Inhibition of CREB binding protein (CBP)

Abstract

To provide inhibition of CREB binding protein (CBP).SOLUTION: The disclosure targets an inhibitor of a bromodomain of CBP / p300 family. The compound may be useful in treatments of diseases or disorders relating to inhibition of the bromodomain of the CBP / p300 family. For example, this disclosure relates to a compound and a composition for inhibiting the bromodomain of the CBP / p300 family, a method for treating, preventing or improving diseases or disorders relating to inhibition of the bromodomain of the CBP / p300 family, and a synthetic method of these compounds.SELECTED DRAWING: None

Description

Technical Field

[0001] Citation of Related Applications Detailed Description of the Invention This application claims the benefit of U.S. Provisional Application No. 62 / 692,593, filed Jun. 29, 2018; International Application No. PCT / US2018 / 051235, filed Sep. 14, 2018; International Application No. PCT / US2018 / 051214, filed Sep. 14, 2018; and U.S. Provisional Application No. 62 / 819,490, filed Mar. 15, 2019. Each of these is hereby incorporated by reference in its entirety.

[0002] Technical Field The present disclosure relates to novel chemical compositions for inhibiting CREB-binding protein (CBP) that are useful in treatments for treating diseases or disorders associated with inhibition of bromodomains of the CBP / p300 family.

Background Art

[0003] Background CBP / p300 is a lysine acetyltransferase that catalyzes the binding of acetyl groups to the lysine side chains of histones and other protein substrates. p300 (also known as EP300 and KAT3B) is a protein with multiple domains that bind to a variety of proteins, including many DNA-binding transcription factors. Cyclic AMP response element-binding protein (CREB)-binding protein (CBP, also known as KAT3A) is a cellular paralog of p300. p300 and CBP share extensive sequence identity and functional similarity and are often referred to as CBP / p300. CBP / p300-catalyzed acetylation of histones and other proteins is extremely important for gene activation. Increased p300 expression and activity have been observed in progressive human cancers, such as prostate and human primary breast cancer specimens. Since it has proven extremely difficult to discover chemical inhibitors of transcription factors, chemical inhibition of CBP / p300, which has intrinsic acetyltransferase enzyme activity, may be more feasible than blocking transcription factors with small molecules. Therefore, there is a need for novel and potent compounds for inhibiting CBP / p300 that are useful as therapeutic agents for treating certain related forms of cancer. Summary of the Invention Means for Solving the Problems

[0004] Overview A first aspect of the present disclosure is of formula (I):

Chemical formula

[0005] Preferably, the compound of formula (I) is of formula (IV):

Chemical formula

Brief Description of the Drawings

[0006]

Figure 1-1

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Figure 1-16

Mode for Carrying Out the Invention

[0007] Description of Embodiments Detailed Description The present disclosure, when tested according to the HTRF biochemical assay protocol in Example 5 below, has the following characteristics: (1) a CBP IC less than 1 μM 50 value; and (2) one or more of the CBP IC 50 values in the range of 0.001 to 1 μM, and relates to CBP inhibitor compounds as defined herein. Compounds of the Present Disclosure

[0008] One aspect of the present disclosure is formula (I):

Chemical formula

[0009] In some examples, the compound of formula (I) is a stereoisomer or enantiomer of formula (I) selected from the group consisting of formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n), (I-o) and (I-p): [Chemical formula] [Chemical formula] and is an enantiomer or stereoisomer of formula (I) selected from the group consisting of:

[0010] The compound of formula (I) can be its stereoisomer (for example, a compound of formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n) or (I-o) where R1 is methyl and R6 is phenyl optionally substituted with one or more R 10 as defined above).

[0011] In some preferred embodiments, the compound of formula (I) is of formula (IV): [Chemical formula] (wherein n is an integer of 0, 1, 2, 3, 4 or 5 (preferably 0, 1 or 2), and R 10 is as defined above) and includes its stereoisomers or a pharmaceutically acceptable salt thereof. Preferably, the compound of formula (IV) is a compound of formula (IV-a) (including, for example, compounds of formula (IV-b), formula (IV-c) or mixtures thereof) or a pharmaceutically acceptable salt thereof, where n is an integer of 0, 1, 2, 3, 4 or 5 (preferably 0, 1 or 2), and R 10 is as defined above). [Chemical formula] [Chemical formula]

[0012] In certain preferred compounds of formula (IV-a) containing a compound of formula (IV-b) and a compound of formula (IV-c), n is 0, 1, 2, 3, 4 or 5, and R 10 is each independently halogen or -OC1-C6 alkyl, and -OC1-C6 alkyl is optionally substituted with one or more halogens. For example, in certain compounds of formula (IV-a), n is 0, 1 or 2, and R 10 is each independently halogen, or -OC1 alkyl optionally substituted with one or more halogens (e.g., fluorine or chlorine). In some compounds of formula (IV-a), n is 2, and R 10 is each independently halogen (e.g., fluorine or chlorine), OC1 alkyl substituted with one, two or three halogens (e.g., fluorine or chlorine), or methoxy.

[0013] Another aspect of the present disclosure is the provision of a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of formula (I). One aspect of the present disclosure relates to a compound that is or can be an inhibitor of one or more bromodomains of the CBP / p300 family (e.g., a compound of formula (I)).

[0014] In some embodiments, the compounds of the present disclosure have the formula (I) [Chemical formula] (wherein R 1 is -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C8 cycloalkyl, -C4-C8 cycloalkenyl, heterocyclyl, heteroaryl, aryl, -OR 5 , -N(R 5 )2 or -NHR 5 ; R 5is -C1-C6 alkyl, -C3-C8 cycloalkyl, heterocyclyl, aryl or heteroaryl; R 6 is -C1-C6 alkyl, -C3-C8 cycloalkyl, -C4-C8 cycloalkenyl, heterocyclyl, aryl, spirocycloalkyl, spiroheterocyclyl, heteroaryl, halogen, oxo, -(CH2) n -OR 8 , -C(O)R 8’ , -C(O)OR 8 or -C(O)NR 8 R 9 wherein the alkyl, cycloalkyl, heterocyclyl, spirocycloalkyl, spiroheterocyclyl, heteroaryl or aryl is each optionally substituted with one or more Rs 10 ; R 8 and R 9 are each independently, each occurrence, -H, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C8 cycloalkyl, -C4-C8 cycloalkenyl, heterocyclyl, aryl, heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is each optionally substituted with one or more Rs 10 or R 11 ; or R 8 and R 9 may be joined to the atom to which they are both attached to form a spiroheterocyclyl, heterocyclyl or heteroaryl, wherein the resulting spiroheterocyclyl, heterocyclyl or heteroaryl is optionally substituted with one or more Rs 10 or R 11 ; R 8’Each is independently, for each occurrence, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C8 cycloalkyl, -C4-C8 cycloalkenyl, heterocyclyl, aryl, heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl are each, one or more R 10 or R 11 optionally substituted; or R 10 Each is independently, for each occurrence, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C8 cycloalkyl, -C4-C8 cycloalkenyl, heterocyclyl, heteroaryl, aryl, -OH, halogen, oxo, -NO2, -CN, -NH2, -OC1-C6 alkyl, -OC3-C6 cycloalkyl, -O aryl, -O heteroaryl, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -S(O)2NH(C1-C6 alkyl), -S(O)2N(C1-C6 alkyl)2, -S(O)2C1-C6 alkyl, -C(O)C1-C6 alkyl, -C(O)NH2, -C(O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -C(O)OC1-C6 alkyl, -N(C1-C6 alkyl)SO2C1-C6 alkyl, -S(O)(C1-C6 alkyl), -S(O)N(C1-C6 alkyl)2 or -N(C1-C6 alkyl)S(O)(C1-C6 alkyl), where alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl or aryl are each, one or more -R 12 optionally substituted; where, any two R 10 when on non-adjacent atoms, may combine to form a bridged cycloalkyl or heterocyclyl; where, any two R 10 when on adjacent atoms, may combine to form a cycloalkyl, heterocyclyl, aryl or heteroaryl; and R12 independently, for each occurrence, is -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C8 cycloalkyl, -C4-C8 cycloalkenyl, heterocyclyl, heteroaryl, aryl, -OH, halogen, oxo, -NO2, -CN, -NH2, -OC1-C6 alkyl, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -S(O)2NH(C1-C6 alkyl), -S(O)2N(C1-C6 alkyl)2, -S(O)2C1-C6 alkyl, -C(O)C1-C6 alkyl, -C(O)NH2, -C(O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -C(O)OC1-C6 alkyl, -N(C1-C6 alkyl)SO2C1-C6 alkyl, -S(O)(C1-C6 alkyl), -S(O)N(C1-C6 alkyl)2 or -N(C1-C6 alkyl)S(O)(C1-C6 alkyl)) or a pharmaceutically acceptable salt, enantiomer, hydrate, solvate, isomer or tautomer thereof.

[0015] In some embodiments, the compounds of the present disclosure have the formula (I)

Chemical formula

[0016] In some embodiments, the compounds of the present disclosure have the formula (I)

Chemical formula

[0017] In some embodiments, the compounds of the present disclosure have the formula (III):

Chemical formula

[0018] Multiple embodiments of the compound of formula (III) are provided herein. In some embodiments, R 12 is halogen. In some embodiments, m is 3. In some embodiments, R 6’ is H. In some embodiments, R 6 is aryl. In some embodiments, R 7 is -C(O)OH. In some embodiments, R 5 is methyl.

[0019] In some embodiments, the compounds of the disclosure are of formula (I):

Chemical formula

[0020] In some embodiments, the compounds of the present disclosure are of formula (I):

Chemical formula

[0021] In some embodiments, R 6 is aryl optionally substituted with one or more R 10 . In some embodiments, R 6 is phenyl optionally substituted with one or more R 10 .

[0022] In some embodiments, R 5 is -C1-C3 alkyl. In some embodiments, R 5 is methyl.

[0023] In some embodiments, R 10 is independently, for each occurrence, halogen or -OC1-C6 alkyl, where -OC1-C6 alkyl is optionally substituted with halogen.

[0024] In some embodiments, R1 is -OR 5 .

[0025] In some embodiments, R 1 is -OR 5 , -N(R 5 )2, -NHR 5 or -C1-C6 alkyl. In some embodiments, R 1 is -OR 5 . In some embodiments, R 1 is -OR 5 or -C1-C6 alkyl. In some embodiments, R 1 of R 5 is -C1-C6 alkyl. In some embodiments, R 1 is -OR 5 ; R 5 is -C1-C6 alkyl. In some embodiments, R 1 is -OCH3. In some embodiments, R 1is -C2~C6 alkenyl, -C2~C6 alkynyl, -C3~C8 cycloalkyl, -C4~C8 cycloalkenyl, heterocyclyl, heteroaryl or aryl. In some embodiments, R 1 is -C1~C6 alkyl. In some embodiments, R 1 is methyl, ethyl or propyl. In some embodiments, R 1 is methyl. In some embodiments, R 1 is -C2~C6 alkenyl. In some embodiments, R 1 is aryl.

[0026] In some embodiments, R 5 is -C1~C6 alkyl, -C3~C8 cycloalkyl, heterocyclyl, aryl or heteroaryl. In some embodiments, R 5 is -C1~C6 alkyl. In some embodiments, R 5 is -C1~C3 alkyl. In some embodiments, R 5 is methyl. In some embodiments, R 5 is ethyl.

