RU2803290C2 - Inhibition of creb-binding protein (cbp) - Google Patents

Abstract

FIELD: pharmaceutical chemistry.

SUBSTANCE: group of inventions includes a compound of formula (I), its pharmaceutically acceptable salts, an enantiomer, a stereoisomer, specific compounds and their pharmaceutically acceptable salts given in the claims, as well as a pharmaceutical composition. In the formula (I) R¹ is -OR⁵; R⁵ is -C₁-C₆alkyl; R⁶ is phenyl optionally substituted with one or more R¹⁰; R¹⁰ is at each occurrence independently -C₁-C₆alkyl, halogen, -OC₁-C₆alkyl, or -OC₃-C₆cycloalkyl, where each alkyl or cycloalkyl is optionally substituted with one or more -R¹²; any two R¹⁰, if present on non-adjacent atoms, may be combined to form a bridged C₃-C₈cycloalkyl; or any two R¹⁰, if present on adjacent atoms, may be combined to form either C₃-C₈cycloalkyl or heterocyclyl or heteroaryl selected from dihydrofuranyl, furanyl, oxazolyl, methyloxazolyl, pyrrolyl, N-methylpyrrolyl and pyrazolyl, and R¹² is at each occurrence independently either -C₁-C₆alkyl, -OH, or halo.

EFFECT: imidazo[4,5-f]quinolin-3-yl]cyclohexane-1-carboxylic acid derivatives having inhibitory activity against CREB-binding protein (CBP) and/or p300.

27 cl, 1 dwg, 5 ex

Description

Cross reference to related applications

[0001] This application claims priority to US Provisional Application No. 62/692593, filed June 29, 2018, International Application No. PCT/US2018/051235, filed September 14, 2018, International Application No. PCT/US2018/051214, filed September 14, 2018 and US Provisional Application No. 62/819,490 filed March 15, 2019, each of which is incorporated by reference in its entirety.

Field of technology

[0002] The present invention relates to novel chemical compositions for inhibiting CREB binding protein (CBP) useful in the treatment of diseases or disorders associated with inhibition of CBP/p300 family bromodomains.

State of the art

[0003] CBP/p300 are lysine acetyltransferases that catalyze the addition of an acetyl group to the lysine side chain of histones and other protein substrates. p300 (also known as EP300 and KAT3B) is a protein with multiple domains that bind to various proteins, including many DNA-binding transcription factors. CREB (cyclic AMP response element-binding protein)-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 critical for gene activation. Increased p300 expression and activity have been observed in advanced human cancers such as prostate cancer and in early-stage human breast cancer samples. Chemical inhibition of CBP/p300, which is characterized by intrinsic acetyltransferase enzymatic activity, is more feasible than blocking transcription factors with small molecules, since the study of chemical inhibitors of transcription factors has proven extremely challenging. Accordingly, there is a need for new and effective compounds for inhibiting CBP/p300 useful as a therapy for the treatment of certain related forms of cancer.

The essence of the invention

[0004] The first aspect of the present invention relates to compounds of formula (I):

or a pharmaceutically acceptable salt, enantiomer, hydrate, solvate, isomer or tautomer thereof,

Where:

R ¹ represents -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, -C ₄ -C ₈ cycloalkenyl, heterocyclyl, heteroaryl, aryl, -OR ⁵ , -N(R ⁵ ) ₂ or -NHR ⁵ ;

R ⁵ represents -C ₁ -C ₆ alkyl, -C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl;

R ⁶ represents -C ₁ -C ₆ alkyl, -C ₃ -C ₈ cycloalkyl, -C ₄ -C ₈ cycloalkenyl, heterocyclyl, aryl, spirocycloalkyl, spiroheterocyclyl, heteroaryl, halogen, oxo, -(CH ₂ ) _n -OR ⁸ , -C(O)R ^8' , -C(O)OR ⁸ or -C(O)NR ⁸ R ⁹ , wherein each alkyl, cycloalkyl, heterocyclyl, spirocycloalkyl, spiroheterocyclyl, heteroaryl or aryl is optionally substituted with one or more R ¹⁰ ;

R ⁸ and R ⁹ are each independently -H, -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, -C ₄ -C ₈ cycloalkenyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more R ¹⁰ or R ¹¹ ; or

R ⁸ and R ⁹ can be combined with the atom to which they are both attached to form spiroheterocyclyl, heterocyclyl or heteroaryl, wherein the resulting spiroheterocyclyl, heterocyclyl or heteroaryl is optionally substituted with one or more R ¹⁰ or R ¹¹ ;

R ^8' in each instance is independently -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, -C ₄ -C ₈ cycloalkenyl, heterocyclyl , aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more R ¹⁰ or R ¹¹ ; or

R ¹⁰ in each case independently represents, -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, -C ₄ -C ₈ cycloalkenyl, heterocyclyl , heteroaryl, aryl, -OH, halogen, oxo, -NO ₂ , -CN, -NH ₂ , -OC ₁ -C ₆ alkyl, -OC ₃ -C ₆ cycloalkyl, -Oaryl, -Oheteroaryl, -NHC ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl) ₂ , -S(O) ₂ NH(C ₁ -C ₆ alkyl), -S(O) ₂ N(C ₁ -C ₆ alkyl) ₂ , -S (O) ₂ C ₁ -C ₆ alkyl, -C(O)C ₁ -C ₆ alkyl, -C(O)NH ₂ , -C(O)NH(C ₁ -C ₆ alkyl), -C(O) )N(C ₁ -C ₆ alkyl) ₂ , -C(O)OS ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl)SO ₂ C ₁ -C ₆ alkyl, -S(O)(C) ₁ -C ₆ alkyl), -S(O)N(C ₁ -C ₆ alkyl) ₂ or -N(C ₁ -C ₆ alkyl)S(O)(C ₁ -C ₆ alkyl), where each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl or aryl is optionally substituted with one or more -R ¹² ;

wherein any two R ¹⁰ , if present on non-adjacent atoms, can be combined to form a bridged cycloalkyl or heterocyclyl;

wherein any two R ¹⁰ , if present on adjacent atoms, can be combined to form cycloalkyl, heterocyclyl, aryl or heteroaryl; And

R ¹² in each case independently represents -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, -C ₄ -C ₈ cycloalkenyl, heterocyclyl, heteroaryl, aryl, -OH, halogen, oxo, -NO ₂ , -CN, -NH ₂ , -OC ₁ -C ₆ alkyl, -NHC ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl) ₂ , -S(O) ₂ NH(C ₁ -C ₆ alkyl), -S(O) ₂ N(C ₁ -C ₆ alkyl) ₂ , -S(O) ₂ C ₁ -C ₆ alkyl, -C(O )C ₁ -C ₆ alkyl, -C(O)NH ₂ , -C(O)NH(C ₁ -C ₆ alkyl), -C(O)N(C ₁ -C ₆ alkyl) ₂ , -C( O)OS ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl)SO ₂ C ₁ -C ₆ alkyl, -S(O)(C ₁ -C ₆ alkyl), -S(O)N(C ₁ -C ₆ alkyl) ₂ or -N(C ₁ -C ₆ alkyl)S(O)(C ₁ -C ₆ alkyl).

[0005] Preferably, the compounds of formula (I) are a compound of formula (IV):

or a pharmaceutically acceptable salt thereof, where:

n is 0, 1, 2, 3, 4 or 5;

R ¹⁰ in each case independently represents -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, -C ₄ -C ₈ cycloalkenyl, heterocyclyl, heteroaryl, aryl, -OH, halogen, -NO ₂ , -CN, -NH ₂ , -OC ₁ -C ₆ alkyl, -OC ₃ -C ₆ cycloalkyl, -Oaryl, -Oheteroaryl,

-NHC ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl) ₂ , -S(O) ₂ NH(C ₁ -C ₆ alkyl), -S(O) ₂ N(C ₁ -C ₆ alkyl) ) ₂ , -S(O) ₂ C ₁ -C ₆ alkyl, -C(O)C ₁ -C ₆ alkyl, -C(O)NH ₂ , -C(O)NH(C ₁ -C ₆ alkyl) , -C(O)N(C ₁ -C ₆ alkyl) ₂ ,

-C(O)OS ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl)SO ₂ C ₁ -C ₆ alkyl, -S(O)(C ₁ -C ₆ alkyl), -S(O) N(C ₁ -C ₆ alkyl) ₂ or -N(C ₁ -C ₆ alkyl)S(O)(C ₁ -C ₆ alkyl), where each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl or aryl is optionally substituted with one or more -R ¹² ;

wherein any two R ¹⁰ , if present on non-adjacent atoms, can be combined to form a bridged cycloalkyl or heterocyclyl;

wherein any two R ¹⁰ , if present on adjacent atoms, can be combined to form cycloalkyl, heterocyclyl, aryl or heteroaryl; And

R ¹² in each case independently represents -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, -C ₄ -C ₈ cycloalkenyl, heterocyclyl, heteroaryl, aryl, -OH, halogen, oxo, -NO ₂ , -CN, -NH ₂ , -OS ₁ -C ₆ alkyl, -NHC ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl) ₂ , -S(O) ₂ NH(C ₁ -C ₆ alkyl), -S(O) ₂ N(C ₁ -C ₆ alkyl) ₂ , -S(O) ₂ C ₁ -C ₆ alkyl, -C(O )C ₁ -C ₆ alkyl, -C(O)NH ₂ , -C(O)NH(C ₁ -C ₆ alkyl), -C(O)N(C ₁ -C ₆ alkyl) ₂ , -C( O)OS ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl)SO ₂ C ₁ -C ₆ alkyl, -S(O)(C ₁ -C ₆ alkyl), -S(O)N(C ₁ -C ₆ alkyl) ₂ or -N(C ₁ -C ₆ alkyl)S(O)(C ₁ -C ₆ alkyl).

Brief description of graphic materials

[0006] In FIG. 1 shows a table of connections in accordance with various embodiments of the invention.

Detailed description

[0007] The present invention relates to CBP inhibitory compounds, defined herein as compounds having one or more of the following characteristics when tested according to the homogeneous time resolved fluorescence (HTRF) biochemical assay protocol below in Example 5 : (1) IC ₅₀ value for SVR is less than 1 µm; and (2) and IC ₅₀ value for SVR from 0.001 to 1 μm.

Compounds according to the invention

[0008] In one aspect of the present invention, compounds of formula (I) are described:

or pharmaceutically acceptable salts, enantiomers, hydrates, solvates, prodrugs, isomers and tautomers thereof, wherein R ¹ and R ⁶ are as described above.

[0009] In some examples, the compound of formula (I) is a stereoisomer or enantiomer of formula (I) selected from the group consisting of formulas (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):

[0010] The compound of formula (I) may be a stereoisomer thereof (for example, a compound of formula (Ia), (Ib), (Ic), (Id), (I-e), (If), (Ig), (Ih ), (Ii), (Ij), (Ik), (Il), (Im), (In) or (Io), where R ₁ represents methyl and R ₆ represents phenyl, optionally substituted by one or more R ¹⁰ ).

