greater specificity" means that the compound binds to the designated target to a greater extent than to another biomolecule or multiple biomolecules that may be present under the relevant binding conditions, wherein binding to such other biomolecules results in a different biological activity than binding to the designated target. Typically, specificity is with reference to a limited set of other biomolecules, such as in the case of EP300, CBP, or even other epigenetic targets. In specific embodiments, greater specificity is at least 2, 3, 4, 5, 8, 10, 50, 100, 200, 400, 500, or 1000 times greater specificity.

[0094] As used herein with respect to binding compounds or ligands, the term "specific for EP300" and terms of similar meaning refer to a particular compound that binds to EP300 to a statistically greater extent than to other epigenetic targets that may be present in a particular sample. In addition, in the context of indicating biological activities other than binding, the term "specific for EP300" means that the particular compound has a greater biological effect associated with binding to EP300 than other enzymes, e.g., inhibition of enzyme activity. Specificity also relates to other biological molecules that may be present in a particular sample (not limited to EP300).

[0095] As used herein with respect to binding compounds or ligands, the term "specific for CBP" and terms of similar meaning refer to the extent to which a particular compound binds to CBP that is statistically greater than the extent to which it binds to other epigenetic targets that may be present in a particular sample. In addition, in the context of indicating biological activities other than binding, the term "specific for CBP" means that a particular compound has a greater biological effect associated with binding to CBP than other enzymes, e.g., inhibition of enzyme activity. Specificity also relates to other biological molecules (not limited to CBP) that may be present in a particular sample.

[0096] 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 referred to as induction therapy, preliminary therapy, and primary treatment. First-line therapy can be a combination administered with one or more agents. An overview of currently recognized first-line treatments for certain diseases can be found in the NCI guidelines for such diseases.

[0097] The term "second line cancer therapy" refers to a cancer therapy administered to a subject who is unresponsive to the first line therapy (i.e., is usually administered the first line therapy) or to a subject whose cancer relapses after remission. In certain embodiments, the second line therapy that may be administered includes repeating the initial successful cancer therapy, which may be any treatment described under "first line cancer therapy". An overview of currently recognized second line treatments for certain diseases is described in the NCI guidelines for such diseases.

[0098] The term "refractory" refers to a condition in which a subject does not respond to or is otherwise resistant to a cancer therapy or treatment. Cancer therapy can be a first-line, second-line, or any subsequently administered treatment. In certain embodiments, refractory refers to a condition in which a subject fails to achieve complete remission after two induction attempts. A subject may be refractory due to intrinsic resistance of cancer cells to a particular therapy, or a subject may be refractory due to acquired resistance that develops during or after the course of a particular therapy.

[0099] In addition, the abbreviations used in this article have the following meanings:

[0100]

[0101] II.Compounds

[0102] Embodiment 1 of the present disclosure relates to a compound of formula I: 1. A compound of formula I:

[0103]

[0104] or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer or deuterated analog thereof, wherein:

[0105] A 1 For R 6 , A 2 For R 7 , A 3 For-LR 1 , A 4 For R 5 , X 1 For CH, X 2 is C, and X 3 is N; or

[0106] A 1 For R 6 , A 2 For R 7 , A 3 For-LR 1 , A 4 For R 5 , X 1 For CH, X 2 is C, and X 3 is CH; or

[0107] A 1 For R 6 , A 2 Does not exist, A 3 For-LR 1 , A 4 For R 5 , X 1 For CH, X 2 is N, and X 3 is CH; or

[0108] A 1 For R 7 , A 2 For R 6 , A 3 For-LR 1 , A 4 For R 5 , X 1 N, X 2 is C, and X 3 is CH; or

[0109] A 1 For R 7 , A 2 For R 6 , A 3 For R 5 , A 4 For-LR 1 , X 1 N, X 2 is C, and X 3 for CH;

[0110] 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 -;

[0111] L 2 is a bond or -C(R 13 ) 2 -;

[0112] R 1 is phenyl, 5-9 membered heteroaryl, C 3 -C 6 Cycloalkyl, C 5 -C 6 Cycloalkenyl,

[0113] 4-9 membered heterocycloalkyl or 5-6 membered heterocycloalkenyl, wherein R 1 Optionally 1G 1 Group and 1-3 G 2 Group substitution;

[0114] R 2 H, C 1 -C 6 Alkyl or OH;

[0115] R 3 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;

[0116] R 4 H, OH, C 1 -C 6 Alkyl or C 1 -C 6 Haloalkyl;

[0117] R 5 When attached to carbon, it is 4-6 membered cycloalkyl, 5-6 membered cycloalkenyl, phenyl, 5-9 membered heteroaryl, 5-6 membered heterocycloalkyl, 4-6 membered cycloalkyl-C 1 -C 6 alkyl, wherein the 4-6 membered cycloalkyl, 5-6 membered cycloalkenyl, phenyl, 5-9 membered heteroaryl or 4-6 membered cycloalkyl-C 1 -C 6 Each alkyl group is optionally substituted by a -L 2 -J 1 Groups and 0-4 J 2 group substitution, provided that J 1 directly bonded to the carbon atom;

[0118] or R5 When attached to nitrogen, it is a 4-6 membered cycloalkyl, a 5-6 membered cycloalkenyl, a phenyl, a 5-9 membered heteroaryl, or a 4-6 membered cycloalkyl-C 1 -C 6 wherein the 4-6 membered cycloalkyl, 5-6 membered cycloalkenyl, phenyl, 5-9 membered heteroaryl or 4-6 membered cycloalkyl-C 1 -C 6 Each alkyl group is optionally substituted with 1 -L 2 -J 1 Group and 1-4 J 2 group substitution, provided that J 1 directly bonded to the carbon atom;

[0119] R 6 is a 5-membered heteroaryl group containing at least one nitrogen atom, wherein the 5-membered heteroaryl group is optionally substituted by 0-2 R 8 Group substitution;

[0120] R 7 is H, halo or C 1 -C 6 alkyl;

[0121] R 8 C 1 -C 6 Alkyl or C 1 -C 3 Alkoxy C 1 -C 3 Alkylene;

[0122] Each R 10 Independently H, C 1 -C 6 Alkyl, C 1 -C 6 haloalkyl or cyclopropyl;

[0123] Each R 11 Independently H, C 1 -C 6 Alkyl or C 1 -C 6 Haloalkyl, or two R 11 Group with two R 11 The carbon atoms to which the groups are attached are linked together to form a cyclopropyl group;

[0124] Each R 12 Independently H, C 1 -C 6 Alkyl, C 1 -C 6 Hydroxyalkyl or C 1 -C 6 Haloalkyl;

[0125] Each R 13 H, CH 3 or F, or each R 13 Together with the carbon atoms to which they are attached, they form C 3 -C 6 Cycloalkyl groups;

[0126] R 14 H, C 1 -C 6 Alkyl or C 1 -C 3 Alkoxy C 1 -C 3 Alkylene;

[0127] G 1 For cyano, C 2 -C 6 Alkenyl, C 1 -C 6 Cyanoalkyl, C 1 -C 6 Cyanoalkylethynylene, C 2 -C 6 Alkenyl C 1 -C 6 Alkylene, C 1 -C 6 Alkylsulfonyl, C 1 -C 6 Alkylsulfonyl C 1 -C 6 Alkylene, -N(R 10 ) 2 2-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)-C3 -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 Alkyne, 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, provided that when G 1 When connected to a nitrogen atom, G 1 Not cyano;

[0128] Each G 2 are independently halo, C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy, OH, oxy, C 1 -C 6 Hydroxyalkyl, provided that when G 2 When connected to a nitrogen atom, G 2 Not a halogenated group, C 1 -C 6 Alkoxy, C 1 -C 6 Haloalkoxy or OH;

[0129] J 1 -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 -C1 -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

[0130] Each J 2 are independently 4-6 membered heterocycloalkyl, -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 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 , the condition is that when J 2 When connected to nitrogen atoms, J 2 Not -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, C3 -C 6 Cycloalkylethynylene or -N(R 10 ) 2 .

[0131] The phrase "where R 1 Optionally 1 G 1 Group and 1-3 G 2 The term "group substitution" is intended to include the following: 1 Optionally 1 G 1 Group substitution; R 1 Optionally 1-3 g 2 Group substitution; and R 1 Optionally 1 G 1 Group and 1-3 G 2 This explanation applies to all variables described in this disclosure (such as R 1 , and about R 5 J 1 and J 2 ), which may optionally be replaced by more than one additional variable (such as G 1 and G 2 or J 1 and J 2 )replace.

[0132] Sub-implementation of implementation plan 1

[0133] 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 -; The condition is when A 1 For R 7 , A 2 For R 6 , A 3 For-LR 1 , A 4 For R 5 , X 1 N, X 2 is C, and X 3 When it is C, then L is a bond.

[0134] Embodiment 1(a2) of the present disclosure relates to embodiment 1, wherein R 5When attached to carbon, it is 4-6 membered cycloalkyl, 5-6 membered cycloalkenyl, phenyl, 5-9 membered heteroaryl, 5-6 membered heterocycloalkyl, wherein the 4-6 membered cycloalkyl, 5-6 membered cycloalkenyl, phenyl or 5-9 membered heteroaryl are each optionally substituted by one -L 2 -J 1 Groups and 0-4 J 2 group substitution, provided that J 1 directly bonded to the carbon atom;

[0135] or R 5 When attached to nitrogen, it is a 4-6 membered cycloalkyl, a 5-6 membered cycloalkenyl, a phenyl or a 5-9 membered heteroaryl, wherein each of the 4-6 membered cycloalkyl, the 5-6 membered cycloalkenyl, the phenyl or the 5-9 membered heteroaryl is optionally substituted by 1 -L 2 -J 1 Group and 1-4 J 2 group substitution, provided that J 1 Directly bonded to the carbon atom.

[0136] Embodiment 1(a) of the present disclosure relates to embodiment 1, wherein:

[0137] A 1 For R 6 , A 2 For R 7 , A 3 For-LR 1 , A 4 For R 5 , X 1 C, X 2 is C, and X 3 is N; or

[0138] A 1 For R 7 , A 2 For R 6 , A 3 For-LR 1 , A 4 For R 5 , X 1 N, X 2 is C, and X 3 is C; or

[0139] A 1 For R 7 , A 2 For R 6 , A 3 For R 5 , A 4 For-LR 1 , X1 N, X 2 is C, and X 3 For C.

[0140] Embodiment 1(b) of the present disclosure relates to embodiment 1, wherein:

[0141] A 1 For R 7 , A 2 For R 6 , A 3 For-LR 1 , A 4 For R 5 , X 1 N, X 2 is C, and X 3 is C; or

[0142] A 1 For R 7 , A 2 For R 6 , A 3 For R 5 , A 4 For-LR 1 , X 1 N, X 2 is C, and X 3 For C.

[0143] Embodiment 1(c) of the present disclosure relates to embodiment 1, wherein:

[0144] A 1 For R 6 , A 2 For R 7 , A 3 For-LR 1 , A 4 For R 5 , X 1 C, X 2 is C, and X 3 is N.

[0145] Embodiment 1(d) of the present disclosure relates to embodiment 1, wherein:

[0146] A 1 For R 6 , A 2 For R 7 , A 3 For-LR 1 , A 4 For R 5 , X 1 C, X 2 is C, and X3 For C.

[0147] Embodiment 1(e) of the present disclosure relates to embodiment 1, wherein:

[0148] A 1 For R 6 , A 2 Does not exist, A 3 For-LR 1 , A 4 For R 5 , X 1 C, X 2 is N, and X 3 For C.

[0149] Embodiment 1(f) of the present disclosure relates to embodiment 1, wherein:

[0150] A 1 For R 7 , A 2 For R 6 , A 3 For-LR 1 , A 4 For R 5 , X 1 N, X 2 is C, and X 3 For C.

[0151] Embodiment 1(g) of the present disclosure relates to embodiment 1, wherein:

[0152] A 1 For R 7 , A 2 For R 6 , A 3 For R 5 , A 4 For-LR 1 , X 1 N, X 2 is C, and X 3 For C.

[0153] Embodiment 1(h) of the present disclosure relates to embodiment 1, 1(al), 1(a2), 1(a), 1(b), 1(c), 1(d), 1(e), 1(f) or 1(g), wherein L is a bond.

[0154] 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 -.

[0155] 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 is -CR 2 R 3 -.

[0156] 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 is -(CH 2 ) 1-2 -CH=CH-(CH 2 ) 0-1 -.

[0157] Embodiment 1(k) of the present disclosure relates to embodiment 1, 1(al), 1(a2), 1(a), 1(b), 1(c), 1(d), 1(e), 1(f) or 1(g), wherein L is -C(O)-.

[0158] 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 -.

[0159] 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), wherein R 1 is phenyl or 5-9 membered heteroaryl, wherein R 1 Optionally 1G 1 Group and 1-3 G 2 Group substitution.

[0160] 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), wherein R 1 is optionally replaced by 1G 1 Group and 1-3 G 2 A phenyl group substituted with a group.

[0161] 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), wherein R 1 is optionally replaced by 1G 1 Group and 1-3 G 2 The 5- to 9-membered heteroaryl group is substituted with a group.

[0162] 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), wherein R 1 It is C 3 -C 6 Cycloalkyl or C 5 -C 6 Cycloalkenyl, where R 1 Optionally 1G 1 Group and 1-3 G 2 Group substitution.

[0163] 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), wherein R 1 is a 4-9 membered heterocycloalkyl or a 5-6 membered heterocycloalkenyl, wherein R 1 Optionally 1G 1 Group and 1-3 G 2 Group substitution.

[0164] 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), wherein R 5 is connected to carbon and is a 4-6 membered cycloalkyl, a 5-6 membered cycloalkenyl, a phenyl, a 5-9 membered heteroaryl, a 5-6 membered heterocycloalkyl, wherein the 4-6 membered cycloalkyl, 5-6 membered cycloalkenyl, phenyl or 5-9 membered heteroaryl are each optionally substituted by one -L 2 -J 1 Groups and 0-4 J 2 group substitution, provided that J 1 Directly bonded to the carbon atom.

[0165] 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), wherein or R 5 is attached to carbon and is a 4-6 membered cycloalkyl, a 5-6 membered cycloalkenyl, a phenyl or a 5-9 membered heteroaryl, wherein the 4-6 membered cycloalkyl, the 5-6 membered cycloalkenyl, the phenyl or the 5-9 membered heteroaryl are each optionally substituted with 1 -L 2 -J 1 Group and 1-4 J 2 group substitution, provided that J 1 Directly bonded to the carbon atom.

[0166] 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), wherein J 1 -C(O)OH or -C(O)OC 1 -C 6 alkyl.

[0167] 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), wherein J 1 It is -C(O)OH.

[0168] 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), wherein J 1 -C(O)OC 1 -C 6 Alkyl or CH 2 -C(O)OC 1 -C 6 alkyl.

[0169] 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), wherein J 1 C(O)N(R 10 ) 2 , -C(O)N(H)-CN or -C(O)N(H)OH.

[0170] Embodiment 1(y) of the present disclosure is related 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), wherein J 1 -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 .

[0171] Embodiment 1(z) of the present disclosure is related 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), wherein J 1 It is a tetrazolyl group.

[0172] J 1 The tetrazolyl group in the definition is a carboxylic acid isostere, and other carboxylic acid isosteres may be used in its place, such as those described in Figure 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.

[0173] In another embodiment of embodiment 1, J 1 It may be a carboxylic acid isostere as described in Meanwell.

[0174] Embodiment 2 of the present disclosure relates to a compound according to Embodiment 1 or Embodiment 1(a1), wherein:

[0175] R 1 is phenyl, 5-6 membered heteroaryl, C 3 -C 6 Cycloalkyl, C 5 -C 6 Cycloalkenyl, 4-6 membered heterocycloalkyl or 5-6 membered heterocycloalkenyl, wherein R 1 Optionally 1 G 1 Group and 1-3 G 2 Group substitution;

[0176] R 3 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;

[0177] R 4 H, OH, C 1 -C 2 Alkyl or C 1 -C 2 Haloalkyl;

[0178] R 5 When attached to carbon, it is 4-6 membered cycloalkyl, cyclohexenyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, wherein the 4-6 membered cycloalkyl, cyclohexenyl, phenyl, 5-6 membered heteroaryl or 5-6 membered heterocycloalkyl are each optionally substituted by one J 1 Groups and 0-4 J 2 group substitution, provided that J 1 directly bonded to the carbon atom;

[0179] or R 5 When attached to nitrogen, it is a 4-6 membered cycloalkyl, cyclohexenyl, phenyl or 5-6 membered heteroaryl, wherein the 4-6 membered cycloalkyl, cyclohexenyl, phenyl or 5-6 membered heteroaryl are each optionally substituted by 1 -L 2 -J 1 Group and 1-4 J 2group substitution, provided that J 1 directly bonded to the carbon atom;

[0180] R 6 is a five-membered heteroaryl group containing at least one nitrogen atom, wherein the heteroaryl group is optionally substituted by 1-2 R 8 Group substitution;

[0181] R 7 is H, halo or C 1 -C 5 alkyl;

[0182] R 8 C 1 -C 4 Alkyl or C 1 -C 2 Alkoxy C 1 -C 2 Alkylene;

[0183] Each R 10 Independently H, C 1 -C 5 Alkyl, C 1 -C 5 haloalkyl or cyclopropyl;

[0184] Each R 11 Independently H, C 1 -C 5 Alkyl or C 1 -C 5 Haloalkyl, or two R 11 Group with two R 11 The carbon atoms to which the groups are attached are linked together to form a cyclopropyl group;

[0185] Each R 12 is H;

[0186] G 1 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 Alkylsulfonyl C 1 -C 5 Alkylene, -N(R 10 ) 2 2-C1 -C 5 Alkylamino-C 1 -C 5 Alkylene, C 1 -C 5 Alkylamino-C 1 -C 5 Alkylene, amino C 1 -C 5 Alkylene, -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 Alkyne, 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, provided that when G 1 When connected to a nitrogen atom, G 1 Not for CN;

[0187] Each G 2 are independently CN, halo, C 1 -C 5 Alkyl, C 1 -C 5 Haloalkyl, C 1 -C 5 Alkoxy, C 1 -C 5 Haloalkoxy, OH, oxy, C 1 -C 5 Hydroxyalkyl, provided that when G2 When connected to a nitrogen atom, G 2 Not CN, halogenated, C 1 -C 5 Alkoxy, C 1 -C 5 Haloalkoxy or OH;

[0188] J 1 -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

[0189] Each J 2 are independently 4-6 membered heterocycloalkyl, -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 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 -C6 Cycloalkylethynylene, C 3 -C 6 Cycloalkyl, 4-6 membered heterocycloalkyl or -N(R 10 ) 2 , the condition is that when J 2 When connected to nitrogen atoms, J 2 Not -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 .

[0190] Sub-implementation of implementation plan 2

[0191] Embodiment 2(a) of the present disclosure relates to embodiment 2, wherein:

[0192] A 1 For R 6 , A 2 For R 7 , A 3 For-LR 1 , A 4 For R 5 , X 1 C, X 2 is C, and X 3 is N; or

[0193] A 1 For R 7 , A 2 For R 6 , A 3 For-LR 1 , A 4 For R 5 , X 1 N, X 2 is C, and X 3 is C; or

[0194] A 1 For R 7 , A 2For R 6 , A 3 For R 5 , A 4 For-LR 1 , X 1 N, X 2 is C, and X 3 For C.

[0195] Embodiment 2(b) of the present disclosure relates to embodiment 2, wherein:

[0196] A 1 For R 7 , A 2 For R 6 , A 3 For-LR 1 , A 4 For R 5 , X 1 N, X 2 is C, and X 3 is C; or

[0197] A 1 For R 7 , A 2 For R 6 , A 3 For R 5 , A 4 For-LR 1 , X 1 N, X 2 is C, and X 3 For C.

[0198] Embodiment 2(c) of the present disclosure relates to embodiment 2, wherein:

[0199] A 1 For R 6 , A 2 For R 7 , A 3 For-LR 1 , A 4 For R 5 , X 1 C, X 2 is C, and X 3 is N.

[0200] Embodiment 2(d) of the present disclosure relates to embodiment 2, wherein:

[0201] A 1 For R 6 , A 2 For R 7 , A 3 For-LR1 , A 4 For R 5 , X 1 C, X 2 is C, and X 3 For C.

[0202] Embodiment 2(e) of the present disclosure relates to embodiment 2, wherein:

[0203] A 1 For R 6 , A 2 Does not exist, A 3 For-LR 1 , A 4 For R 5 , X 1 C, X 2 is N, and X 3 For C.

[0204] Embodiment 2(f) of the present disclosure relates to embodiment 2, wherein:

[0205] A 1 For R 7 , A 2 For R 6 , A 3 For-LR 1 , A 4 For R 5 , X 1 N, X 2 is C, and X 3 For C.

[0206] Embodiment 2(g) of the present disclosure relates to embodiment 2, wherein:

[0207] A 1 For R 7 , A 2 For R 6 , A 3 For R 5 , A 4 For-LR 1 , X 1 N, X 2 is C, and X 3 For C.