[0027] In some embodiments, R 6 is -C1~C6 alkyl, -C3~C8 cycloalkyl, -C4~C8 cycloalkenyl, heterocyclyl or aryl. In some embodiments, R 6 is -C1~C6 alkyl optionally substituted with one or more R 10 . In some embodiments, R 6 is aryl optionally substituted with one or more R 10 . In some embodiments, R 6 is heteroaryl optionally substituted with one or more R 10 . In some embodiments, R 6 is -C(O)OH. In some embodiments, R 6 is halogen. In some embodiments, R6 is -C1-C6 alkyl, -C3-C8 cycloalkyl, -C4-C8 cycloalkenyl, heterocyclyl, aryl, spirocycloalkyl, spiroheterocyclyl, heteroaryl, halogen, oxo, -(CH2) n -OR 8 , -C(O)R 8’ , -C(O)OR 8 or -C(O)NR 8 R 9 wherein alkyl, cycloalkyl, heterocyclyl, spirocycloalkyl, spiroheterocyclyl, heteroaryl or aryl are each optionally substituted with one or more R 10 groups.

[0028] In some embodiments, R 8 is -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C8 cycloalkyl, -C4-C8 cycloalkenyl, heterocyclyl, aryl, heteroaryl, wherein alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl are each optionally substituted with one or more R 10 or R 11 groups. In some embodiments, R 8 is -H. In some embodiments, R 8 is -C1-C6 alkyl, -C3-C8 cycloalkyl, -C4-C8 cycloalkenyl, heterocyclyl or aryl, wherein R 8 is R 10 or R 11 groups. In some embodiments, R 8 is -C1-C6 alkyl optionally substituted with one or more R 10 or R 11 groups. In some embodiments, R 8 is aryl optionally substituted with one or more R 10 or R 11 groups. In some embodiments, R8 is a heteroaryl optionally substituted with one or more R 10 or R 11 Here, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl are each optionally substituted with one or more R

[0029] In some embodiments, R 8’ is -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C8 cycloalkyl, -C4-C8 cycloalkenyl, heterocyclyl, aryl, heteroaryl, where the alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is each optionally substituted with one or more R 10 or R 11 Here, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl are each optionally substituted with one or more R 8’ is -C1-C6 alkyl, -C3-C8 cycloalkyl, -C4-C8 cycloalkenyl, heterocyclyl or aryl, where R 8’ is R 10 or R 11 Here, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl are each optionally substituted with one or more R 8’ is -C1-C6 alkyl optionally substituted with one or more R 10 or R 11 Here, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl are each optionally substituted with one or more R 8’ is aryl optionally substituted with one or more R 10 or R 11 Here, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl are each optionally substituted with one or more R 8’ is heteroaryl optionally substituted with one or more R 10 or R 11 Here, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl are each optionally substituted with one or more R

[0030] In some embodiments, R 9is -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C8 cycloalkyl, -C4-C8 cycloalkenyl, heterocyclyl, aryl, heteroaryl, where alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl are each optionally substituted with one or more R 10 or R 11 and is optionally substituted. In some embodiments, R 9 is -H. In some embodiments, R 9 is -C1-C6 alkyl, -C3-C8 cycloalkyl, -C4-C8 cycloalkenyl, heterocyclyl or aryl, where R 9 is R 10 or R 11 and is optionally substituted. In some embodiments, R 9 is -C1-C6 alkyl optionally substituted with one or more R 10 or R 11 . In some embodiments, R 9 is aryl optionally substituted with one or more R 10 or R 11 . In some embodiments, R 9 is heteroaryl optionally substituted with one or more R 10 or R 11 .

[0031] In some embodiments, R 10is -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C8 cycloalkyl, -C4-C8 cycloalkenyl, heterocyclyl, heteroaryl, aryl, -OH, halogen, oxo, -NO2, -CN, -NH2, -OC1-C6 alkyl, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -S(O)2NH(C1-C6 alkyl), -S(O)2N(C1-C6 alkyl)2, -S(O)2C1-C6 alkyl, -C(O)C1-C6 alkyl, -C(O)NH2, -C(O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -C(O)OC1-C6 alkyl, -N(C1-C6 alkyl)SO2C1-C6 alkyl, -S(O)(C1-C6 alkyl), -S(O)N(C1-C6 alkyl)2 or -N(C1-C6 alkyl)S(O)(C1-C6 alkyl), where alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl or aryl are each optionally substituted by one or more -R 12 as required. In some embodiments, R 10 is -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C8 cycloalkyl, -C4-C8 cycloalkenyl, heterocyclyl, heteroaryl, aryl, where R 10 is substituted by R 12 as required. In some embodiments, R 10 is halogen. In some embodiments, R 10Each is independently, for each occurrence, -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C8 cycloalkyl, -C4-C8 cycloalkenyl, heterocyclyl, heteroaryl, aryl, -OH, halogen, oxo, -NO2, -CN, -NH2, -OC1-C6 alkyl, -OC3-C6 cycloalkyl, O-aryl, O-heteroaryl, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -S(O)2NH(C1-C6 alkyl), -S(O)2N(C1-C6 alkyl)2, -S(O)2C1-C6 alkyl, -C(O)C1-C6 alkyl, -C(O)NH2, -C(O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -C(O)OC1-C6 alkyl, -N(C1-C6 alkyl)SO2C1-C6 alkyl, -S(O)(C1-C6 alkyl), -S(O)N(C1-C6 alkyl)2 or -N(C1-C6 alkyl)S(O)(C1-C6 alkyl), where alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl or aryl are each, one or more -R 12 optionally substituted with 12 ; where any two R 10 when on non-adjacent atoms, may combine to form a bridged cycloalkyl or heterocyclyl; where any two R 10 when on adjacent atoms, may combine to form a cycloalkyl, heterocyclyl, aryl or heteroaryl. In some embodiments, R 10 each is independently, for each occurrence, halogen or -OC1-C6 alkyl, -OC3-C6 cycloalkyl, -O-aryl, -O-heteroaryl, where alkyl, cycloalkyl, aryl or heteroaryl are each, one or more -R 12 optionally substituted with 12 .

[0032] In some embodiments, R 11is -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C8 cycloalkyl, -C4-C8 cycloalkenyl, heterocyclyl, heteroaryl, aryl, -OH, halogen, oxo, -NO2, -CN, -NH2, -OC1-C6 alkyl, -NHC1-C6 alkyl, -N(C1 -C6 alkyl)2, -S(O)2NH(C1-C6 alkyl), -S(O)2N(C1-C6 alkyl)2, -S(O)2C1-C6 alkyl, -C(O)C1-C6 alkyl, -C(O)NH2, -C(O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -C(O)OC1-C6 alkyl, -N(C1-C6 alkyl)SO2C1-C6 alkyl, -S(O)(C1-C6 alkyl), -S(O)N(C1-C6 alkyl)2 or -N(C1-C6 alkyl)S(O)(C1-C6 alkyl), wherein alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl or aryl is each optionally substituted with one or more -R 12 as required. In some embodiments, R 11 is -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C8 cycloalkyl, -C4-C8 cycloalkenyl, heterocyclyl, heteroaryl, aryl, wherein R 11 is substituted with R 12 as required. In some embodiments, R 11 is halogen.

[0033] In some embodiments, R 12is -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C8 cycloalkyl, -C4-C8 cycloalkenyl, heterocyclyl, heteroaryl, aryl, -OH, halogen, oxo, -NO2, -CN, -NH2, -OC1-C6 alkyl, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -S(O)2NH(C1-C6 alkyl), -S(O)2N(C1-C6 alkyl)2, -S(O)2C1-C6 alkyl, -C(O)C1-C6 alkyl, -C(O)NH2, -C(O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -C(O)OC1-C6 alkyl, -N(C1-C6 alkyl)SO2C1-C6 alkyl, -S(O)(C1-C6 alkyl), -S(O)N(C1-C6 alkyl)2 or -N(C1-C6 alkyl)S(O)(C1-C6 alkyl). In some embodiments, R 12 is -H. In some embodiments, R 12 is halogen.

[0034] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0035] In some embodiments, R 1 is -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C8 cycloalkyl, -C4-C8 cycloalkenyl, heterocycloalkyl, heteroaryl or aryl.

[0036] Preferably, the compound is a CBP inhibitor compound of formula (I), where R1 is -OCH3. In some embodiments, the CBO inhibitor compound of formula (I) has R1 as -OCH3 and R6 is one or more R 10It includes being a C6 aryl (phenyl) optionally substituted by R. In some embodiments, for the CBO inhibitor compound of formula (I), R1 is -OCH3 and R6 is one or more Rs selected from the group consisting of halogen (e.g., fluorine) and methoxy 10 It includes being a C6 aryl (phenyl) optionally substituted by R, where methoxy is one or more Rs 12 optionally substituted by R. In some embodiments, for the CBO inhibitor compound of formula (I), R1 is -OCH3 and R6 is one or more Rs selected from the group consisting of halogen (e.g., fluorine) and methoxy 10 It includes being a C6 aryl (phenyl) optionally substituted by R, where methoxy is one or more Rs 12 optionally substituted by R, and R 12 is halogen (preferably fluorine).

[0037] In some embodiments, the compounds of the present disclosure are compounds selected from Figure 1 or pharmaceutically acceptable salts thereof is a pharmaceutically acceptable salt. Method for synthesizing the compound

[0038] The compounds of the present disclosure can be prepared by various methods including standard chemistry. Suitable synthetic routes are shown in the examples below.

[0039] The compounds of the present disclosure, namely, the compounds of formula (I) or pharmaceutically acceptable salts, enantiomers, hydrates, solvates, prodrugs, isomers or tautomers thereof, can be prepared by methods known in the art of organic synthesis, which are described in part in the following synthetic schemes. In the schemes described below, it is fully understood that protecting groups for sensitive or reactive groups are used where necessary in accordance with general principles or chemistry. Protecting groups are manipulated in accordance with standard methods of organic synthesis (T.W. Greene and P.G.M. Wuts, “Protective Groups in Organic Synthesis”, 3rd Edition, Wiley, New York 1999). These groups are removed at convenient stages of compound synthesis using methods readily apparent to those skilled in the art. The selection process and reaction conditions and the order in which they are carried out are consistent with the preparation of the compounds of formula (I).

[0040] One skilled in the art will recognize the presence of stereocenters in the compounds of formula (I). Accordingly, the present disclosure includes both possible stereoisomers (unless otherwise specified in the synthesis), including not only racemic compounds but also the individual enantiomers and / or diastereomers. If it is desired that the compound be a single enantiomer or diastereomer, it can be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, intermediate or starting material can be achieved by appropriate methods known in the art. See, for example, “Stereochemistry of Organic Compounds”, E.L. Eliel, S.H. Wilen, and L.N. Mander (Wiley-Interscience, 1994).

[0041] The compounds described herein can be made from commercially available starting materials or synthesized using known organic, inorganic and / or enzymatic processes.

[0042] The present disclosure also includes a pharmaceutical composition comprising one or more CBP inhibitor compounds described herein or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical compositions reported herein may be provided in unit dosage forms (e.g., capsules, tablets, etc.). The pharmaceutical composition comprising the compound of formula (I) may be provided in an oral dosage form, such as a capsule or a tablet. The oral dosage form may optionally contain one or more fillers, disintegrants, lubricants, glidants, anti-adhesives and / or anti-static agents as required. In some embodiments, the oral dosage form is prepared by dry mixing. In some embodiments, the oral dosage form is a tablet and is prepared by dry granulation. For example, the CBP inhibitor compounds of the present disclosure may be administered at a therapeutically effective frequency of 1 mg to 1 g. The pharmaceutical composition may be orally administered in any orally acceptable dosage form. Thus, a patient and / or subject may be selected for treatment with the compounds described herein by first evaluating the patient and / or subject to determine whether the subject requires inhibition of CBP and, if it is determined that the subject requires inhibition of CBP, administering the composition described herein to the subject.