[0011] In some preferred embodiments, the compound of formula (I) is a compound of formula (IV), including stereoisomers 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 R10 is as defined above. 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 pharmaceutically acceptable salts thereof, where n is an integer of 0, 1, 2, 3, 4 or 5 (preferably 0, 1 or 2), and R10 is as defined above.

[0012] In some preferred cases, compounds of formula (IV-a) are provided, including compounds of formula (IV-b) and compounds of formula (IV-c), where n is 0, 1, 2, 3, 4 or 5 and each R ₁₀ independently represents halogen or -OC ₁ -C ₆ alkyl, and where -OC ₁ -C ₆ alkyl is optionally substituted with one or more halogen atoms. For example, in certain compounds of formula (IV-a), n is 0, 1 or 2, and each R ₁₀ is independently halogen or -OC ₁ alkyl, optionally substituted with one or more halogen atoms (eg, fluorine or chlorine). In some compounds of formula (IV-a), n is 2 and each R ₁₀ is independently a halogen (eg fluorine or chlorine), OC ₁ alkyl substituted with 1, 2 or 3 halogen atoms (eg fluorine or chlorine), or methoxy.

[0013] Another aspect of the present invention is to provide pharmaceutical compositions containing therapeutically effective amounts of at least one compound of formula (I). An aspect of the present invention relates to compounds that are or may be inhibitors of one or more bromodomains of the CBP/p300 family (eg, compounds of formula (I)).

[0014] In some embodiments, the compounds of the invention have formula (I):

or a pharmaceutically acceptable salt, enantiomer, hydrate, solvate, isomer or tautomer thereof, wherein:

R ¹ represents -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, -C ₄ -C ₈ cycloalkenyl, heterocyclyl, heteroaryl, aryl, -OR ⁵ , -N(R ⁵ ) ₂ or -NHR ⁵ ;

R ⁵ represents -C ₁ -C ₆ alkyl, -C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl;

R ⁶ represents -C ₁ -C ₆ alkyl, -C ₃ -C ₈ cycloalkyl, -C ₄ -C ₈ cycloalkenyl, heterocyclyl, aryl, spirocycloalkyl, spiroheterocyclyl, heteroaryl, halogen, oxo, -(CH ₂ ) _n -OR ⁸ , -C(O)R ⁸ ', -C(O)OR ⁸ or -C(O)NR ⁸ R ⁹ , wherein each alkyl, cycloalkyl, heterocyclyl, spirocycloalkyl, spiroheterocyclyl, heteroaryl or aryl is optionally substituted with one or more R ¹⁰ ;

R ⁸ and R ⁹ are each independently -H, -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, -C ₄ -C ₈ cycloalkenyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more R ¹⁰ or R ¹¹ ; or

R ⁸ and R ⁹ can be combined with the atom to which they are both attached to form spiroheterocyclyl, heterocyclyl or heteroaryl, wherein the resulting spiroheterocyclyl, heterocyclyl or heteroaryl is optionally substituted with one or more R ¹⁰ or R ¹¹ ;

R ^8' in each instance is independently -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, -C ₄ -C ₈ cycloalkenyl, heterocyclyl , aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more R ¹⁰ or R ¹¹ ; or

R ¹⁰ in each case independently represents -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, -C ₄ -C ₈ cycloalkenyl, heterocyclyl, heteroaryl, aryl, -OH, halogen, oxo, -NO ₂ , -CN, -NH ₂ , -OC ₁ -C ₆ alkyl, -OC ₃ -C ₆ cycloalkyl, -Oaryl, -Oheteroaryl, -NHC ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl) ₂ , -S(O) ₂ NH(C ₁ -C ₆ alkyl), -S(O) ₂ N(C ₁ -C ₆ alkyl) ₂ , -S( O) ₂ C ₁ -C ₆ alkyl, -C(O)C ₁ -C ₆ alkyl, -C(O)NH ₂ , -C(O)NH(C ₁ -C ₆ alkyl), -C(O) N(C ₁ -C ₆ alkyl) ₂ , -C(O)OS ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl)SO ₂ C ₁ -C ₆ alkyl, -S(O)(C ₁ -C ₆ alkyl), -S(O)N(C ₁ -C ₆ alkyl) ₂ or -N(C ₁ -C ₆ alkyl)S(O)(C ₁ -C ₆ alkyl), where each alkyl, alkenyl , alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl or aryl is optionally substituted with one or more -R ¹² ;

wherein any two R ¹⁰ , if present on non-adjacent atoms, can be combined to form a bridged cycloalkyl or heterocyclyl;

wherein any two R ¹⁰ , if present on adjacent atoms, can be combined to form cycloalkyl, heterocyclyl, aryl or heteroaryl; And

R ¹² in each case independently represents -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, -C ₄ -C ₈ cycloalkenyl, heterocyclyl, heteroaryl, aryl, -OH, halogen, oxo, -NO ₂ , -CN, -NH ₂ , -OC ₁ -C ₆ alkyl, -NHC ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl) ₂ , -S(O) ₂ NH(C ₁ -C ₆ alkyl), -S(O) ₂ N(C ₁ -C ₆ alkyl) ₂ , -S(O) ₂ C ₁ -C ₆ alkyl, -C(O )C ₁ -C ₆ alkyl, -C(O)NH ₂ , -C(O)NH(C ₁ -C ₆ alkyl), -C(O)N(C ₁ -C ₆ alkyl) ₂ , -C( O)OS ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl)SO ₂ C ₁ -C ₆ alkyl, -S(O)(C ₁ -C ₆ alkyl), -S(O)N(C ₁ -C ₆ alkyl) ₂ or -N(C ₁ -C ₆ alkyl)S(O)(C ₁ -C ₆ alkyl).

[0015] In some embodiments, the compounds of the invention have formula (I):

or a pharmaceutically acceptable salt, enantiomer, hydrate, solvate, isomer or tautomer thereof, wherein:

R ¹ is -OR ⁵ ;

R ⁵ represents -C ₁ -C ₆ alkyl;

R ⁶ is phenyl, optionally substituted with one or more R ¹⁰ ;

R ¹⁰ in each case independently represents -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, -C ₄ -C ₈ cycloalkenyl, heterocyclyl, heteroaryl, aryl, -OH, halogen, -NO ₂ , -CN, -NH ₂ , -OC ₁ -C ₆ alkyl, -OC ₃ -C ₆ cycloalkyl, -Oaryl, -Oheteroaryl,

-NHC ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl) ₂ , -S(O) ₂ NH(C ₁ -C ₆ alkyl), -S(O) ₂ N(C ₁ -C ₆ alkyl ) ₂ , -S(O) ₂ C ₁ -C ₆ alkyl, -C(O)C ₁ -C ₆ alkyl, -C(O)NH ₂ , -C(O)NH(C ₁ -C ₆ alkyl) , -C(O)N(C ₁ -C ₆ alkyl) ₂ , -C(O)OC ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl)SO ₂ C ₁ -C ₆ alkyl, -S (O)(C ₁ -C ₆ alkyl), -S(O)N(C ₁ -C ₆ alkyl) ₂ or -N(C ₁ -C ₆ alkyl)S(O)(C ₁ -C ₆ alkyl) wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl or aryl is optionally substituted with one or more -R ¹² ;

wherein any two R ¹⁰ , if present on non-adjacent atoms, can be combined to form a bridged cycloalkyl or heterocyclyl;

wherein any two R ¹⁰ , if present on adjacent atoms, can be combined to form cycloalkyl, heterocyclyl, aryl or heteroaryl; And

R ¹² in each case independently represents -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, -C ₄ -C ₈ cycloalkenyl, heterocyclyl, heteroaryl, aryl, -OH, halogen, oxo, -NO ₂ , -CN, -NH ₂ , -OC ₁ -C ₆ alkyl, -NHC ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl) ₂ , -S(O) ₂ NH(C ₁ -C ₆ alkyl), -S(O) ₂ N(C ₁ -C ₆ alkyl) ₂ , -S(O) ₂ C ₁ -C ₆ alkyl, -C(O )C ₁ -C ₆ alkyl, -C(O)NH ₂ , -C(O)NH(C ₁ -C ₆ alkyl), -C(O)N(C ₁ -C ₆ alkyl) ₂ , -C( O)OS ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl)SO ₂ C ₁ -C ₆ alkyl, -S(O)(C ₁ -C ₆ alkyl), -S(O)N(C ₁ -C ₆ alkyl) ₂ or -N(C ₁ -C ₆ alkyl)S(O)(C ₁ -C ₆ alkyl).

[0016] In some embodiments, the compounds of the invention have formula (I):

or a pharmaceutically acceptable salt, enantiomer, hydrate, solvate, isomer or tautomer thereof, wherein:

R ¹ is -OR ⁵ ;

R ⁵ represents -C ₁ -C ₃ alkyl;

R ⁶ is phenyl, optionally substituted with one or more R ¹⁰ ;

R ¹⁰ is in each instance independently halogen, -OC ₁ -C ₆ alkyl, -OC ₃ -C ₆ cycloalkyl, -Oaryl, or -Heteroaryl, wherein each alkyl, cycloalkyl, aryl or heteroaryl is optionally substituted by one or more -R ¹² ;

R ¹² represents halogen.

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

or a pharmaceutically acceptable salt thereof, wherein

R ¹ is -OR ⁵ ;

R ⁵ represents -C ₁ -C ₆ alkyl, -C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl;

R ⁶ represents -C ₃ -C ₈ cycloalkyl, -C ₄ -C ₈ cycloalkenyl, heterocyclyl, heteroaryl, aryl, wherein each cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl or aryl is optionally substituted by one or more -R ¹⁰ ;

R ^6' represents -H or -C ₁ -C ₆ alkyl;

R ⁷ represents -H, halogen, -OH, -CN, -OC ₁ -C ₆ alkyl, -NH ₂ , -NHC ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl) ₂ , -S( O) ₂ NH(C ₁ -C ₆ alkyl), -S(O) ₂ N(C ₁ -C ₆ alkyl) ₂ , -S(O) ₂ C ₁ -C ₆ alkyl, -S(O) ₂ OH , -C(O)C ₁ -C ₆ alkyl, -C(O)NH ₂ , -C(O)NH(C ₁ -C ₆ alkyl), -C(O)N(C ₁ -C ₆ alkyl) ₂ , -C(O)OH, -C(O)OS ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl)SO ₂ C ₁ -C ₆ alkyl, -S(O)(C ₁ -C ₆ alkyl), -S(O)N(C ₁ -C ₆ alkyl) ₂ , -S(O) ₂ NH ₂ , -N(C ₁ -C ₆ alkyl)S(O)(C ₁ -C ₆ alkyl ) or tetrazole;