[0208] 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.

[0209] 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 -.

[0210] 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 -.

[0211] 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 -(CH 2 ) 1-2 -CH=CH-(CH 2 ) 0-1 -.

[0212] 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)-.

[0213] 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 -.

[0214] 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), wherein R 1 is phenyl or 5-6 membered heteroaryl, wherein R 1 Optionally 1 G 1 Group and 1-3 G 2 Group substitution.

[0215] 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), wherein R 1 is optionally replaced by 1G 1 Group and 1-3 G 2 A phenyl group substituted with a group.

[0216] 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), wherein R 1 is optionally replaced by 1G 1 Group and 1-3 G 2 A 5- to 6-membered heteroaryl group substituted with a group.

[0217] 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), wherein R 1 It is C 3 -C 6 Cycloalkyl or C 5 -C 6 Cycloalkenyl, where R 1 Optionally 1 G 1 Group and 1-3 G 2 Group substitution.

[0218] 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), wherein R 1 is a 4-9 membered heterocycloalkyl or a 5-6 membered heterocycloalkenyl, wherein R 1 Optionally 1 G 1 Group and 1-3 G 2 Group substitution.

[0219] 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 is connected to carbon and is a 4-6 membered cycloalkyl, cyclohexenyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, wherein the 4-6 membered cycloalkyl, cyclohexenyl, phenyl, 5-6 membered heteroaryl or 5-6 membered heterocycloalkyl are each optionally substituted by one -L 2 -J 1 Groups and 0-4 J 2 group substitution, provided that J 1 Directly bonded to the carbon atom.

[0220] 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), wherein or R 5 is attached to nitrogen and is a 4-6 membered cycloalkyl, cyclohexenyl, phenyl or 5-6 membered heteroaryl, wherein the 4-6 membered cycloalkyl, cyclohexenyl, phenyl or 5-6 membered heteroaryl are each optionally substituted with 1 -L 2 -J 1 Group and 1-4 J 2 group substitution, provided that J 1 Directly bonded to the carbon atom.

[0221] 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), wherein J 1 -C(O)OH or -C(O)OC 1 -C 5 alkyl.

[0222] 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), wherein J 1 It is -C(O)OH.

[0223] 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), wherein J 1 -C(O)OC 1 -C 5 Alkyl or -CH 2 -C(O)OC 1 -C 5 alkyl.

[0224] 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), wherein J 1 -C(O)N(R 10 ) 2 , -C(O)N(H)-CN or -C(O)N(H)OH.

[0225] 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), wherein J 1 -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 .

[0226] 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), wherein J 1 It is a tetrazolyl group.

[0227] Embodiment 3 of the present disclosure relates to a compound according to Embodiment 1 or 2, wherein the compound has formula II (a), II (b) or II (c)

[0228]

[0229] or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer or deuterated analog thereof.

[0230] Sub-implementation of implementation plan 3

[0231] Embodiment 3(a1) of the present disclosure relates to Embodiment 3 having Formula II(a) or II(b).

[0232] Embodiment 3(a) of the present disclosure relates to Embodiment 3 having Formula II(a).

[0233] Embodiment 3(b) of the present disclosure relates to Embodiment 3 having Formula II(b).

[0234] Embodiment 3(c) of the present disclosure relates to Embodiment 3 having Formula II(c).

[0235] 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.

[0236] 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 -.

[0237] 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 -.

[0238] 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), wherein R 1 is phenyl or 5-6 membered heteroaryl, wherein R 1 Optionally 1G 1 Group and 1-3 G 2 Group substitution.

[0239] 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), wherein R 1 is optionally replaced by 1G 1 Group and 1-3 G 2 A phenyl group substituted with a group.

[0240] 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 is optionally replaced by 1G 1 Group and 1-3 G 2 A 5- to 6-membered heteroaryl group substituted with a group.

[0241] 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), wherein R 1 It is C 3 -C 6 Cycloalkyl or C 5 -C 6 Cycloalkenyl, where R 1 Optionally 1 G 1 Group and 1-3 G 2 Group substitution.

[0242] 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), wherein R 1 is a 4-9 membered heterocycloalkyl or a 5-6 membered heterocycloalkenyl, wherein R 1 Optionally 1 G 1 Group and 1-3 G 2 Group substitution.

[0243] 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), wherein R 5 is attached to carbon and is a 4-6 membered cycloalkyl, cyclohexenyl, phenyl, 5-6 membered heteroaryl, 5-6-membered heterocycloalkyl, wherein the 4-6-membered cycloalkyl, cyclohexenyl, phenyl, 5-6-membered heteroaryl or 5-6-membered heterocycloalkyl are each optionally substituted by one -L 2 -J 1 Groups and 0-4 J 2 group substitution, provided that J 1 Directly bonded to the carbon atom.

[0244] 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), wherein or R 5 is attached to nitrogen and is a 4-6 membered cycloalkyl, cyclohexenyl, phenyl or 5-6 membered heteroaryl, wherein the 4-6 membered cycloalkyl, cyclohexenyl, phenyl or 5-6 membered heteroaryl are each optionally substituted with 1 -L 2 -J 1 Group and 1-4 J 2 group substitution, provided that J 1 Directly bonded to the carbon atom.

[0245] 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), wherein J 1 -C(O)OH or -C(O)OC 1 -C 5 alkyl.

[0246] 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), wherein J 1 It is -C(O)OH.

[0247] 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), wherein J 1 -C(O)OC 1 -C 5 Alkyl or CH 2 -C(O)OC 1 -C 5 alkyl.

[0248] 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), wherein J 1 -C(O)N(R 10 ) 2 , -C(O)N(H)-CN or -C(O)N(H)OH.

[0249] 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), wherein J 1 -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 .

[0250] 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), wherein J 1 It is a tetrazolyl group.

[0251] Embodiment 4 of the present disclosure relates to a compound according to any one of Embodiments 1-3 (including any sub-embodiments thereof), the compound having any one of Formulas III(a)-III(f):

[0252]

[0253] or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer or deuterated analog thereof.

[0254] Sub-implementation of Implementation 4

[0255] Embodiment 4(a1) of the present disclosure relates to Embodiment 4 having any one of Formula III(a), III(c), III(d), III(e) or III(f).

[0256] Embodiment 4(a2) of the present disclosure relates to Embodiment 4 having any one of Formula III(a), III(c) or III(d).

[0257] Embodiment 4(a) of the present disclosure relates to Embodiment 4 having any one of Formula III(a), III(b), III(c) or III(d).

[0258] Embodiment 4(b) of the present disclosure relates to Embodiment 4 having any one of Formula III(e) or III(f).

[0259] Embodiment 4(c) of the present disclosure relates to Embodiment 4 having Formula III(a).

[0260] Embodiment 4(d) of the present disclosure relates to Embodiment 4 having Formula III(b).

[0261] Embodiment 4(e) of the present disclosure relates to Embodiment 4 having Formula III(c).

[0262] Embodiment 4(f) of the present disclosure relates to Embodiment 4 having Formula III(d).

[0263] Embodiment 4(g) of the present disclosure relates to Embodiment 4 having Formula III(e).

[0264] Embodiment 4(h) of the present disclosure relates to Embodiment 4 having Formula III(f).

[0265] 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), wherein R 1 is phenyl or 5-6 membered heteroaryl, wherein R 1 Optionally 1 G 1 Group and 1-3 G 2 Group substitution.

[0266] Embodiment 4(j) 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), wherein R 1 is optionally replaced by 1G 1 Group and 1-3 G 2 A phenyl group substituted with a group.

[0267] 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), wherein R 1 is optionally replaced by 1G 1 Group and 1-3 G 2 A 5- to 6-membered heteroaryl group substituted with a group.

[0268] Embodiment 4(1) 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), wherein R 1 It is C 3 -C 6 Cycloalkyl or C 5 -C 6 Cycloalkenyl, where R 1 Optionally 1 G 1 Group and 1-3 G 2 Group substitution.

[0269] 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), wherein R 1 is a 4-9 membered heterocycloalkyl or a 5-6 membered heterocycloalkenyl, wherein R 1Optionally 1 G 1 Group and 1-3 G 2 Group substitution.

[0270] 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), wherein R 5 is attached to carbon and is a 4-6 membered cycloalkyl, cyclohexenyl, phenyl, 5-6 membered heteroaryl, 5-6-membered heterocycloalkyl, wherein the 4-6-membered cycloalkyl, cyclohexenyl, phenyl, 5-6-membered heteroaryl or 5-6-membered heterocycloalkyl are each optionally substituted by one -L 2 -J 1 Groups and 0-4 J 2 group substitution, provided that J 1 Directly bonded to the carbon atom.

[0271] 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), wherein or R 5 is attached to nitrogen and is a 4-6 membered cycloalkyl, cyclohexenyl, phenyl or 5-6 membered heteroaryl, wherein the 4-6 membered cycloalkyl, cyclohexenyl, phenyl or 5-6 membered heteroaryl are each optionally substituted with 1 -L 2 -J 1 Group and 1-4 J 2 group substitution, provided that J 1 Directly bonded to the carbon atom.

[0272] 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), wherein J 1 -C(O)OH or -C(O)OC 1 -C 5 alkyl.

[0273] 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), wherein J 1It is -C(O)OH.

[0274] 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), wherein J 1 -C(O)OC 1 -C 5 Alkyl or -CH 2 -C(O)OC 1 -C 5 alkyl.

[0275] 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), wherein J 1 -C(O)N(R 10 ) 2 , -C(O)N(H)-CN or -C(O)N(H)OH.

[0276] 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), wherein J 1 -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 .

[0277] 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), wherein J 1 It is a tetrazolyl group.

[0278] Embodiment 5 of the present disclosure relates to a compound according to any one of embodiments 1-4 (including any sub-embodiments thereof), wherein R 6 for:

[0279]

[0280] Embodiment 6 of the present disclosure relates to a compound according to any one of embodiments 1-5 (including any sub-embodiments thereof), wherein R 6 for:

[0281]

[0282] Sub-implementation of implementation plan 6:

[0283] Embodiment 6(a) of the present disclosure relates to embodiment 6, wherein R 6 for:

[0284]

[0285] Embodiment 6(b) of the present disclosure relates to embodiment 6, wherein R 6 for:

[0286]

[0287] Embodiment 6(c) of the present disclosure relates to embodiment 6, wherein R 6 for:

[0288]

[0289] Embodiment 7 of the present disclosure relates to a compound according to any one of Embodiments 1 to 6 (including any sub-embodiments thereof), wherein R 4 H, OH, CF 3 or CH 3 .

[0290] Sub-implementation of implementation plan 7

[0291] Embodiment 7(a) of the present disclosure relates to embodiment 7, wherein R 4 H, CF 3 or CH 3 .

[0292] Embodiment 7(b) of the present disclosure relates to embodiment 7, wherein R 4 For H.

[0293] Embodiment 7(c) of the present disclosure relates to embodiment 7, wherein R 4 For CF 3 or CH 3 .

[0294] Embodiment 7(d) of the present disclosure relates to embodiment 7, wherein R 4 CH 3 .

[0295] Embodiment 8 of the present disclosure relates to compounds according to any one of embodiments 1, 2, 3, 5, 6 or 7 (including any subembodiments thereof where applicable), 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 )(Pyridinyl)-, -S(O) 2 - or -C(H)(CH 2 CN)-.

[0296] As used in the embodiments and sub-embodiments of the present disclosure, the term "where applicable" is intended to exclude inapplicability where the preceding sub-embodiment is narrower in scope than the following embodiment. For example, Embodiment 8 is broader in scope than Embodiments 2(h)-2(l), and therefore Embodiment 8 cannot be applied to Sub-embodiments 2(h)-2(l). This interpretation of the embodiments and sub-embodiments in the present disclosure applies to all cases, regardless of whether the term "where applicable" is used.

[0297] Sub-implementation of implementation plan 8

[0298] Embodiment 8(a) of the present disclosure relates to embodiment 8, wherein L is a bond.

[0299] 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 )-.

[0300] Embodiment 8(c) of the present disclosure relates to embodiment 8, wherein L is -C(O)- or -S(O) 2 -.

[0301] Embodiment 8(d) of the present disclosure relates to embodiment 8, wherein L is -CH(C 3 -C 6Cycloalkyl)-.

[0302] Embodiment 8(e) of the present disclosure relates to embodiment 8, wherein L is -CH(pyridyl)- or -C(CH 3 )(pyridinyl)-.

[0303] Embodiment 8(f) of the present disclosure relates to embodiment 8, wherein L is -C(H)(CH 2 CN)-.

[0304] Embodiment 9 of the present disclosure relates to compounds according to any one of embodiments 1-8 (including any sub-embodiments thereof where 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, tetrahydrothiophenyl or thiophenyl, wherein R 1 Optionally 1 G 1 Group and 1-3 G 2 Group substitution.

[0305] Sub-implementation of implementation plan 9

[0306] Embodiment 9(a) of the present disclosure relates to embodiment 9, wherein R 1 is phenyl, pyridyl or pyrimidinyl, wherein R 1 Optionally 1 G 1 Group and 1-3 G 2 Group substitution.

[0307] Embodiment 9(b) of the present disclosure relates to embodiment 9, wherein R 1 C 3 -C 6 Cycloalkyl or cyclohexynyl, where R 1 Optionally 1 G 1 Group and 1-3 G 2 Group substitution.

[0308] Embodiment 9(c) of the present disclosure relates to embodiment 9, wherein R 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, wherein R 1 Optionally 1 G1 Group and 1-3 G 2 Group substitution.

[0309] Embodiment 9(d) of the present disclosure relates to embodiment 9, wherein R 1 is optionally replaced by 1G 1 Group and 1-3 G 2 A phenyl group substituted with a group.

[0310] Embodiment 9(f) of the present disclosure relates to embodiment 9, wherein R 1 is optionally replaced by 1G 1 Group and 1-3 G 2 A pyridinyl group substituted with a group.

[0311] Embodiment 9(g) of the present disclosure relates to embodiment 9, wherein R 1 is optionally replaced by 1G 1 Group and 1-3 G 2 A pyrimidinyl group substituted with a group.

[0312] Embodiment 9(h) of the present disclosure relates to embodiment 9, wherein R 1 For optionally 1G 1 Group and 1-3 G 2 C 3 -C 6 Cycloalkyl.

[0313] Embodiment 9(j) of the present disclosure relates to embodiment 9, wherein R 1 is optionally replaced by 1G 1 Group and 1-3 G 2 A morpholinyl group substituted with a group.

[0314] Embodiment 9(k) of the present disclosure relates to embodiment 9, wherein R 1 is optionally replaced by 1G 1 Group and 1-3 G 2 A piperazinyl substituted with a group.

[0315] Embodiment 9(1) of the present disclosure relates to embodiment 9, wherein R 1 is optionally replaced by 1G 1 Group and 1-3 G 2 A piperidinyl group substituted with a group.

[0316] Embodiment 9(m) of the present disclosure relates to embodiment 9, wherein R 1 is optionally replaced by 1G 1 Group and 1-3 G 2 A pyrrolidinyl group substituted with a group.

[0317] Embodiment 9(n) of the present disclosure relates to embodiment 9, wherein R 1 is optionally replaced by 1G 1 Group and 1-3 G 2 Tetrahydro-2H-furanyl substituted with a group.

[0318] Embodiment 9(o) of the present disclosure relates to embodiment 9, wherein R 1 is optionally replaced by 1G 1 Group and 1-3 G 2 Tetrahydro-2H-pyranyl substituted with a group.

[0319] Embodiment 9(p) of the present disclosure relates to embodiment 9, wherein R 1 is optionally replaced by 1G 1 Group and 1-3 G 2 Tetrahydro-2H-thiopyranyl substituted with a group.

[0320] Embodiment 10 of the present disclosure relates to a compound according to any one of embodiments 1-9 (including any sub-embodiments thereof where applicable), wherein:

[0321] R 1 is one of (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l), or (m):

[0322] (a) optionally 1-3 G 2 C 3 -C 6 Cycloalkyl, where G 2 is F, cyano or -CH 2 CN;

[0323] (b) optionally by 1 G 1 Group and 1-3 G 2 A phenyl group substituted with 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 Independently -OCHF 2 、Cl、F、-OCH 3 、-OCF 3 , CH 3 CF 3 and -C(CH 3 )2 -OH;

[0324] (c) optionally replaced by 1 G 1 Group and 1-2 G 2 A pyridyl substituted with a group, wherein G 1 -C(O)OH, -C(O)NH 2 , cyclopropyl or cyclopropylalkynylene; and each G 2 F, CN, OCH independently 3 CF 3 , CH 3 , OH, -CH(CH 3 ) 2 and Cl;

[0325] (d) optionally by 1 G 1 Group and 1-2 G 2 substituted pyrazolyl, provided that when R 1 When it is pyrazolyl, L is a bond, wherein G can replace the hydrogen atom of -NH- or =CH- 1 -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 ; and each G that can replace a hydrogen atom of -NH- or =CH- 2 Independently for C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl and hydroxyl C 1 -C 6 alkyl;

[0326] (e) optionally with -NH 2 、-N(CH 3 ) 2 、OCH 3 , N-azetidinyl or cyclopropyl substituted pyrimidinyl;

[0327] (f) pyridazinyl;

[0328] (g) is optionally replaced by 1-2 each independently being C 1 -C 6 Alkyl, C1 -C 6 Haloalkyl, hydroxyl C 1 -C 6 tetrahydro-2H-pyranyl substituted with alkyl, Cl and F groups;

[0329] (h) is optionally replaced by 1-2 each independently being C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, hydroxyl C 1 -C 6 tetrahydro-2H-furanyl substituted with alkyl, Cl and F groups;

[0330] (i) optionally 1-2 each independently being C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl and hydroxyl C 1 -C 6 Alkyl group substituted morpholinyl;

[0331] (j) oxetanyl;

[0332] (k) is optionally replaced by 1-2 each independently being C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl and hydroxyl C 1 -C 6 an alkyl group substituted piperidinyl;

[0333] (l) is optionally substituted by 1-2 each independently being C 1 -C 6 Alkyl, C 1 -C 6 Haloalkyl, hydroxyl C 1 -C 6 Alkyl, Cl and F substituted cyclohexenyl; or

[0334] (m) thienyl.

[0335] Sub-implementation of implementation plan 10

[0336] Embodiment 11 of the present disclosure relates to a compound according to any one of embodiments 1-7 (including any sub-embodiments thereof where applicable), wherein -LR 1 for:

[0337]

[0338]

[0339]

[0340] in:

[0341] G 3 H、OCH 3 , N-azetidinyl, NH 2 、-N(CH 3 ) 2 , cyclopropyl;

[0342] G 4 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 ;

[0343] G 5 is H or OH;

[0344] G 6 H or CH 3； and

[0345] G 7 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(CH 3 ) 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 .

[0346] Sub-implementation of implementation plan 11

[0347] Embodiment 11(a) of the present disclosure relates to embodiment 11, wherein -LR 1 for:

[0348]

[0349] Embodiment 11(b) of the present disclosure relates to embodiment 11, wherein -LR 1 for:

[0350]

[0351] Embodiment 11(c) of the present disclosure relates to embodiment 11, wherein -LR 1 for:

[0352]

[0353] Embodiment 11(d) of the present disclosure relates to embodiment 11, wherein -LR 1 for:

[0354]

[0355] Embodiment 12 of the present disclosure relates to a compound according to embodiment 11 (including any sub-embodiments thereof where applicable), wherein:

[0356] G 1 is benzyloxy, -C(=CH 2 )CH 3 、-C(O)OH、-C(O)NH 2 、-C(O)N(H)-cyclopropyl、cyclopropyl、-CH 2 -cyclopropyl, cyclopropyl alkynylene, -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

[0357] Each G 2 Independently -OCHF 2 、-OCH 2 F, Cl, F, -OCH 3 ,OH,-OCF 3 , CH 3 、-CH(CH 3 ) 2 CF 3 、-CH 2 CN, CH 2 C(CH 3 ) 2 (OH) and -C(CH 3 ) 2 -OH.

[0358] Embodiment 13 of the present disclosure relates to compounds according to embodiment 11, wherein -LR 1 for:

[0359]

[0360] Embodiment 14 of the present disclosure relates to compounds according to embodiment 13, wherein G 1 is benzyloxy, -C(=CH 2 )CH 3 、-C(O)OH、-C(O)NH 2 、-C(O)N(H)-cyclopropyl、cyclopropyl、-CH 2 -cyclopropyl, cyclopropyl alkynylene, -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

[0361] Each G 2 Independently -OCHF 2 、-OCH 2 F, Cl, F, -OCH 3 ,OH,-OCF 3 , CH 3 、-CH(CH 3 ) 2 CF 3 、-CH 2 CN, CH 2 C(CH 3 ) 2 (OH) and -C(CH 3 ) 2 -OH.