[0043] The pharmaceutical composition may include one or more compounds of formula (I) including any of the compounds disclosed in the following examples as provided herein. In one example, the active pharmaceutical ingredient (API) may include about 90% or more of the compound of formula (I) and up to about 10% (preferably up to about 5%, most preferably up to about 2.5% including up to about 1.5%) of the compound of formula (I). The oral dosage form comprising the compound of formula (I) may be prepared as a drug in capsule (DiC), an encapsulated simple dry mix granulate, and a lipid solution in a hard shell capsule. The capsule may contain pharmaceutically acceptable excipients and the encapsulated capsule may be packaged in a high density polyethylene induction sealed bottle.

Examples

[0044] The following schemes and definitions used elsewhere in this specification are as follows: ACN acetonitrile Ac2O acetic anhydride (±)BINAP (±)-2,2’-bis(diphenylphosphino)-1,1’-binaphthalene Boc tert-butoxycarbonyl n-BuOH butanol cm centimeter DCE 1,2-dichloroethane DCM dichloromethane or methylene chloride DEA diethylamine DMC 2-chloro-4,5-dihydro-1,3-dimethyl-1H-imidazolium chloride DMP Dess-Martin periodinane DMTMM 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride DIEA N,N-diisopropylethylamine DMAP 4-(dimethylamino)pyridine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide DPPA diphenylphosphoryl azide dppf bis(diphenylphosphino)ferrocene ES electrospray ionization Et3N triethylamine EtOAc ethyl acetate EtOH ethanol FA formic acid FCC flash column chromatography h hour HATU 2-(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate HCl hydrogen chloride HOAc acetic acid HPLC high performance liquid chromatography (i-Pr)2NEt N,N-Diisopropylethylamine L liter LC / MS Liquid Chromatography / Mass Spectrometry LDA Lithium Diisopropylamine K2CO3 Potassium Carbonate MeOH Methanol mL Milliliter mmol Millimole mg Milligram MHz Megahertz MS Mass Spectrometry m / z Mass / Charge Ratio NBS N-Bromosuccinimide nm Nanometer NMM 4-Methylmorpholine NMR Nuclear Magnetic Resonance Pd2(dba)3 Tris(dibenzylideneacetone)dipalladium Ph3P Triphenylphosphine PhCHO Benzaldehyde PhMe Toluene ppm Parts Per Million rt Room Temperature RT Retention Time SFC Supercritical Fluid Chromatography STAB Sodium Triacetoxyborohydride p-TSA p-Toluenesulfonic Anhydride p-TsOH p-Toluenesulfonic Acid TFA Trifluoroacetic Acid TFAA Trifluoroacetic Anhydride THF Tetrahydrofuran UV Ultraviolet XPhos 2-Dicyclohexylphosphino-2’,4’,6’-triisopropylbiphenyl

[0045] Materials Unless otherwise noted, all materials were obtained from commercial suppliers and used without further purification. Anhydrous solvents were obtained from Sigma - Aldrich (Milwaukee, WI) and used directly. All reactions involving air - or moisture - sensitive reagents were carried out under a nitrogen atmosphere, and all reactions utilizing microwave irradiation were performed on a Biotage Initiator EXP EU instrument. Unless otherwise noted, (1) a Waters Acquity ultra - performance liquid chromatography (UPLC) system equipped with a sample organizer and a Waters Micromass ZQ mass spectrometer for UV detection at 220 nm and low - resolution electrospray positive ion mode (ESI) (column: Acquity UPLC BEH C18, 1.7 μm 2.1×50 mm; gradient: 5 - 100% solvent B (95 / 5 / 0.09%: acetonitrile / water / formic acid) in solvent A (95 / 5 / 0.1%: 10 mM ammonium formate / acetonitrile / formic acid) for 2.2 min, then 100 - 5% solvent B in solvent A for 0.01 min, then 5% solvent B in solvent A for 0.29 min), or (2) a Waters HT2790 Alliance high - performance liquid chromatography (HPLC) system equipped with a Waters 996 PDA and a Waters ZQ Single Quad mass spectrometer for UV detection at 220 nm and 254 nm and low - resolution electrospray ionization (positive / negative) mode (ESI) (column: XBridge Phenyl or C18, 5 μm 4.6×50 mm, gradient: 5 - 95% solvent B (95% methanol / 5% water, 0.1% formic acid) in solvent A (95% water / 5% methanol, 0.1% formic acid) for 2.5 min, then 95% solvent B in solvent A for 1 min (for purity and low - resolution MS only)) were used to perform mass - trigger HPLC purification and / or measure data for purity and low - resolution mass spectra. General method for compound preparation

[0046] Methods for synthesizing the compounds of the present disclosure are described herein. The compounds of the present disclosure can be synthesized according to the synthetic schemes provided below. The preparation of the starting materials (“Intermediate 1”) for Schemes 1 and 2 is described below. The preparation of the starting materials for Schemes 3 and 4 can be found in Part A of Example 1 of U.S. Patent No. 4,404,207.

[0047] Unless otherwise specified, the substituents R 2 and R 3 are defined as follows, and R 6 is as defined in the present specification and the claims.

Chemical formula

[0048] Scheme 1 provides a method useful for synthesizing the compound of formula I. Scheme 1

Chemical formula

[0049] Scheme 2 provides a method useful for synthesizing the compound of formula I. Scheme 2

Chemical formula

[0050] Alternatively, Scheme 3 provides a method useful for synthesizing a specific compound of formula I. Scheme 3

Chemical formula

[0051] Alternatively, Scheme 4 provides a method useful for synthesizing a specific compound of formula I. Scheme 4

Chemical formula

Chemical Structure

[0052] In a 5 L four-necked round-bottom flask purged and maintained under an inert nitrogen atmosphere, 2-chloro-5-methoxyaniline (250 g, 1.59 mol) was dissolved in 1-butanol (1200 mL). Then, hydrochloric acid (aqueous solution, 36.5%, 526.5 mL) and chloranil (456.5 g, 1.86 mol) were added. The resulting mixture was stirred at 100 °C for 1 h under a nitrogen atmosphere. Then, a solution of (E)-but-2-enal (169 mL, 2.06 mol) in 1-butanol (300 mL) was added dropwise. The resulting solution was stirred at 100 °C for 1 h under a nitrogen atmosphere. The oil bath was cooled to 70 °C, and tetrahydrofuran (1500 mL) was added. Then, the resulting mixture was stirred at 70 °C for 1 h. The reaction mixture was cooled to 0 °C, and the solid was filtered. The solid was washed with tetrahydrofuran (3 L) at 0 °C. Thereby, the title compound (300 g, 77%) was obtained as a yellow solid. MS: (ES, m / z): 208, 210 [M+H] + . Then, it was dried in an oven to obtain 8-chloro-5-methoxy-2-methylquinoline hydrochloride (83.0 g, 74%) as a yellow solid. MS (ES, m / z): 208 [M+H] + . Step 2. 5-Methoxy-2-methylquinoline

[0053] In a 1000 mL three-necked round-bottom flask, 8-chloro-5-methoxy-2-methylquinoline hydrochloride (50 g, 204.82 mmol) was dissolved in methanol (300 mL). Then, sodium hydroxide (3 M, 205 mL) and 10% palladium on carbon (25 g) were added. Hydrogen (g) was charged into the reaction mixture. The reaction mixture was stirred at room temperature for 3 hours under a hydrogen atmosphere. The reaction was vented with nitrogen, and the solid was filtered through celite. The filtered solution was concentrated under vacuum. The residue was subjected to purification by FCC eluting with ethyl acetate / petroleum ether (1:5). Thereby, the title compound (28.5 g, 80%) was obtained as a yellow oil. MS: (ES, m / z): 174 [M+H] + . Step 3. (2S)-5-methoxy-2-methyl-1,2,3,4-tetrahydroquinoline

[0054] In a 30 mL pressure tank reactor (50 atm), 5-methoxy-2-methylquinoline (4.0 g, 23.09 mmol) was dissolved in methanol (10 mL). Then, Ru(OTf)(η6-hexamethylbenzene)((S,S)-TsDPEN) ([N-[(1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-4-methylbenzenesulfonamidato-κN][(1,2,3,4,5,6-η)-1,2,3,4,5,6-hexamethylbenzene](1,1,1-trifluoromethanesulfonato-κO)-ruthenium (150 mg, 0.23 mmol) prepared according to the procedure of J. Am. Chem. Soc. 2011, 133, 9878-9891) was added. Hydrogen was introduced as above. The resulting solution was stirred at room temperature for 6 hours. The resulting mixture was concentrated under vacuum. The residue was subjected to purification by FCC eluting with ethyl acetate / petroleum ether (1:4). Thereby, the title compound (3.0 g, 73%) was obtained as a yellow oil. MS: (ES, m / z): 178 [M+H] + . Step 4. Methyl (S)-5-methoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate

[0055] In a 250 mL round-bottom flask, (2S)-5-methoxy-2-methyl-1,2,3,4-tetrahydroquinoline (18 g, 99.52 mmol) was dissolved in dichloromethane (100 mL). Then, pyridine (23.6 g, 298.36 mmol) was added, followed by methyl carbonochloridate (9.4 g, 99.47 mmol). The resulting solution was stirred at room temperature for 1 hour. The resulting solution was diluted with 100 mL of dichloromethane and washed with 3 × 200 mL of water. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to purification by FCC eluting with ethyl acetate / petroleum ether (1:3). Thereby, the title compound (21 g, 89%) was obtained as a yellow oil. MS: (ES, m / z): 236 [M+H] + . Step 5. Methyl (S)-5-hydroxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate

[0056] In a 500 mL three-necked round-bottom flask, methyl (2S)-5-methoxy-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate (21 g, 89.36 mmol) was dissolved in dichloromethane (150 mL). Then, boron tribromide (150 mL, 0.15 mol, 1 M in CH2Cl2) was added. The resulting solution was stirred at room temperature for 1 hour. Then, the reaction was quenched by adding 300 mL of water. The resulting mixture was extracted with 3 × 300 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to purification by FCC eluting with ethyl acetate / petroleum ether (1:2). Thereby, the title compound (13.5 g, 68%) was obtained as a yellow solid. MS: (ES, m / z): 222 [M+H] + . Step 6. Methyl (S)-2-methyl-5-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydroquinoline-1(2H)-carboxylate

[0057] In a 250 mL round-bottomed flask, methyl (2S)-5-hydroxy-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate (5 g, 18.08 mmol) was dissolved in dichloromethane (50 mL). Then, pyridine (14.3 g, 180.78 mmol) and trifluoromethanesulfonic anhydride (10.2 g, 36.15 mmol) were added. The resulting solution was stirred at room temperature for 1 hour. The resulting mixture was washed with 3 × 100 mL of water. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to purification by FCC eluting with ethyl acetate / petroleum ether (1:3). This gave the title compound (5.5 g, 86%) as a yellow oil. M S:(ES,m / z):354[M+H] + . Step 7. Methyl (S)-5-((diphenylmethylene)amino)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate

[0058] In a 500 mL round-bottomed flask purged and maintained under an inert nitrogen atmosphere, methyl (2S)-2-methyl-5-[(trifluoromethane)sulfonyloxy]-1,2,3,4-tetrahydroquinoline-1-carboxylate (23.5 g, 65.18 mmol) was dissolved in toluene (100 mL). Then, diphenylmethanimine (17.9 g, 97.78 mmol), tris(dibenzylideneacetone)dipalladium-chloroform adduct (1.19 g, 1.30 mmol), (+ / -)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (2.43 g, 3.90 mmol) and cesium carbonate (42.4 g, 130.13 mmol) were added. The resulting solution was stirred at 100 °C overnight under a nitrogen atmosphere. The reaction mixture was cooled and the solid was filtered off. The residue was subjected to purification by FCC eluting with ethyl acetate / petroleum ether (1:3). This gave the title compound (33 g, 80%) as a yellow oil. MS:(ES,m / z):385[M+H] + . Step 8. Methyl (S)-5-amino-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate

[0059] In a 500 mL round-bottomed flask with a round bottom, methyl (2S)-5-[(diphenylmethylene)amino]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate (33 g, 85.93 mmol) was dissolved in methanol (200 mL). Then, sodium acetate (17 g, 207.23 mmol) and hydroxylamine hydrochloride (12.3 g, 177.00 mmol) were added. The resulting solution was stirred at room temperature for 2 hours. The solid was filtered off. The resulting mixture was concentrated under vacuum. The residue was subjected to purification by FCC eluting with ethyl acetate / petroleum ether (1:2). Thereby, the title compound (12.5 g, 66%) was obtained as a yellow solid. MS: (ES, m / z): 221 [M+H] + . Step 9. Methyl (S)-5-amino-6-bromo-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (Intermediate 1)

[0060] In a 100 mL three-necked round-bottomed flask, methyl (2S)-5-amino-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate (1 g, 4.09 mmol) was dissolved in acetonitrile (20 mL). Then, N-bromosuccinimide (730 mg, 4.10 mmol) was added. The resulting solution was stirred at room temperature for 30 minutes. The resulting mixture was concentrated under vacuum. The residue was subjected to purification by FCC eluting with ethyl acetate / petroleum ether (1:1). Thereby, the title compound (1.1 g, 90%) was obtained as a yellow solid. MS: (ES, m / z): 299, 301 [M+H] + . 1H-NMR: (400 MHz, CD3OD, ppm): 7.19 (d, J = 8.8 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 4.73 - 4.69 (m, 1H), 3.74 (s, 3H), 2.64 - 2.57 (m, 1H), 2.55 - 2.44 (m, 1H), 2.12 - 2.05 (m, 1H), 1.82 - 1.79 (m, 1H), 1.17 (d, J = 6.9 Hz, 3H).

[0061] The present disclosure is further illustrated by the following examples and synthetic schemes, which should not be construed as limiting the scope or spirit of the present disclosure to the specific procedures described herein. The examples are provided to illustrate specific embodiments and it should be understood that they are not intended to limit the scope of the present disclosure. It should be further understood that various other embodiments, modifications and their equivalents that may be suggested to those skilled in the art without departing from the spirit and / or scope of the appended claims may be employed.

[0062] The synthetic scheme is presented for the synthesis of specific compounds disclosed herein. BE The process and results of assays testing the effect of T family bromodomain inhibition and cancer cell line proliferation are also described. Example 1: Methyl (S)-2-(2-(1H-pyrazol-1-yl)ethyl)-7-methyl-3-(2-(((1-methyl-1H-pyrazol-3-yl)methyl)amino)ethyl)-3,7,8,9-tetrahydro-6H-imidazo[4,5-f]quinoline-6-carboxylate [Chemical formula] Step 1. 6-Fluoro-2-methyl-5-nitroquinoline

[0063] A solution of trifluoromethanesulfonic acid (82.0 mL, 0.923 mol) in HNO3 (19.6 mL, 0.437 mol) was stirred at 0 °C for 20 minutes. Then, 6-fluoro-2-methylquinoline (50.0 g, 0.310 mol) in dichloromethane (300 mL) was added at 0 °C. The resulting mixture was stirred at room temperature (25 °C) for 15 hours. The reaction mixture was diluted with water (300 mL). The pH value of the solution was adjusted to 8 with sodium bicarbonate (saturated aqueous solution). The resulting solution was extracted with dichloromethane (3 × 300 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:4 ethyl acetate / petroleum ether) to give 6-fluoro-2-methyl-5-nitroquinoline as a light yellow solid (60.0 g, 94%). LCMS (ES, m / z): 207 [M+H] + . Step 2. (2S)-6-Fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline

[0064] (S)-(-)-MeO-BIPHEP (1.03 g, 1.77 mmol), a solution of chloro(1,5-cyclooctadiene)iridium(I) dimer (538 mg, 0.80 mmol) in toluene (100 mL) was stirred at room temperature (25 °C) for 30 minutes under a nitrogen atmosphere. Then, I2 (410 mg, 1.62 mmol) and 6-fluoro-2-methyl-5-nitroquinoline (33.0 g, 0.160 mol) in toluene (100 mL) were added. The resulting mixture was stirred at room temperature (25 °C) for 20 hours under hydrogen (50 atm). The resulting mixture was concentrated under vacuum, and silica gel chromatography (1:1 ethyl acetate / Purified by elution with petroleum ether to obtain the crude product (35.0 g). The crude product was dissolved in ethyl acetate (230 mL), and then D-camphorsulfonic acid (36.9 g, 0.158 mol) was added. The resulting solution was stirred at 60 °C for 1 hour and then cooled to room temperature. The solid was collected by filtration and rinsed with ethyl acetate (120 mL). The solid was dissolved in water (50 mL). The pH value of the solution was adjusted to 8 with sodium bicarbonate (saturated aqueous solution). The resulting solution was extracted with ethyl acetate (3 × 120 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain (2S)-6-fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline as a red solid (25.5 g, 76%). LCMS (ES, m / z): 211 [M+H] + . Step 3. Methyl (2S)-6-fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate

[0065] A solution of (2S)-6-fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline (25.3 g, 0.120 mol), pyridine (39.0 mL, 0.484 mol) and methyl carbonochloridate (18.7 mL, 0.242 mol) in dichloromethane (150 mL) was stirred at room temperature (25 °C) for 3 hours. The reaction mixture was washed with 1N hydrochloric acid (aqueous solution, 2 × 70 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain methyl (2S)-6-fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate as a yellow solid (29.8 g, 92%). LCMS (ES, m / z): 269 [M+H] + . Step 4. Methyl (2S)-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate A solution of methyl (2S)-6-fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate (29.6 g, 0.110 mol), pyridine (29.6 mL, 0.368 mol), potassium carbonate (30.5 g, 0.220 mol) and methyl (1R,3R)-3-aminocyclohexane-1-carboxylate (25.6 g, 162.84 mmol) in DMSO (270 mL) was stirred at 90 °C for 15 h and then cooled to room temperature. The reaction was quenched by adding water (200 mL) and extracted with ethyl acetate (3 × 300 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography (eluting with 1:1 ethyl acetate / petroleum ether) to give methyl (2S)-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate as a red oil (32 g, 72%). LCMS (ES, m / z): 406 [M+H] + . Step 5. Methyl (2S)-5-amino-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate

[0066] A solution of methyl (2S)-2-methyl-5-nitro-6-[[(1R,3R)-4-(methoxycarbonyl)cyclohexyl]amino]-1,2,3,4-tetrahydroquinoline-1-carboxylate (31.0 g, 76.46 mmol), NH4Cl (24.3 g, 454.28 mmol) and Fe (powder, 64.3 g, 1.15 mol) in tetrahydrofuran (300 mL), ethanol (300 mL) and water (100 mL) was stirred at 80 °C for 1 hour and then cooled to room temperature. The solid was filtered off by filtration. The resulting solution was diluted with water (300 mL) and extracted with ethyl acetate (3 × 400 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum to give methyl (2S)-5-((R)-2-hydroxy-2-phenylacetamido)-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate as a dark green solid (27.5 g, 92%) Obtained. LCMS (ES, m / z): 376 [M+H] + . Step 6. Methyl (2S)-5-[2-(4-chlorophenyl)-2-hydroxyacetamido]-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate

[0067] A solution of 2-(4-chlorophenyl)-2-hydroxyacetic acid (112 mg, 0.60 mmol), HATU (304 mg, 0.80 mmol), methyl (2S)-5-amino-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate (150 mg, 0.40 mmol) and DIEA (155 mg, 1.20 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature (25 °C) for 15 h. The resulting solution was diluted with water (30 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (2 × 25 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (eluting with 1:1 ethyl acetate / petroleum ether) to give methyl (2S)-5-[2-(4-chlorophenyl)-2-hydroxyacetamido]-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate as a yellow oil (70.0 mg, 32%). LCMS (ES, m / z): 544 [M+H] + . Step 7. Methyl (7S)-2-[(4-chlorophenyl)(hydroxy)methyl]-3-[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinoline-6-carboxylate

[0068] A solution of methyl (2S)-5-[2-(4-chlorophenyl)-2-hydroxyacetamido]-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate (60.0 mg, 0.11 mmol) in AcOH (2 mL) was stirred at 40 °C for 15 h and then cooled to room temperature. The reaction mixture was diluted with water (10 mL). The pH value of the solution was adjusted to 8 with sodium bicarbonate (saturated aqueous solution). The resulting solution was extracted with ethyl acetate (3 × 15 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated under vacuum. The obtained crude product was purified by silica gel chromatography (eluting with 1:1 ethyl acetate / petroleum ether) to give methyl (7S)-2-[(4-chlorophenyl)(hydroxy)methyl]-3-[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinoline-6-carboxylate as a yellow oil (46.0 mg, 79%). LCMS (ES, m / z): 526 [M+H] + . Step 8. (1R,3R)-3-[(7S)-2-[(R)-(4-chlorophenyl)(hydroxy)methyl]-6-(methoxycarbonyl)-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinolin-3-yl]cyclohexane-1-carboxylic acid (PH-FMA-PJ00136-1145-0A); (1R,3R)-3-[(7S)-2-[(S)-(4-chlorophenyl)(hydroxy)methyl]-6-(methoxycarbonyl)-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinolin-3-yl]cyclohexane-1-carboxylic acid (PH-FMA-PJ00136-1145-0B)

[0069] A solution of methyl (7S)-2-[(4-chlorophenyl)(hydroxy)methyl]-3-[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinoline-6-carboxylate (50.0 mg, 0.10 mmol) and LiOH (11.4 mg, 0.48 mmol) in tetrahydrofuran (1 mL) and water (1 mL) was stirred at 25 °C for 15 h. The resulting mixture was concentrated under vacuum. The crude product was purified by preparative HPLC (column: XBridge Shield RP18 OBD column, 5 μm, 19×150 mm; mobile phase, A: water (containing 10 mmol / L NH4HCO3) and B: ACN (10% - 37% over 12 min); detector: UV254 nm). The product fractions were lyophilized to give (1R,3R)-3-[(7S)-2-[(R)-(4-chlorophenyl)(hydroxy)methyl]-6-(methoxycarbonyl)-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinolin-3-yl]cyclohexane-1-carboxylic acid (413) as a white solid (10.5 mg, 43%); (1R,3R)-3-[(7S)-2-[(S)-(4-chlorophenyl)(hydroxy)methyl]-6-(methoxycarbonyl)-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinolin-3-yl]cyclohexane-1-carboxylic acid (501) as a white solid (7.0 mg, 29%). First eluted isomer (413): 1 1H-NMR (CD3OD, 400 MHz) δ (ppm): 7.49 (d, J = 9.0 Hz, 1H), 7.42 - 7.33 (m, 5H), 6.19 (s, 1H), 4.92 - 4.90 (m, 1H), 4.82 - 4.72 (m, 1H), 3.79 (s, 3H), 3.34 - 3.20 (m, 1H), 3.02 - 2.94 (m, 1H), 2.90 - 2.87 (m, 1H), 2.36 - 2.09 (m, 4H), 1.99 - 1.96 (m, 1H), 1.80 - 1.42 (m, 5H), 1.16 (d, J = 6.6 Hz, 3H). LCMS (ES, m / z): 512 [M+H] + . Second eluted isomer (501):1 1H-NMR (CD3OD, 400 MHz) δ (ppm): 7.52 - 7.33 (m, 6H), 6.22 (s, 1H), 4.84 - 4.73 (m, 2H), 3.78 (s, 3H), 3.27 - 3.16 (m, 1H), 3.04 - 2.92 (m, 1H), 2.90 - 2.88 (m, 1H), 2.46 - 2.35 (m, 2H), 2.30 - 2.22 (m, 1H), 2.15 - 2.02 (m, 2H), 1.82 - 1.71 (m, 1H), 1.63 - 1.55 (m, 2H), 1.40 - 1.28 (m, 1H), 1.15 (d, J = 6.6 Hz, 4H). LCMS (ES, m / z): 512 [M+H] + .