R ¹⁰ in each case independently represents -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, -C ₄ -C ₈ cycloalkenyl, heterocyclyl, heteroaryl, aryl, -OH, halogen, oxo, -NO ₂ , -CN, -NH ₂ , -OS ₁ -C ₆ alkyl, -OS ₃ -C ₆ cycloalkyl, -Oaryl, -Oheteroaryl, -NHC ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl) ₂ , -S(O) ₂ NH(C ₁ -C ₆ alkyl), -S(O) ₂ N(C ₁ -C ₆ alkyl) ₂ , -S( O) ₂ C ₁ -C ₆ alkyl, -C(O)C ₁ -C ₆ alkyl, -C(O)NH ₂ , -C(O)NH(C ₁ -C ₆ alkyl), -NHC(O) C ₁ -C ₆ alkyl, -C(O)N(C ₁ -C ₆ alkyl) ₂ , -C(O)OC ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl)SO ₂ C ₁ - C ₆ alkyl, -S(O)(C ₁ -C ₆ alkyl), -S(O)N(C ₁ -C ₆ alkyl) ₂ or -N(C ₁ -C ₆ alkyl)S(O)(C ₁ -C ₆ alkyl), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl or aryl is optionally substituted with one or more -R ¹² ;

R ¹² in each case independently represents -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, -C ₄ -C ₈ cycloalkenyl, heterocyclyl, heteroaryl, aryl, -OH, halogen, oxo, -NO ₂ , -CN, -NH ₂ , -OC ₁ -C ₆ alkyl, -NHC ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl) ₂ , -S(O) ₂ NH(C ₁ -C ₆ alkyl), -S(O) ₂ N(C ₁ -C ₆ alkyl) ₂ , -S(O) ₂ C ₁ -C ₆ alkyl, -C(O )C ₁ -C ₆ alkyl, -C(O)NH ₂ , -C(O)NH(C ₁ -C ₆ alkyl), -C(O)N(C ₁ -C ₆ alkyl) ₂ , -C( O)OS ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl)SO ₂ C ₁ -C ₆ alkyl, -S(O)(C ₁ -C ₆ alkyl), -S(O)N(C ₁ -C ₆ alkyl) ₂ or -N(C ₁ -C ₆ alkyl)S(O)(C ₁ -C ₆ alkyl);

m is an integer from 0 to 5; And

q is an integer between 0 and 4.

[0018] Many embodiments of the compounds 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 invention have formula (I):

or a pharmaceutically acceptable salt thereof, where:

R ¹ is -OR ⁵ ;

R ⁵ represents -C ₁ -C ₆ alkyl; And

R ⁶ is phenyl, optionally substituted with one or more R ¹⁰ ;

R ¹⁰ in each case independently represents -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, -C ₄ -C ₈ cycloalkenyl, heterocyclyl, heteroaryl, aryl, -OH, halogen, -NO ₂ , -CN, -NH ₂ , -OC ₁ -C ₆ alkyl, -OC ₃ -C ₆ cycloalkyl, -Oaryl, -Oheteroaryl, -NHC ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl) ₂ , -S(O) ₂ NH(C ₁ -C ₆ alkyl), -S(O) ₂ N(C ₁ -C ₆ alkyl) ₂ , -S(O) ₂ C ₁ -C ₆ alkyl, -C(O)C ₁ -C ₆ alkyl, -C(O)NH ₂ , -C(O)NH(C ₁ -C ₆ alkyl), -NHC(O)C ₁ -C ₆ alkyl, -C(O)N(C ₁ -C ₆ alkyl) ₂ , -C(O)OS ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl)SO ₂ C ₁ -C ₆ alkyl, -S(O)(C ₁ -C ₆ alkyl), -S(O)N(C ₁ -C ₆ alkyl) ₂ or -N(C ₁ -C ₆ alkyl)S(O)(C ₁ - C ₆ alkyl), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl or aryl is optionally substituted with one or more -R ¹² ; And

R ¹² in each case independently represents -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, -C ₄ -C ₈ cycloalkenyl, heterocyclyl, heteroaryl, aryl, -OH, halogen, oxo, -NO ₂ , -CN, -NH ₂ , -OC ₁ -C ₆ alkyl, -NHC ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl) ₂ , -S(O) ₂ NH(C ₁ -C ₆ alkyl), -S(O) ₂ N(C ₁ -C ₆ alkyl) ₂ , -S(O) ₂ C ₁ -C ₆ alkyl, -C(O) )C ₁ -C ₆ alkyl, -C(O)NH ₂ , -C(O)NH(C ₁ -C ₆ alkyl), -C(O)N(C ₁ -C ₆ alkyl) ₂ , -C( O)OS ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl)SO ₂ C ₁ -C ₆ alkyl, -S(O)(C ₁ -C ₆ alkyl), -S(O)N(C ₁ -C ₆ alkyl) ₂ or -N(C ₁ -C ₆ alkyl)S(O)(C ₁ -C ₆ alkyl).

[0020] In some embodiments, the compounds of the invention have formula (I):

or a pharmaceutically acceptable salt thereof, where:

R ¹ is -OR ⁵ ;

R ⁵ represents -C ₁ -C ₃ alkyl;

R ⁶ is phenyl, optionally substituted with one or more R ¹⁰ ;

R ¹⁰ in each instance is independently halogen, -OC ₁ -C ₆ alkyl, -OC ₃ -C ₆ cycloalkyl, -Oaryl or -Heteroaryl, wherein each alkyl, cycloalkyl, aryl or heteroaryl is optionally substituted by one or more -R ¹² ; And

R ¹² represents halogen.

[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 -C ₁ -C ₃ alkyl. In some embodiments, R ⁵ is methyl.

[0023] In some embodiments, R ¹⁰ is each independently halogen or -OC ₁ -C ₆ alkyl, wherein -OC ₁ -C ₆ alkyl is optionally substituted with halogen.

[0024] In some embodiments, R ₁ is -OR ⁵ .

[0025] In some embodiments, R ¹ is -OR ⁵ , -N(R ⁵ ) ₂ , -NHR ⁵ or -C ₁ -C ₆ alkyl. In some embodiments, R ¹ is -OR ⁵ . In some embodiments, R ¹ is -OR ⁵ or -C ₁ -C ₆ alkyl. In some embodiments, R ⁵ in R ¹ is -C ₁ -C ₆ alkyl. In some embodiments, R ¹ is -OR ⁵ ; and R ⁵ represents -C ₁ -C ₆ alkyl. In some embodiments, R ¹ is -OCH ₃ . In some embodiments, R ¹ is -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, -C ₄ -C ₈ cycloalkenyl, heterocyclyl, heteroaryl, or aryl. In some embodiments, R ¹ is -C ₁ -C ₆ alkyl. In some embodiments, R ¹ is methyl, ethyl or propyl. In some embodiments, R ¹ is methyl. In some embodiments, R ¹ is C ₂ -C ₆ alkenyl. In some embodiments, R ¹ is aryl.

[0026] In some embodiments, R ⁵ is -C ₁ -C ₆ alkyl, -C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl. In some embodiments, R ⁵ is -C ₁ -C ₆ alkyl. In some embodiments, R ⁵ is -C ₁ -C ₃ alkyl. In some embodiments, R ⁵ is methyl. In some embodiments, R ⁵ is ethyl.

[0027] In some embodiments, R ⁶ is -C ₁ -C ₆ alkyl, -C ₃ -C ₈ cycloalkyl, -C ₄ -C ₈ cycloalkenyl, heterocyclyl, or aryl. In some embodiments, R ⁶ is -C ₁ -C ₆ 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, R ⁶ is -C ₁ -C ₆ alkyl, -C ₃ -C ₈ cycloalkyl, -C ₄ -C ₈ cycloalkenyl, heterocyclyl, aryl, spirocycloalkyl, spiroheterocyclyl, heteroaryl, halogen, oxo, -(CH ₂ ) _n -OR ⁸ , -C(O)R ^8' , -C(O)OR ⁸ or -C(O)NR ⁸ R ⁹ , wherein each alkyl, cycloalkyl, heterocyclyl, spirocycloalkyl, spiroheterocyclyl, heteroaryl or aryl is optionally substituted one or more R ¹⁰ .

[0028] In some embodiments, R ⁸ is -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, -C ₄ -C ₈ cycloalkenyl , heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more R ¹⁰ or R ¹¹ . In some embodiments, R ⁸ is -H. In some embodiments, R ⁸ is -C ₁ -C ₆ alkyl, -C ₃ -C ₈ cycloalkyl, -C ₄ -C ₈ cycloalkenyl, heterocyclyl, or aryl, wherein R ⁸ is optionally substituted with R ¹⁰ or R ¹¹ . In some embodiments, R ⁸ is -C ₁ -C ₆ alkyl, optionally substituted with one or more R ¹⁰ or R ¹¹ . In some embodiments, R ⁸ is aryl, optionally substituted with one or more R ¹⁰ or R ¹¹ . In some embodiments, R ⁸ is heteroaryl, optionally substituted with one or more R ¹⁰ or R ¹¹ .

[0029] In some embodiments, R ^8' is -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, -C ₄ -C ₈ cycloalkenyl, heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more R ¹⁰ or R ¹¹ . In some embodiments, R ^8' is -C ₁ -C ₆ alkyl, -C ₃ -C ₈ cycloalkyl,

-C ₄ -C ₈ cycloalkenyl, heterocyclyl or aryl, where R ^8' is optionally substituted with R ¹⁰ or R ¹¹ . In some embodiments, R ^8' is -C ₁ -C ₆ alkyl, optionally substituted with one or more R ¹⁰ or R ¹¹ . In some embodiments, R ^8' is aryl, optionally substituted with one or more R ¹⁰ or R ¹¹ . In some embodiments, R ^8' is heteroaryl, optionally substituted with one or more R ¹⁰ or R ¹¹ .