[0362] Embodiment 15 of the present disclosure relates to a compound according to any one of embodiments 1-14 (including any sub-embodiments thereof where applicable), wherein R 5 When connected to carbon:

[0363]

[0364] Sub-implementation of implementation plan 15

[0365] Embodiment 15(a) of the present disclosure relates to embodiment 15, wherein R 5 for:

[0366]

[0367] Embodiment 15(b) of the present disclosure relates to embodiment 15, wherein R 5 for:

[0368]

[0369] Embodiment 15(c) of the present disclosure relates to embodiment 15, wherein R 5 for:

[0370]

[0371] Embodiment 15(d) of the present disclosure relates to embodiment 15, wherein R 5 for:

[0372]

[0373] Embodiment 15(d) of the present disclosure relates to embodiment 15, wherein R 5 for:

[0374]

[0375] Embodiment 15(e) of the present disclosure relates to embodiment 15, wherein R 5 for:

[0376]

[0377] Embodiment 16 of the present disclosure relates to a compound according to any one of embodiments 1-14 (including any sub-embodiments thereof where applicable), wherein R 5 for:

[0378]

[0379] Sub-implementation of implementation plan 16

[0380] Embodiment 16(a) of the present disclosure relates to embodiment 16, wherein R 5 for:

[0381]

[0382] Embodiment 16(b) of the present disclosure relates to embodiment 16, wherein R 5 for:

[0383]

[0384] Embodiment 16(c) of the present disclosure relates to embodiment 16, wherein R 5 for:

[0385]

[0386] Embodiment 16(d) of the present disclosure relates to embodiment 16, wherein R5 for:

[0387]

[0388] Embodiment 16(e) of the present disclosure relates to embodiment 16, wherein R 5 for:

[0389]

[0390] Embodiment 16(f) of the present disclosure relates to embodiment 16, wherein R 5 for:

[0391]

[0392] Embodiment 16(g) of the present disclosure relates to embodiment 16, wherein R 5 for:

[0393]

[0394] Embodiment 16(h) of the present disclosure relates to embodiment 16, wherein R 5 for:

[0395]

[0396] Embodiment 17 of the present disclosure relates to a compound according to any one of embodiments 1-14 (including any sub-embodiments thereof where applicable), wherein R 5 for:

[0397]

[0398] Embodiment 18 of the present disclosure relates to a compound according to any one of embodiments 1-14 (including any sub-embodiments thereof where applicable), wherein R 5 for:

[0399]

[0400] Sub-implementation of implementation plan 18

[0401] Embodiment 18(a) of the present disclosure relates to embodiment 18, wherein R 5 for:

[0402]

[0403] Embodiment 18(b) of the present disclosure relates to embodiment 18, wherein R 5 for:

[0404]

[0405] Embodiment 18(c) of the present disclosure relates to embodiment 18, wherein R 5 for:

[0406]

[0407] Embodiment 18(d) of the present disclosure relates to embodiment 18, wherein R 5 for:

[0408]

[0409] Embodiment 18(e) of the present disclosure relates to embodiment 18, wherein R 5 for:

[0410]

[0411] Embodiment 19 of the present disclosure relates to a compound according to any one of embodiments 15-18 (including any sub-embodiments thereof where applicable), wherein R 5 for:

[0412] 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

[0413] 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 、-CH2 CH 3 、-OCH 2 CH 3 、-OCH 2 CH 2 CH 3 and CH 3 .

[0414] Embodiment 20 of the present disclosure relates to compounds according to embodiment 19, wherein:

[0415] J 1 -C(O)OH or -C(O)OCH 3 ;and

[0416] 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 CH 3 .

[0417] Embodiment 21 of the present disclosure relates to compounds according to Embodiment 1, having any one of Formulas IV(a)-IV(c):

[0418]

[0419] or a pharmaceutically acceptable salt, solvate, tautomer, stereoisomer or deuterated analog thereof, wherein:

[0420] R 5 for:

[0421]

[0422] J 1 -C(O)OH or -C(O)OCH 3 ;

[0423] 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 CH 3 ;

[0424] -LR 1 for

[0425]

[0426] Among them G 1 is benzyloxy, -C(=CH 2 )CH 3 、-C(O)OH、-C(O)NH 2 、-C(O)N(H)-cyclopropyl、cyclopropyl、-CH 2 -cyclopropyl, cyclopropyl alkynylene, -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

[0427] Each G 2 Independently -OCHF 2 、-OCH2 F, Cl, F, -OCH 3 ,OH,-OCF 3 , CH 3 、-CH(CH 3 ) 2 CF 3 、CN、-CH 2 CN, CH 2 C(CH 3 ) 2 (OH) and -C(CH 3 ) 2 -OH.

[0428] Sub-implementation of implementation plan 21

[0429] Embodiment 21(a1) of the present disclosure relates to Embodiment 21 having Formula IV(a) or Formula IV(c).

[0430] Embodiment 21(a) of the present disclosure relates to Embodiment 21 having Formula IV(a).

[0431] Embodiment 21(b) of the present disclosure relates to Embodiment 21 having Formula IV(b).

[0432] Embodiment 21(c) of the present disclosure relates to Embodiment 21 having Formula IV(c).

[0433] Embodiment 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 for:

[0434]

[0435] Embodiment 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 for:

[0436]

[0437] Embodiment 21(f) of the present disclosure relates to any one of Embodiments 21, 21(a1), 21(a), 21(b) or 21(c), wherein R 5 for:

[0438]

[0439] Embodiment 21(g) of the present disclosure relates to any one of Embodiments 21, 21(a1), 21(a), 21(b) or 21(c), wherein R5 for:

[0440]

[0441] Embodiment 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 for:

[0442]

[0443] Embodiment 21(h) of the present disclosure relates to any one of Embodiments 21, 21(a1), 21(a), 21(b) or 21(c), wherein R 5 for:

[0444]

[0445] Embodiment 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 for:

[0446]

[0447] Embodiment 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 for:

[0448]

[0449] Embodiment 21(k) of the present disclosure relates to any one of embodiments 21, 21(a1), 21(a), 21(b) or 21(c), wherein R 5 for:

[0450]

[0451] Embodiment 21(1) of the present disclosure relates to any one of Embodiments 21, 21(a1), 21(a), 21(b) or 21(c), wherein R 5 for:

[0452]

[0453] Embodiment 21(m) of the present disclosure relates to any one of embodiments 21, 21(a1), 21(a), 21(b) or 21(c), 21(d), 21(e), 21(f), 21(g), 21(h), 21(i), 21(j), 21(k) or 21(l), wherein -LR1 for:

[0454]

[0455] Embodiment 21(n) of the present disclosure relates to any one of embodiments 21, 21(a1), 21(a), 21(b) or 21(c), 21(d), 21(e), 21(f), 21(g), 21(h), 21(i), 21(j), 21(k) or 21(l), wherein -LR 1 for:

[0456]

[0457] Embodiment 21(o) of the present disclosure relates to any one of embodiments 21, 21(a1), 21(a), 21(b) or 21(c), 21(d), 21(e), 21(f), 21(g), 21(h), 21(i), 21(j), 21(k) or 21(l), wherein -LR 1 for:

[0458]

[0459] Embodiment 21(p) of the present disclosure relates to any one of embodiments 21, 21(a1), 21(a), 21(b) or 21(c), 21(d), 21(e), 21(f), 21(g), 21(h), 21(i), 21(j), 21(k) or 21(l), wherein -LR 1 for:

[0460]

[0461] Embodiment 21(q) of the present disclosure relates to any one of embodiments 21, 21(a1), 21(a), 21(b) or 21(c), 21(d), 21(e), 21(f), 21(g), 21(h), 21(i), 21(j), 21(k) or 21(l), wherein -LR 1 for:

[0462]

[0463] Embodiment 21(r) of the present disclosure relates to any one of embodiments 21, 21(a1), 21(a), 21(b) or 21(c), 21(d), 21(e), 21(f), 21(g), 21(h), 21(i), 21(j), 21(k) or 21(l), wherein -LR 1 for:

[0464]

[0465] Embodiment 21(s) of the present disclosure relates to any one of embodiments 21, 21(a1), 21(a), 21(b) or 21(c), 21(d), 21(e), 21(f), 21(g), 21(h), 21(i), 21(j), 21(k) or 21(l), wherein -LR 1 for:

[0466]

[0467] Embodiment 21(t) of the present disclosure relates to any one of embodiments 21, 21(a1), 21(a), 21(b) or 21(c), 21(d), 21(e), 21(f), 21(g), 21(h), 21(i), 21(j), 21(k) or 21(l), wherein -LR 1 for:

[0468]

[0469] Embodiment 21(u) of the present disclosure relates to any one of embodiments 21, 21(a1), 21(a), 21(b) or 21(c), 21(d), 21(e), 21(f), 21(g), 21(h), 21(i), 21(j), 21(k) or 21(l), wherein -LR 1 for:

[0470]

[0471] Embodiment 21(v) of the present disclosure relates to any one of embodiments 21, 21(a1), 21(a), 21(b) or 21(c), 21(d), 21(e), 21(f), 21(g), 21(h), 21(i), 21(j), 21(k) or 21(l), wherein -LR 1 for:

[0472]

[0473] Embodiment 21(w) of the present disclosure relates to any one of embodiments 21, 21(a1), 21(a), 21(b) or 21(c), 21(d), 21(e), 21(f), 21(g), 21(h), 21(i), 21(j), 21(k) or 21(l), wherein -LR 1 for:

[0474]

[0475] Embodiment 21(x) of the present disclosure relates to any one of embodiments 21, 21(a1), 21(a), 21(b) or 21(c), 21(d), 21(e), 21(f), 21(g), 21(h), 21(i), 21(j), 21(k) or 21(l), wherein -LR 1 for:

[0476]

[0477] Embodiment 22 relates to a compound selected from Table 1 of the present disclosure or a pharmaceutically acceptable salt thereof according to Embodiment 1 of the present disclosure.

[0478] The compounds contemplated herein are described with reference to general chemical formulae and specific compounds. In addition, the compounds described herein may exist in many different forms or derivatives, all of which are within the scope of the present disclosure. These compounds include, for example, tautomers, stereoisomers, racemic mixtures, regioisomers, salts, prodrugs (e.g., carboxylic acid esters), solvated forms, and active metabolites.

[0479] It should be understood that some compounds can exhibit tautomerism. In such cases, the chemical formulas provided herein explicitly depict only one of the possible tautomeric forms. Therefore, it should be understood that the chemical formulas provided herein are intended to represent any tautomeric form of the compound depicted, and are not limited to the specific tautomeric form depicted by drawing the chemical formula.

[0480] Likewise, some compounds according to the present disclosure may exist in stereoisomeric forms as defined herein. All such single stereoisomers, racemates and mixtures thereof are intended to be within the scope of the present disclosure. Unless otherwise specified, all such stereoisomeric forms are included in the chemical formula provided herein.

[0481] In some embodiments, the chiral compounds of the present disclosure are in the form of a single isomer containing at least 80% (60% enantiomeric excess ("ee") or diastereomeric excess ("de")), 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 is generally understood by those skilled in the art, an optically pure compound having one chiral center is an optically pure compound that consists essentially of one of the two possible enantiomers (i.e., is enantiomerically pure), and an optically pure compound having more than one chiral center is an optically pure compound that is both diastereomerically pure and enantiomerically pure. In some embodiments, the compound is present in an optically pure form.

[0482] For compounds where the synthesis involves the addition of a single group at a double bond, especially a carbon-carbon double bond, the addition may be performed at either of the double bond-bonded atoms. For such compounds, the disclosure includes both such regioisomers.

[0483] In addition to the chemical formulae and compounds of the invention described herein, the present disclosure also includes prodrugs (generally pharmaceutically acceptable prodrugs), active metabolic derivatives (active metabolites), and pharmaceutically acceptable salts thereof.

[0484] Unless specified to the contrary, references to compounds herein include pharmaceutically acceptable salts of such compounds.

[0485] In some embodiments, the compounds of the present disclosure are compounded with acids or bases, including base addition salts such as ammonium, diethylamine, ethanolamine, ethylenediamine, diethanolamine, tert-butylamine, piperazine, meglumine; acid addition salts such as acetate, acetylsalicylate, benzenesulfonate, camphorsulfonate, citrate, formate, fumarate, glutarate, hydrochloride, maleate, mesylate, nitrate, oxalate, phosphate, succinate, sulfate, tartrate, thiocyanate and toluenesulfonate; 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 form of the complex is facilitated by a mixture of the parent compound and an acid or base by additional processing (such as by spray drying, mechanochemical methods such as roller pressing, or microwave irradiation). Such methods may also include the addition of ionic and / or nonionic polymer systems, including but not limited to hydroxypropylmethylcellulose acetate succinate (HPMCAS) and methacrylic acid copolymers (e.g. L100-55), which further stabilizes the amorphous nature of the composite. Such amorphous composites provide several advantages. For example, lowering the melting temperature for the free base facilitates additional processing (such as hot melt extrusion) to further improve the biopharmaceutical properties of the compound. In addition, the amorphous composite is brittle, which provides improved compression for loading the solid into capsule or tablet form.

[0486] In addition, the chemical formula is intended to cover hydrated or solvated as well as non-hydrated or non-solvated forms of the identified structure. For example, the indicated compound includes both hydrated and non-hydrated forms. Other examples of solvates include structures combined with suitable solvents such as isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid or ethanolamine.

[0487] III. Formulation and Administration

[0488] Embodiment 23 of the present disclosure relates to a pharmaceutical composition comprising a compound in one of the embodiments of the present disclosure or a compound according to any one of embodiments 1-22 (including any sub-embodiments thereof), and a pharmaceutically acceptable carrier.

[0489] Embodiment 24 of the present disclosure relates to a pharmaceutical composition of embodiment 23, further comprising a second agent.

[0490] Suitable dosage forms depend in part on the use or route of administration, e.g., oral, transdermal, transmucosal, inhaled, or by injection (parenteral). Such dosage forms should allow 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 block the compound or composition from exerting its effect. Techniques and formulations generally can be found in The Science and Practice of Pharmacy, 21st edition, Lippincott, Williams and Wilkins, Philadelphia, PA, 2005 (hereby incorporated herein by reference).

[0491] The compounds of the present disclosure (ie, any of the compounds described in Embodiments 1-22, including any embodiments thereof) can be formulated as pharmaceutically acceptable salts.

[0492] A carrier or excipient can be used to produce the composition. The carrier or excipient can be selected to facilitate the administration of the compound. Examples of carriers include calcium carbonate, calcium phosphate; various sugars, such as lactose, glucose or sucrose; or various types of starch, cellulose derivatives, gelatin, vegetable oils, polyethylene glycol, and physiologically compatible solvents. Examples of physiologically compatible solvents include water for injection (WFI), physiological saline solutions, and sterile solutions of dextrose.

[0493] The compound can be administered by different routes including intravenous, intraperitoneal, subcutaneous, intramuscular, oral, transmucosal, rectal, transdermal or inhalation. In some embodiments, the compound can be administered by oral administration. For oral administration, for example, the compound can be formulated into conventional oral dosage forms such as capsules, tablets and liquid preparations such as syrups, elixirs and concentrated drops.

[0494] For inhalants, the compounds of the present disclosure can be formulated into dry powders or suitable solutions, suspensions or aerosols. Powders and solutions can be formulated with suitable additives known in the art. For example, powders can include suitable powder bases, such as lactose or starch, and solutions can include propylene glycol, sterile water, ethanol, sodium chloride and other additives, such as acids, alkalis and buffer salts. The solution or suspension can be administered by inhalation via a sprayer, pump, atomizer or sprinkler. The compounds of the present disclosure may also be used in combination with other inhaled therapies, such as 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; vasodilators, such as treprostinil and iloprost; enzymes, such as DNA enzymes; therapeutic proteins; immunoglobulin antibodies; oligonucleotides, such as single-stranded or double-stranded DNA or RNA, siRNA; antibiotics, such as tobramycin; muscarinic receptor antagonists; leukotriene antagonists; cytokine antagonists; protease inhibitors; sodium cromoglycate; nedocril sodium; and sodium cromoglycate.

[0495] Pharmaceutical preparations for oral use can be obtained, for example, by combining the active compound with a solid excipient, optionally grinding the resulting mixture and, if desired, processing the mixture of granules, after adding suitable auxiliaries, to obtain tablets or dragee cores. Specifically, 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, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose (CMC) and / or polyvinylpyrrolidone (PVP: povidone). If desired, disintegrants, such as cross-linked polyvinylpyrrolidone, agar or alginic acid or its salts, such as sodium alginate, can be added.

[0496] The dragee core has a suitable coating. For this purpose, a concentrated sugar solution can be used, which can optionally contain, for example, gum arabic, talc, polyvinyl pyrrolidone, carbomer gel, polyethylene glycol (PEG) and / or titanium dioxide, lacquer solution and a suitable organic solvent or solvent mixture. Dyes or pigments can be added to tablets or dragee coatings for identification or characterization of different combinations of active compound dosages.

[0497] Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin ("gel capsules"), and soft sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Push-fit capsules may contain a mixture of the active ingredient with a filler, such as lactose, a binder, such as starch, and / or a lubricant, such as talc or magnesium stearate, and optionally a stabilizer. In soft capsules, the active compound may be dissolved or suspended in a suitable liquid, such as a fatty oil, liquid paraffin, or liquid polyethylene glycol (PEG). In addition, a stabilizer may be added.

[0498] Alternatively, injection (parenteral administration) may be used, such as intramuscular, intravenous, intraperitoneal and / or subcutaneous injection. For injection, the compounds of the present disclosure are formulated in a sterile liquid solution, such as a physiologically compatible buffer or solution, such as saline solution, Hank's solution or Ringer's solution. In addition, the compounds can be formulated in solid form and re-dissolved or suspended immediately before use. Lyophilized forms can also be produced.

[0499] Administration can also be carried out by transmucosal, topical, transdermal or inhalation. For transmucosal, topical or transdermal administration, a penetrant suitable for the barrier to be infiltrated is used in the formulation. Such penetrants are generally known in the art, and include, for example, bile salts and fusidic acid derivatives for transmucosal administration. In addition, detergents can be used to promote penetration. For example, transmucosal administration can be carried out by nasal sprays or by suppositories (rectum or vagina).

[0500] The topical compositions of the present disclosure are formulated as oils, creams, emulsions, ointments, etc. by selecting appropriate carriers known in the art. Suitable carriers include vegetable oils or mineral oils, white paraffin (white soft paraffin), branched chain fats or oils, animal fats and high molecular weight alcohols (greater than C). 12 ). In another embodiment, the carrier is one in which the active ingredient is soluble. If necessary, emulsifiers, stabilizers, moisturizers and antioxidants and agents that impart color or fragrance may also be included. Creams for topical application are prepared from a mixture of mineral oil, self-emulsifying beeswax and water, in which the active ingredient dissolved in a small amount of solvent (e.g., oil) is mixed. In addition, transdermal patches or dressings such as bandages impregnated with active ingredients and optional one or more carriers or diluents known in the art may be used transdermally. In order to be used in the form of a transdermal delivery system, the dosage administration will of course be continuous rather than intermittent throughout the dosage regimen.

[0501] The amount of each compound to be administered can be determined by standard procedures, taking into account the amount of compound IC. 50The dosage will be determined based on the factors of the amount of the compound, 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 ordinary skill in the art. In general, the dosage will be between about 0.01 and 50 mg / kg or 0.1 and 20 mg / kg of the subject being treated. Multiple doses may be used.

[0502] The compounds of the present disclosure may also be used in combination with other therapies for the treatment of the same disease. Such combined use includes administering the compound and one or more other therapeutic agents at different times, or co-administering the compound and one or more other therapies. In some embodiments, the dosage may be changed by methods well known to those of ordinary skill in the art for one or more compounds of the present disclosure or other therapeutic agents used in combination, for example, to reduce the dosage relative to a compound or therapy used alone.

[0503] It should be understood that the combined use includes the use with other therapies, drugs, medical procedures, etc., wherein the other therapies or procedures can be administered at a different time from the compounds of the present disclosure (e.g., within a short period of time, such as within a few hours (e.g., 1, 2, 3, 4-24 hours) or within a longer period of time (e.g., 1-2 days, 2-4 days, 4-7 days, 1-4 weeks)), or administered simultaneously with the compounds of the present disclosure. The combined use also includes the use with therapies or medical procedures (such as surgery) that are administered once or infrequently, and the compounds of the present disclosure that are administered within a short time or a longer time before or after the other therapies or procedures. In some embodiments, the present disclosure provides the delivery of the compounds of the present disclosure and one or more other drug therapeutic agents delivered by different routes of administration or by the same route of administration. The combined use of any route of administration includes the delivery of the compounds of the present disclosure and one or more other drug therapeutic agents delivered together in any formulation by the same route of administration, the formulation including a formulation in which the two compounds are chemically linked in a manner such that they maintain their therapeutic activity when administered. In one aspect, other drug therapies can be co-administered with one or more compounds of the present disclosure. The preparation of the compound of the compound of common preparation or chemical bonding is used in combination by co-administration, or two or more compounds administered by the same or different routes are administered in a separate preparation form within a short time (e.g., within one hour, 2 hours, 3 hours to 24 hours) from each other. The co-administration of the separate preparation includes co-administration by delivery via a device, such as the same inhalation device, the same syringe, etc., or is administered by a separate device within a short time from each other. The co-formulation of the disclosed compound and one or more other drug therapies delivered by the same route includes preparing the material together so that it can be administered by a device, including combining the separate compound in a preparation, or modifying the compound so that it is chemically bonded but still maintains its biological activity. Such chemically connected compounds can have a key that is substantially maintained in vivo, or the key can be decomposed in vivo, so as to separate the two active components.