[0070] Using standard chemical operations and procedures similar to those described herein, the compounds listed in Figure 1 were prepared. In Figure 1, "elution isomers" refer to the order in which the compounds eluted by preparative HPLC. Example 2: Compounds 424 and 660: (1R,3R)-3-[(7S)-2-[(R)-(5-Fluoro-2-methoxyphenyl)(hydroxy)methyl]-6-(methoxycarbonyl)-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinolin-3-yl]cyclohexane-1-carboxylic acid (424); (1R,3R)-3-[(7S)-2-[(S)-(5-Fluoro-2-methoxyphenyl)(hydroxy)methyl]-6-(methoxycarbonyl)-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinolin-3-yl]cyclohexane-1-carboxylic acid (660)

Chem.

[0071] A solution of ZnI2 (1.6 mg, 0.01 mmol), 5-fluoro-2-methoxybenzaldehyde (1.54 g, 9.99 mmol) in trimethylsilylcarbonitrile (1.5 mL, 11.25 mmol) was stirred at room temperature for 1 hour. The resulting mixture was concentrated under vacuum. The obtained crude product was purified by silica gel chromatography (eluted with 1:1 ethyl acetate / petroleum ether) to give 2-(5-fluoro-2-methoxyphenyl)-2-[(trimethylsilyl)oxy]acetonitrile as a white solid (2.0 g, 79%). Step 2. 2-(5-Fluoro-2-methoxyphenyl)-2-hydroxyacetic acid

[0072] A solution of 2-(5-fluoro-2-methoxyphenyl)-2-[(trimethylsilyl)oxy]acetonitrile (1.50 g, 5.92 mmol) in hydrochloric acid (10 mL, 12 M) was stirred at 25 °C for 1 hour and then at 70 °C for 2 hours. The reaction mixture was cooled and concentrated under vacuum. The crude product was purified by reverse-phase chromatography (column: C18; mobile phase, A: water (containing 0.05% TFA) and B: ACN (5% - 20% over 30 minutes); detector, UV 254 nm) to give 2-(5-fluoro-2-methoxyphenyl)-2-hydroxyacetic acid as a white solid (1.10 g, 93%). Step 3. 6-Fluoro-2-methyl-5-nitroquinoline

[0073] Trifluoromethanesulfonic acid (82.0 mL, 0.923 mol) of HNO3 (19 The solution in (0.6 mL, 0.437 mol) was stirred at 0 °C for 20 minutes. Thereafter, 6-fluoro-2-methylquinoline (50.0 g, 0.310 mol) in dichloromethane (300 mL) was added at 0 °C. The resulting mixture was stirred at room temperature (25 °C) for 15 hours. The reaction mixture was diluted with water (300 mL). The pH value of the solution was adjusted to 8 with sodium bicarbonate (saturated aqueous solution). The resulting solution was extracted with dichloromethane (3 × 300 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (eluted with 1:4 ethyl acetate / petroleum ether) to obtain 6-fluoro-2-methyl-5-nitroquinoline as a bright yellow solid (60.0 g, 94%). LCMS (ES, m / z): 207 [M+H] + . Step 4. (2S)-6-Fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline

[0074] (S)-(-)-MeO-BIPHEP (1.03 g, 1.77 mmol) and dichloro(1,5-cyclooctadiene)iridium(I) dimer (538 mg, 0.80 mmol) in toluene (100 mL) were stirred at room temperature (25 °C) for 30 minutes under a nitrogen atmosphere. Then, I2 (410 mg, 1.62 mmol) and 6-fluoro-2-methyl-5-nitroquinoline (33.0 g, 0.160 mol) in toluene (100 mL) were added. The resulting mixture was stirred at room temperature (25 °C) for 20 hours under hydrogen (50 atm). The resulting mixture was concentrated under vacuum and purified by silica gel chromatography (eluting with 1:1 ethyl acetate / petroleum ether) to obtain a crude product (35.0 g). The crude product was dissolved in ethyl acetate (230 mL), and then D-camphorsulfonic acid (36.9 g, 0.158 mol) was added. The resulting solution was stirred at 60 °C for 1 hour and then cooled to room temperature. The solid was collected by filtration and rinsed with ethyl acetate (120 mL). The solid was dissolved in water (50 mL). The pH value of the solution was adjusted to 8 with sodium bicarbonate (saturated aqueous solution). The resulting solution was extracted with ethyl acetate (3 × 120 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain (2S)-6-fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline as a red solid (25.5 g, 76%). LCMS (ES, m / z): 211 [M+H] + . Step 5. Methyl (2S)-6-fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate

[0075] (2S)-6-Fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline (25.3 g, 0.120 mol), pyridine (39.0 mL, 0.484 mol), and methyl carbonochloridate (18.7 mL, 0.242 mol) in dichloromethane (150 mL) were stirred at room temperature (25 °C) for 3 hours. The reaction mixture was washed with 1 M hydrochloric acid (2 × 70 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give methyl (2S)-6-fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate as a yellow solid (29.8 g, 92%). LCMS (ES, m / z): 269 [M+H] + . Step 6. Methyl (2S)-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate

[0076] A solution of methyl (2S)-6-fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate (29.6 g, 0.110 mol), pyridine (29.6 mL, 0.368 mol), potassium carbonate (30.5 g, 0.220 mol), and methyl (1R,3R)-3-aminocyclohexane-1-carboxylate (25.6 g, 162.84 mmol) in DMSO (270 mL) was stirred at 90 °C for 15 hours and then cooled to room temperature. The reaction was quenched by adding water (200 mL), and the mixture was extracted with ethyl acetate (3 × 300 mL). The combined organic layers were dried over anhydrous sodium sulfate and filtered, and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (eluting with 1:1 ethyl acetate / petroleum ether) to give methyl (2S)-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate as a red oil (32 g, 72%). LCMS (ES, m / z): 406 [M+H] + . Project 7. Methyl (2S)-5-amino-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate

[0077] A solution of methyl (2S)-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate (31.0 g, 76.46 mmol), NH4Cl (24.3 g, 454.28 mmol), and Fe (64.3 g, 1.15 mol) in tetrahydrofuran (300 mL), ethanol (300 mL), and water (100 mL) was stirred at 80 °C for 1 hour and then cooled to room temperature. The solid was filtered off. The resulting solution was diluted with water (300 mL) and extracted with ethyl acetate (3 × 400 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give methyl (2S)-5-amino-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate as a dark green solid (27.5 g, 92%). LCMS (ES, m / z): 376 [M+H] + . Project 8. Methyl (2S)-5-[2-(5-fluoro-2-methoxyphenyl)-2-hydroxyacetamido]-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate

[0078] 2-(5-Fluoro-2-methoxyphenyl)-2-hydroxyacetic acid (240 mg, 1.20 mmol), HATU (228 mg, 0.60 mmol), methyl (2S)-5-amino-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate (150 mg, 0.40 mmol), and DIEA (0.19 mL, 1.20 mmol) in N,N-dimethylformamide (10 mL) were stirred at 25 °C for 1 h. The resulting solution was diluted with H2O (10 mL). The resulting solution was extracted with ethyl acetate (3 × 15 mL), and the organic layers were combined. The resulting mixture was washed with brine (2 × 20 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (eluting with 3:2 ethyl acetate / petroleum ether) to give methyl (2S)-5-[2-(5-fluoro-2-methoxyphenyl)-2-hydroxyacetamido]-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate as a yellow solid (180 mg, 81%). LCMS (ES, m / z): 558 [M+H] + . Step 9. Methyl (7S)-2-[(5-fluoro-2-methoxyphenyl)(hydroxy)methyl]-3-[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinoline-6-carboxylate.

[0079] A solution of methyl (2S)-5-[2-(5-fluoro-2-methoxyphenyl)-2-hydroxyacetamido]-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate (180 mg, 0.32 mmol) in AcOH (8 mL) was stirred at 60 °C overnight. The reaction mixture was cooled and concentrated under vacuum. The resulting crude product was subjected to silica gel chroma Purified by chromatography (eluting with 1:1 ethyl acetate / petroleum ether) to give methyl (7S)-2-[(5-fluoro-2-methoxyphenyl)(hydroxy)methyl]-3-[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinoline-6-carboxylate as a yellow solid (120 mg, 69%). LCMS (ES, m / z): 540 [M+H] + . Step 10. (1R,3R)-3-[(7S)-2-[(R)-(5-fluoro-2-methoxyphenyl)(hydroxy)methyl]-6-(methoxycarbonyl)-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinolin-3-yl]cyclohexane-1-carboxylic acid; (1R,3R)-3-[(7S)-2-[(S)-(5-fluoro-2-methoxyphenyl)(hydroxy)methyl]-6-(methoxycarbonyl)-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinolin-3-yl]cyclohexane-1-carboxylic acid

[0080] A solution of methyl (7S)-2-[(5-fluoro-2-methoxyphenyl)(hydroxy)methyl]-3-[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinoline-6-carboxylate (120 mg, 0.22 mmol) and LiOH (16 mg, 0.67 mmol) in tetrahydrofuran (2.0 mL), methanol (2.0 mL) and water (2.0 mL) was stirred at 25 °C overnight. The resulting mixture was concentrated under vacuum. The crude product was purified by preparative HPLC (column, XBridge Prep C18 OBD column, 19×150 mm, 5 μm; mobile phase, A: water (containing 10 mmol / L NH4HCO3) and B: ACN (from 15.0% to 29.0% over 14 minutes); detector, UV220 / 254 nm). The product was separated by chiral preparative HPLC (column, CHIRALPAK IE, 2×25 cm, 5 μm; mobile phase, A: Hex (containing 0.1% FA) and B: ethanol (holding 50.0% ethanol over 12 minutes); detector, UV220 / 254 nm). The product fractions were concentrated to give (1R,3R)-3-[(7S)-2-[(R)-(5-fluoro-2-methoxyphenyl)(hydroxy)methyl]-6-(methoxycarbonyl)-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinolin-3-yl]cyclohexane-1-carboxylic acid as a white solid (23.6 mg, 20%); (1R,3R)-3-[(7S)-2-[(S)-(5-fluoro-2-methoxyphenyl)(hydroxy)methyl]-6-(methoxycarbonyl)-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinolin-3-yl]cyclohexane-1-carboxylic acid was obtained as a white solid (23.8 mg, 20%). The enantiomeric purity was determined by HPLC: column: CHIRALPAK IE-3, column size: 0.46×5 cm; 3 μm; mobile phase: Hex(0.1% FA):EtOH = 50:50, flow rate: 1.0 ml / min. First elution isomer (424): 1H-NMR (CD3OD, 400 MHz) δ (ppm): 7.56 - 7.47 (m, 1H), 7.47 - 7.31 (m, 1H), 7.21 - 7.09 (m, 1H), 7.09 - 6.89 (m, 2H), 6.53 (s, 1H), 4.81 - 4.61 (m, 2H), 3.85 (s, 3H), 3.78 (s, 3H), 3.31 - 3.18 (m, 1H), 3.06 - 2.82 (m, 2H), 2.57 - 2.41 (m, 1H), 2.41 - 2.31 (m, 1H), 2.31 - 2.09 (m, 3H), 1.83 - 1.58 (m, 3H), 1.49 - 1.21 (m, 2H), 1.16 (d, J = 6.8 Hz, 3H). LCMS (ES, m / z): 526 [M + H]+. Second elution isomer (660): 1H-NMR (CD3OD, 400 MHz) δ (ppm): 7.69 - 7.44 (m, 2H), 7.44 - 7.29 (m, 1H), 7.12 - 6.99 (m, 1H), 6.98 - 6.82 (m, 1H), 6.37 (s, 1H), 5.03 - 4.91 (m, 1H), 4.81 - 4.69 (m, 1H), 3.78 (s, 3H), 3.61 (s, 3H), 3.22 - 3.04 (m, 1H), 3.02 - 2.87 (m, 2H), 2.54 - 2.41 (m, 1H), 2.41 - 2.27 (m, 1H), 2.27 - 2.08 (m, 3H), 1.82 - 1.58 (m, 3H), 1.58 - 1.41 (m, 2H), 1.14 (d, J = 6.4 Hz, 3H). LCMS (ES, m / z): 526 [M + H]+.