[0030] In some embodiments, R ⁹ is -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, -C ₄ -C ₈ cycloalkenyl , heterocyclyl, aryl, heteroaryl, wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, aryl or heteroaryl is optionally substituted with one or more R ¹⁰ or R ¹¹ . In some embodiments, R ⁹ is -H. In some embodiments, R ⁹ is -C ₁ -C ₆ alkyl, -C ₃ -C ₈ cycloalkyl, -C ₄ -C ₈ cycloalkenyl, heterocyclyl, or aryl, wherein R ⁹ is optionally substituted with R ¹⁰ or R ¹¹ . In some embodiments, R ⁹ is -C ₁ -C ₆ 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 ¹⁰ is -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, -C ₄ -C ₈ cycloalkenyl , heterocyclyl, heteroaryl, aryl, -OH, halogen, oxo, -NO ₂ , -CN, -NH ₂ , -OC ₁ -C ₆ alkyl, -NHC ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl ) ₂ , -S(O) ₂ NH(C ₁ -C ₆ alkyl), -S(O) ₂ N(C ₁ -C ₆ alkyl) ₂ , -S(O) ₂ C ₁ -C ₆ alkyl, - C(O)C ₁ -C ₆ alkyl, -C(O)NH ₂ , -C(O)NH(C ₁ -C ₆ alkyl), -C(O)N(C ₁ -C ₆ alkyl) ₂ , -C(O)OS ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl)SO ₂ C ₁ -C ₆ alkyl, -S(O)(C ₁ -C ₆ alkyl), -S(O) N(C ₁ -C ₆ alkyl) ₂ or -N(C ₁ -C ₆ alkyl)S(O)(C ₁ -C ₆ alkyl), where each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl or aryl is optionally substituted with one or more -R ¹² . In some embodiments, R ¹⁰ is -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, -C ₄ -C ₈ cycloalkenyl, heterocyclyl, heteroaryl, aryl, where R ¹⁰ is substituted with R ¹² . In some embodiments, R ¹⁰ is halogen. In some embodiments, R ¹⁰ is, in each instance, independently -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, -C ₄ -C ₈ cycloalkenyl, heterocyclyl, heteroaryl, aryl, -OH, halogen, oxo, -NO ₂ , -CN, -NH ₂ , -OC ₁ -C ₆ alkyl, -OC ₃ -C ₆ cycloalkyl, Oaryl, Oheteroaryl, -NHC ₁ - C ₆ alkyl, -N(C ₁ -C ₆ alkyl) ₂ , -S(O) ₂ NH(C ₁ -C ₆ alkyl), -S(O) ₂ N(C ₁ -C ₆ alkyl) ₂ , - S(O) ₂ C ₁ -C ₆ alkyl, -C(O)C ₁ -C ₆ alkyl, -C(O)NH ₂ , -C(O)NH(C ₁ -C ₆ alkyl), -C( O)N(C ₁ -C ₆ alkyl) ₂ , -C(O)OC ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl)SO ₂ C ₁ -C ₆ alkyl, -S(O)( C ₁ -C ₆ alkyl), -S(O)N(C ₁ -C ₆ alkyl) ₂ or -N(C ₁ -C ₆ alkyl)S(O)(C ₁ -C ₆ alkyl), where each alkyl , alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl, or aryl is optionally substituted with one or more -R ¹² ; wherein any two R ¹⁰ , if present on non-adjacent atoms, can be combined to form a bridged cycloalkyl or heterocyclyl; where any two R ¹⁰ , if present on adjacent atoms, can be combined to form cycloalkyl, heterocyclyl, aryl or heteroaryl. In some embodiments, R ¹⁰ is each independently halogen or -OC ₁ -C ₆ alkyl, -OC ₃ -C ₆ cycloalkyl, -Oaryl, -Oheteroaryl, wherein each alkyl, cycloalkyl, aryl or heteroaryl is optionally substituted by one or more -R ¹² .

[0032] In some embodiments, R ¹¹ is -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, -C ₄ -C ₈ cycloalkenyl , heterocyclyl, heteroaryl, aryl, -OH, halogen, oxo, -NO ₂ , -CN, -NH ₂ , -OC ₁ -C ₆ alkyl, -NHC ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl ) ₂ , -S(O) ₂ NH(C ₁ -C ₆ alkyl), -S(O) ₂ N(C ₁ -C ₆ alkyl) ₂ , -S(O) ₂ C ₁ -C ₆ alkyl, - C(O)C ₁ -C ₆ alkyl, -C(O)NH ₂ , -C(O)NH(C ₁ -C ₆ alkyl), -C(O)N(C ₁ -C ₆ alkyl) ₂ , -C(O)OS ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl)SO ₂ C ₁ -C ₆ alkyl, -S(O)(C ₁ -C ₆ alkyl), -S(O) N(C ₁ -C ₆ alkyl) ₂ or -N(C ₁ -C ₆ alkyl)S(O)(C ₁ -C ₆ alkyl), where each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl or aryl is optionally substituted with one or more -R ¹² . In some embodiments, R ¹¹ is -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, -C ₄ -C ₈ cycloalkenyl, heterocyclyl, heteroaryl, aryl, where R ¹¹ is substituted with R ¹² . In some embodiments, R ¹¹ is halogen.

[0033] In some embodiments, R ¹² is -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, -C ₄ -C ₈ cycloalkenyl , heterocyclyl, heteroaryl, aryl, -OH, halogen, oxo, -NO ₂ , -CN, -NH ₂ , -OC ₁ -C ₆ alkyl, -NHC ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl ) ₂ , -S(O) ₂ NH(C ₁ -C ₆ alkyl), -S(O) ₂ N(C ₁ -C ₆ alkyl) ₂ , -S(O) ₂ C ₁ -C ₆ alkyl, - C(O)C ₁ -C ₆ alkyl, -C(O)NH ₂ , -C(O)NH(C ₁ -C ₆ alkyl), -C(O)N(C ₁ -C ₆ alkyl) ₂ , -C(O)OS ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl)SO ₂ C ₁ -C ₆ alkyl, -S(O)(C ₁ -C ₆ alkyl), -S(O) N(C ₁ -C ₆ alkyl) ₂ or -N(C ₁ -C ₆ alkyl)S(O)(C ₁ -C ₆ 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 -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, -C ₄ -C ₈ cycloalkenyl , heterocycloalkyl, heteroaryl or aryl.

[0036] Preferably, the compound is a CBP-inhibiting compound of formula (I), wherein R ₁ is -OCH ₃ . In some embodiments, the CBP inhibitory compound of formula (I) contains R ₁ representing -OCH ₃ and R ₆ representing C ₆ aryl (phenyl), optionally substituted by one or more R ₁₀ . In some embodiments, the CBP inhibitory compound of formula (I) contains R ₁ being -OCH ₃ and R ₆ being C ₆ aryl (phenyl), optionally substituted with one or more R ₁₀ selected from the group consisting of halogen (eg fluorine) and methoxy, where methoxy is optionally substituted with one or more R ₁₂ . In some embodiments, the CBP inhibitory compound of formula (I) contains R ₁ being -OCH ₃ and R ₆ being C ₆ aryl (phenyl) optionally substituted by one or more R ₁₀ selected from the group consisting of halogen (eg fluorine) and methoxy, where methoxy is optionally substituted with one or more R ₁₂ and R ₁₂ is halogen (preferably fluorine).

[0037] In some embodiments, the compound of the invention is the compound selected in FIG. 1, or a pharmaceutically acceptable salt thereof.

Method of synthesis of compounds

[0038] The compounds of the present invention can be prepared by a variety of methods, including standard chemical methods. Suitable synthesis methods are shown in the examples below.

[0039] The compounds of the present invention, that is, the compounds of formula (I) or a pharmaceutically acceptable salt, enantiomer, hydrate, solvate, prodrug, isomer or tautomer thereof, can be prepared by methods known in the field of organic synthesis, as indicated in part in the following schemes synthesis. It should be understood that in the schemes described below, protecting groups for sensitive or reactive groups are used where necessary, in accordance with general principles or chemical structure. Protecting groups are used according to standard methods of organic synthesis (T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999). These groups are removed at a convenient stage in the synthesis of the compound using methods that are apparent to those skilled in the art. The selection processes, as well as the reaction conditions and the order in which they are carried out, must be consistent with the preparation of the compounds of formula (I).

[0040] Those skilled in the art will understand whether a stereocenter exists in compounds of formula (I). Accordingly, the present invention includes both possible stereoisomers (unless otherwise indicated in the synthesis) and includes not only racemic compounds, but also individual enantiomers and/or diastereomers. When a compound is desired as a single enantiomer or diastereomer, it can be prepared by stereospecific synthesis or resolution of the final product or any suitable intermediate. The separation of the final product, intermediate or starting material can be influenced by any suitable method known in the art. See, for example, "Stereochemistry of Organic Compounds" by E.L. Eliel, S.H. Wilen and L.N. Mander (Wiley-Interscience, 1994).

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

[0042] The invention also includes pharmaceutical compositions containing one or more CBP inhibitory compounds as described herein, or a pharmaceutically acceptable salt and a pharmaceutically acceptable excipient thereof. In some embodiments, the pharmaceutical compositions described herein may be provided in unit dosage form (eg, capsules, tablets, etc.). Pharmaceutical compositions containing a compound of formula (I) may be provided in an oral dosage form such as a capsule or tablet. The oral dosage form optionally contains one or more fillers, disintegrants, lubricants, lubricants, release agents and/or antistatic agents. In some embodiments, the oral dosage form is prepared by dry mixing. In some embodiments, the oral dosage form is a tablet that is prepared by dry granulation. For example, the CBP inhibitory compound of the present invention can be dosed from 1 mg to 1 g at a therapeutically effective frequency. The pharmaceutical compositions can be administered orally in any orally acceptable dosage form. Accordingly, a patient and/or subject may be selected for treatment with a compound described herein by first evaluating the patient and/or subject to determine whether the subject requires SBP inhibition, and if the subject is determined to require SBP inhibition, and then administering to the subject the composition described herein.

[0043] The pharmaceutical composition may contain one or more compounds of formula (I), including any compound disclosed in the examples below, as provided herein. In one example, the active pharmaceutical ingredient (API) may contain about 90% or more of a compound of formula (I) and up to about 10% (preferably up to about 5%, most preferably up to about 2.5%, including about 1.5 %) of the compound of formula (I). Oral dosage forms containing a compound of formula (I) can be prepared as a drug capsule (DiC) encapsulated by simple granular dry mixing and a lipid-based solution in a hard shell capsule. The capsules may contain pharmaceutically acceptable excipients, and the encapsulated capsules may be packaged in induction sealed HDPE bottles.

EXAMPLES

Definitions used in the following diagrams and elsewhere in this document:

ACN - acetonitrile

Ac ₂ O - 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 periodinan

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

ESI (ES) - electrospray ionization

Et ₃ N - triethylamine

EtOAc - ethyl acetate

EtOH - ethanol

FA - formic acid

KFKh (FCC) - flash column chromatography

h. - hours

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) ₂ NEt - N,N-diisopropylethylamine

l - liter

LC/MS (LC/MS) - liquid chromatography/mass spectrometry

LDA - lithium diisopropylamine

K ₂ CO ₃ - potassium carbonate

MeOH - methanol

ml - milliliter

mmol - millimole

mg - milligram

MHz - megahertz

MS (MS) - mass spectrometry

m/z - mass to charge ratio

NBSN - bromosuccinimide

nm - nanometer

NMM4 - methylmorpholine

NMR - nuclear magnetic resonance

Pd ₂ (dba) ₃ - tris(dibenzylideneacetone)dipalladium

Ph ₃ P - triphenylphosphine

PhCHO benzaldehyde

PhMe - toluene

ppm - parts per million

room temperature

RT - retention time

SFC - supercritical liquid chromatography

STAB - sodium triacetoxyborohydride

p-TSA - para-toluenesulfonic anhydride

p-TsOH - para-toluenesulfonic acid

TFA - trifluoroacetic acid

TFAA - trifluoroacetic anhydride

THF - tetrahydrofuran

UV - ultraviolet radiation

XPhos - 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

Materials

[0044] 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 using microwave irradiation were carried out on a Biotage Initiator EXP EU instrument.