[0504] IV. How to use

[0505] The methods and compounds will typically be used in therapy for human subjects. However, they can also be used to treat similar or identical indications in other animal subjects.

[0506] In certain embodiments, the patient is 60 years of age or older and has relapsed after a first line of cancer therapy. In certain embodiments, the patient is 18 years of age or older and has relapsed or is refractory after a second line of cancer therapy. In certain embodiments, the patient is 60 years of age or older and is substantially refractory to first line cancer therapy. In certain embodiments, the patient is 70 years of age or older and has not been previously treated. In certain embodiments, the patient is 70 years of age or older and is ineligible for inclusion and / or is unlikely to benefit from cancer therapy.

[0507] 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 dose. 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.

[0508] In certain embodiments, provided herein is a method for treating a disease or condition mediated by EP300 or CBP by administering to a mammal having the disease or condition 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 per day of any compound described in one of Embodiments 1-22, or a pharmaceutically acceptable salt, deuterated analog, tautomer, or stereoisomer thereof, and wherein the compound is administered on an empty stomach.

[0509] Embodiment 25 of the present disclosure relates to a method for treating a subject suffering from a disease or condition mediated by EP300 or CBP, the method comprising administering to the subject an effective amount of a compound according to one of Embodiments 1-22, or a pharmaceutically acceptable salt, deuterated analog, tautomer or stereoisomer thereof, or a pharmaceutical composition according to one of Embodiments 23-24.

[0510] 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 having an inactivating mutation in CBP or EP300, or a cancer in which EP300 or CBP activation is present.

[0511] 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 a cancer expressing an androgen receptor.

[0512] Embodiment 28 of the present disclosure relates to a method for treating a subject suffering from a disease or condition according to embodiment 25, wherein the disease or condition is a neoplastic disorder, cancer, an age-related disease, an inflammatory disorder, a cognitive disorder and / or a neurodegenerative disease.

[0513] Embodiment 29 of the present disclosure relates to a method for treating a subject having a disease or condition according to claim 25, wherein the disease or condition is acral melanoma, acute eosinophilic leukemia, acute erythroid leukemia, acute lymphoblastic leukemia, acute megakaryocytic 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 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-cell 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.

[0514] 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.

[0515] 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.

[0516] Embodiment 29(c) of the present disclosure relates to a method for treating a subject suffering from a disease or condition according to embodiment 29, wherein the disease or condition is prostate cancer.

[0517] Embodiment 29(d) of the present disclosure relates to a method for treating a subject suffering from a disease or condition according to embodiment 29, wherein the disease or condition is prostate cancer.

[0518] 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.

[0519] Embodiment 31 of the present disclosure relates to a method for treating a subject suffering from a disease or condition according to embodiment 29, wherein the disease or condition is Alzheimer's disease or Parkinson's disease.

[0520] V. Combination Therapy

[0521] EP300 and CBP modulators can be usefully combined with another pharmacologically active compound or with two or more other pharmacologically active compounds, particularly in the treatment of cancer. In one embodiment, the composition includes any one or more compounds as described herein and one or more compounds that are therapeutically effective for the same disease indication, wherein the compounds have a synergistic effect on the disease indication. In one embodiment, the composition includes any one or more compounds as described herein that are effective in treating cancer and one or more other compounds that are effective in treating the same cancer, further wherein the compounds are synergistically effective in treating cancer.

[0522] In another embodiment, the disclosure provides methods for treating a disease or condition mediated by EP300 or CBP by administering to a subject an effective amount of a composition comprising any one or more compounds described herein in combination with one or more other suitable therapies for treating the disease.

[0523] Embodiment 32 of the present disclosure relates to the method according to any one of embodiments 25-31 or any sub-embodiments thereof, further comprising administering one or more additional therapeutic agents.

[0524] Embodiment 33 of the present disclosure relates to the method according to embodiment 32, wherein the one or more additional therapeutic agents are one or more of the following: i) an alkylating agent selected from the group consisting of adolesin, hexamethylmelamine, biszelexin, busulfan, carboplatin, carboquinone, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, estramustine, fotemustine, hepsulfam, ifosfamide, improsulfam, ilofofen, lomustine, dichloromethane ... ii) an antibiotic selected from the group consisting of bleomycin, actinomycin D, daunorubicin, doxorubicin, epirubicin, idarubicin, menolide, mitomycin, mitoxantrone, neocarcinostatis, pentostatin and plicamycin; iii) an antimetabolite selected from the group consisting of azacitidine, capecitabine, cladribine, clofarabine, cytarabine doxycycline, decitabine, floxuridine, fludarabine, 5-fluorouracil, furofluuracil, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, nelarabine, pemetrexed, raltitrexed, thioguanine and trimetrexate; iv) an antibody therapeutic (including a PD-1 or PD-L1 inhibitor) selected from alemtuzumab, bevacizumab, cetuximab, galiximab, gemtuzumab, nivolumab, panitumumab, pembrolizumab, pertuzumab, rituximab, tosimol 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, megestrol acetate, raloxifene, tamoxifen and toremifene; vi) a taxane selected from the group consisting of 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) an anti-angiogenic agent selected from AE-941 (GW786034, neovastatin), ABT-510, 2-methoxyestradiol, lenalidomide and thalidomide; x) a topoisomerase inhibitor selected from amsacrine, edokalem, exatecan, irinotecan, SN-38 (7-ethyl-10-hydroxy-camptothecin), rubitecan, topotecan and 9-aminocamptothecin;xi) a kinase inhibitor selected from the group consisting of erlotinib, gefitinib, flavopiridol, imatinib mesylate, lapatinib, sorafenib, sunitinib malate, AEE-788, AG-013736, AMG 706, AMN107, BMS-354825, BMS-599626, UCN-01 (7-hydroxystaurosporine), vemurafenib, dabrafenib, trametinib, cobimetinib, selumetinib and vatalanib; xii) a targeted signal transduction inhibitor selected from bortezomib, geldanamycin and rapamycin; xiii) a biological response modifier selected from imiquimod, interferon-α and interleukin-2; xiv) an IDO inhibitor; and xv) a chemotherapeutic agent selected from 3-AP (3-amino-2-carboxaldehyde thiosemicarbazone), atrasentan, aminoglutethimide, anaphylactoids. Gray, asparaginase, bryostatin-1, cilengitide, ilisimol, eribulin mesylate (E7389), ixabepilone, lonidamine, masoprofen, mitoguanidine, olimus, sulindac, testosterone lactone, thiazole carboxamide nucleoside, mTOR inhibitor, PI3K inhibitor, Cdk4 inhibitor, Akt inhibitor, Hsp90 inhibitor, farnesyl transferase inhibitor or aromatase inhibitor (anastrozole letrozole exemestane); xvi) Mek inhibitor; xvii) tyrosine kinase inhibitor; xviii) c-Kit mutation inhibitor; xix) EGFR inhibitor, PD-1 inhibitor; or xx) epigenetic modulator. ;

[0525] Embodiment 33(a) of the present disclosure relates to a method according to embodiment 32, wherein the one or more additional therapeutic agents are one or more of the following: i) an alkylating agent selected from the group consisting of adolesin, altretinoin, biszelexin, busulfan, carboplatin, carboquinone, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, estramustine, fotemustine, hepsufan, ifosfamide, improsufan, ilofofen, lomustine, mesotrione, melphalan, oxaliplatin, piposufan, semustine, streptozotocin, temozolomide, thiotepa and treoxosufan; ii) an antibiotic selected from the group consisting of bleomycin, actinomycin D, daunorubicin, doxorubicin, epirubicin, idarubicin, menocril, mitomycin, mitoxantrone, neocarcinostatin, pentostatin and plicamycin; iii) an antimetabolite selected from the group consisting of The antimetabolite is selected from the group consisting of azacitidine, capecitabine, cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, 5-fluorouracil, furofluuracil, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, nelarabine, pemetrexed, raltitrexed, thioguanine and trimetrexate; iv) an immunotherapeutic agent selected from a PD-1 or PD-L1 inhibitor; v) Hormones or hormone antagonists selected from the group consisting of enzalutamide, abiraterone, anastrozole, androgens, buserelin, diethylstilbestrol, exemestane, flutamide, fulvestrant, goserelin, idoxifene, letrozole, leuprolide, megestrol acetate, raloxifene, tamoxifen and toremifene; vi) taxanes selected from the group consisting of DJ-927, docetaxel, TPI 287, paclitaxel and DHA-paclitaxel; vii) a retinoid selected from alitretinoin, bexarotene, fenretinide, isotretinoin and tretinoin; viiii) an alkaloid selected from etoposide, homoharringtonine, teniposide, vinblastine, vincristine, vindesine and vinorelbine; ix) an anti-angiogenic agent selected from AE-941 (GW786034, neovastat), ABT-510, 2-methoxyestradiol, levofloxacin, 1,2-diol ... lenalidomide and thalidomide; x) a topoisomerase inhibitor selected from the group consisting of amsacrine, edokalem, exatecan, irinotecan, SN-38 (7-ethyl-10-hydroxy-camptothecin), rubitecan, topotecan and 9-aminocamptothecin; xi) a kinase inhibitor selected from the group consisting of erlotinib, gefitinib, flavopiridol, imatinib mesylate, lapatinib, sorafenib, sunitinib malate, AEE-788, AG-013736, AMG 706, AMN107, BMS-354825, BMS-599626, UCN-01 (7-hydroxystaurosporine), vemurafenib, dabrafenib, trametinib, cobimetinib, selumetinib and vatalanib;xii) a targeted signal transduction inhibitor selected from bortezomib, geldanamycin and rapamycin; xiii) a biological response modifier selected from imiquimod, interferon-α and interleukin-2; xiv) an IDO inhibitor; and xv) a chemotherapeutic agent selected from 3-AP (3-amino-2-formaldehyde thiosemicarbazone), atrasentan, aminoglutethimide, anagrelide, asparaginase, bryostatin-1, cilengitide, ilisimol, eribulin mesylate (E7389), Ixabepilone, lonidamine, masoprofen, mitoguanidine, olimus, sulindac, testosterone lactone, thiazole carboxamide nucleoside, mTOR inhibitor, PI3K inhibitor, Cdk4 inhibitor, Akt inhibitor, Hsp90 inhibitor, farnesyl transferase inhibitor or aromatase inhibitor (anastrozole letrozole exemestane); xvi) Mek inhibitor; xvii) tyrosine kinase inhibitor; xviii) c-Kit mutation inhibitor; xix) EGFR inhibitor, PD-1 inhibitor; or xx) epigenetic modulator. ;

[0526] Embodiment 34 of the present disclosure relates to the method according to embodiment 33, wherein the one or more additional therapeutic agents are epigenetic modulators selected from the group consisting of:

[0527] (a) DNA methyltransferase;

[0528] (b) histone or protein methyltransferase;

[0529] (c) histone demethylase;

[0530] (d) histone deacetylase inhibitors;

[0531] (f) other chromatin remodeling agents; and

[0532] (g) BRD4 inhibitors.

[0533] Embodiment 35 of the present disclosure relates to the method according to embodiment 34, wherein the epigenetic regulator is a histone deacetylase inhibitor selected from the group consisting of vorinostat, romidepsin, cedamide, panobinostat, belinostat, valproic acid, mocetinostat, abexinostat, entinostat, resminostat, givinostat and quisinostat.

[0534] Embodiment 36 of the present disclosure relates to the method according to embodiment 34, wherein the epigenetic regulator is a BRD4 inhibitor.

[0535] Embodiment 37 of the present disclosure relates to the 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.

[0536] Embodiment 38 of the present disclosure relates to the 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.

[0537] Embodiment 39 of the present disclosure relates to the 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.

[0538] Bromodomains (e.g., BET proteins such as BRD2, BRD3, BRD4 and / or BRDT) and diseases associated with abnormal expression of bromodomains, for example, include cell proliferative diseases, cancer, chronic autoimmune diseases, inflammation, etc. Non-limiting examples of BET inhibitors include PLX1107, GSK1210151A, and GSK525762.

[0539] Histone deacetylase inhibitors (HDAC inhibitors) are cell growth inhibitors that inhibit tumor cells from growing in culture and in vivo by inducing cell cycle arrest, differentiation and / or apoptosis. HDAC inhibitors exert their anti-tumor effects by regulating the acetylation / deacetylation of histones and / or non-histone proteins such as transcription factors by inducing changes in the expression of oncogenes or tumor suppressors. Histone acetylation and deacetylation play an important role in the regulation of chromatin topology and the regulation of gene transcription. Non-limiting examples of HDAC inhibitors include vorinostat, romidepsin, cedabenamide, panobinostat, belinostat, valproic acid, mosinostat, abexinostat, entinostat, reminostat, ginostat and quisinostat. HDAC inhibitors have been widely used in psychiatry and neurology as mood stabilizers and anti-epileptic drugs. One example is valproic acid, which is sold as a drug under the trade names Depakene, Depakote and Divalproex. HDAC inhibitors are also used as agents to alleviate neurodegenerative diseases, such as Alzheimer's disease and Huntington's disease.

[0540] In another embodiment, the present disclosure provides a method of 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 effective for 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, 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), high temperature heating (e.g., microwaves, 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, adenovirus vector encoding MDA7, adenovirus 5-tumor necrosis factor alpha), photodynamic therapy (e.g., aminolevulinic acid, motexafin lutetium), surgery, or bone marrow and stem cell transplantation.

[0541] VI. Kit

[0542] On the other hand, the present disclosure provides a kit, the kit includes one or more compounds as described in any one of the compounds or pharmaceutically acceptable salts, deuterated analogs, tautomers or stereoisomers in one of the embodiments 1-22, or a pharmaceutical composition in one of the embodiments 23-24. In some embodiments, the compound or composition is packaged in, for example, a vial, a bottle, a flask, which may be further packaged in, for example, a box, an envelope or a bag. The compound or composition may be approved by the U.S. Food and Drug Administration or similar regulatory agencies for use in mammals, such as humans. The compound or composition may be approved for use in mammals, such as humans, to treat diseases or conditions mediated by EP300 or CBP. The kit described herein may include instructions for use and / or other indications that the compound or composition is suitable for or approved for use in mammals, such as humans, to treat diseases or conditions mediated by EP300 or CBP. The compound or composition may be packaged in unit dose or single dose form, such as single dose pills, capsules, etc.

[0543] VII. Binding Assay

[0544] The method of the present disclosure may involve an assay capable of detecting the binding of a compound to a target molecule. This binding is at a statistically significant level, with a confidence level of at least 90%, or at least 95%, 97%, 98%, 99% or greater, i.e., the assay signal represents binding to the target molecule, i.e., distinguished from background. In some embodiments, controls are used to distinguish target binding from non-specific binding. A variety of assays for indicating binding of different target types are known, and they can be used in the present disclosure.

[0545] Binding compounds can be characterized by their effect on the activity of the target molecule. Thus, the inhibitory concentration (IC 50 ) or effective concentration (EC 50 ) is greater than 1 μM under standard conditions. “Very low activity” means IC 50 or EC 50 Above 100 μM under standard conditions. “Very low activity” means IC 50 or EC 50 Above 1 mM under standard conditions. “Moderately active” means IC 50 or EC 50 200 nM to 1 μM under standard conditions. “Moderately active” means IC 50 or EC 50 1nM to 200nM. “High activity” means IC 50 or EC 50 Under standard conditions, IC 50 or EC 50 It is defined as the concentration of compound at which the measured activity of the target molecule (e.g., enzyme or other protein) loses or gains 50% activity relative to the range of activity observed in the absence of the compound. Activity can be measured using methods known to those of ordinary skill in the art, such as by measuring any detectable product or signal generated by the enzymatic reaction, or other activity of the protein being measured.

[0546] "Background signal" with respect to a binding assay refers to the signal recorded under standard conditions of a particular assay in the absence of a test compound, molecular scaffold or ligand that binds to a target molecule. One of ordinary skill in the art will recognize that there are well-established methods and they are widely available for determining background signal.

[0547] "Standard deviation" refers to the square root of the variance. Variance is a measure of how dispersed a distribution is. It is calculated as the average of the squares of the deviations of each value from its mean. For example, for the values ​​1, 2, and 3, the mean is 2 and the variance is:

[0548]

[0549] Surface plasmon resonance

[0550] Binding parameters can be measured using surface plasmon resonance, for example, using a Chip (Biacore, Japan). Surface plasmon resonance is used to characterize the microscopic association and dissociation constants of the reaction between sFv or other ligands against target molecules. Such methods are generally described in the following references, which are incorporated herein by reference. Vely F. et al., (2000) 用于测试磷酸肽 - SH2结构域相互作用的分析,《分子生物学方法》。121:313 - 21;Liparoto等人,(1999)白细胞介素 - 2受体复合物的生物传感器分析,《分子识别杂志》。12:316 - 21;Lipschultz等人,(2000)使用表面等离子体共振分析复杂动力学的实验设计,《方法》。20(3):310 - 8;Malmqvist.,(1999)BIACORE:用于表征生物分子相互作用的亲和生物传感器系统,《生物化学学会会报》27:335 - 40;Alfthan,(1998)表面等离子体共振生物传感器作为抗体工程中的工具,《生物传感器与生物电子学》。13:653 - 63;Fivash等人,(1998)用于大分子相互作用的BIAcore,《生物技术当前观点》。9:97 - 101;Price等人;(1998)ISOBM TD - 4研讨会总结报告:针对MUC1粘蛋白的56种单克隆抗体的分析。《肿瘤生物学》19增刊1:1 - 20;Malmqvist等人,(1997)生物分子相互作用分析:用于蛋白质功能分析的亲和生物传感器技术,《化学生物学当前观点》。1:378-83; O'Shannessy et al., (1996) Interpretation of deviations from pseudo-first-orderkinetic behavior in the characterization of ligand binding by biosensortechnology, Analytical Biochemistry. 236:275-83; Malmborg et al., (1995) BIAcore as atool in antibody engineering, Journal of Immunological Methods.183:7-13; VanRegenmortel, (1994) Use of biosensors to characterize recombinant proteins, Developments in Biological Standardization.83:143-51; and O'Shannessy, (1994) Determination of kinetic rate and equilibrium binding constants formacromolecular interactions: a critique of the surface plasmon literature, Current resonance Opinions in Biotechnology.5:65-71. .

[0551] The optical properties of surface plasmon resonance (SPR) are used to detect changes in the concentration of proteins bound to a dextran matrix (dextran biosensor matrix) located on the surface of a gold / glass sensor chip interface. In simple terms, proteins are covalently bound to the dextran matrix at a known concentration, and the ligands of the proteins are injected through the dextran matrix. The near-infrared light directed to the opposite side of the sensor chip surface is reflected and also induces evanescent waves in the gold film, which in turn causes the intensity of the reflected light to decrease at a specific angle, which is referred to as the resonance angle. If the refractive index of the sensor chip surface changes (e.g., by binding to the ligand of the bound protein), a shift occurs in the resonance angle. This angular shift can be measured and expressed as a resonance unit (RU) so that 1000RU is equivalent to 1ng / mm 2These changes are shown versus time along the y-axis of the sensorgram, which depicts the association and dissociation of any biological response.

[0552] High Throughput Screening (HTS) Assays

[0553] HTS typically uses automated assays to search for a large number of compounds for the desired activity. Typically, HTS assays are used to find new drugs by screening chemicals that act on specific enzymes or molecules. For example, if a chemical inactivates an enzyme, it can be proven to effectively prevent the disease-causing process in the cell. High-throughput methods enable researchers to use robotic handling systems and automated result analysis to rapidly assay thousands of different chemicals for each target molecule.

[0554] 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 are screened using robotic screening assays. Ultra-high throughput screening (uHTS) generally refers to high throughput screening accelerated to greater than 100,000 tests per day.

[0555] In order to achieve high throughput screening, it is advantageous to place the sample on a multi-container carrier or platform. The multi-container carrier helps to measure the reaction of multiple candidate compounds simultaneously. Multi-porous microplates can be used as carriers. Such multi-porous microplates and their methods for numerous assays are known in the art and commercially available.

[0556] Screening assays can include controls for the purpose of calibration and confirmation of the correct operation of the assay components. Blank wells containing all reactants but not containing members of the chemical library are generally included. For another example, a known inhibitor (or activator) of an enzyme for which a modulator is sought can be cultivated with a sample of the assay, and the resulting enzyme activity reduction (or increase) is used as a comparator or control. It should be understood that modulators can also be combined with enzyme activators or inhibitors to find modulators that inhibit enzyme activation or inhibition caused by the presence of known enzyme modulators in other cases.