[0081] In a preferred embodiment, the present disclosure provides a first elution isomer obtained from step 10 of the process described in Example 2 above or a pharmaceutically acceptable salt thereof. Preferred embodiments, the present disclosure has the following structure:

Chemical formula

[0082] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound 424 of the above structure or a pharmaceutically acceptable salt thereof with a purity of at least 90%, for example, more than 90%, more than 91%, more than 92%, more than 93%, more than 94%, more than 95%, more than 96%, more than 97%, more than 98% or more than 99% compared to one or more of its related stereoisomers. For example, the present disclosure provides a compound 424 of the above structure or a pharmaceutically acceptable salt thereof with a purity of at least 90%, for example, more than 90%, more than 91%, more than 92%, more than 93%, more than 94%, more than 95%, more than 96%, more than 97%, more than 98% or more than 99% compared to compound 660 and other stereoisomers of compound 424 below if necessary. In some embodiments, the present disclosure provides a pharmaceutical composition comprising a compound 424 of the above structure or a pharmaceutically acceptable salt thereof with a purity of at least 95%.

[0083] The composition of formula (I) may comprise one or more compounds of formula (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), (I-l), (I-m), (I-n) and / or (I-o). For example, in some embodiments, the present disclosure provides a composition comprising a compound 424 of the above structure or a pharmaceutically acceptable salt thereof with a purity of at least 90%, wherein the total content of one or more of the following stereoisomers of compound 424 represented by the following formula (II-a) to (II-o) is less than 10%, for example, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2% or less than 1%:

Chemical formula

Chemical formula

[0084] In any of the above embodiments, the percentage of purity described can be determined by HPLC. In some embodiments, the percentage of purity is determined using the following HPLC method: Sample Preparation: Prepare at 0.2 mg / mL in 70 / 30 water / acetonitrile. LCMS Information: Equipment: MS: Waters QDa MS HPLC: Waters Alliance e2695 UV: Waters 2998 PDA Conditions: Mobile Phase A: 10 mM ammonium acetate Mobile Phase B: Acetonitrile Column: Waters XSelect Phenyl-Hexyl, 3.5 μm, 4.6×150 mm Column Temperature: 35 °C LC Gradient: Runtime: 25 minutes LC Flow Rate: 1 mL / min UV Wavelength: 238 nm Ionization Mode: Electrospray Ionization Positive Injection Volume: 8 μL

[0085] For example, the present disclosure provides a pharmaceutical composition comprising compound 424 or a pharmaceutically acceptable salt thereof having a purity of at least 95% as determined by the HPLC method described above. The present disclosure also provides a pharmaceutical composition comprising compound 424 having a purity of at least 95% as determined by the HPLC method described above.

[0086] The present disclosure provides a compound of formula II obtained by the method exemplified in Example 2:

Chemical Formula

[0087] It will be apparent to those skilled in the art that each stereoisomer of the compound of formula (II) can be obtained by changing the stereochemistry of the appropriate reagents used in the method of Example 2 above. For example, by adjusting the reagents used in Step 4 of Example 2, compounds such as the compounds of formula (II-m) and (II-n) can be synthesized. Similarly, in Step 6 of Example 2, by using the reagent methyl (1S,3R)-3-aminocyclohexane-1-carboxylate instead of methyl (1R,3R)-3-aminocyclohexane-1-carboxylate, the compounds of formula (II-b) and (II-e) can be obtained. By combining these types of modifications to the process described in Example 2, it will be apparent to those skilled in the art that each of the above (II -a) to (II-o) compounds can be synthesized. Example 3: (1R,3R)-3-[(7S)-2-[(R)-Hydroxy(phenyl)methyl]-6-(methoxycarbonyl)-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinolin-3-yl]cyclohexane-1-carboxylic acid (462)

[0088] A composition containing Compound 462 can be prepared as shown in the following scheme:

Chemical formula

[0089] A solution of trifluoromethanesulfonic acid (82.0 mL, 0.923 mol) in HNO3 (19.6 mL, 0.437 mol) was stirred at 0 °C for 20 minutes. Then, 6-fluoro-2-methylquinoline (50.0 g, 0.310 mol) in dichloromethane (300 mL) was added at 0 °C. The resulting mixture was stirred at room temperature (25 °C) for 15 hours. The reaction mixture was diluted with water (300 mL). The pH value of the solution was adjusted to 8 with sodium bicarbonate (saturated aqueous solution). The resulting solution was extracted with dichloromethane (3 × 300 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:4 ethyl acetate / petroleum ether) to give 6-fluoro-2-methyl-5-nitroquinoline as a light yellow solid (60.0 g, 94%). LCMS (ES, m / z): 207 [M+H] + . Step 2. (2S)-6-Fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline

[0090] (S)-(-)-MeO-BIPHEP (1.03 g, 1.77 mmol), a solution of chloro(1,5-cyclooctadiene)iridium(I) dimer (538 mg, 0.80 mmol) in toluene (100 mL) was stirred at room temperature (25 °C) for 30 minutes under a nitrogen atmosphere. Then, I2 (410 mg, 1.62 mmol), 6-fluoro-2-methyl-5-nitroquinoline (33.0 g, 0.160 mol) in toluene (100 mL) were added. The resulting mixture was stirred at room temperature (25 °C) for 20 hours under hydrogen (50 atm). The resulting The resulting mixture was concentrated under vacuum and purified by silica gel chromatography (eluting with 1:1 ethyl acetate / petroleum ether) to afford the crude product (35.0 g). The crude product was dissolved in ethyl acetate (230 mL), and subsequently, D-camphorsulfonic acid (36.9 g, 0.158 mol) was added. The resulting solution was stirred at 60 °C for 1 h and then cooled to room temperature. The solid was collected by filtration and rinsed with ethyl acetate (120 mL). The solid was dissolved in water (50 mL). The pH value of the solution was adjusted to 8 with sodium bicarbonate (saturated aqueous solution). The resulting solution was extracted with ethyl acetate (3 × 120 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give (2S)-6-fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline as a red solid (25.5 g, 76%). LCMS (ES, m / z): 211 [M+H] + . Step 3. Methyl (2S)-6-fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate

[0091] (2S)-6-Fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline (25.3 g, 0.120 mol), pyridine (39.0 mL, 0.484 mol), and methyl carbonochloridate (18.7 mL, 0.242 mol) in dichloromethane (150 mL) were stirred at room temperature (25 °C) for 3 h. The reaction mixture was washed with 1 M hydrogen chloride (2 × 70 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give methyl (2S)-6-fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate as a yellow solid (29.8 g, 92%). LCMS (ES, m / z): 269 [M+H] + . Step 4. Methyl (2S)-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate

[0092] Methyl (2S)-6-fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate (29.6 g, 0.110 mol), pyridine (29.6 mL, 0.368 mol), potassium carbonate (30.5 g, 0.220 mol), and methyl (1R,3R)-3-aminocyclohexane-1-carboxylate (25.6 g, 162.84 mmol) in DMSO (270 mL) were stirred at 90 °C for 15 h and then cooled to room temperature. The reaction was quenched by adding water (200 mL), and the mixture was extracted with ethyl acetate (3 × 300 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (eluting with 1:1 ethyl acetate / petroleum ether) to give methyl (2S)-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate as a red oil (32 g, 72%). LCMS (ES, m / z): 406 [M+H] + . Step 5. Methyl (2S)-5-amino-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate

[0093] (2S)-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate (31.0 g, 76.46 mmol), NH4Cl (24.3 g, 454.28 mmol), and Fe (64.3 g, 1.15 mol) in tetrahydrofuran (300 mL), ethanol (300 mL), and water (100 mL) were stirred at 80 °C for 1 h and then cooled to room temperature. The solid was filtered off. The resulting solution was diluted with water (300 mL) and extracted with ethyl acetate (3 × 400 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give methyl (2S)-5-amino-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-1 ,2,3,4-Tetrahydroquinoline-1-carboxylate was obtained as a dark green solid (27.5 g, 92%). LCMS (ES, m / z): 376 [M+H] + . Step 6. Methyl (2S)-5-((R)-2-hydroxy-2-phenylacetamido)-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate

[0094] (R)-2-Hydroxy-2-phenylacetic acid (972 mg, 6.39 mmol), HATU (1.20 g, 3.16 mmol), methyl (2S)-5-amino-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate (800 mg, 2.13 mmol), and DIEA (1.08 mL, 6.20 mmol) in N,N-dimethylformamide (10 mL) were stirred at room temperature (25 °C) for 5 h. The resulting solution was diluted with water (30 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with brine (2 × 25 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (eluting with 1:1 ethyl acetate / petroleum ether) to give methyl (2S)-5-((R)-2-hydroxy-2-phenylacetamido)-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate as a colorless oil (600 mg, 55%). LCMS (ES, m / z): 510 [M+H] + Step 7. Methyl (7S)-2-[(R)-hydroxy(phenyl)methyl]-3-[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinoline-6-carboxylate

[0095] A solution of methyl (2S)-5-((R)-2-hydroxy-2-phenylacetamido)-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate (600 mg, 1.18 mmol) in glacial acetic acid (5 mL, 98%) was stirred at 40 °C overnight and then cooled to room temperature. The reaction mixture was diluted with water (10 mL). The pH value of the solution was adjusted to 8 with sodium bicarbonate (saturated aqueous solution). The resulting solution was extracted with ethyl acetate (3 × 15 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (eluting with 1:1 ethyl acetate / petroleum ether) to give methyl (7S)-2-[(R)-hydroxy(phenyl)methyl]-3-[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinoline-6-carboxylate (400 mg, 69%) as a colorless oil. LCMS (ES, m / z): 492 [M+H] + . Step 8. (1R,3R)-3-[(7S)-2-[(R)-hydroxy(phenyl)methyl]-6-(methoxycarbonyl)-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinolin-3-yl]cyclohexane-1-carboxylic acid