[0045] Unless otherwise noted, mass-triggered HPLC purification and/or purity and low-resolution mass spectral data were measured using the following: (1) an ultra-performance liquid chromatography (UPLC) system from Waters Acquity ( Waters Acquity UPLC with sampling device and Waters Micromass ZQ mass spectrometer with UV detection at 220 nm and low resonance positive electrospray ionization (ESI) mode (column: Acquity UPLC WEN C18, 1.7 µm, 2.1x50 mm; gradient: 5-100% solvent B (95/5/0.09%: acetonitrile/water/formic acid) in solvent A (95/5/0.1%: 10 mM formate ammonium/acetonitrile/formic acid) for 2.2 minutes, then 100-5% solvent B in solvent A for 0.01 minutes, then holding at 5% solvent B in solvent A for 0.29 minutes. ), or (2) Waters HT2790 Alliance high-performance liquid chromatography (HPLC) systems (Waters 996 PDA and Waters ZQ single quadrupole mass spectrometer) with UV detection at 220 nm and 254 nm and low-resonance electrospray ionization mode (positive/ negative) (ESI) (column: XBridge Phenyl or C18, 5 µm, 4.6×50 mm; gradient: 5-95% solvent B (95% methanol/5% water with 0.1% formic acid) in solvent A (95% water/5% methanol with 0.1% formic acid) over 2.5 min. , then holding at 95% solvent B in solvent A for 1 min. (purity and low resolution MS only).

General methods for obtaining compounds

[0046] This document describes methods for synthesizing the compounds of the present invention. The compounds of the present invention can be synthesized according to the synthesis schemes given below. Preparation of the starting material for Schemes 1 and 2 (“Intermediate 1”) is described below. Preparation of the starting material for Schemes 3 and 4 can be found in Example 1 of Part A of US Pat. No. 4,404,207.

[0047] Unless otherwise indicated, the substituents R ² and R ³ in the following reaction schemes are defined as follows, and R ⁶ is defined in the specification and claims.

[0048] Scheme 1 presents methods applicable to the synthesis of compounds of formula I.

Scheme 1

[0049] Scheme 2 presents methods applicable to the synthesis of compounds of formula I.

Scheme 2

[0050] Alternatively, Scheme 3 presents methods useful for the synthesis of certain compounds of formula I.

Scheme 3

[0051] Alternatively, Scheme 4 presents methods useful for the synthesis of certain compounds of formula I.

Scheme 4

Preparation of intermediate 1: methyl (S)-5-amino-6-bromo-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate

Step 1. 8-Chloro-5-methoxy-2-methylquinoline hydrochloride

[0052] In a 4-neck, 5 L round bottom flask that was purged with nitrogen and maintained under an inert nitrogen atmosphere, 2-chloro-5-methoxyaniline (250 g, 1.59 mol) was dissolved in 1-butanol (1200 mL). Hydrochloric acid (aq, 36.5%, 526.5 ml) and chloranil (456.5 g, 1.86 mol) were then added. The resulting mixture was stirred for 1 hour at 100°C under a nitrogen atmosphere. A solution of (E)-but-2-enal (169 ml, 2.06 mol) in 1-butanol (300 ml) was then added dropwise. The resulting solution was stirred for 1 hour at 100°C in a nitrogen atmosphere. The oil bath was cooled to 70°C and tetrahydrofuran (1500 ml) was added. Then the resulting mixture was stirred for 1 hour at 70°C. The reaction mixture was cooled to 0°C and the solids were filtered. The solids were washed with tetrahydrofuran (3 L) at 0°C. This provided the title compound (300 g, 77%) as a yellow solid. MS: (IER, m/z): 208, 210 [M+H] ⁺ . It was then dried in an oven to obtain 8-chloro-5-methoxy-2-methylquinoline hydrochloride (83.0 g, 74%) as a yellow solid. MS (IER, m/z): 208 [M+H] ⁺ .

Step 2. 5-Methoxy-2-methylquinoline

[0053] In a 1000 mL 3-neck round bottom flask, 8-chloro-5-methoxy-2-methylquinoline hydrochloride (50 g, 204.82 mmol) was dissolved in methanol (300 mL). Sodium hydroxide (3 M, 205 ml) and 10% palladium on carbon (25 g) were then added. Hydrogen (gas) was loaded into the reaction mixture. The reaction mixture was stirred under a hydrogen atmosphere for 3 hours at room temperature. The reaction mixture was purged with nitrogen and the solids were filtered over celite. The filtered solution was concentrated in vacuo. The residue was purified by FCC, eluting with ethyl acetate/petroleum ether (1:5). This provided the title compound (28.5 g, 80%) as a yellow oil. MS: (IER, m/z): 174 [M+H] ⁺ .

Step 3. (2S)-5-Methoxy-2-methyl-1,2,3,4-tetrahydroquinoline

[0054] In a 30 mL (50 atm) high pressure reaction vessel, 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-methylbenzenesulfonamidate) was added κN][(1,2,3,4,5,6-η)-1,2,3,4,5,6-hexamethylbenzene](1,1,1-trifluoromethanesulfonato-κO)-ruthenium, prepared according to with procedure in J. Am. Chem. Soc. 2011, 133, 9878-9891), (150 mg, 0.23 mmol). Hydrogen was introduced into the above. The resulting solution was stirred for 6 hours at room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by FCC, eluting with ethyl acetate/petroleum ether (1:4). This provided the title compound (3.0 g, 73%) as a yellow oil. MS: (IER, 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). Pyridine (23.6 g, 298.36 mmol) was then added followed by methyl carbonochloridate (9.4 g, 99.47 mmol). The resulting solution was stirred for 1 hour at room temperature. 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 in vacuo. The residue was purified by FCC, eluting with ethyl acetate/petroleum ether (1:3). This provided the title compound (21 g, 89%) as a yellow oil. MS: (IER, m/z): 236 [M+H] ⁺ .

Step 5. Methyl (S)-5-hydroxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate

[0056] In a 500 mL 3-neck 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). Boron tribromide (150 ml, 0.15 mol, 1 M in CH ₂ Cl ₂ ) was then added. The resulting solution was stirred for 1 hour at room temperature. The reaction mixture was then quenched by adding 300 ml of water. The resulting mixture was extracted with 3×300 ml dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by FCC, eluting with ethyl acetate/petroleum ether (1:2). This provided the title compound (13.5 g, 68%) as a yellow solid. MS: (IER, 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 bottom 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). Pyridine (14.3 g, 180.78 mmol) and trifluoromethanesulfonic anhydride (10.2 g, 36.15 mmol) were then added. The resulting solution was stirred for 1 hour at room temperature. The resulting mixture was washed with 3×100 ml of water. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by FCC, eluting with ethyl acetate/petroleum ether (1:3). This provided the title compound (5.5 g, 86%) as a yellow oil. MS: (IER, 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 bottom flask that was purged with nitrogen and maintained under an inert atmosphere of nitrogen, 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). Diphenylmethanimine (17.9 g, 97.78 mmol), tris(dibenzylideneacetone)dipalladium-chloroform adduct (1.19 g, 1.30 mmol), (+/-)-2,2'-bis(diphenylphosphino) was then added -1,1'-binaphthyl (2.43 g, 3.90 mmol) and cesium carbonate (42.4 g, 130.13 mmol). The resulting solution was stirred overnight at 100°C under a nitrogen atmosphere. The reaction mixture was cooled and the solids were filtered off. The residue was purified by FCC, eluting with ethyl acetate/petroleum ether (1:3). This provided the title compound (33 g, 80%) as a yellow oil. MS: (IER, 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 bottom flask, methyl (2S)-5-[(diphenylmethylidene)amino]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate (33 g, 85.93 mmol) dissolved in methanol (200 ml). Sodium acetate (17 g, 207.23 mmol) and hydroxylamine hydrochloride (12.3 g, 177.00 mmol) were then added. The resulting solution was stirred for 2 hours at room temperature. Solids were filtered off. The resulting mixture was concentrated in vacuo. The residue was purified by FCC, eluting with ethyl acetate/petroleum ether (1:2). This provided the title compound (12.5 g, 66%) as a yellow solid. MS: (IER, 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 3-neck round bottom 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). N-bromosuccinimide (730 mg, 4.10 mmol) was then added. The resulting solution was stirred for 30 minutes. at room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by FCC, eluting with ethyl acetate/petroleum ether (1:1). This provided the title compound (1.1 g, 90%) as a yellow solid. MS: (IER, m/z): 299, 301 [M+H] ⁺ .

H-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 invention is further illustrated by the following examples and synthesis schemes, which should not be construed as limiting the scope or spirit of the present invention to the specific procedures described herein. It should be understood that the examples are presented to illustrate certain embodiments and are not intended to limit the scope of the invention. In addition, it should be understood that resort to various other embodiments, modifications and equivalents thereof may be suggested by those skilled in the art without departing from the spirit of the present invention and/or the scope of the appended claims.

[0062] Synthesis schemes are provided for the synthesis of certain compounds disclosed herein. The process and results of BET family bromodomain inhibition testing assays 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

Stage 1. 6-Fluoro-2-methyl-5-nitroquinoline

[0063] A solution of trifluoromethanesulfonic acid (82.0 ml, 0.923 mol) in HNO ₃ (19.6 ml, 0.437 mol) was stirred for 20 minutes. at 0°C. This was followed by the addition of 6-fluoro-2-methylquinoline (50.0 g, 0.310 mol) in dichloromethane (300 ml) at 0°C. The resulting mixture was stirred for 15 hours at room temperature (25°C). The reaction mixture was diluted with water (300 ml). The pH of the solution was adjusted to 8 using 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 in vacuo. The residue was purified by silica gel chromatography (eluting with ethyl acetate/petroleum ether 1:4) to give 6-fluoro-2-methyl-5-nitroquinoline as a light yellow solid (60.0 g, 94%). LC-MS (ESI, m/z): 207 [M+H] ⁺ .