[0557] Measuring enzymatic and binding reactions during screening assays

[0558] Techniques for measuring the progress of enzyme and binding reactions, for example in multi-container vehicles, are known in the art and include, but are not limited to, the following.

[0559] Spectrophotometric and spectrofluorometric assays are well known in the art. Examples of such assays include detection of peroxide using a colorimetric assay 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, p. 437.

[0560] Fluorescence spectroscopy can be used to monitor the generation 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 a review, 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.

[0561] In the spectrofluorometric method, the enzyme is exposed to a substrate that changes its intrinsic fluorescence when processed by the target enzyme. Typically, the substrate is non-fluorescent and is converted to a fluorophore through one or more reactions. As a non-limiting example, SMase activity can be measured using Red reagent (Molecular Probes, Eugene, OR). Red measures sphingomyelinase activity, which proceeds through the following reactions. First, SMase hydrolyzes sphingomyelin to give ceramide and phosphorylcholine. Second, alkaline phosphatase hydrolyzes phosphorylcholine to give choline. Third, choline is oxidized to betaine by choline oxidase. Finally, H 2 O 2 In the presence of horseradish peroxidase Red reacts to produce the fluorescent product Resorufin, and its signal is detected using spectrofluorimetry.

[0562] Fluorescence polarization (FP) is based on the reduction in the molecular rotation rate of the fluorophore that occurs after binding to a larger molecule (such as a receptor protein), resulting in polarized fluorescence emission from 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. Fluorophores produce a larger polarization signal when they are bound to a larger molecule (i.e., a receptor), slowing down the molecular rotation of the fluorophore. The magnitude of the polarization signal is quantitatively related to the degree of binding of the fluorescent ligand. Therefore, the polarization of the "bound" signal depends on the maintenance of high-affinity binding.

[0563] FP is a homogeneous technique and reacts very quickly, taking seconds to minutes to reach equilibrium. The reagents are stable and can be prepared in large quantities, resulting in high reproducibility. Due to these characteristics, FP has been shown to be 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.

[0564] FP is particularly desirable because its 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 is therefore insensitive to the presence of colored compounds that quench fluorescence emission. FP and FRET (see below) are well suited for identifying compounds that block the interaction between sphingolipid receptors and their ligands. See, e.g., 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.

[0565] Fluorophores derived from sphingolipids that can be used for FP assays are commercially available. For example, Molecular Probes (Eugene, OR) currently sells sphingomyelin and a ceramide fluorophore. These are N-(4,4-difluoro-5,7-dimethyl-4-boron-3a,4a-diaza-s-dicyclopentadienylbenzo-3-pentanoyl)sphingosylphosphocholine ( FL C5-sphingomyelin); N-(4,4-difluoro-5,7-dimethyl-4-boron-3a,4a-diaza-s-dicyclopentadienylbenzo-3-dodecanoyl)sphingosine phosphorylcholine ( FL C12-sphingomyelin); and N-(4,4-difluoro-5,7-dimethyl-4-boron-3a,4a-diaza-s-dicyclopentadienylbenzo-3-pentanoyl)sphingosine ( FL C5-ceramide). U.S. Pat. No. 4,150,949 (Immunoassay for gentamicin) discloses fluorescein-labeled gentamicin, including fluorescein thiocarbonyl gentamicin. Other fluorophores can be prepared using methods well known to skilled artisans.

[0566] Exemplary normal and polarized fluorescence readers include Fluorescence polarization system (Tecan AG, Hombrechtikon, Switzerland). Universal multiwell plate readers for other assays are available, such as Reader and Multi-well plate spectrophotometer (both from Molecular Devices).

[0567] Fluorescence resonance energy transfer (FRET) is another assay suitable 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 energy transfer between two closely adjacent fluorescent substances with known excitation and emission wavelengths. For example, a protein can be expressed as a fusion protein fused to 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 another 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.).

[0568] The scintillation proximity assay (SPA) is an assay particularly useful for detecting interactions with target molecules. SPA is widely used in the pharmaceutical industry and has been described (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. A commercially available system uses Scintillator-coated plates (NEN Life Science Products, Boston, MA).

[0569] The target molecule can be bound to the scintillator plate by a variety of well-known means. Scintillator plates are available that are derivatized to bind to fusion proteins (such as GST, His6 or Flag fusion proteins). In the case where the target molecule is a protein complex or multimer, one protein or subunit can be first attached to the plate, followed by the addition of the other components of the complex later under binding conditions to produce a bound complex.

[0570] In a typical SPA assay, the gene product in the expression pool has been radiolabeled and added to the wells and allowed to interact with the solid phase, which is the immobilized target molecule and the scintillator coating in the wells. The assay can be measured immediately or allowed to reach equilibrium. Either way, when the radiolabel becomes close enough to the scintillator coating, its production can be determined by, for example, The signal is detected by a microplate scintillation counter (Packard BioScience Co., Meriden Conn.) If the radiolabeled expression product binds to the target molecule, the radiolabel remains in close proximity to the scintillant long enough to generate a detectable signal.

[0571] In contrast, the labeled protein that is not bound to the target molecule or only briefly bound will not stay near the scintillator for a time sufficient to generate a signal above the background. Any time spent near the scintillator caused by random Brownian motion does not generate a large amount of signal. Similarly, the residual unincorporated radiolabel used during the expression step may exist, but will not generate a significant signal because it will be in solution rather than interacting with the target molecule. These non-binding interactions will therefore result in a certain background signal level that can be mathematically removed. If too many signals are obtained, salt 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).

[0572] General Synthesis

[0573] The disclosed compounds can be prepared using methods disclosed herein and conventional modifications thereof, which will be apparent to the disclosure herein and methods well known in the art. In addition to the teachings herein, conventional and well-known synthetic methods can be used. The synthesis of representative compounds described herein can be completed as described in the following examples. If available, reagents can be purchased commercially, for example, from Sigma Aldrich or other chemical suppliers.

[0574] The compounds disclosed herein can be prepared from readily available starting materials using, for example, the following general methods and procedures. It should be understood that, unless otherwise indicated, other process conditions may also be used when typical or preferred process conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) are given. Optimum reaction conditions may vary with the specific reactants or solvents used, but such conditions may be determined by conventional optimization procedures by those skilled in the art.

[0575] In addition, it will be apparent to those skilled in the art that conventional protecting groups may be necessary to prevent certain functional groups from undergoing undesirable reactions. Suitable protecting groups for various functional groups and suitable conditions for protecting and deprotecting specific functional groups are well known in the art. For example, many protecting 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.

[0576] Compounds of the present disclosure may contain one or more asymmetric or chiral centers. Therefore, if desired, such compounds can be prepared or separated into pure stereoisomers, i.e., single enantiomers or diastereomers or mixtures of enriched stereoisomers. Unless otherwise indicated, all such stereoisomers (and enriched mixtures) are included within the scope of the present disclosure. Pure stereoisomers (or enriched mixtures) can be prepared using, for example, optically active starting materials or stereoselective reagents known in the art. Alternatively, racemic mixtures of such compounds can be separated using, for example, chiral column chromatography, supercritical fluid chromatography, chiral seed crystals, chiral resolution agents, etc.

[0577] The starting materials for the following reactions are generally known compounds or can be prepared by known methods or obvious modifications thereof. For example, many starting materials can be obtained from the following suppliers: Aldrich Chemical Co. (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemce or Sigma (St. Louis, Missouri, USA). Other starting materials can be prepared by procedures described in the following standard reference texts, or obvious modifications thereof: 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).

[0578] It should also be understood that in each scheme, the addition of any substituent may result in the production of a variety of isomeric products (including but not limited to enantiomers or one or more diastereomers), any one of which or all of which may be separated and purified using conventional techniques. When enantiomerically pure or enriched compounds are required, chiral chromatography and / or enantiomerically pure or enriched starting materials may be used, as conventionally used in the art or as described in the examples.

[0579] The compounds disclosed herein can be synthesized according to the general reaction schemes and / or examples described below. The general scheme can be changed by replacing the starting material with other materials having similar structures to produce the corresponding products. The structure of the desired product usually makes the desired starting material clear to those skilled in the art.

[0580] Schemes 1 and 2 provide exemplary synthetic routes for synthesizing compounds provided herein (e.g., compounds of Formula I). ​​Compounds of Formula I or other formulas or compounds disclosed herein are generally prepared by first providing a core formula X(a) or X(d) and then attaching the desired substituents using appropriate conditions (e.g., coupling).

[0581] In some embodiments, the synthesis of compounds of Formula I is carried out according to Scheme 1.

[0582] Solution 1

[0583]

[0584] In Scheme 1, A 1 , A 2 , L, R 1 , R 4 , R 5 , X 1 , X 2 and X 3 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). The compound of Formula X(b) or Formula X(c) can then be converted to a compound of Formula I, respectively.

[0585] In Scheme 1, Z 1 , Z 2 , Z 3 and Z 4 Each of the following is independently a suitable leaving group such as a halide or hydroxide ion (e.g., in the presence of triphenylphosphine and a dialkyl azodicarboxylate), a suitable coupling partner such as a halide, boronic acid, borate or hydrogen (e.g., of a terminal alkyne), or a suitable electrophile such as an aldehyde or ketone.

[0586] In Scheme 1, R 51 For R 5a , hydrogen or a suitable leaving group such as a halide or hydroxide ion (eg in the presence of triphenylphosphine and dialkyl azodicarboxylates) or a suitable coupling partner such as a halide, boronic acid, borate. 5a For R 5 or a suitable precursor, for example, when R 5 When carboxylic acid is included, R 5aIt may contain esters. 5 When a carboxylic acid is involved, the conversion of Formula X(b) to Formula I or the conversion of Formula X(a) to Formula X(c) may include a step of hydrolyzing the ester. 18 For-LR 1 R is preferably selected from the group consisting of: hydrogen or a suitable leaving group such as a halide or hydroxide ion (e.g., in the presence of triphenylphosphine and dialkyl azodicarboxylates), a suitable coupling partner such as a halide, boronic acid, borate, or a suitable electrophile such as an aldehyde or ketone. 41 For R 4 . A 11 , A 12 and A 13 Each of A 1 . A 21 , A 22 and A 23 Each of A 2 Or for additional A 2 A suitable moiety, for example a suitable coupling partner, such as a halide, boronic acid, borate or hydrogen.

[0587] Those skilled in the art will appreciate that any compound of formula X(a), X(b) or X(c) may be obtained from commercial suppliers of particular embodiments. Alternative syntheses of compounds of formula X(a), X(b) or X(c) may be as described herein or as known to those skilled in the art.

[0588] In some embodiments, the synthesis of compounds of Formula I is carried out according to Scheme 2.

[0589] Solution 2

[0590]

[0591] In Scheme 2, A 1 , A 2 , L, R 1 , R 4 , R 5 , X 1 , X 2 and X 3 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). The compound of Formula X(e) or Formula X(f) can then be converted to a compound of Formula I, respectively.

[0592] In Scheme 2, Z 5 , Z 6 , Z 7 and Z 8Each of the following is independently a suitable leaving group such as a halide or hydroxide ion (e.g., in the presence of triphenylphosphine and a dialkyl azodicarboxylate), a suitable coupling partner such as a halide, boronic acid, borate or hydrogen (e.g., of a terminal alkyne), or a suitable electrophile such as an aldehyde or ketone.

[0593] In Scheme 2, R 52 For R 5b , hydrogen or a suitable leaving group such as a halide or hydroxide ion (eg in the presence of triphenylphosphine and dialkyl azodicarboxylates) or a suitable coupling partner such as a halide, boronic acid, borate. 5b For R 5 or a suitable precursor, for example, when R 5 When carboxylic acid is included, R 5b It may contain esters. 5 When a carboxylic acid is involved, the conversion of Formula X(e) to Formula I or the conversion of Formula X(d) to Formula X(f) may include a step of hydrolyzing the ester. 19 For-LR 1 R is preferably a halogen, a hydrogen or a suitable leaving group such as a halide or hydroxide ion (e.g. in the presence of triphenylphosphine and dialkyl azodicarboxyl) , a suitable coupling partner such as a halide, a boronic acid, a borate 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 For R 4 or for additional R 4 A suitable moiety, such as hydrogen. 14 , A 15 and A 16 Each of A 1 Or for additional A 1 A suitable moiety, for example a suitable coupling partner such as a halide, boronic acid, borate or hydrogen. 24 , A 25 and A 26 Each of A 2 .

[0594] Those skilled in the art will appreciate that any compound of formula X(d), X(e) or X(f) may be obtained from commercial suppliers of particular embodiments. Alternative syntheses of compounds of formula X(d), X(e) or X(f) may be as described herein or as known to those skilled in the art.

[0595] Palladium coupling conditions

[0596] Where appropriate, formula X(a), X(b), X(c), X(d), X(e) or X(f) is coupled with compound 501, 502, 503, 504, 505, 506, 507 or 508, with the formation of a (hetero)aryl carbon-(hetero)aryl carbon bond, wherein 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 a boronic acid or 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 (e.g., aqueous 1,4-dioxane or aqueous N,N-dimethylformamide) in the presence of a weak base (e.g., potassium acetate, potassium carbonate, sodium carbonate, or sodium bicarbonate). The reaction is generally carried out in the presence of a metal catalyst with an appropriate ligand (e.g., dichlorobis(triphenylphosphine)palladium(II) or dichloro1,1'-bis(diphenylphosphino)ferrocenepalladium(II)) at a temperature of about 60°C to 150°C for about 10 minutes to about 12 hours. When the reaction is substantially complete, the product is isolated by conventional methods.

[0597] Copper ("Buchwald") Coupling Conditions

[0598] Where appropriate, for example, in the case of forming a (hetero)aryl carbon-nitrogen bond, formula X(a), X(b), X(c), X(d), X(e) or X(f) is coupled with compound 501, 502, 503, 504, 505, 506, 507 or 508, wherein Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 or Z 8is 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 (e.g., toluene or N,N-dimethylformamide) in the presence of a weak base (e.g., potassium carbonate or tripotassium phosphate). The reaction is generally carried out at a temperature of about 60°C to 150°C for about 10 minutes to about 7 days in the presence of a metal catalyst (e.g., copper iodide (I), copper bromide (I) or copper acetate (II) monohydrate) with an appropriate ligand (e.g., trans-N,N'-dimethylcyclohexane-1,2-diamine). When the reaction is substantially complete, the product is isolated by conventional methods.

[0599] Aryl nucleophilic displacement conditions

[0600] Where appropriate, for example, in the case of forming a (hetero)aryl carbon-nitrogen bond, formula X(a), X(b), X(c), X(d), X(e) or X(f) is coupled with compound 501, 502, 503, 504, 505, 506, 507 or 508, wherein Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 or Z 8 is a suitable leaving group, such as fluoride, in nucleophilic substitution-aromatic ("SN Ar ”) in a suitable solvent (e.g., DMSO, DMF, etc.), optionally under an inert atmosphere. The reaction is carried out in an inert solvent (e.g., DMSO) in the presence of a weak base (e.g., potassium carbonate or cesium carbonate). The reaction is typically carried out at a temperature of about 60° C. to 150° C. for about 1 hour to about 7 days. When the reaction is substantially complete, the product is isolated by conventional methods.

[0601] Alkyne coupling conditions

[0602] Where appropriate, for example, in the case of forming an alkynyl carbon-nitrogen bond, Formula X(a), X(b), X(c), X(d), X(e) or X(f) is coupled with Compound 501, 502, 503, 504, 505, 506, 507 or 508, wherein Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , Z 6 , Z 7 or Z 8For hydrogen or trialkylsilane, under copper catalyzed coupling conditions (e.g., using a palladium catalyst and / or 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 (e.g., toluene or N,N-dimethylformamide) in the presence of a weak base (e.g., triethylamine). The reaction is generally carried out at a temperature of about 60°C to 150°C for about 10 minutes to about 1 day in the presence of a metal catalyst (e.g., bis(triphenylphosphine)palladium dichloride (II), cuprous iodide (I) or cuprous bromide (I)) optionally with a suitable ligand (e.g., trans-N,N'-dimethylcyclohexane-1,2-diamine). When the reaction is substantially complete, the product is separated by conventional methods.

[0603] Ester hydrolysis conditions

[0604] Where appropriate, for example, in the case of carboxylic acid esters R 1a or R 5a R 1 or R 5 In the case of forming a carboxylic acid, Formula X(a), X(b), X(c), X(d), X(e) or X(f) is subjected to ester hydrolysis conditions. Ester hydrolysis conditions may include, for example, in a suitable solvent (e.g., water, dioxane, alcohol and / or THF), at a temperature of about 0°C to 100°C, using 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) for about 10 minutes to about 24 hours. When the reaction is substantially complete, the product is isolated by conventional methods.

[0605] Example

[0606] The following examples describe the general synthesis procedures of compounds described herein. The synthesis of compounds described herein is not limited by these examples and schemes. Those skilled in the art will appreciate that other procedures can be used to synthesize compounds described herein, and the procedures described in the examples and schemes are only one of the procedures. In the following description, those of ordinary skill in the art will recognize that specific reaction conditions, added reagents, solvents, and reaction temperatures can be changed for the synthesis of specific compounds within the scope of the present disclosure. Unless otherwise specified, the intermediate compounds in the following examples that do not contain a description of their manufacturing methods are commercially available to those skilled in the art, or can be synthesized in other ways by skilled technicians using commercially available precursor molecules and synthetic methods known in the art.

[0607] The following schemes and synthetic examples are intended to illustrate but not to limit or define the scope of the present disclosure.

[0608] Example 1

[0609]

[0610] Step 1: Preparation of 4-(5-(3,5-dimethylisoxazol-4-yl)-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)picolinic acid methyl ester 2: To a microwave pressure vial charged with 4-[1-(phenylsulfonyl)-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-dioxaborol-2-yl)pyridine-2-carboxylic acid methyl ester (167 mg, 0.635 mmol), 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (26.6 mg, 0.033 mmol) was added 1,4-dioxane (3 ml). The flask was purged with argon, and then 2.5M potassium carbonate aqueous solution (0.376ml) was added. The vial was sealed and stirred in an oil bath at 120°C for 2 hours. The reaction was cooled to room temperature and the biphasic mixture was filtered through diatomaceous earth, which was washed with THF and ethyl acetate. The filtrate was concentrated under reduced pressure and the substance was purified by silica gel flash column chromatography with a gradient elution of 0-100% ethyl acetate in hexane. This gave methyl 4-(5-(3,5-dimethylisoxazol-4-yl)-1-(benzenesulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)picolinate (2). MS(ESI)[M+H + ] + =489.0.

[0611] 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. Then, 3 ml of 1 M LiOH(aq) was added. After 30 minutes, 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. The volatiles were removed by rotary evaporation 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 2H) to purify the resulting residue 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.

[0612] Example 2

[0613]

[0614] Step 1: Preparation of 4-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,5-dimethylisoxazole 4: In 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 hour, and then 4-methylbenzenesulfonyl chloride (6.80 g, 35.7 mmol) was added. 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 hexanes 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.

[0615] 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) chloride (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 and then methyl 2,2-dimethylbut-3-ynoate (53 mg, 0.42 mmol) was added. The mixture was heated at 90° C. for 2 hours. The mixture was concentrated under reduced pressure and purified by flash chromatography eluting with 20% ethyl acetate in hexanes 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.

[0616] 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 1 M TBAF in THF (0.400 ml). The mixture was stirred at 70° C. for 15 hours. The reaction was diluted with ethyl acetate, which was washed with saturated sodium bicarbonate (aq), water, and brine. The layers were separated and the organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure and triturated with 5% ethyl acetate in hexanes to afford 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.

[0617] 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 minutes and then bromomethylbenzene (21.75 mg, 0.13 mmol) was added. The resulting mixture was stirred at 60°C for 2 hours. The mixture was diluted with water, extracted with ethyl acetate, and the organic layer was washed with water and brine sequentially. 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 hexanes 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.

[0618] 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-ynoate (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 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 purify the material 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.

[0619] Example 3

[0620]

[0621] 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 a solution of 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-pyridinyl)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 and then diisopropyl azodicarboxylate (0.738 g, 3.65 mmol) was added dropwise. After 1 hour, the reaction was removed from the ice bath and warmed to room temperature for 1 hour. The reaction was concentrated under reduced pressure and purified by silica gel column chromatography eluting with 20% to 100% ethyl acetate in hexanes to provide (S)-4-(3-iodo-1-(1-(pyridin-2-yl)ethyl)-1H-pyrrolo[3,2-b]pyridin-6-yl)-3,5-dimethylisoxazole (9).

[0622] 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 trifluoromethylsulfinate (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 warmed to ambient temperature and then placed in an oil bath at 50 °C and stirred overnight. After 22 hours, LCMS showed about 10% product formation. An additional 1.27 g of zinc trifluoromethylsulfinate was added, followed by 1 ml of tert-butyl hydroperoxide. The reaction was allowed to continue at 50° C. for another 17 hours. The reaction was extracted with saturated sodium bicarbonate and ethyl acetate. The organic layer was separated and the aqueous layer was extracted with 5 mL of ethyl acetate three more times. The organic layers were combined and the volatiles were 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.