[0096] A solution of methyl (7S)-2-[(R)-hydroxy(phenyl)methyl]-3-[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinoline-6-carboxylate (400 mg, 0.81 mmol) and LiOH (100 mg, 4.17 mmol) in tetrahydrofuran (5 mL) and water (2 mL) was stirred at room temperature (25 °C) overnight. The resulting mixture was concentrated under vacuum. The crude product was purified by preparative HPLC (column: XBridge Shield RP18 OBD column, 5um, 19×150 mm; mobile phase, A: water (containing 10 mmol / L NH4HCO3) and B: ACN (3% - 30% over 21 minutes); detector: UV254 nm). The product fraction was lyophilized to give (1R,3 R)-3-[(7S)-2-[(R)-hydroxy(phenyl)methyl]-6-(methoxycarbonyl)-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinolin-3-yl]cyclohexane-1-carboxylic acid as a white solid (83.7 mg, 22%). The enantiomeric excess was determined by HPLC: column: CHIRALPAK IE-3, column size: 0.46×5 cm; 3μm; mobile phase: Hex(0.1% FA):EtOH = 85:15, flow rate: 1.0 ml / min. 1 1H-NMR (CD3OD, 400 MHz) δ (ppm): 7.47 - 7.28 (m, 7H), 6.12 (s, 1H), 4.84 - 4.74 (m, 2H), 3.79 (s, 3H), 3.33 - 3.25 (m, 1H), 3.03 - 2.96 (m, 1H), 2.86 - 2.82 (m, 1H), 2.38 - 2.25 (m, 2H), 2.25 - 2.07 (m, 3H), 1.79 - 1.72 (m, 1H), 1.64 - 1.57 (m, 2H), 1.40 - 1.29 (m, 2H), 1.16 (d, J = 6.8 Hz, 3H). LCMS (ES, m / z): 478 [M+H] + ; 99.13% ee. Example 4: (1R,3R)-3-[(7S)-2-[(S)-[2-(Difluoromethoxy)-5-fluorophenyl](hydroxy)methyl]-6-(methoxycarbonyl)-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinolin-3-yl]cyclohexane-1-carboxylic acid (452), (1R,3R)-3-[(7S)-2-[(R)-[2-(Difluoromethoxy)-5-fluorophenyl](hydroxy)methyl]-6-(methoxycarbonyl)-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinolin-3-yl]cyclohexane-1-carboxylic acid (515)

Chemical formula

Chemical formula

[0097] A solution of 5-fluoro-2-hydroxybenzaldehyde (2.0 g, 14.3 mmol), diethyl (bromodifluoromethyl)phosphonate (5.69 g, 21.3 mmol), and potassium hydroxide (16.0 g, 285 mmol) in MeCN (100 mL) and water (50 mL) was stirred at -30 °C for 1 hour. The reaction mixture was diluted with water (20 mL). The resulting solution was extracted with ethyl acetate (3 × 100 mL), the organic layers were combined, and dried over anhydrous sodium sulfate. The solid was filtered off. The resulting mixture was concentrated under vacuum. The obtained crude product was purified by silica gel chromatography (eluting with 1:1 ethyl acetate / petroleum ether) to give 2-(difluoromethoxy)-5-fluorobenzaldehyde as a yellow solid (1.46 g, 54%). LCMS (ES, m / z): 191 [M+H] + . Step 2. 2-[2-(Difluoromethoxy)-5-fluorophenyl]-2-[(trimethylsilyl)oxy]acetonitrile

[0098] A solution of 2-(difluoromethoxy)-5-fluorobenzaldehyde (1.46 g, 7.68 mmol), TMSCN (760 mg, 7.66 mmol), and ZnI2 (50 mg, 0.16 mmol) in dichloromethane (3 mL) was stirred at room temperature (25 °C) for 2 h. The resulting mixture was concentrated under vacuum. The obtained crude product was purified by silica gel chromatography (eluting with 1:1 ethyl acetate / petroleum ether) to give 2-[2-(difluoromethoxy)-5-fluorophenyl]-2-[(trimethylsilyl)oxy]acetonitrile as a yellow solid (800 mg, 36%). LCMS (ES, m / z): 290 [M+H] +. Step 3. 2-[2-(Difluoromethoxy)-5-fluorophenyl]-2-hydroxyacetic acid

[0099] A solution of 2-[2-(difluoromethoxy)-5-fluorophenyl]-2-[(trimethylsilyl)oxy]acetonitrile (800 mg, 2.77 mmol), 1,4-dioxane (2.0 mL), and hydrogen chloride (1.0 mL, 12 M) in water (2 mL) was stirred at 70 °C for 12 h and then cooled to room temperature. The resulting solution was concentrated under vacuum. The crude product was purified by reverse-phase column chromatography (water (containing 0.05% TFA) / MeCN) to give 2-[2-(difluoromethoxy)-5-fluorophenyl]-2-hydroxyacetic acid (400 mg, 61%). LCMS (ES, m / z): 237 [M+H] + . Step 4. 6-Fluoro-2-methyl-5-nitroquinoline

[0100] A solution of trifluoromethanesulfonic acid (82.0 mL, 0.923 mol) in HNO3 (19.6 mL, 0.437 mol) was stirred at 0 °C for 20 minutes. Then, 6-fluoro-2-methylquinoline (50.0 g, 0.310 mol) in dichloromethane (300 mL) was added at 0 °C. The resulting mixture was stirred at room temperature (25 °C) for 15 hours. The reaction mixture was diluted with water (300 mL). The pH value of the solution was adjusted to 8 with sodium bicarbonate (saturated aqueous solution). The resulting solution was extracted with dichloromethane (3 × 300 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (eluting with 1:4 ethyl acetate / petroleum ether) to give 6-fluoro-2-methyl-5-nitroquinoline as a bright yellow solid (60.0 g, 94%). LCMS (ES, m / z): 207 [M+H] +. Step 5. (2S)-6-Fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline (S)-(-)-MeO-BIPHEP (1.03 g, 1.77 mmol), a solution of dichloro(1,5-cyclooctadiene)iridium(I) dimer (538 mg, 0.80 mmol) in toluene (100 mL) was stirred at room temperature (25 °C) for 30 minutes under a nitrogen atmosphere. Thereafter, I2 (410 mg, 1.62 mmol) and 6-fluoro-2-methyl-5-nitroquinoline (33.0 g, 0.160 mol) in toluene (100 mL) were added. The resulting mixture was stirred at room temperature (25 °C) for 20 hours under hydrogen (50 atm). The resulting mixture was concentrated under vacuum and purified by silica gel chromatography (eluting with 1:1 ethyl acetate / petroleum ether) to obtain a crude product (35.0 g). The crude product was dissolved in ethyl acetate (230 mL), and subsequently, D-camphorsulfonic acid (36.9 g, 0.158 mol) was added. The resulting solution was stirred at 60 °C for 1 hour and then cooled to room temperature. The solid was collected by filtration and rinsed with ethyl acetate (120 mL). The solid was dissolved in water (50 mL). The pH value of the solution was adjusted to 8 with sodium bicarbonate (saturated aqueous solution). The resulting solution was extracted with ethyl acetate (3 × 120 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain (2S)-6-fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline as a red solid (25.5 g, 76%). LCMS (ES, m / z): 211 [M+H] + . Step 6. Methyl (2S)-6-fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate

[0101] (2S)-6-Fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline (25.3 g, 0.120 mol), pyridine (39.0 mL, 0.484 mol), a solution of methyl carbonochloridate (18.7 mL, 0.242 mol) in dichloromethane (150 mL) was stirred at room temperature (25 °C) for 3 hours. The reaction mixture was washed with 1 M hydrogen chloride (2 × 70 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain methyl (2S)-6-fluoro-2-methyl-5-nitro-1,2,3 ,4-Tetrahydroquinoline-1-carboxylate was obtained as a yellow solid (29.8 g, 92%). LCMS (ES, m / z): 269 [M+H] + . Step 7. Methyl (2S)-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate

[0102] A solution of methyl (2S)-6-fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate (29.6 g, 0.110 mol), pyridine (29.6 mL, 0.368 mol), potassium carbonate (30.5 g, 0.220 mol), and methyl (1R,3R)-3-aminocyclohexane-1-carboxylate (25.6 g, 162.84 mmol) in DMSO (270 mL) was stirred at 90 °C for 15 hours and then cooled to room temperature. The reaction was quenched by adding water (200 mL), and the mixture was extracted with ethyl acetate (3 × 300 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The resulting crude product was purified by silica gel chromatography (eluting with 1:1 ethyl acetate / petroleum ether) to give methyl (2S)-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate as a red oil (32 g, 72%). LCMS (ES, m / z): 406 [M+H] + . Step 8. Methyl (2S)-5-amino-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate

[0103] A solution of methyl (2S)-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate (31.0 g, 76.46 mmol), NH4Cl (24.3 g, 454.28 mmol), and Fe (64.3 g, 1.15 mol) in tetrahydrofuran (300 mL), ethanol (300 mL), and water (100 mL) was stirred at 80 °C for 1 hour and then cooled to room temperature. The solid was filtered off. The resulting solution was diluted with water (300 mL) and extracted with ethyl acetate (3 × 400 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to give methyl (2S)-5-amino-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate as a dark green solid (27.5 g, 92%). LCMS (ES, m / z): 376 [M+H] + . Step 9. Methyl (2S)-5-[2-[2-(difluoromethoxy)-5-fluorophenyl]-2-hydroxyacetamido]-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate

[0104] Methyl (2S)-5-amino-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate (200 mg, 0.53 mmol), 2-[2-(difluoromethoxy)-5-fluorophenyl]-2-hydroxyacetic acid (220 mg, 0.93 mmol), and DMTMM (350 mg, 1.26 mmol) in dichloromethane (5 mL) were stirred at room temperature (25 °C) for 1 hour. The resulting solution was concentrated under vacuum. The obtained crude product was purified by silica gel chromatography (eluting with 1:1 ethyl acetate / petroleum ether) to give methyl (2S)-5-[2-[2-(difluoromethoxy)-5-fluorophenyl]-2-hydroxyacetamido]-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate as a yellow solid (70.0 mg, 22%). LCMS (ES, m / z): 594 [M+H] + . Step 10. Methyl (7S)-2-[[2-(difluoromethoxy)-5-fluorophenyl](hydroxy)methyl]-3-[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinoline-6-carboxylate

[0105] A solution of methyl (2S)-5-[2-[2-(difluoromethoxy)-5-fluorophenyl]-2-hydroxyacetamido]-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate (70.0 mg, 0.12 mmol) in glacial acetic acid (2.0 mL) was stirred at 40 °C overnight and then cooled to room temperature. The resulting solution was concentrated under vacuum. The obtained crude product was purified by silica gel chromatography (eluting with 1:2 ethyl acetate / petroleum ether) to give methyl (7S)-2-[[2-(difluoromethoxy)-5-fluorophenyl](hydroxy)methyl]-3-[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinoline-6-carboxylate as a yellow solid (50.0 mg, 74%). LCMS (ES, m / z): 576 [M+H] + . Step 11. (1R,3R)-3-[(7S)-2-[(S)-[2-(difluoromethoxy)-5-fluorophenyl](hydroxy)methyl]-6-(methoxycarbonyl)-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinolin-3-yl]cyclohexane-1-carboxylic acid; (1R,3R)-3-[(7S)-2-[(R)-[2-(difluoromethoxy)-5-fluorophenyl](hydroxy)methyl]-6-(methoxycarbonyl)-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinolin-3-yl]cyclohexane-1-carboxylic acid

[0106] A solution of methyl (7S)-2-[[2-(difluoromethoxy)-5-fluorophenyl](hydroxy)methyl]-3-[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinoline-6-carboxylate (50.0 mg, 0.09 mmol) and LiOH (10.0 mg, 0.42 mmol) in tetrahydrofuran (2.0 mL) and water (2.0 mL) was stirred at room temperature (25 °C) overnight. The resulting mixture was concentrated under vacuum. The crude product was purified by preparative HPLC (column, XBridge Shield RP18 OBD column, 30×150 mm, 5 μm; mobile phase, A: water (containing 10 mmol / L NH4HCO3) and B: ACN (25.0% - 35.0% over 8 minutes); detector, UV254 / 220 nm). The product fractions were concentrated to give (1R,3R)-3-[(7S)-2-[(S)-[2-(difluoromethoxy)-5-fluorophenyl](hydroxy)methyl]-6-(methoxycarbonyl)-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinolin-3-yl]cyclohexane-1-carboxylic acid (452) as a white solid (4.50 mg, 9%) and (1R,3R)-3-[(7S)-2-[(R)-[2-(difluoromethoxy)-5-fluorophenyl](hydroxy)methyl]-6-(methoxycarbonyl)-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-f]quinolin-3-yl]cyclohexane-1-carboxylic acid (515) as a white solid (4.30 mg, 9%). HPLC: column: CHIRALPAK IE-3, column size: 0.46×5 cm; 3 μm; co-solvent: IPA (20 mM NH3) gradient (B%): 10% - 50% over 4.0 minutes, held at 50% for 2.0 minutes to determine the enantiomeric excess. The first eluted isomer (452): 11H-NMR (CD3OD, 400 MHz) δ (ppm): 7.63 - 7.61 (m, 1H), 7.53 (d, J = 8.8 Hz, 1H), 7.41 (d, J = 9.2 Hz, 1H), 7.20 - 7.13 (m, 2H), 6.67 - 6.30 (m, 2H), 4.98 - 4.95 (m, 1H), 4.76 - 4.71 (m, 1H), 3.78 (s, 3H), 3.15 - 2.86 (m, 3H), 2.46 - 2.20 (m, 5H), 1.81 - 1.53 (m, 5H), 1.13 (d, J = 6.8 Hz, 3H). LCMS (ES, m / z): 562 [M+H] + . Second elution isomer (515): 1 1H-NMR (CD3OD, 400 MHz) δ (ppm): 7.55 - 7.53 (m, 1H), 7.47 - 7.4 2 (m, 2H), 7.40 - 7.12 (m, 2H), 6.85 - 6.44 (m, 2H), 4.94 - 4.91 (m, 1H), 4.76 - 4.71 (m, 1H), 3.78 (s, 3H), 3.22 - 2.84 (m, 3H), 2.46 - 2.23 (m, 5H), 1.84 - 1.61 (m, 5H), 1.14 (d, J = 6.4 Hz, 3H). LCMS (ES, m / z): 562 [M+H] + ; >99.99% ee.