Step 2. (2S)-6-Fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline

[0064] A solution of (S)-(-)-MeO-BIPHEP (1.03 g, 1.77 mmol), chloro(1,5-cyclooctadiene)iridium(I) dimer (538 mg, 0.80 mmol) in toluene (100 ml) was stirred for 30 minutes. at room temperature (25°C) in a nitrogen atmosphere. This was followed by the addition of I ₂ (410 mg, 1.62 mmol) and 6-fluoro-2-methyl-5-nitroquinoline (33.0 g, 0.160 mol) in toluene (100 ml). The resulting mixture was stirred for 20 hours at room temperature (25°C) in a hydrogen atmosphere (50 atm.). The resulting mixture was concentrated in vacuo and purified by silica gel chromatography (eluting with ethyl acetate/petroleum ether 1:1) to give the crude product (35.0 g). The crude product was dissolved in ethyl acetate (230 ml), then D-camphorsulfonic acid (36.9 g, 0.158 mol) was added. The resulting solution was stirred for 1 hour at 60°C and then cooled to room temperature. The solids were collected by filtration and washed with ethyl acetate (120 ml). The solids were dissolved in water (50 ml). The pH of the solution was adjusted to 8 using 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 in vacuo to give (2S)-6-fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline as a red solid (25.5 g, 76%). LC-MS (ESI, 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 for 3 hours at room temperature (25°C). The reaction mixture was washed with 1 N. hydrogen chloride (aq., 2×70 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give methyl (2S)-6-fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate as yellow solids (29.8 g, 92%). LC-MS (ESI, 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) were stirred in for 15 hours at 90°C and then cooled to room temperature. The reaction mixture 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 ethyl acetate/petroleum ether 1:1) to give methyl-(2S)-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino] -2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate as red oil (32 g, 72%). LC-MS (ESI, 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] 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), NH ₄ Cl (24.3 g, 454.28 mmol) and Fe (powder, 64.3 g, 1.15 mol) in tetrahydrofuran (300 ml), ethanol (300 ml), water (100 ml) was stirred for 1 hour at 80°C and then cooled to room temperature. Solids were filtered out 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 in vacuo 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%). LC-MS (ESI, 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] 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 for 15 hours at room temperature (25°C). The resulting solution was diluted with water (30 ml) and extracted with ethyl acetate (3×50 ml). The organic layers were combined and washed with brine (2×25 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 ethyl acetate/petroleum ether 1:1) 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%). LC-MS (ESI, 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 for 15 hours at 40°C and then cooled to room temperature. The reaction mixture was diluted with water (10 ml). The pH of the solution was adjusted to 8 using sodium bicarbonate (saturated aqueous solution). The resulting solution was extracted with ethyl acetate (3×15 ml). The organic layers were combined and dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography (eluting with ethyl acetate/petroleum ether 1:1) 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 %). LC-MS (ESI, 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; (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

[0069] 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 for 15 hours at 25°C. The resulting mixture was concentrated in vacuo. The crude product was purified by preparative HPLC (column: XBridge Shield RP18 OBD column, 5 µm, 19 x 150 mm; mobile phase, A: water (containing 10 mmol/l NH ₄ HCO ₃ ) and B: ACN (10% to 37% within 12 min.); detector: UV, 254 nm). 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%) and (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 H-NMR (CD ₃ OD, 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). LC-MS (ESI, m/z): 512 [M+H] ⁺ .

Second eluted isomer (501): ¹ H-NMR (CD ₃ OD, 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) . LC-MS (ESI, m/z): 512 [M+H] ⁺ .

[0070] The compounds listed in FIG. 1 were prepared using standard chemical manipulations and procedures similar to those described herein. In fig. 1 "eluted isomer" refers to the order in which a compound is 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)

Step 1. 2-(5-Fluoro-2-methoxyphenyl)-2-[(trimethylsilyl)oxy]acetonitrile

[0071] A solution of ZnI ₂ (1.6 mg, 0.01 mmol), 5-fluoro-2-methoxybenzaldehyde (1.54 g, 9.99 mmol) in trimethylsilanecarbonitrile (1.5 ml, 11.25 mmol) was stirred for 1 hour at room temperature. The resulting mixture was concentrated in vacuo. The resulting crude product was purified by silica gel chromatography (eluting with ethyl acetate/petroleum ether 1:1) to give 2-(5-fluoro-2-methoxyphenyl)-2-[(trimethylsilyl)oxy]acetonitrile as a white solid substances (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, 12M) was stirred for 1 hour at 25°C and then stirred for 2 hours at 70°C. The reaction mixture was cooled and concentrated in vacuo. The crude product was purified by reverse phase chromatography (column: C18; mobile phase, A: water (containing 0.05% TFA) and B: ACN (5% to 20% over 30 min); detector: UV, 254 nm) to give 2-(5-fluoro-2-methoxyphenyl)-2-hydroxyacetic acid as a white solid (1.10 g, 93%).

Stage 3. 6-Fluoro-2-methyl-5-nitroquinoline

[0073] A solution of trifluoromethanesulfonic acid (82.0 ml, 0.923 mol) in HNO ₃ (19.6 ml, 0.437 mol) was stirred for 20 minutes. at 0°C. This was followed by the addition of 6-fluoro-2-methylquinoline (50.0 g, 0.310 mol) in dichloromethane (300 ml) at 0°C. The resulting mixture was stirred for 15 hours at room temperature (25°C). The reaction mixture was diluted with water (300 ml). The pH of the solution was adjusted to 8 using 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 in vacuo. The residue was purified by silica gel chromatography (eluting with ethyl acetate/petroleum ether 1:4) to give 6-fluoro-2-methyl-5-nitroquinoline as a light yellow solid (60.0 g, 94%). LC-MS (ESI, m/z): 207 [M+H] ⁺ .

Step 4. (2S)-6-Fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline

[0074] A solution of (S)-(-)-MeO-BIPHEP (1.03 g, 1.77 mmol), chloro(1,5-cyclooctadiene)iridium(I) dimer (538 mg, 0.80 mmol) in toluene (100 ml) was stirred for 30 minutes. at room temperature (25°C) in a nitrogen atmosphere. This was followed by the addition of I ₂ (410 mg, 1.62 mmol), 6-fluoro-2-methyl-5-nitroquinoline (33.0 g, 0.160 mol) in toluene (100 ml). The resulting mixture was stirred for 20 hours at room temperature (25°C) in a hydrogen atmosphere (50 atm.). The resulting mixture was concentrated in vacuo and purified by silica gel chromatography (eluting with ethyl acetate/petroleum ether 1:1) to give the crude product (35.0 g). The crude product was dissolved in ethyl acetate (230 ml), then D-camphorsulfonic acid (36.9 g, 0.158 mol) was added. The resulting solution was stirred for 1 hour at 60°C and then cooled to room temperature. The solids were collected by filtration and washed with ethyl acetate (120 ml). The solids were dissolved in water (50 ml). The pH of the solution was adjusted to 8 using 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 in vacuo to give (2S)-6-fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline as a red solid (25.5 g, 76%). LC-MS (ESI, m/z): 211 [M+H] ⁺ .

Step 5. Methyl (2S)-6-fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate

[0075] 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), Methyl chloroformate (18.7 ml, 0.242 mol) in dichloromethane (150 ml) was stirred for 3 hours at room temperature (25°C). 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 in vacuo to give methyl (2S)-6-fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate as yellow solids (29.8 g, 92%). LC-MS (ESI, 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] 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), methyl (1R,3R)-3-aminocyclohexane-1-carboxylate (25.6 g, 162.84 mmol) in DMSO (270 ml) stirred for 15 hours at 90°C and then cooled to room temperature. The reaction mixture 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 ethyl acetate/petroleum ether 1:1) to give methyl-(2S)-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino] -2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate as red oil (32 g, 72%). LC-MS (ESI, m/z): 406 [M+H] ⁺ .

Step 7. Methyl-(2S)-5-amino-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate

[0077] 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), NH ₄ Cl (24.3 g, 454.28 mmol), Fe (64.3 g, 1.15 mol) in tetrahydrofuran (300 ml), ethanol (300 ml) and water (100 ml) were stirred for 1 hour at 80°C and then cooled to room temperature. Solids were filtered out 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 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%). LC-MS (ESI, m/z): 376 [M+H] ⁺ .

Step 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] Solution of 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), DIEA ( 0.19 ml, 1.20 mmol) in N,N-dimethylformamide (10 ml) was stirred for 1 hour at 25°C. The resulting solution was diluted with H ₂ O (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 saline (2×20 ml). The mixture was dried over anhydrous sodium sulfate and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography (eluting with ethyl acetate/petroleum ether 3:2) 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-tetra-hydroquinoline-1-carboxylate as a yellow solid (180 mg, 81%) . LC-MS (ESI, 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] 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 overnight at 60°C. The reaction mixture was cooled and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography (eluting with ethyl acetate/petroleum ether 1:1) 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%). LC-MS (ESI, 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] 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) were stirred overnight at 25°C. The resulting mixture was concentrated in vacuo. The crude product was purified using preparative HPLC (column, XBridge Prep C18 OBD column, 19x150 mm, 5 μm; mobile phase, A: water (containing 10 mmol/l NH ₄ HCO ₃ ) and B: ACN (from 15.0 % up to 29.0% within 14 min.); detector, UV 220/254 nm). The product was separated by chiral preparative HPLC (column, CHIRALPAK IE, 2 x 25 cm, 5 µm; mobile phase, A: Hex (containing 0.1% FA) and B: ethanol (holding 50.0% ethanol for 12 min .); detector, UV 220/254 nm). 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%) and (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 as a white solid (23.8 mg, 20%). Stereoisomeric 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 eluted 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). LC-MS (ESI, m/z): 526 [M+H]+.

Second eluted 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). LC-MS (ESI, m/z): 526 [M+H]+.

[0081] In a preferred embodiment, the invention provides the first eluted isomer obtained in step 10 of the process described in Example 2 above, or a pharmaceutically acceptable salt thereof. In a preferred embodiment, the invention provides compound 424 having the following structure:

or a pharmaceutically acceptable salt, hydrate, solvate or tautomer thereof.

[0082] In some embodiments, the invention provides a pharmaceutical composition comprising compound 424 of the above structure or a pharmaceutically acceptable salt thereof with a purity of at least 90%, such as greater than 90%, 91%, 92%, 93%, 94%, 95 %, 96%, 97%, 98% or 99% relative to one or more of its related stereoisomers. For example, the specification provides compound 424 of the above structure or a pharmaceutically acceptable salt thereof with a purity of at least 90%, e.g. greater than 90% purity, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98 % or 99% relative to compound 660 and possibly other stereoisomers of compound 424 shown below. In some embodiments, the invention provides a pharmaceutical composition comprising 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 contain a compound of one or more formulas (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 invention provides a composition containing compound 424 of the above structure or a pharmaceutically acceptable salt thereof with a purity of at least 90%, where the composition contains less than 10%, for example less than 9%, less than 8%, less than 7%, less 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1% in the aggregate of one or more of the following stereoisomers of compound 424 represented by formulas (II-a)-(II-o) below:

[0084] In any of the above embodiments, said percentage of purity can be determined using HPLC. In some embodiments, the percentage purity is determined using the following HPLC method.

Sample Preparation:

Prepare 0.2 mg/mL in 70/30 Water/Acetonitrile.

LCMS Information:

Instruments:

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 min

LC Flow Rate: 1 mL/min

UV Wavelength: 238 nm

Ionization Mode: Electrospray Ionization +ive

Injection Volume: 8 μL

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

[0086] The invention provides a compound of formula II prepared by the above method shown in Example 2:

or a pharmaceutically acceptable salt, enantiomer, hydrate, solvate, isomer or tautomer thereof.

[0087] It will be apparent to the skilled reader that each of the stereoisomers of the compound of formula (II) can be prepared by altering the stereochemistry of the corresponding reagents used in the method of Example 2 above. For example, by adjusting the reagent used in step 4 of example 2, compounds such as compounds of formulas (II-m) and (II-n) can be synthesized. Similarly, in step 6 of Example 2, the control methyl (1S,3R)-3-aminocyclohexane-1-carboxylate can be used instead of methyl (1R,3R)-3-aminocyclohexane-1-carboxylate to give compounds of formulas (II-b) and (II-e). It will be apparent to the experienced reader that by combining these types of modifications to the process outlined in Example 2, each of the compounds (II-a)-(II-o) depicted above 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] Compositions containing compound 462 can be prepared as shown in the diagram below.