[0623] 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: Add (S)-4-(3-iodo-1-(1-(pyridin-2-yl)ethyl)-2-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridin-6-yl)-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 to a flask containing 1% paraformaldehyde and 1% paraformaldehyde. A reaction vial containing a solution of methylisoxazole (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) chloride dichloromethane complex (9.8 mg, 0.012 mmol) in dioxane (2 ml) was purged with nitrogen and 2.5 M K 2 CO 3Aqueous solution (0.144 ml). 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 eluted with 100% ethyl acetate by flash chromatography, and then purified by reverse phase 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

[0624] Example 4

[0625]

[0626] Step 1: Preparation of (3-(benzyloxy)phenyl)(6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methanol 12: To a solution of 3,5-dimethyl-4-(1H-pyrrolo[3,2-b]pyridin-6-yl)isoxazole (11, 0.24 g, 1.11 mmol) in methanol (5 ml) were 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 and 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.

[0627] 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 solution of (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 hour. 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 afford (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.

[0628] 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) was added DMSO (3 ml). The reaction mixture was heated 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 product 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) The crude material was purified 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.

[0629] Example 5

[0630]

[0631] 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), tripotassium phosphate (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 purged with argon. The reaction mixture was then 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, which was washed with ethyl acetate. The material was purified by silica gel column chromatography (0-50% ethyl acetate in hexanes) to afford ethyl 4-(6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-1-yl)-3,5-diethoxybenzoate (14).

[0632] 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: To 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 placed under N 2 The mixture was stirred at 0 ° C and cooled to 0 ° C, and then N-bromosuccinimide (246 mg, 1.38 mmol) was slowly added. The reaction mixture was stirred at 0 ° C and warmed to room temperature for 2 hours. The reaction was diluted with ethyl acetate and distributed 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 hexane) to obtain 4-(3-bromo-6-(3,5-dimethylisoxazole-4-yl)-1H-pyrrolo[3,2-b]pyridine-1-yl)-3,5-diethoxybenzoic acid ethyl ester (15).

[0633] 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: 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-dichloropalladium(II) dichloromethane complex (8.7 mg, 0.011 mmol) and 2.5 M K 2 CO 3 The aqueous solution (0.09 ml) was 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.

[0634] Example 6

[0635]

[0636] 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-pyridinyl)ethanol (646 mg, 5.25 mmol) and triphenylphosphine (1377 mg, 5.25 mmol) in THF (35 ml) was slowly added diisopropyl azodicarboxylate (1.04 ml, 5.25 mmol) under nitrogen. The mixture was stirred and allowed to reach room temperature for 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.

[0637] 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-dichloropalladium(II) dichloromethane complex (149 mg, 0.182 mmol) in dioxane (20 ml) was purged with nitrogen and then 2.5 M K was added. 2 CO 3 (2.5 ml). 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.

[0638] 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 to reach room temperature for 2 hours. The mixture was washed with saturated Na 2 S 2 O 3 The aqueous solution was diluted, extracted with ethyl acetate, and the organic layer was washed with water and brine in sequence. 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.

[0639] 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)dichloropalladium(II) (63 mg, 0.09 mmol) and cuprous(I) iodide (17 mg, 0.09 mmol) in (1:3) triethylamine in acetonitrile (20.0 ml) was purged with nitrogen 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% dichloromethane in hexane to give methyl 4-bromo-3-(cyclopropylethynyl)benzoate (21). MS (ESI) [M+H + ] + =280.9.

[0640] Step 5: Preparation of methyl 3-(cyclopropylethynyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)benzoate 22: A mixture of methyl 4-bromo-3-(cyclopropylethynyl)benzoate (21, 307 mg, 1.1 mmol), bis(pinacol)diboron (419 mg, 1.65 mmol), 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) 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 hours. The mixture was diluted with ethyl acetate, 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.

[0641] 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)benzoic acid methyl ester 23: To (S)-4-(3-iodo-1-(1-(pyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,5-dimethylisoxazole (19, 2.5 M K 2-nitropropene (62 mg, 0.14 mmol), methyl 3-(2-cyclopropylethynyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)benzoate (22, 150 mg, 0.46 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (11.43 mg, 0.013 mmol) in dioxane (2 ml) were added. 2 CO 3 (0.170 ml). The mixture was heated at 100°C for 4 hours. The sample was diluted with ethyl acetate, washed with water, brine and dried over anhydrous magnesium sulfate. The organic layer was filtered and concentrated under reduced pressure. The substance 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)benzoic acid methyl ester (23). MS (ESI) [M+H + ] + =517.2.

[0642] 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)-methyl 3-(cyclopropylethynyl)-4-(5-(3,5-dimethylisoxazol-4-yl)-1-(1-(pyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)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 3 M HCl / MeOH, diluted with ethyl acetate and concentrated under reduced pressure. The HPLC was performed 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 2O, 0.1% HCO 2 H) to purify the material 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.

[0643] Example 7

[0644]

[0645] Step 1: Preparation of methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-3-(trifluoromethoxy)benzoate 25: A mixture of methyl 4-bromo-3-(trifluoromethoxy)benzoate (344 mg, 1.15 mmol), bis(pinacol)diboron (24,584 mg, 2.3 mmol), and 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) 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, 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 hexanes 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.

[0646] 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: To a nitrogen-purged 1-((5-(3,5-dimethylisoxazol-4-yl)-3-iodo-1H-pyrrolo[2,3-b]pyridin-1-yl)methyl)cyclobutane-1-carbonitrile (26, 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-dichloropalladium(II) dichloromethane complex (9.8 mg, 0.012 mmol) in dioxane (2 ml) were added 2.5 M aqueous potassium carbonate solution (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 hexanes 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.

[0647] 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 a solution 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, 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 1 N HCl in MeOH and concentrated under reduced pressure. The HPLC was performed 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 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.

[0648] Example 8

[0649]

[0650] Step 1: Preparation of methyl 4-ethoxypicolinate 29: 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) were stirred at room temperature overnight. The reaction mixture was poured into water (200 mL) and extracted with ethyl acetate / hexane = 1 / 1 (600 mL). The organic layer was separated, washed with water (2×100 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered through a short silica gel pad and concentrated under reduced pressure. This gave methyl 4-ethoxypicolinate (29).

[0651] 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) at 0°C was added mCPBA (77%, 3.755 g, 16.76 mmol) portionwise and stirred at room temperature for 22 hours. Additional mCPBA (77%, 1.876 g, 8.38 mmol) was added and the mixture was stirred for another 5 hours. The reaction was diluted with ethyl acetate (200 mL) and saturated aqueous sodium bicarbonate solution (50 mL). The separated aqueous phase was extracted with DCM / MeOH=9 / 1 (5×50 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).

[0652] 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) was added trifluoroacetic anhydride (1.57 mL, 11.86 mmol) dropwise at 0°C over 5 minutes. The mixture was stirred at 0°C for another 4 hours. The reaction was diluted with dichloromethane (200 mL) and extracted with a mixed solution of saturated aqueous sodium bicarbonate (10 mL) and brine (50 mL). The organic layer was separated and dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The 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.

[0653] 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) was added iodoethane (0.255 mL, 3.18 mmol) and the mixture was stirred at room temperature overnight. The reaction was diluted with ethyl acetate / hexanes (1 / 1, 150 ml) and extracted with water (50 ml, 3x) and brine (30 ml). The organic layer was dried over anhydrous sodium sulfate, filtered through a short pad of silica gel and concentrated under reduced pressure. The resulting material was purified by silica gel column chromatography (0-20% ethyl acetate in hexanes) to give methyl 4,6-diethoxypicolinate (32).

[0654] 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) was added N-bromosuccinimide (76 mg, 0.43 mmol) and the mixture was stirred at 50 °C overnight. Another 2 equivalents of N-bromosuccinimide (15 mg, 0.18 mmol) were added and stirred for another hour. LC / MS showed that the reaction was incomplete, so another 2 equivalents of N-bromosuccinimide (15 mg, 0.18 mmol) were added and stirred for another hour. LC / MS showed that all the 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 (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 afford methyl 5-bromo-4,6-diethoxypicolinate (33).

[0655] 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 hours. Additional 2,4-difluorobromobenzene (2.26 mL, 20.00 mmol) was added and the reaction 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).

[0656] 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 minutes and then at room temperature for 20 minutes before 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, filtered and concentrated under reduced pressure. The material was purified by silica gel column chromatography (0-20% ethyl acetate in hexanes) to provide 4-(3-bromo-1-(2,4-difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,5-dimethylisoxazole (36).

[0657] 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-dimethylisoxazole ( A mixture of 4-(1-(2,4-difluorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,5-dimethylisoxazole (37) was prepared by column chromatography on silica gel (0-10% ethyl acetate in dichloromethane).

[0658] 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), 5-bromo-4,6-diethoxypicolinic acid methyl ester (33, 29 mg, 0.095 mmol), Pd(OAc) and ... 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 hours. Then, 1N HCl aqueous solution (1 ml) was added, and the mixture was diluted with dichloromethane / methanol (10 / 1, 20 ml) and filtered through diatomaceous earth. The mother liquor was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by silica gel column chromatography (0-10% methanol in dichloromethane) to give the methyl ester of P-0329 (85 mg). The material was dissolved in THF (0.75 ml) and methanol (0.25 ml) and 2N LiOH aqueous solution (0.25 ml) was added to the solution and the resulting mixture was stirred at room temperature for 2 hours. 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.

[0659] Example 9

[0660]

[0661] 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 hours. The reaction was diluted with saturated aqueous sodium thiosulfate solution and extracted with ethyl acetate, washed with water and 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.

[0662] 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 solution (10 ml) was slowly added sodium nitrite (193 mg, 2.79 mmol) 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 over 3 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The material was purified by silica gel column chromatography (20% dichloromethane in hexane) to give methyl 4-bromo-3-chloro-5-(trifluoromethoxy)benzoate (40).

[0663] 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: A 1 M solution of diisopropyl azodicarboxylate in THF (19.46 mL, 19.46 mmol, 1.5 eq) 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 eq), tetrahydro-2H-pyran-4-ol (1.99 g, 19.5 mmol, 1.5 eq) and triphenylphosphine (5.10 g, 19.46 mmol, 1.5 eq) 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 (ca. 100 mL) and filtered to afford 4-(3-iodo-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,5-dimethylisoxazole (41).

[0664] 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: A 2M solution of isopropylmagnesium chloride (9.1 mL, 18.15 mmol, 2.4 eq) in THF 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 eq) in THF (76 mL) at 0°C. The reaction was warmed to room temperature and stirred for 30 min resulting in dissolution at which point metal / halogen exchange was complete as determined by 1H NMR. The solution was cooled to 0 ° C and pinacol borane (3.29 mL, 22.68 mmol, 3 equivalents) was added. The reaction was warmed 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 to 100% ethyl acetate in heptane). This gave 3,5-dimethyl-4-(1-(tetrahydro-2H-pyran-4-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1H-pyrrolo[2,3-b]pyridine-5-yl)isoxazole (42).

[0665] 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: To 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-3-yl)-5-(trifluoromethoxy)benzoic acid To a mixture of [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-dichloropalladium(II) dichloromethane complex (20 mg, 0.025 mmol) in dioxane (3 ml) was added 1 M aqueous potassium carbonate solution (0.47 ml). The reaction was stirred at 100°C for 3 hours. The reaction was cooled, 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 hexanes). The resulting methyl ester of P-0355 was dissolved in methanol / THF (1:1, 4 ml) and 1 M aqueous lithium hydroxide solution (1.18 ml) was added. The mixture was stirred at room temperature for 3 hours. The reaction was quenched with solid extracted sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The product was analyzed 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 purify the material 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.

[0666] Example 10

[0667]

[0668] Step 1: Preparation of 5-bromo-2-(methoxycarbonyl)-4-methylpyridine 1-oxide 44: To a solution of methyl 5-bromo-4-methylpicolinate (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.

[0669] Step 2: Preparation of 5-bromo-6-hydroxy-4-methylpicolinic acid methyl ester 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) was added trifluoroacetic anhydride (0.7 ml, 5.04 mmol) under argon and cooled to 0°C. The reaction mixture was warmed 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 and 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 hexanes). This gave 5-bromo-6-hydroxy-4-methylpicolinic acid methyl ester (45). MS (ESI) [M+H + ] + =246.0.

[0670] Step 3: Preparation of 5-bromo-6-ethoxy-4-methylpicolinic acid methyl ester 46: A mixture of 5-bromo-6-hydroxy-4-methylpicolinic acid methyl ester (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 minutes. Then, iodoethane (0.5 ml, 5.18 mmol) was added and the reaction was stirred at 90 ° C for 4 hours. 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 hexanes). This gave 5-bromo-6-ethoxy-4-methylpicolinic acid methyl ester (46). MS (ESI) [M+H + ] + =274.0 and 276.0.

[0671] 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 eq) 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 eq), compound 10 (8.93 g, 80 mmol, 1.5 eq) and triphenylphosphine (34.8 g, 133 mmol, 2.5 eq) 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 an approximately 1:1 mixture of MTBE and heptane (approximately 50 ml) to give 4-(1-(dicyclopropylmethyl)-3-iodo-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,5-dimethylisoxazole (47).

[0672] 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: 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 eq) in THF (90 ml) was added to a 2M solution of isopropylmagnesium chloride (11.1 ml, 22.16 mmol, 2.4 eq) in THF at 0° C. After stirring for 30 min, the metal / halogen exchange was complete as determined by 1H NMR. Isopropyl pinacol borate (11.3ml, 55.4mmol, 6 equivalents) was added and the reaction was allowed to warm to room temperature and stirred overnight. The reaction was poured into water (200ml) and the pH was adjusted to 6 with 10% aqueous acetic acid solution (about 40ml). The mixture was extracted with ethyl acetate (200ml). The organic layer was washed with saturated brine (200ml) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (0-100% ethyl acetate in heptane) to obtain 4-(1-(dicyclopropylmethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1H-pyrrolo[2,3-b]pyridine-5-yl)-3,5-dimethylisoxazole (48).

[0673] 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: To 4-(1-(dicyclopropylmethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-5-yl)-1H-pyrrolo[2,3-b]pyridine-5-yl)-6-ethoxy-4-methylpicolinate 49, 4-(1-(dicyclopropylmethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-5-yl)-1H-pyrrolo[2,3-b]pyridine-5-yl)-1H-pyrrolo[2,3-b]pyridine-5-yl)-1H-pyrrolo[2,3-b]pyridine-3-yl)-6-ethoxy-4-methylpicolinate 49, 4-(1-(dicyclopropylmethyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-5-yl)-1H-pyrrolo[2,3-b]pyridine-3 ...3-yl)-1H-pyrrolo[2,3-b]pyridine-5-yl)-1 To a solution of 1,4-dioxane (2 ml) was added 1 M potassium carbonate solution (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 and brine in turn and then dried over anhydrous magnesium sulfate. The volatiles were removed under reduced pressure. The substance was purified by silica gel column chromatography (0-75% ethyl acetate in hexane). 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.

[0674] 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 a solution of 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 1 M aqueous lithium hydroxide solution (5 ml). The reaction mixture was stirred at room temperature for 5 hours. After adding aqueous formic acid, the organic layer of the reaction mixture was separated and concentrated under reduced pressure. The product 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 purify the material 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.

[0675] Embodiment 11

[0676]

[0677] Step 1: Preparation of 4-(3-iodo-1-tosyl-1H-pyrrolo[3,2-b]pyridin-6-yl)-3,5-dimethylisoxazole 50: To a solution of 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 and brine, then dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The substance 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.

[0678] 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 2M isopropylmagnesium chloride in THF (1.5 ml). The reaction mixture was slowly warmed to 0 °C for about 1 hour. The reaction mixture was cooled to -55 °C and then dicyclopropyl ketone (0.35 ml, 3.05 mmol) was added. The reaction mixture was slowly warmed to room temperature over 1-2 hours and maintained at room temperature for 90 minutes. The reaction was quenched with 1N aqueous HCl (3 ml). The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and brine, then dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The substance was purified by silica gel column chromatography (0-80% ethyl acetate in hexane). This gave 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.

[0679] 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 1 M solution of 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 and brine, and 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).

[0680] 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: Toluene (2 ml) was added dicyclopropyl(6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-b]pyridin-3-yl)methanol (52, 100 mg, 0.309 mmol), tripotassium phosphate (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-diethoxybenzoate (160 mg, 0.504 mmol). The reaction mixture was heated to 110 °C for 16 hours. The reaction mixture was filtered and the filtrate was concentrated 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.

[0681] 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 a solution 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, 17 mg, 0.030 mmol) in THF (10 ml) was added 1 M 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 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 purify the material 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.

[0682] Example 12

[0683]

[0684] 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 hours. The mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and 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.

[0685] 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 hours. The reaction was quenched with saturated aqueous potassium carbonate solution and extracted with ethyl acetate. The organic layer was washed with water and 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.

[0686] 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 a solution of 3,5-dimethyl-4-(3-(pyridin-2-ylmethyl)-1H-pyrrolo[3,2-b]pyridin-6-yl)isoxazole (55, 33 mg, 0.108 mmol) and cuprous 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 minutes. Then, sodium hydroxide (100 mg, 2.50 mmol) and copper (II) acetate monohydrate (10 mg, 0.050 mmol) were 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.

[0687] The organic layer was washed with water and 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 obtain 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.

[0688] Embodiment 13

[0689]

[0690] Step 1: Preparation of ethyl 4-bromo-3,5-diethoxy-2-fluorobenzoate 57: To a solution of 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-diazobicyclo[2.2.2]octane ditetrafluoroborate (2.08 g, 5.87 mmol). The reaction mixture was immediately heated to 60°C. After 18 hours, the reaction mixture was diluted with ethyl acetate and extracted with water (+HCl). The organic layer was washed with saturated aqueous sodium bicarbonate solution and brine in sequence. 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 to 20% ethyl acetate / DCM 40 / 60 in hexanes). The downstream mixed fractions were combined and purified with a second column. The reflux mixed fractions were combined and purified with a third column. This gave the mono-F product ethyl 4-bromo-3,5-diethoxy-2-fluorobenzoate (57). MS (ESI) [M+H + ] + =334.9.

[0691] Step 2: Preparation of 4-(1-(2,4-difluorophenyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,5-dimethylisoxazole 58: In a pressure vial with a magnetic stir bar were 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-difluoro-benzene (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). Then, (1R, 2R)-N1, N2-dimethylcyclohexane-1,2-diamine (0.524 g, 3.68 mmol) was added, the reaction was purged with argon, sealed and stirred in an oil bath at 120 ° C. After 17 hours, the reaction was filtered through diatomaceous earth and washed with ethyl acetate. The filtrate was extracted with 1M HCl aqueous solution (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 with a gradient elution of 20% to 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.

[0692] 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 hours. TLC indicated that all the 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 sequentially with additional saturated aqueous sodium thiosulfate solution and brine, dried over anhydrous magnesium sulfate and filtered. The volatiles were removed by rotary evaporation and the resulting residue was purified by flash column chromatography on silica gel eluting with 0-20% ethyl acetate in hexanes. This afforded 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.

[0693] Step 4: Preparation of 4-(1-(2,4-difluorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-2-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,5-dimethylisoxazole 60: In 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 pinacol borane (1.23 ml, 8.48 mmol) was added 1,4-dioxane (16 ml). The stirred solution was purged with argon, then triethylamine (1.48 ml, 10.6 mmol) was added and the reaction was placed in an oil bath at 60 ° C under an 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 celite, washed 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.

[0694] 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 vial with a magnetic stir bar, add 4-(1-(2,4-difluorophenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3,5-diethoxy-2-fluorobenzoate pyrrol [2,3-b] pyridine -5-yl) -3,5- dimethylisoxazole (60,662mg, 1.47mmol), 4- bromo -3,5- diethoxy -2- fluoro - benzoic acid ethyl ester (57,485mg, 1.45mmol), dichloro [1,1 '- bis (diphenylphosphino) ferrocene] palladium (II) dichloromethane adduct (239mg, 0.293mmol) and 1,4- dioxane (7ml). Then, 2.5M potassium carbonate aqueous solution (2.32ml) was added, and the reaction was purged with argon, sealed and immediately heated at 120 ° C in an oil bath for 15 minutes. The reaction mixture was cooled and poured into water (20ml) and ethyl acetate (20ml) and filtered through diatomaceous earth. The organic layer was washed with 1M HCl aqueous solution to produce a black solid substance, which was removed by diatomaceous earth filtration. 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 using a gradient of 20% to 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.

[0695] 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 a solution 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, 142 mg, 0.25 mmol) dissolved in THF (8.7 ml) was added 1 M aqueous lithium hydroxide solution (4.6 ml) and the two-phase mixture was stirred at room temperature for 5 hours. The reaction was quenched with 2N aqueous HCl solution (3 ml) and diluted with ethyl acetate (20 ml). The organic layer was washed with brine and 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 to 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.