[0107] In some embodiments, the present disclosure provides a first elution isomer obtained from step 11 of the process described in Example 4. In some embodiments, the present disclosure provides a second elution isomer obtained from step 11 of the process described in Example 4. Example 5: HTRF biochemical assay for CBP and BRD4 activities

[0108] The following HTRF biochemical assay for CBP and BRD4 activities was used to determine the ability of compounds of Formula I to selectively inhibit CBP. The assay was performed in an assay buffer with a final volume of 6 μL containing 50 mM Hepes (pH 7.5, (0.5 M Hepes, pH 7.5 solution; Teknova H1575)), 0.5 mM GSH, 0.01% BGG (filtered at 0.22 μM, Sigma, G7516 - 25G), 0.005% BSA (filtered at 0.22 μM, EMD Millipore Cosporation, 126575) and 0.01% Triton X - 100 (Sigma, T9284 - 10L). Nanoliter amounts of 10 - point 3 - fold serial dilutions in DMSO were pre - dispensed into a 1536 - well assay plate (Corning, #3724BC) at final test concentrations of 33 μM to 1.7 nM (highest dose to lowest dose respectively). 3 μL of 2× protein and 3 μL of 2× peptide ligand were added to the assay plate (pre - stamped with the compound). The plate was incubated at room temperature for various times before measuring the signal. Time - resolved fluorescence resonance energy transfer (TR - FRET) was measured by a PHERAstar plate reader (BMG, equipped with HTRF optical module [337 / 520 / 490]) or an Envision plate reader (PerkinElmer, equipped with a TRF laser unit, a TRF dual - mirror D400 / D505, and emission filters M520 and M495). The data was reported as the percentage of inhibition compared to control wells based on the following formula: %inh = 1 - ((TR - FRET ratio - AveLow) / (AveHigh - AveLow)), where the TR - FRET ratio = (fluorescence at 520 nm / fluorescence at 490 nm)×10000, AveLow = the average TR - FRET ratio of the enzyme - free control (n = 32) and AveHigh = the average TR - FRET ratio of the DMSO control (n = 32). The IC50 value was determined by curve fitting using the standard 4 - parameter logistic fitting algorithm included in the Activity Base software package: IDBS XE Designer Model205. The Levenburg Marquardt algorithm was used to fit the data.For all assay formats, data were reported as percentage of inhibition compared to control wells based on the following formula: %inh=100×((FLU-AveLow) / (AveHigh-AveLow)), where FLU=measured fluorescence, AveLow=mean fluorescence of no enzyme controls (n=32) and AveHigh=mean fluorescence of DMSO controls (n=32). IC50 values ​​were determined by curve fitting with a standard 4-parameter logistic fitting algorithm: IDBS XE Designer Model205 included in the Activity Base software package. Data are fitted using the Levenburg Marquardt algorithm. IC. 50 Values ​​are shown in Figure 1. IC values ​​less than or equal to 0.01 μM where noted in Figure 1. 50 Values ​​are marked with "++++"; values ​​greater than 0.01 μM and less than or equal to 0.1 μM are marked with "+++"; values ​​greater than 0.1 μM and less than or equal to 1 μM are marked with "++" and values ​​greater than 1 μM are marked with "+". Compounds that were not tested in a particular assay are marked with "NT".

[0109] In some embodiments, the CBP inhibitor compound also exhibits an IC50 value for CBP inhibition in a HTRF biochemical assay of CBP (which is a HTRF assay of BRD4 activity according to Example 5). The CBP inhibitor composition is selective for CBP activity relative to BRD4 activity, as determined by obtaining a CBP activity lower than the corresponding IC50 value obtained in the RF biochemical assay. The CBP inhibitor composition may contain an amount of a compound of the present disclosure or a pharma- ceutically acceptable salt thereof and an amount of one or more stereoisomers of said compound, up to an amount that retains sufficient activity of the composition with respect to CBP inhibition and selectivity for CBP over BRD4. Using the methods provided herein, the CBP inhibitor composition may contain 95% or more of the compound of the present disclosure or a pharma- ceutically acceptable salt thereof by HPLC and up to 5% of one or more stereoisomers of said compound by HPLC.

[0110] In a preferred embodiment, the present disclosure has an IC for inhibition of CBP of less than or equal to 0.01 μM and for inhibition of BRD4 of greater than 0.1 μM and less than or equal to 1 μM, as determined by the HTRF biochemical assay for CBP and BRD4 activities described in Example 5 herein. 50 value and relates to Compound 424 having an IC for inhibition of BRD4 of greater than 0.1 μM and less than or equal to 1 μM. 50 value.

[0111] In some embodiments, the present disclosure has an IC for inhibition of CBP of less than or equal to 0.01 μM and for inhibition of BRD4 of greater than 0.1 μM and less than or equal to 1 μM, as determined by the HTRF biochemical assay for CBP and BRD4 activities described in Example 5 herein. 50 value and relates to Compound 424 and a compound of Formula (II) selected from the group consisting of its related stereoisomers of Structures (II-a) to (II-o) above having an IC for inhibition of BRD4 of greater than 0.1 μM and less than or equal to 1 μM. 50 value.

[0112] Further embodiments of the present disclosure are described in the items of the following numbers: 1. Formula (III):

Chemical formula

Chemical formula

Chemical formula

[0113] Summary of the present disclosure The present disclosure is directed to inhibitors of the bromodomains of the CBP / p300 family. The compounds may be useful in the treatment of diseases or disorders associated with inhibition of the bromodomains of the CBP / p300 family. For example, the present disclosure relates to compounds and compositions for the inhibition of the bromodomains of the CBP / p300 family, methods of treating, preventing or ameliorating diseases or disorders associated with inhibition of the bromodomains of the CBP / p300 family, and methods of synthesizing these compounds. Examples of embodiments of the present disclosure include the following items: Item 1. Formula (I): [Chemical formula] (In the formula, R 1 is -OR 5 ; R 5 is -C1-C6 alkyl; R 6 is phenyl optionally substituted with one or more R 10 ; R 10 are each independently, each occurrence, -C1-C6 alkyl, -C2-C6 alkene nil, -C2~C6 alkynyl, -C3~C8 cycloalkyl, -C4~C8 cycloalkenyl, heterocyclyl, heteroaryl, aryl, -OH, halogen, -NO2, -CN, -NH2, -OC1~C6 alkyl, -OC3~C6 cycloalkyl, -O aryl, -O heteroaryl, -NHC1~C6 alkyl, -N(C1~C6 alkyl)2, -S(O)2NH(C1~C6 alkyl), -S(O)2N(C1~C6 alkyl)2, -S(O)2C1~C6 alkyl, -C(O)C1~C6 alkyl, -C(O)NH2, -C(O)NH(C1~C6 alkyl), -C(O)N(C1~C6 alkyl)2, -C(O)OC1~C6 alkyl, -N(C1~C6 alkyl)SO2C1~C6 alkyl, -S(O)(C1~C6 alkyl), -S(O)N(C1~C6 alkyl)2 or -N(C1~C6 alkyl)S(O)(C1~C6 alkyl), where alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl or aryl is each optionally substituted with one or more -R 12 optionally substituted as needed with wherein any two R 10 when on non-adjacent atoms, may combine to form a bridged cycloalkyl or heterocyclyl, wherein any two R 10 when on adjacent atoms, may combine to form a cycloalkyl, heterocyclyl, aryl or heteroaryl; R 12independently, for each occurrence, is -C1-C6 alkyl, -C2-C6 alkenyl, -C2-C6 alkynyl, -C3-C8 cycloalkyl, -C4-C8 cycloalkenyl, heterocyclyl, heteroaryl, aryl, -OH, halogen, oxo, -NO2, -CN, -NH2, -OC1-C6 alkyl, -NHC1-C6 alkyl, -N(C1-C6 alkyl)2, -S(O)2NH(C1-C6 alkyl), -S(O)2N(C1-C6 alkyl)2, -S(O)2C1-C6 alkyl, -C(O)C1-C6 alkyl, -C(O)NH2, -C(O)NH(C1-C6 alkyl), -C(O)N(C1-C6 alkyl)2, -C(O)OC1-C6 alkyl, -N(C1-C6 alkyl)SO2C1-C6 alkyl, -S(O)(C1-C6 alkyl), -S(O)N(C1-C6 alkyl)2 or -N(C1-C6 alkyl)S(O)(C1-C6 alkyl)), or a pharmaceutically acceptable salt, enantiomer, hydrate, solvate, isomer or tautomer thereof. Item 2.R 5 is -C1-C3 alkyl; R 10 each independently, for each occurrence, is halogen or -OC1-C6 alkyl, -OC3-C6 cycloalkyl, -O aryl, -O heteroaryl, where the alkyl, cycloalkyl, aryl or heteroaryl is each optionally substituted with one or more -R 12 as appropriate; R 12 is halogen, a compound according to any one of the above items or a pharmaceutically acceptable salt, enantiomer, hydrate, solvate, isomer or tautomer thereof. Item 3. Any two R 10 when on non-adjacent atoms, may combine to form a bridged cycloalkyl or heterocyclyl, a compound according to any one of the above items or a pharmaceutically acceptable salt thereof. Item 4. Any two R 10which, when on an adjacent atom, may combine to form a cycloalkyl, heterocyclyl, aryl or heteroaryl, a compound according to any one of the above items or a pharmaceutically acceptable salt thereof. Item 5.R 5 is methyl. A compound according to any one of the above items. Item 6. At least one R 10 is -OC1-C6 alkyl, a compound according to any one of the above items. Item 7.R 12 is halogen, a compound according to any one of the above items. Item 8. At least one R 10 is -C1-C6 alkyl, a compound according to any one of the above items. Item 9.R 12 is halogen, a compound according to any one of the above items. Item 10. At least one R 10 is -OC3-C6 cycloalkyl, according to any one of the above items is a compound. Item 11.R 12 is halogen, a compound according to any one of the above items. Item 12. Each R 12 is fluorine, a compound according to any one of the above items. Item 13. The above compound is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Claims

[Claim 1] A transcription factor as described in the specification.

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