Stage 1. 6-Fluoro-2-methyl-5-nitroquinoline

[0089] A solution of trifluoromethanesulfonic acid (82.0 ml, 0.923 mol) in HNO ₃ (19.6 ml, 0.437 mol) was stirred for 20 minutes. at 0°C. This was followed by the addition of 6-fluoro-2-methylquinoline (50.0 g, 0.310 mol) in dichloromethane (300 ml) at 0°C. The resulting mixture was stirred for 15 hours at room temperature (25°C). The reaction mixture was diluted with water (300 ml). The pH of the solution was adjusted to 8 using 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 in vacuo. The residue was purified by silica gel chromatography (eluting with ethyl acetate/petroleum ether 1:4) to give 6-fluoro-2-methyl-5-nitroquinoline as a light yellow solid (60.0 g, 94%). LC-MS (ESI, m/z): 207 [M+H] ⁺ .

Step 2. (2S)-6-Fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline

[0090] A solution of (S)-(-)-MeO-BIPHEP (1.03 g, 1.77 mmol), chloro(1,5-cyclooctadiene)iridium(I) dimer (538 mg, 0.80 mmol) in toluene (100 ml) was stirred for 30 minutes. at room temperature (25°C) in a nitrogen atmosphere. This was followed by the addition of I ₂ (410 mg, 1.62 mmol), 6-fluoro-2-methyl-5-nitroquinoline (33.0 g, 0.160 mol) in toluene (100 ml). The resulting mixture was stirred for 20 hours at room temperature (25°C) in a hydrogen atmosphere (50 atm.). The resulting mixture was concentrated in vacuo and purified by silica gel chromatography (eluting with ethyl acetate/petroleum ether 1:1) to give the crude product (35.0 g). The crude product was dissolved in ethyl acetate (230 ml), then D-camphorsulfonic acid (36.9 g, 0.158 mol) was added. The resulting solution was stirred for 1 hour at 60°C and then cooled to room temperature. The solids were collected by filtration and washed with ethyl acetate (120 ml). The solids were dissolved in water (50 ml). The pH of the solution was adjusted to 8 using 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 in vacuo to give (2S)-6-fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline as a red solid (25.5 g, 76%). LC-MS (ESI, m/z): 211 [M+H] ⁺ .

Step 3. Methyl (2S)-6-fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate

[0091] 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), Methyl chloroformate (18.7 ml, 0.242 mol) in dichloromethane (150 ml) was stirred for 3 hours at room temperature (25°C). 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 in vacuo to give methyl (2S)-6-fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate as yellow solids (29.8 g, 92%). LC-MS (ESI, 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] 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), methyl (1R,3R)-3-aminocyclohexane-1-carboxylate (25.6 g, 162.84 mmol) in DMSO (270 ml) stirred for 15 hours at 90°C and then cooled to room temperature. The reaction mixture 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 ethyl acetate/petroleum ether 1:1) to give methyl-(2S)-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino] -2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate as red oil (32 g, 72%). LC-MS (ESI, 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] Solution of (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), NH ₄ Cl (24.3 g, 454.28 mmol), Fe (64.3 g, 1.15 mol) in tetrahydrofuran (300 ml), ethanol (300 ml) , water (100 ml) was stirred for 1 hour at 80°C and then cooled to room temperature. Solids were filtered out 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 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%). LC-MS (ESI, 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] Solution of (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), DIEA (1, 08 ml, 6.20 mmol) in N,N-dimethylformamide (10 ml) was stirred for 5 hours at room temperature (25°C). The resulting solution was diluted with water (30 ml) and extracted with ethyl acetate (3×50 ml). The organic layers were combined and washed with brine (2×25 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 ethyl acetate/petroleum ether 1:1) 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%). LC-MS (ESI, 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 overnight at 40°C and then cooled to room temperature. The reaction mixture was diluted with water (10 ml). The pH of the solution was adjusted to 8 using sodium bicarbonate (saturated aqueous solution). The resulting solution was extracted with ethyl acetate (3×15 ml). The organic layers were combined and dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography (eluting with ethyl acetate/petroleum ether 1:1) 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 colorless oil . LC-MS (ESI, 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] 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), LiOH (100 mg, 4.17 mmol) in tetrahydrofuran (5 ml) and water (2 ml) stirred overnight at room temperature (25°C). The resulting mixture was concentrated in vacuo. The crude product was purified by preparative HPLC (column: XBridge Shield RP18 OBD column, 5 μm, 19 x 150 mm; mobile phase, A: water (containing 10 mmol/L NH ₄ HCO ₃ ) and B: ACN (3% to 30% for 21 min.); detector: UV, 254 nm). Product fractions were lyophilized to give (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 as a white solid (83.7 mg, 22%). The enantiomeric purity of the product was determined by HPLC: Column: CHIRALPAK IE-3, column size: 0.46×5 cm; 3 µm; mobile phase: Hex (0.1%FA) : EtOH=85:15, flow rate: 1.0 ml/min. ¹ H-NMR (CD ₃ OD, 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). LC-MS (ESI, m/z): 478 [M+H] ⁺ ; enantiomeric purity 99.13%.

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]quinoline -3-yl]cyclohexane-1-carboxylic acid (515)

Step 1. 2-(Difluoromethoxy)-5-fluorobenzaldehyde

[0097] A solution of 5-fluoro-2-hydroxybenzaldehyde (2.0 g, 14.3 mmol), diethyl (bromodifluoromethyl)phosphonate (5.69 g, 21.3 mmol), potassium hydroxide (16.0 g, 285 mmol) in MeCN (100 ml) and water (50 ml) was stirred for 1 hour at -30°C. The reaction mixture was diluted with water (20 ml). The resulting solution was extracted with ethyl acetate (3×100 ml) and the organic layers were combined and dried over anhydrous sodium sulfate. Solids were filtered off. The resulting mixture was concentrated in vacuo. The resulting crude product was purified by silica gel chromatography (eluting with ethyl acetate/petroleum ether 1:1) to give 2-(difluoromethoxy)-5-fluorobenzaldehyde as a yellow solid (1.46 g, 54%). LC-MS (ESI, 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), ZnI ₂ (50 mg, 0.16 mmol) in dichloromethane ( 3 ml) was stirred for 2 hours at room temperature (25°C). The resulting mixture was concentrated in vacuo. The resulting 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 yellow solid (800 mg, 36%). LC-MS (ESI, m/z): 290 [M+H] ⁺

Step 3. 2-[2-(Difluoromethoxy)-5-fluorophenyl]-2-hydroxyacetic acid

[0099] Solution of 2-[2-(difluoromethoxy)-5-fluorophenyl]-2-[(trimethylsilyl)oxy]acetonitrile (800 mg, 2.77 mmol), 1,4-dioxane (2.0 ml), hydrogen chloride (1.0 ml, 12 M) in water (2 ml) was stirred for 12 hours at 70°C and then cooled to room temperature. The resulting solution was concentrated in vacuo. 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%) . LC-MS (ESI, m/z): 237 [M+H] ⁺ .

Step 4. 6-Fluoro-2-methyl-5-nitroquinoline

[00100] A solution of trifluoromethanesulfonic acid (82.0 ml, 0.923 mol) in HNO ₃ (19.6 ml, 0.437 mol) was stirred for 20 minutes. at 0°C. This was followed by the addition of 6-fluoro-2-methylquinoline (50.0 g, 0.310 mol) in dichloromethane (300 ml) at 0°C. The resulting mixture was stirred for 15 hours at room temperature (25°C). The reaction mixture was diluted with water (300 ml). The pH of the solution was adjusted to 8 using 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 in vacuo. The residue was purified by silica gel chromatography (eluting with ethyl acetate/petroleum ether 1:4) to give 6-fluoro-2-methyl-5-nitroquinoline as a light yellow solid (60.0 g, 94%). LC-MS (ESI, m/z): 207 [M+H] ^+.

Step 5. (2S)-6-Fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline

A solution of (S)-(-)-MeO-BIPHEP (1.03 g, 1.77 mmol), chloro(1,5-cyclooctadiene)iridium(I) dimer (538 mg, 0.80 mmol) in toluene (100 ml) was stirred for 30 min. at room temperature (25°C) in a nitrogen atmosphere. This was followed by the addition of I ₂ (410 mg, 1.62 mmol), 6-fluoro-2-methyl-5-nitroquinoline (33.0 g, 0.160 mol) in toluene (100 ml). The resulting mixture was stirred for 20 hours at room temperature (25°C) in a hydrogen atmosphere (50 atm.). The resulting mixture was concentrated in vacuo and purified by silica gel chromatography (eluting with ethyl acetate/petroleum ether 1:1) to give the crude product (35.0 g). The crude product was dissolved in ethyl acetate (230 ml), then D-camphorsulfonic acid (36.9 g, 0.158 mol) was added. The resulting solution was stirred for 1 hour at 60°C and then cooled to room temperature. The solids were collected by filtration and washed with ethyl acetate (120 ml). The solids were dissolved in water (50 ml). The pH of the solution was adjusted to 8 using 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 in vacuo to give (2S)-6-fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline as a red solid (25.5 g, 76%). LC-MS (ESI, m/z): 211 [M+H] ^+.

Step 6. Methyl (2S)-6-fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate

[00101] 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), Methyl chloroformate (18.7 ml, 0.242 mol) in dichloromethane (150 ml) was stirred for 3 hours at room temperature (25°C). 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 in vacuo to give methyl (2S)-6-fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate as yellow solids (29.8 g, 92%). LC-MS (ESI, 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

[00102] 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), methyl (1R,3R)-3-aminocyclohexane-1-carboxylate (25.6 g, 162.84 mmol) in DMSO (270 ml) stirred for 15 hours at 90°C and then cooled to room temperature. The reaction mixture 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 ethyl acetate/petroleum ether 1:1) to give methyl-(2S)-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino] -2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate as red oil (32 g, 72%). LC-MS (ESI, 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

[00103] 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), NH ₄ Cl (24.3 g, 454.28 mmol), Fe (64.3 g, 1.15 mol) in tetrahydrofuran (300 ml), ethanol (300 ml), water (100 ml) was stirred for 1 hour at 80°C and then cooled to room temperature. Solids were filtered out 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 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%). LC-MS (ESI, 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

[00104] Solution of 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), DMTMM (350 mg, 1.26 mmol) in dichloromethane (5 ml) was stirred for 1 hour at room temperature (25°C). The resulting solution was concentrated in vacuo. The resulting crude product was purified by silica gel chromatography (eluting with ethyl acetate/petroleum ether 1:1) 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%). LC-MS (ESI, 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

[00105] Methyl-(2S)-5-[2-[2-(difluoromethoxy)-5-fluorophenyl]-2-hydroxyacetamido]-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino solution ]-2-methyl-1,2,3,4-tetrahydroquinoline-1-carboxylate (70.0 mg, 0.12 mmol) in glacial acetic acid (2.0 ml) was stirred overnight at 40°C and then cooled to room temperature. The resulting solution was concentrated in vacuo. The resulting crude product was purified by silica gel chromatography (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%). LC-MS (ESI, 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

[00106] 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), LiOH (10.0 mg, 0.42 mmol) in tetrahydrofuran (2.0 ml) and water (2.0 ml) were stirred overnight at room temperature (25°C). The resulting mixture was concentrated in vacuo. 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 NH ₄ HCO ₃ ) and B: ACN (from 25.0 % to 35.0% for 8 min.); detector, UV, 254/220 nm). 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%). The enantiomeric purity of the product was determined by HPLC: Column: CHIRALPAK IE-3, column size: 0.46×5 cm; 3 µm; co-solvent: IPA (20 mM NH ₃ ), gradient (V%): 10% to 50% in 4.0 min, hold 2.0 min. at 50%.