[0696] Embodiment 14

[0697]

[0698] 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), 1 M aqueous potassium carbonate solution (15.59 ml), 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (0.76 g, 0.93 mmol) and dioxane (10 ml). The reaction was heated to 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 to 100% ethyl acetate in hexanes) to give 4-(6-chloropyridin-3-yl)-3,5-dimethylisoxazole (64). MS (ESI) [M+H + ] + =209.1.

[0699] Step 2: Preparation of 5-(3,5-dimethylisoxazol-4-yl)-N-(3-methyltetrahydrofuran-3-yl)pyridin-2-amine 65: In a 20 mL microwave vial, 4-(6-chloropyridin-3-yl)-3,5-dimethylisoxazole (64, 0.5 g, 2.4 mmol) was dissolved in DME (2 ml). Then, 3-methyloxolane-3-amine (0.3 ml, 2.88 mmol), sodium tert-butoxide (345 mg, 3.59 mmol) and RuPhos (196 mg, 0.24 mmol) were added and the vial was sealed and heated to 120 °C in an oil bath under nitrogen for 18 hours. The reaction mixture was filtered through celite and then evaporated onto silica. The product 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 purify the material to give 5-(3,5-dimethylisoxazol-4-yl)-N-(3-methyltetrahydrofuran-3-yl)pyridin-2-amine (65). MS (ESI) [M+H + ] + =274.2.

[0700] Step 3: Preparation of 5-(3,5-dimethylisoxazol-4-yl)-3-iodo-N-(3-methyltetrahydrofuran-3-yl)pyridin-2-amine 66: In a 20 ml microwave vial, 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). 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 onto sodium thiosulfate, filtered, and then evaporated onto silica gel. The product was isolated by silica gel flash column chromatography (0 to 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.

[0701] Step 4: Preparation of 3,5-dimethyl-4-(1-(3-methyltetrahydrofuran-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)isoxazole 67: In a 5 ml microwave vial, 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-ethoxyethylene-2-boronic acid pinacol ester (0.413 ml, 1.88 mmol) were dissolved in DMF (3 ml). Then, 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (92 mg, 0.11 mmol) and lithium hydroxide (90 mg, 3.76 mmol) were added and the vial was sealed and heated to 80 °C in an oil bath under nitrogen atmosphere for 6 hours. The reaction was then cooled to 50 °C and 25% aqueous HCl (0.37 ml, 2.5 mmol) was added via syringe and the reaction was stirred for 2 hours. The reaction was poured into saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The organic layer was evaporated onto silica gel and purified by silica gel flash column chromatography (0 to 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.

[0702] 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. Then, a solution of N-iodosuccinimide (309 mg, 1.37 mmol) in DMF (2 mL) was added. The reaction was stirred for 2 hours 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 afford 4-(3-iodo-1-(3-methyltetrahydrofuran-3-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,5-dimethylisoxazole (68).

[0703] 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. 12mmol) and methyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-(trifluoromethoxy)benzoate (25, 61mg, 0.18mmol) were dissolved in dioxane (3ml) and then 1M aqueous potassium carbonate solution (0.24ml) and 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (9mg, 0.01mmol) were added. The reaction was stirred at 110°C for 4 hours. 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 to 100% ethyl acetate in hexanes). The isolated product was dissolved in MeOH / THF (4ml) and 1M aqueous lithium hydroxide solution (0.59ml) and stirred at room temperature for 4 hours. The reaction was poured into saturated aqueous ammonium chloride solution and extracted with ethyl acetate. The organic layer was evaporated onto silica gel and 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-(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.

[0704] Embodiment 15

[0705]

[0706] 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-dichloropalladium(II) dichloromethane complex (695 mg, 0.852 mmol) in dioxane (60 ml) purged with nitrogen was added 2.5 M aqueous potassium carbonate solution (12 ml). The mixture was heated to 110°C for 3 hours. The reaction was cooled and 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.

[0707] 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 hours. The reaction was diluted with saturated aqueous sodium thiosulfate solution and extracted with ethyl acetate. The organic layer was washed with water and 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.

[0708] 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 hours. The reaction was cooled and 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.

[0709] 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: To a nitrogen-purged 2-(5-(3,5-dimethylisoxazol-4-yl)-3-iodo-2-methyl-1H-pyrrolo[2,3-b]pyridin-1-yl)nicotinonitrile (72, 100 mg, 0.003 mmol) was added 1% paraffin wax and 1% paraffin wax; To a mixture of 1,4-dimethyl-1,3-dioxaborolan-2-yl (25, 99 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-dichloropalladium(II) dichloromethane complex (18 mg, 0.022 mmol) in dioxane (2 ml) was added 2.5 M aqueous potassium carbonate solution (0.270 ml). The reaction was heated to 110° C. for 3 hours. The reaction was cooled to room temperature and 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.

[0710] 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 hours. The reaction was diluted with ethyl acetate, acidified with 1 N HCl in MeOH and concentrated under reduced pressure. The precipitate 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.

[0711] Example 16

[0712]

[0713] 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 dropwise isobutyl chloroformate (7.13 mL, 55 mmol) at 0°C over 5 minutes. The mixture was then stirred at 0°C for 5 minutes and at room temperature for 10 minutes. The precipitate was removed by filtration and rinsed with THF (50 mL), and the mother liquor and rinsed solution were 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 at 0°C over 15 minutes. Water (35 mL) was then also added carefully. The resulting mixture was stirred at 0°C for 1 hour and then at room temperature for 30 minutes. After the reaction mixture was cooled to 0°C, 4N aqueous sulfuric acid solution (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. This gave (3-methylisoxazol-5-yl)methanol (75).

[0714] 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) at 0°C was added Dess-Martin periodinane (13.9 g, 32.7 mmol) and the mixture was stirred at room temperature for 6.5 hours. The mixture was diluted with dichloromethane (500 mL) and washed with 5% aqueous sodium thiosulfate solution (150 mL) and saturated aqueous sodium bicarbonate solution (150 mL). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The material was purified by silica gel flash column chromatography (0 to 40% ethyl acetate in hexanes) to give 3-methylisoxazole-5-carbaldehyde (76).

[0715] 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 dropwise ((trimethylsilyl)methyl)magnesium chloride solution (1.0 M in THF, 25.8 mL, 25.8 mmol) at 0°C over 5 minutes. After stirring at 0°C for 1 hour, the solution was allowed to warm to room temperature and stirred for 6.5 hours. At 0°C, 1N aqueous sulfuric acid solution (25 mL) was added and the reaction was extracted with ethyl acetate (100 mL). The organic layer was washed with saturated aqueous sodium bicarbonate solution (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 at 0°C over 5 minutes. The mixture was then stirred at room temperature for 2 hours. The mixture was poured into an ice-cooled saturated aqueous sodium bicarbonate solution (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).

[0716] 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 hour. After the catalyst was removed by filtration through celite, the mixture was concentrated under reduced pressure to give 5-ethyl-3-methylisoxazole (78).

[0717] 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) was added N-bromosuccinimide (3.13 g, 17.6 mmol) and the mixture was stirred at room temperature overnight. After the addition of additional N-bromosuccinimide (522 mg, 2.93 mmol), the mixture was stirred at room temperature for another 5 hours. The reaction was diluted with ethyl acetate and hexanes (1 / 1, 300 mL) and washed with 5% aqueous sodium thiosulfate (90 mL), 1N 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. The 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).

[0718] 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 stirring the mixture at -78°C for 20 min, 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolan (0.31 mL, 1.53 mmol) was added and the mixture was stirred at -78°C for another 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. The material was purified by silica gel flash column chromatography (0 to 10% ethyl acetate in hexanes) to afford 5-ethyl-3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole (80).

[0719] 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 triphenylphosphine (3.93 g, 15.0 mmol) in THF (50 mL) was added diisopropyl azodicarboxylate (2.95 mL, 15.0 mmol) dropwise over 5 minutes 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 to 35% ethyl acetate in hexanes). Impure fractions were further repurified by chromatography or by suspending the solid product in ethyl acetate / hexanes (1 / 3 ratio) and then filtering. This afforded 5-bromo-3-iodo-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridine (82).

[0720] 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-dioxaborolan-2-yl)-3-(trifluoromethoxy)benzoate (25, 281 mg, 0.811 mmol), PdCl2 (Ph 3 P) 2 A mixture of 4-(5-bromo-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-(trifluoromethoxy)benzoic acid (83) was stirred overnight at 60 °C. The reaction was concentrated under reduced pressure and then partitioned between ethyl acetate (50 mL) and water (10 mL). The organic layer was separated and washed with brine (10 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel flash column chromatography (0 to 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).

[0721] 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) and 4-(5-bromo-1-(tetrahydro-2H-pyran-4-yl)-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-(trifluoromethoxy)benzoate were added. 2 (1.2 mg, 0.006 mmol), S-Phos (2.3 mg, 0.006 mol) and K 3 PO 4 A mixture of 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) and 1,4-dioxaborolan-2-yl was stirred at 105°C for 15 hours. 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) and Pd(OAc) were added. 2 (1.2 mg, 0.006 mmol), S-Phos (2.3 mg, 0.006 mol) and K 3 PO 4(58mg, 0.275mmol), and the mixture was stirred at 105°C for another 6 hours. The reaction was cooled, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure. The resulting mixture of compound 84 and P-0401 was dissolved in DMF (0.5mL), potassium carbonate (30mg, 0.220mmol) and iodomethane (0.014mL, 0.220mmol) were added, and the mixture was stirred at room temperature overnight. The reaction was diluted with ethyl acetate (50mL), and the solution was washed with 0.2N HCl aqueous solution (5mL), water (2×5mL) and brine (5mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The material was purified by silica gel flash column chromatography (0 to 50% ethyl acetate in hexanes) to afford 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.

[0722] 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 a solution 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, 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 hours. The reaction was quenched by the addition of 1N aqueous HCl (0.5 mL) and the mixture was concentrated under reduced pressure. The material was purified by silica gel flash column chromatography (0 to 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.

[0723] Embodiment 17

[0724]

[0725] 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-dioxaborolan-2-yl)isoxazole (84, 26 mg, 0.110 mmol, prepared in 6 steps from 5-methylisoxazole-3-carboxylic acid in a similar manner to compound 80 described in Example 16), methyl 4-(5-bromo-1-tetrahydropyran-4-yl-pyrrolo[2,3-b]pyridin-3-yl)-3-(trifluoromethoxy)benzoate (83, 55 mg, 0.110 mmol), Pd(OAc) and 4-(5-bromo-1-tetrahydropyran-4-yl-pyrrolo[2,3-b]pyridin-3-yl)-3-(trifluoromethoxy)benzoate were added. 2 A mixture of 1-(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 mol) and potassium phosphate (58 mg, 0.275 mmol) in dioxane (1.0 mL) and water (0.25 mL) was stirred at 105° C. overnight. Additional 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) and potassium phosphate (58 mg, 0.275 mmol) were added. 2 (1.2 mg, 0.006 mmol), S-Phos (2.3 mg, 0.006 mol) and potassium phosphate (58 mg, 0.275 mmol) and the reaction was continued at 105 ° C for another 6 hours. Then, the reaction was cooled and filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure. The resulting mixture of compound 85 and P-0400 was dissolved in DMF (0.5 mL), potassium carbonate (30 mg, 0.220 mmol) and iodomethane (0.014 mL, 0.220 mmol) were added. The reaction was stirred overnight at room temperature. The reaction was diluted with ethyl acetate (50 mL), and the solution was washed with 0.2N HCl aqueous solution (5 mL), water (2×5 mL) and brine (5 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The material was purified by silica gel flash column chromatography (0 to 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.

[0726] Step 2: Preparation of 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-0400: To a solution 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, 47 mg) dissolved in THF (0.75 mL) and MeOH (0.25 mL) was added 2N LiOH aqueous solution (0.25 mL, 0.500 mmol) and stirred at room temperature for 2.5 hours. Then, 1N HCl aqueous solution (0.5 mL) was added and the mixture was concentrated under reduced pressure. The material was purified by silica gel flash column chromatography (0 to 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-0400). MS (ESI) [M+H + ] + =516.1.

[0727] Embodiment 18

[0728]

[0729] 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: (S)-5-bromo-1-(1-(pyridin-2-yl)ethyl)-1H-pyrrolo[2,3-b]pyridine (17, 199 mg, 0.66 mmol), 1,4-dimethyl- A mixture of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)triazole (177 mg, 0.79 mmol) and 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (48 mg, 0.059 mmol) in dioxane (6.0 ml) was purged with nitrogen 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.

[0730] 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: To 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 added N-bromosuccinimide (29 mg, 0.16 mmol). The mixture was stirred and warmed to room temperature for 2 hours. The reaction was diluted with saturated aqueous sodium thiosulfate and extracted with ethyl acetate. The organic layer was washed with water and 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.

[0731] 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)benzoic acid methyl ester 88: (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( A mixture of 1,4-dichloro-2-(4-(4-(4-(2-( ... The material was purified by silica gel flash column chromatography (30% ethyl acetate) to give (S)-methyl 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). MS (ESI) [M+H + ] + =453.2.

[0732] Step 4: 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)benzoic acid P-0449: To a solution of (S)-methyl 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 purified by reverse phase silica gel flash column chromatography (0-100% B; A: 5% CHCl 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 purify the material 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.

[0733] Embodiment 19

[0734]

[0735] 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 mmol), 4-(3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-3,5-dimethylisoxazole (4, 1.01 g, 2.05 mmol), and 3-(trifluoromethoxy)benzoate were added to a flask purged with nitrogen. To a mixture of methyl (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-dichloropalladium(II) dichloromethane complex (167 mg, 0.205 mmol) in dioxane (20 ml) was added 2.5 M aqueous potassium carbonate solution (2.5 ml). The reaction vial was sealed and heated at 110 °C for 3 hours. The reaction was cooled and diluted with ethyl acetate, dried over anhydrous magnesium sulfate, filtered and concentrated. The 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.

[0736] 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) in THF (15 ml) was added 1 M 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.

[0737] 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-cyclobutyleneacetonitrile (45 mg, 0.48 mmol) in acetonitrile (1 ml) was stirred at 80°C for 15 hours. The reaction mixture 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.

[0738] 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 (0.050 ml). The reaction was stirred at 70 °C for 3 hours. The reaction was diluted with ethyl acetate, acidified with 1 N HCl in MeOH and concentrated under reduced pressure. The precipitate 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.

[0739] Embodiment 20

[0740]

[0741] Step 1: Preparation of 3-(cyclobutylmethyl)-6-(3,5-dimethyl-4H-1,2,4-triazol-4-yl)-1H-pyrrolo[3,2-b]pyridine 93: 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, 1.0 g, 3.8 mmol, A mixture of trans-N,N'-dimethylcyclohexane-1,2-diamine (1.1 mL, 7.0 mmol) and cesium carbonate (2.5 g, 7.67 mmol) in toluene (5 mL) and DMF (5 ML) was 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 desiccant and solvent, the residue was purified by silica gel flash 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.

[0742] 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)-1H-pyrrolo[3,2-b]pyridine (93,2 A mixture of 1,000 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) in toluene (5 ml) and DMF (5 ml) was purged with nitrogen and stirred at 120°C overnight. The reaction mixture was filtered and analyzed 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 purify the filtrate to obtain 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.

[0743] Embodiment 21

[0744]

[0745] 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 2 steps from 6-bromo-1H-pyrrolo[3,2-c]pyridine and cyclobutanecarbaldehyde in a similar manner to compound 55 described 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 afford tert-butyl 6-bromo-3-(cyclobutylmethyl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (95).

[0746] 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-dioxaborol-2-yl)isoxazole (343 mg, 1.54 mmol), 2.5 M aqueous potassium carbonate solution (0.55 ml) and 1,1'-bis(diphenylphosphino)ferrocene-dichloropalladium(II) dichloromethane complex (50 mg, 0.061 mmol) were combined in acetonitrile and dioxane, then purged with argon and irradiated to 125°C in a microwave reactor for 1 hour. The reaction is then filtered through diatomite and distributed between ethyl acetate and aqueous ammonium chloride solution. The organic layer is dried over magnesium sulfate, filtered and concentrated under reduced pressure. The substance is dissolved in DCM (3ml) and trifluoroacetic acid (0.53ml, 6.84mmol). The reaction is stirred for 2 hours and then concentrated under reduced pressure. The resulting material is dissolved in ethyl acetate and washed with sodium bicarbonate aqueous solution. The organic layer is further washed with brine, then dried over anhydrous magnesium sulfate and filtered. The filtrate is concentrated under reduced pressure and the substance is purified by silica gel flash column chromatography (0 to 5% methanol in DCM solution) to obtain 4- (3- (cyclobutylmethyl) -1H- pyrrolo [3,2-c] pyridine -6- bases) -3,5- dimethylisoxazole (96).

[0747] 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 to 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 2O, 0.1% HCO 2 H) was further purified to obtain 3,5-dichloro-4-(3-(cyclobutylmethyl)-6-(3,5-dimethylisoxazol-4-yl)-1H-pyrrolo[3,2-c]pyridin-1-yl)benzoic acid (P-0149). MS (ESI) [M+H + ] + =471.0.

[0748] All of the compounds listed below in Table 1 can be prepared according to the synthetic examples described in this disclosure and by making any necessary substitutions to starting materials that are commercially or otherwise available to the skilled artisan.

[0749] Table 1

[0750]

[0751]

[0752]

[0753]

[0754]

[0755]

[0756]

[0757]

[0758]

[0759]

[0760]

[0761]

[0762]

[0763]

[0764]

[0765]

[0766]

[0767]

[0768]

[0769]

[0770]

[0771]

[0772]

[0773]

[0774]

[0775]

[0776]

[0777]

[0778]

[0779]

[0780]

[0781]

[0782]

[0783]

[0784]

[0785]

[0786]

[0787]

[0788]

[0789]

[0790]

[0791]

[0792]

[0793]

[0794]

[0795]

[0796]

[0797]

[0798]

[0799]

[0800]

[0801]

[0802]

[0803]

[0804]

[0805]

[0806]

[0807]

[0808]

[0809]

[0810]

[0811]

[0812]

[0813]

[0814]

[0815]

[0816]

[0817]

[0818]

[0819]

[0820]

[0821]

[0822]

[0823]

[0824]

[0825]

[0826]

[0827]

[0828]

[0829]

[0830]

[0831]

[0832]

[0833]

[0834]

[0835]

[0836]

[0837]

[0838]

[0839]

[0840]

[0841]

[0842]

[0843]

[0844]

[0845]

[0846]

[0847]

[0848]

[0849]

[0850]

[0851]

[0852]

[0853]

[0854] Biological Examples

[0855] Biological test methods

[0856] The compounds of the present disclosure were tested using the following assays:

[0857] EP300 Alphascreen Binding Assay

[0858] Using Alphascreen TM Binding assays were performed to evaluate the binding of compounds of formula (I) to EP300. Recombinant EP300 protein, acetylated histone 3 peptide and AlphaScreen TM The technology quantitatively measures the inhibition of the interaction between the EP300 bromodomain and its acetylated target proteins. TM In the case of EP300 protein bound to nickel-chelated receptor beads, the AlphaScreen TM The acetylated histone 3 peptide immobilized on streptavidin-coated beads interacts. This interaction brings the donor and acceptor beads into close proximity. The proximity allows singlet oxygen generated by laser excitation of the donor beads to reach the acceptor beads and generate a luminescent signal. EP300 inhibitors cause a decrease in the proximity signal by inhibiting the EP300–acetylated peptide interaction.

[0859] Recombinant human EP300 containing bromodomains (EP300-BD(1040-1161)) was prepared and purified as described in the Protein Expression and Purification section. The peptide is human histone H3 45-64 K56 Ac -Biotin (Anaspec CA, USA).

[0860] 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 buffer and 4 μL volumes were transferred to the Alphaplate. 5.5 μL EP300 protein and 5.5 μL peptide were added to wells containing 4 μL of various concentrations of test compound of formula (I) or DMSO vehicle in an Alphaplate (PerkinElmer GA, USA) and incubated at room temperature for 1 hour. Then 5 μL of donor and acceptor bead mixture was added to a final concentration of 7.5 μg / ml. 60 minutes after the addition of beads, the spectrometer was set up on an Envision spectrometer (λ Ex 680nm, λ Em The Alpha signal was read at 520-620 nm. The final concentrations of bromodomain proteins and peptides were as follows.

[0861] Determination name EP300 protein (nM) Peptide (nM) EP300-BD 50 150

[0862] All data were normalized to the mean of 16 high and 16 low control wells per plate. A four-parameter curve fit was then applied using the following formula:

[0863] Y=A+((BA) / (1+((C / x)^D)))

[0864] Where "A" is the minimum value, "B" is the maximum value, "C" is the IC50, and "D" is the Hill slope.

[0865] Protein expression and purification

[0866] Recombinant human EP300 bromodomain (EP300-BD(1040-1161)) was expressed in E. coli cells with an N-terminal hexa-histone tag (in a modified pET vector) and purified using a combination of both IMAC (Ni affinity) and size exclusion chromatography steps.

[0867] The recombinant EP300 protein was expressed using the E. coli strain BL21-CodonPlus (DE3) (Agilent Technologies CA, USA). The cells were grown in Terrific Broth (TB) medium at 37°C to an OD600 of 0.7, at which time the temperature was lowered to 18°C, the protein was induced with 1.0 mM isopropyl-β-D-thiogalactopyranoside ("IPTG") for 20 hours, and harvested by centrifugation at 8500 x g for 20 minutes. The cells were resuspended in 0.1 M K 2 PO 4pH 8.0, 250mM NaCl, 10% glycerol, 0.75% NP-40, 25mM imidazole, 0.2mg / ml lysozyme, 0.2mM phenylmethylsulfonyl fluoride ("PMSF"), 25μg / ml DNase I, incubated on ice for 30 minutes and lysed with a cell disruptor (MicroFluidics MA, USA). The lysate was clarified by centrifugation at 20,000xg for 1 hour. Proteins were captured with Ni-NTA resin (Life Technologies, USA). Contaminating proteins were washed away with 50mM HEPES pH7.5, 500mM NaCl and 5% glycerol. After 3 washing steps, proteins were gradually eluted using 10, 25, 50, 100, 150 and 250mM imidazole in 50mM HEPES pH 7.5, 500mM 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.

[0868] BRD4 Alphascreen binding assay

[0869] Binding of compounds of formula (I) to BRD4 was assessed using the Alphascreen binding assay. Recombinant BRD4 protein, acetylated histone 4 peptides and AlphaScreen TM The inhibition of the interaction between BRD4 and its acetylated target proteins was quantitatively measured by the AlphaScreen TM In the case of BRD4 protein bound to nickel-chelated receptor beads, the AlphaScreen TM Streptavidin-coated beads interact with acetylated histone 4 peptides immobilized on them. This interaction brings the donor and acceptor beads into close proximity. The proximity allows singlet oxygen generated by laser excitation of the donor beads to reach the acceptor beads and generate a luminescent signal. BRD4 inhibitors cause a decrease in the proximity signal by inhibiting the BRD4–acetylated peptide interaction.

[0870] Recombinant human BRD4 containing two bromodomains (BRD4-BD12(1-477)) was prepared and purified as described in the Protein Expression and Purification section. The peptide is human histone H4 1-21 K5 Ac K8 Ac K12 Ac K16 Ac -Biotin (Anaspec CA, USA).

[0871] BRD4 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 buffer and 4 μL volumes were transferred to the 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 compound of formula (I) or DMSO vehicle in the Alphaplate (PerkinElmer GA, USA) and incubated at room temperature for 1 hour. Then 5 μL of donor and acceptor bead mixture was added to a final concentration of 7.5 μg / ml. 30 minutes after the addition of beads, the spectrometer was monitored on an Envision spectrometer (λ Ex 680nm, λ Em The Alpha signal was read at 520-620 nm. The final concentrations of bromodomain proteins and peptides were as follows.

[0872] Determination name BRD protein (nM) Peptide (nM) BRD4-BD12 3.6 36

[0873] All data were normalized to the mean of 16 high and 16 low control wells per plate. A four-parameter curve fit was then applied using the following formula:

[0874] Y=A+((BA) / (1+((C / x)^D)))

[0875] Where "A" is the minimum value, "B" is the maximum value, "C" is the IC50, and "D" is the Hill slope.

[0876] Protein expression and purification

[0877] Recombinant human BRD4 containing a double bromodomain (BRD4-BD12(1-477)) was expressed in E. coli cells with an N-terminal hexa-histone tag (in a modified pET vector) and purified using a combination of both IMAC (Ni affinity) and size exclusion chromatography steps.

[0878] Escherichia coli strain BL21-CodonPlus (DE3) (Agilent Technologies CA, USA) was used to express recombinant BRD4. Cells were grown in Terrific Broth (TB) medium at 37°C to an OD600 of 2.0, at which point the temperature dropped to 18°C, induced with 0.1 mM isopropyl-β-D-thiogalactopyranoside ("IPTG") for 12-18 hours, and harvested by centrifugation at 8000 x 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, 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 disruptor (MicroFluidics MA, USA). The lysate was clarified by centrifugation at 20,000xg for 2 hours. Proteins were captured with Ni-NTA resin (Life Technologies, USA). Contaminating proteins were washed out with 40mM Tris-HCl pH 8.0, 0.5M NaCl, 25mM imidazole, 5% glycerol and 5mM BME. After 3 washing steps, the protein was gradually eluted into a washing buffer containing 50, 100, 150, 500mM imidazole. The protein was further purified using a gel filtration column 16 / 60 Superdex 200 (GE Biosciences NJ, USA) in 10mM HEPES pH 8.0, 150mM NaCl and 5mM DTT. Glycerol was added to a final concentration of 12%, and the protein was aliquoted and snap frozen in liquid nitrogen.

[0879] CBP Alphascreen binding assay

[0880] Using Alphascreen TM Binding assays were performed to evaluate the binding of compounds of formula (I) to CBP. Recombinant CBP, acetylated histone 3 peptides and AlphaScreen TM The technique quantitatively measures the inhibition of the interaction between the CBP bromodomain and its acetylated target protein. TM In the case of CBP protein bound to nickel-chelated receptor beads, the AlphaScreen TMThe CBP inhibitors interact with the acetylated histone 3 peptide immobilized on streptavidin-coated beads. This interaction brings the donor and acceptor beads into close proximity. The proximity allows singlet oxygen generated by laser excitation of the donor beads to reach the acceptor beads and generate a luminescent signal. CBP inhibitors cause a decrease in the proximity signal by inhibiting the CBP–acetylated peptide interaction.

[0881] Recombinant human CBP containing bromodomains (CBP-BD(1043-1159)) was prepared and purified as described in the protein expression and purification section. The peptide was human histone H345-64K56Ac-biotin (Anaspec CA, USA).

[0882] CBP assay protocol: All components are prepared in a buffer consisting of 50mM HEPES pH 7.5, 50mM NaCl, 0.01% BSA, 0.01% Triton X-100, 2mM DTT. Test compounds and DMSO vehicles are diluted 1:50 in buffer and 4 μL volumes are transferred to Alphaplate. 5.5 μL CBP protein and 5.5 μL peptide are added to the wells containing 4 μL of various concentrations of test compounds of formula (I) or DMSO vehicles in Alphaplate (PerkinElmer GA, USA) and incubated for 1 hour at room temperature. Then 5 μL of donor and acceptor bead mixture is added to a final concentration of 7.5 μg / ml. After 60 minutes of bead addition, the Alpha signal is read on an Envision spectrometer (λEx 680nm, λEm 520-620nm). The final concentrations of bromodomain proteins and peptides are as follows.

[0883] Determination name CBP protein (nM) Peptide (nM) BD 50 150

[0884] All data were normalized to the mean of 16 high and 16 low control wells per plate. A four-parameter curve fit was then applied using the following formula:

[0885] Y=A+((BA) / (1+((C / x)^D)))

[0886] Where "A" is the minimum value, "B" is the maximum value, "C" is the IC50, and "D" is the Hill slope.

[0887] Protein expression and purification

[0888] Recombinant human CBP bromodomain (CBP-BD(1043-1159)) was expressed in E. coli cells (in a modified pET vector) with an N-terminal hexa-histone tag and purified using a combination of both IMAC (Ni affinity) and size exclusion chromatography steps.

[0889] The recombinant CBP protein was expressed using the E. coli strain BL21-CodonPlus (DE3) (Agilent Technologies CA, USA). The cells were grown in Terrific Broth (TB) medium at 37°C to an OD600 of 0.92, at which point the temperature was reduced to 20°C, the protein was induced for 20 hours with 1.0 mM isopropyl-β-D-thiogalactopyranoside ("IPTG"), and harvested by centrifugation at 8500 x g for 20 minutes. The cells were resuspended in 0.1 M K2PO4 pH 8.0, 250 mM NaCl, 10% glycerol, 0.75% NP-40, 25 mM imidazole, 0.2 mg / ml lysozyme, 0.2 mM phenylmethylsulfonyl fluoride ("PMSF"), 0.5 β-mercaptoethanol ("BME"), 25 μg / ml DNase I, incubated on ice for 30 minutes and lysed with a cell disruptor (MicroFluidics MA, USA). Lysate was clarified by centrifugation at 20,000xg for 1 hour. Protein was captured with Ni-NTA resin (Life Technologies, USA). Contaminated proteins were washed out with 40mM HEPES pH 7.5, 500mM NaCl, 5% glycerol, 5mM imidazole and 5mM BME. After 3 washing steps, 400mM imidazole in 40mM HEPES pH 7.5, 400mM NaCl and 5mM BME was used to elute the protein. A size exclusion column (26 / 600 Superdex 200, GE Biosciences NJ, USA) was used to further purify the protein in 40mM HEPES pH 7.5, 250mM NaCl, 5mM BME. The protein was aliquoted and snap frozen in liquid nitrogen.

[0890] Table 2 below provides data demonstrating the biochemical and / or cytostatic activity of exemplary compounds as described herein in Table 1. In Table 2 below, the activity is provided as follows: +++ = 0.0001 μM <IC 50 <1μM;++=1μM <IC 50 <8μM, +=8μM <IC 50 <1000 μM.

[0891] Table 2

[0892]

[0893]

[0894]

[0895]

[0896]

[0897]

[0898]

[0899]

[0900]

[0901]

[0902]

[0903]

[0904]

[0905]

[0906]

[0907] All patents and other references cited herein are indicative of the level of skill of those skilled in the art to which the present disclosure pertains and are incorporated by reference in their entirety, including any tables and figures, to the same extent as if each reference had been individually incorporated by reference in its entirety.

[0908] Those skilled in the art will readily appreciate that the present disclosure is well suited to obtain the objects and advantages mentioned as well as those inherent therein. The methods, variations and compositions described herein as presently representing the embodiments described herein are exemplary and are not intended to be limiting of the scope of the present disclosure. Those skilled in the art will envision changes and other uses therein, which are encompassed within the spirit of the present disclosure and are limited by the scope of the claims.

[0909] It will be 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, changes may be made to provide additional compounds of the disclosed compounds and / or various methods of administration may be used. Therefore, such additional embodiments are within the scope of the disclosure and the appended claims.

[0910] The present disclosure illustratively described herein may be appropriately implemented in the absence of any one or more elements, one or more limitations not specifically described herein. The terms and expressions that have been adopted are used as terms of description rather than limitation, and in the use of such terms and expressions, it is not desired to exclude any equivalents or portions thereof of the features shown and described, but it should be recognized that various modifications within the scope of the claimed disclosure are possible. Therefore, it should be understood that although the present disclosure has been specifically described by embodiments and optional features, those skilled in the art may modify and change the concepts described herein, and the modifications and changes are considered to be within the scope of the present disclosure as defined by the appended claims.

[0911] In addition, where features or aspects of the disclosure are described in terms of groupings of alternative terms, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual member or subgroup of members of the group described herein.

[0912] In addition, unless otherwise indicated, where various numerical values ​​are provided for an embodiment, additional embodiments are described by taking any two different values ​​as endpoints of the range. Such ranges are also within the scope of the present disclosure.

[0913] Accordingly, additional embodiments are within the scope of the disclosure and the following claims.

Claims

1. A compound of formula IV(a): or a pharmaceutically acceptable salt thereof, wherein: R 5 for: J 1 is -C(O)OH or -C(O)OCH3; Each J 2 are independently F, Cl, -OCH3, -OCHF2, OCF3, -OCH2CF3, -OCH2CHF2, -OCH(CH3)2, -CH2CH3, -OCH2CH3, -OCH2CH2CH3, and CH3; -LR 1 for Among them G 1 is benzyloxy, -C(=CH2)CH3, -C(O)OH, -C(O)NH2, -C(O)N(H)-cyclopropyl, cyclopropyl, -CH2-cyclopropyl, cyclopropylalkynylene, -CH2-SO2-CH3, -(CH2)N(CH3)2, -(CH2)2-N(CH3)2, -(CH2)2-CN, -C(O)OC(CH3)3, -C(O)CH3, -C(O)C(CH3)3, -CH2C(O)N(CH3)2, CN or -SO2CH3; and Each G 2 are independently -OCHF2, -OCH2F, Cl, F, -OCH3, OH, -OCF3, CH3, -CH(CH3)2, CF3, CN, -CH2CN, CH2C(CH3)2(OH) and -C(CH3)2-OH.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein -LR 1 for 3. A compound or a pharmaceutically acceptable salt thereof, the compound being selected from P-0158 P-0175 P-0204 P-0255 P-0282 P-0314 P-0329 P-0362 P-0419 or P-0441 4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein the compound is P-0175 5. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein the compound is P-0204 6. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein the compound is P-0255 7. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein the compound is P-0158 8. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein the compound is P-0282 9. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein the compound is P-0314 10. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein the compound is P-0329 11. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein the compound is P-0362 12. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein the compound is P-0419 13. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein the compound is P-0441 14. A pharmaceutical composition comprising the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

15. The pharmaceutical composition of claim 14, further comprising a second agent.

16. Use of a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 14 to 15, in the preparation of a medicament for treating a subject suffering from a disease or condition mediated by EP300 or CBP.

17. The use according to claim 16, wherein the disease or condition is a cancer with an inactivating mutation in CBP or EP300, or a cancer in which there is activation of EP300 or CBP.

18. The use according to claim 16, wherein the disease or condition is cancer expressing androgen receptor.

19. Use according to claim 16, wherein the disease or condition is a neoplastic disorder, an inflammatory disorder, a cognitive disorder and / or a neurodegenerative disease.

20. The use according to claim 19, wherein the neoplastic disorder is cancer.

21. The use of claim 16, wherein the disease or condition is bladder cancer, adenocarcinoma, bone cancer, glioma, gastric cancer, leukemia, lymphoma, small cell lung cancer, non-small cell lung cancer, malignant peripheral nerve sheath tumor, mantle cell lymphoma, marginal zone B-cell lymphoma, breast cancer, medulloblastoma, melanoma, Merkel cell carcinoma, mesothelioma, multiple myeloma, neuroblastoma, neurofibroma, osteosarcoma, ovarian cancer, prostate cancer, pancreatic cancer, skin cancer, Alzheimer's disease, Parkinson's disease, or colorectal cancer.

22. The use according to claim 21, wherein the leukemia is selected from acute eosinophilic leukemia, acute erythroid leukemia, acute megakaryocytic leukemia, acute monocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia / lymphoma, aggressive NK-cell leukemia, B-cell prolymphocytic leukemia, acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia or mast cell leukemia; wherein the melanoma is selected from acral melanoma, nodular melanoma, melanoma or uveal melanoma; wherein the lymphoma is selected from AIDS-related lymphoma, anaplastic large cell lymphoma, angioimmunoblastic T-cell lymphoma, B-cell lymphoma, Burkitt's lymphoma, cutaneous T-cell lymphoma, enteropathy-associated T-cell lymphoma, follicular lymphoma, hepatosplenic T-cell lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, MALT lymphoma, precursor T-cell lymphoma, primary central nervous system lymphoma, primary effusion lymphoma or T-cell lymphoma.

23. The use according to claim 21, wherein the disease or condition is small cell lung cancer, non-small cell lung cancer, bladder cancer, non-Hodgkin lymphoma, acute myeloid leukemia, multiple myeloma, diffuse large B-cell lymphoma, breast cancer or prostate cancer.

24. The use according to claim 21, wherein the disease or condition is Alzheimer's disease or Parkinson's disease.

25. The use according to claim 21, wherein the disease or condition is glioblastoma multiforme, acute lymphoblastic leukemia, B-cell chronic lymphocytic leukemia or diffuse large B-cell lymphoma.

26. The use according to any one of claims 16-25, wherein the treatment further comprises administration of one or more additional therapeutic agents.

27. The use according to claim 26, wherein the one or more additional therapeutic agents are one or more of the following: i) alkylating agents; ii) antibiotics; iii) antimetabolites; iv) immunotherapeutics; v) hormones or hormone antagonists; vi) taxanes; vii) retinoids; viiii) alkaloids; ix) anti-angiogenic agents; x) topoisomerase inhibitors; xi) kinase inhibitors; xii) targeted signal transduction inhibitors; xiii) biological response modifiers; xiv) IDO inhibitors; and xv) chemotherapeutics; xvi) c-Kit mutation inhibitors; xvii) EGFR inhibitors; xviii) PD-1 inhibitors; or xix) epigenetic modulators.

28. The use according to claim 27, wherein the kinase inhibitor is a Mek inhibitor or a tyrosine kinase inhibitor; 29. The use according to claim 27, wherein the one or more additional therapeutic agents are epigenetic modulators selected from the group consisting of: (a) DNA methyltransferase; (b) histone or protein methyltransferase; (c) histone demethylase; (d) histone deacetylase inhibitors; (e) histone acetyltransferase; (f) other chromatin remodeling agents; and (g) BET inhibitors.

30. The use according to claim 29, wherein the epigenetic regulator is a histone deacetylase inhibitor selected from the group consisting of vorinostat, romidepsin, cedamide, panobinostat, belinostat, valproic acid, mosinostat, abexinostat, entinostat, reminostat, ginosinostat and quisinostat.

31. The use according to claim 29, wherein the epigenetic regulator is a BRD4 inhibitor.

32. The use of claim 27, wherein the one or more additional therapeutic agents is a PD-1 inhibitor, quizartinib, enzalutamide, abiraterone, or a BRD4 inhibitor.

33. The use according to claim 27, wherein i) the alkylating agent is selected from adolesin, hexamethylmelamine, biszelexin, busulfan, carboplatin, carboquinone, carmustine, chlorambucil, cisplatin, cyclophosphamide, dacarbazine, estramustine, fotemustine, hepsufan, ifosfamide, improsufan, ilofofen, lomustine, dichloromethyl diethylamine, melphalan, oxaliplatin, piposufan, semustine, streptozotocin, temozolomide, thiotepa and treoxosufan; ii) the antibiotic is selected from bleomycin, actinomycin D, daunorubicin, doxorubicin, epirubicin, idarubicin, menolipir, mitomycin, mitoxantrone, neocarcinostatin, pentostatin and plicamycin; iii) the antimetabolite is selected from the group consisting of: azacitidine, capecitabine, cladribine, clofarabine, cytarabine, decitabine, floxuridine, fludarabine, 5-fluorouracil, furofluuracil, gemcitabine, hydroxyurea, mercaptopurine, methotrexate, nelarabine, pemetrexed, raltitrexed, thioguanine and trimetrexate; iv) the immunotherapeutic agent is selected from PD-1 or PD-L1 inhibitors; v) the hormone or hormone antagonist is selected from the group consisting of enzalutamide, abiraterone, anastrozole, androgen, buserelin, diethylstilbestrol, exemestane, flutamide, fulvestrant, goserelin, idoxifene, letrozole, leuprolide, megestrol acetate, raloxifene, tamoxifen and toremifene; vi) the taxane is selected from DJ-927, docetaxel, TPI 287, paclitaxel and DHA-paclitaxel; vii) the retinoid is selected from alitretinoin, bexarotene, fenretinide, isotretinoin and tretinoin; viiii) the alkaloid is selected from etoposide, homoharringtonine, teniposide, vinblastine, vincristine, vindesine and vinorelbine; ix) the anti-angiogenic agent is selected from AE-941 (GW786034, neovastat), ABT-510, 2-methoxyestradiol, lenalidomide, vinorelbine, vinblastine, vinblastine, vindesine and vinorelbine; x) the topoisomerase inhibitor is selected from amsacrine, edokalem, exatecan, irinotecan, SN-38 (7-ethyl-10-hydroxy-camptothecin), rubitecan, topotecan and 9-aminocamptothecin; xi) the kinase inhibitor is selected from erlotinib, gefitinib, flavopiridol, imatinib mesylate, lapatinib, sorafenib, sunitinib malate, AEE-788, AG-013736, AMG 706, AMN107, BMS-354825, BMS-599626, UCN-01 (7-hydroxystaurosporine), vemurafenib, dabrafenib, trametinib, cobimetinib, selumetinib and vatalanib; xii) the targeted signal transduction inhibitor is selected from bortezomib, geldanamycin and rapamycin; xiii) the biological response modifier is selected from imiquimod, interferon-α and interleukin-2;xv) the chemotherapeutic agent is selected from 3-AP (3-amino-2-formaldehyde thiosemicarbazone), atrasentan, aminoglutethimide, anagrelide, asparaginase, bryostatin-1, cilengitide, ilisimol, eribulin mesylate (E7389), ixabepilone, lonidamine, masoprofen, mitoguanidine, olimosin, sulindac, testosterone lactone, thiazole carboxamide nucleoside, mTOR inhibitor, PI3K inhibitor, Cdk4 inhibitor, Akt inhibitor, Hsp90 inhibitor, farnesyl transferase inhibitor or aromatase inhibitor. ;

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