First eluted isomer (452): ¹ H-NMR (CD ₃ OD, 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). LC-MS (ESI, m/z): 562 [M+H] ⁺ .

Second eluted isomer (515): ¹ H-NMR (CD ₃ OD, 400 MHz) δ (ppm): 7.55-7.53 (m, 1H), 7.47-7.42 (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). LC-MS (ESI, m/z): 562 [M+H] ⁺ ; enantiomeric purity >99.99%.

[00107] In some embodiments, the invention provides a first eluted isomer obtained in step 11 of the process described in Example 4. In some embodiments, the invention provides a second eluted isomer obtained in step 11 of the process described in Example 4.

Example 5 Biochemical Analysis by HTRF for CBP and BRD4 Activity

[00108] The ability of compounds of formula I to selectively inhibit CBP was determined using the following biochemical assay by HTRF for CBP and BRD4 activity. The assay was performed in a final volume of 6 μl in assay buffer containing 50 mM Hepes (pH 7.5, (0.5 M Hepes, pH 7.5 solution; Teknova H1575)), 0.5 mM GSH, 0.01% BGG (0.22 μM filtered, Sigma, G7516-25G), 0.005% BSA (0.22 μM filtered, EMD Millipore Cosporation, 126575), and 0.01% Triton X-100 (Sigma, T9284-10L). Nanoliter quantities of a 10-point 3-fold serial dilution in DMSO were predispensed into 1536 assay plates (Corning, #3724BC) for a final test concentration of 33 μM to 1.7 nM, maximum to minimum dose, respectively. 3 µl of 2x protein and 3 µl of 2x peptide ligand were added to assay plates (pre-stamped with compound). Before measuring the signal, the plates were incubated for various times at room temperature. TR-FRET (time-resolved fluorescence resonance energy transfer) was measured on a PHERAstar plate reader (BMG, equipped with an HTRF optical module [337/520/490]) or on an Envision plate reader (PerkinElmer, equipped with a TRF laser unit, double mirror TRF D400/D505 and emission filters M520 and M495). Data were presented as percentage inhibition compared to control wells based on the following equation: %inh=1-((TR-FRET coefficient - AveLow) / (AveHigh - AveLow)), where TR-FRET coefficient = (fluorescence at 520 nm /fluorescence at 490 nm) * 10000), AveLow = average TR-FRET coefficient of non-enzyme control (n=32), and AveHigh = average TR-FRET coefficient of DMSO control (n=32). IC50 values were determined by curve fitting of the standard 4-parameter logistic fitting algorithm included in the Activity Base: IDBS XE Designer Model205 software package. Data are selected using the Levenberg-Marquardt algorithm. For all assay formats, data were presented as percent inhibition compared to control wells based on the following equation: %inh=100*((FLU - AveLow) / (AveHigh - AveLow)) where FLU = measured fluorescence value, AveLow = average value fluorescence of non-enzyme control (n=32) and AveHigh = average fluorescence value of DMSO control (n=32). IC50 values were determined by curve fitting of the standard 4-parameter logistic fitting algorithm included in the Activity Base: IDBS XE Designer Model205 software package. Data are selected using the Levenberg-Marquardt algorithm. The IC ₅₀ values are shown in FIG. 1. As shown in FIG. 1, an IC ₅₀ value that is less than or equal to 0.01 μM is indicated as “++++”; a value that is greater than 0.01 μM and less than or equal to 0.1 μM is designated as “+++”; a value that is greater than 0.1 μM and less than or equal to 1 μM is designated as “++”; and values that are greater than 1 µM are indicated as “+”. Compounds that were not tested in a particular assay are labeled “NT.”

[00109] In some embodiments, the CBP inhibitory compound is also selective for CBP activity over BRD4 activity, as determined by obtaining an IC50 value for CBP inhibition in the HTRF biochemical assay for CBP that is lower than corresponding IC50 value obtained for biochemical analysis by HTRF for BRD4 activity according to Example 5. The CBP inhibitory composition may contain an amount of a compound of the invention or a pharmaceutically acceptable salt thereof and amounts of one or more stereoisomers of the compound up to amounts that preserve sufficient activity of the composition in relation to inhibition of SBP and selectivity for SBP compared to BRD4. When using the methods presented herein, the CBP inhibitory compositions may contain 95% by HPLC or more of a compound disclosed herein or a pharmaceutically acceptable salt thereof and up to 5% by HPLC of one or more stereoisomers of the compound.

[00110] In a preferred embodiment, the present invention provides compound 424 having an IC ₅₀ value that is less than or equal to 0.01 μM for CBP inhibition and an IC ₅₀ value that is greater than 0.1 μM and less than or equal to 1 μM for inhibition of BRD4, as determined by the HTRF assay for CBP and BRD4 activity described herein in Example 5.

[00111] In some embodiments, the present invention provides a compound of formula (II) selected from the group consisting of compound 424 and related stereoisomers with structures (II-a)-(II-o) depicted above, having an IC value of ₅₀ , which is less than or equal to 0.01 μM, for inhibition of CBP, and an IC ₅₀ value that is greater than 0.1 μM and less than or equal to 1 μM, for inhibition of BRD4, as determined by biochemical analysis by HTRF relative to the activity of CBP and BRD4 described in this document in example 5.

[00112] Additional embodiments of the invention are set forth in the following numbered paragraphs.

1. Compound of formula (III):

or a pharmaceutically acceptable salt thereof, wherein

R ¹ is -OR ⁵ ;

R ⁵ represents -C ₁ -C ₆ alkyl, -C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl;

R ⁶ represents -C ₃ -C ₈ cycloalkyl, -C ₄ -C ₈ cycloalkenyl, heterocyclyl, heteroaryl, aryl, wherein each cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl or aryl is optionally substituted by one or more -R ¹⁰ ;

R ^6' represents H or -C ₁ -C ₆ alkyl;

R ⁷ represents H, halogen, -OH, -CN, -OC ₁ -C ₆ alkyl, -NH ₂ , -NHC ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl) ₂ , -S(O ) ₂ NH(C ₁ -C ₆ alkyl), -S(O) ₂ N(C ₁ -C ₆ alkyl) ₂ , -S(O) ₂ C ₁ -C ₆ alkyl, -S(O) ₂ OH, -C(O)C ₁ -C ₆ alkyl, -C(O)NH ₂ , -C(O)NH(C ₁ -C ₆ alkyl), -C(O)N(C ₁ -C ₆ alkyl) ₂ , -C(O)OH, -C(O)OS ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl)SO ₂ C ₁ -C ₆ alkyl, -S(O)(C ₁ -C ₆ alkyl), -S(O)N(C ₁ -C ₆ alkyl) ₂ , -S(O) ₂ NH ₂ , -N(C ₁ -C ₆ alkyl)S(O)(C ₁ -C ₆ alkyl) or tetrazole;

R ¹⁰ in each case independently represents -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, -C ₄ -C ₈ cycloalkenyl, heterocyclyl, heteroaryl, aryl, -OH, halogen, oxo, -NO ₂ , -CN, -NH ₂ , -OC ₁ -C ₆ alkyl, -OC ₃ -C ₆ cycloalkyl, -Oaryl, -Oheteroaryl, -NHC ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl) ₂ , -S(O) ₂ NH(C ₁ -C ₆ alkyl), -S(O) ₂ N(C ₁ -C ₆ alkyl) ₂ , -S( O) ₂ C ₁ -C ₆ alkyl, -C(O)C ₁ -C ₆ alkyl, -C(O)NH ₂ , -C(O)NH(C ₁ -C ₆ alkyl), -NHC(O) C ₁ -C ₆ alkyl, -C(O)N(C ₁ -C ₆ alkyl) ₂ , -C(O)OS ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl)SO ₂ C ₁ - C ₆ alkyl, -S(O)(C ₁ -C ₆ alkyl), -S(O)N(C ₁ -C ₆ alkyl) ₂ , or -N(C ₁ -C ₆ alkyl)S(O)( C ₁ -C ₆ alkyl), wherein each alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocyclyl, heteroaryl or aryl is optionally substituted with one or more -R ¹² ;

R ¹² in each case independently represents -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -C ₃ -C ₈ cycloalkyl, -C ₄ -C ₈ cycloalkenyl, heterocyclyl, heteroaryl, aryl, -OH, halogen, oxo, -NO ₂ , -CN, -NH ₂ , -OC ₁ -C ₆ alkyl, -NHC ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl) ₂ , -S(O) ₂ NH(C ₁ -C ₆ alkyl), -S(O) ₂ N(C ₁ -C ₆ alkyl) ₂ , -S(O) ₂ C ₁ -C ₆ alkyl, -C(O )C ₁ -C ₆ alkyl, -C(O)NH ₂ , -C(O)NH(C ₁ -C ₆ alkyl), -C(O)N(C ₁ -C ₆ alkyl) ₂ , -C( O)OS ₁ -C ₆ alkyl, -N(C ₁ -C ₆ alkyl)SO ₂ C ₁ -C ₆ alkyl, -S(O)(C ₁ -C ₆ alkyl), -S(O)N(C ₁ -C ₆ alkyl) ₂ or -N(C ₁ -C ₆ alkyl)S(O)(C ₁ -C ₆ alkyl);

m is an integer from 0 to 5, and q is an integer from 0 to 4.

2. The compound according to point 1, where R ¹² represents a halogen.

3. Connection according to any of points 1-2, where m is equal to 3.

4. The compound according to any of paragraphs 1-3, where R ^6' represents H.

5. The compound according to any of paragraphs 1-4, where R ⁶ represents aryl.

6. The compound according to any of paragraphs 1-5, where R ⁷ represents -C(O)OH.

7. The compound according to any of paragraphs 1-6, where R ⁵ represents methyl.

8. The compound according to paragraph 1, where the compound is represented by formula (III-c):

or a pharmaceutically acceptable salt thereof, wherein R ⁵ represents -C ₁ -C ₆ alkyl; and R ⁶ is phenyl, optionally substituted with one or more R ¹⁰ .

9. The compound according to claim 1, where the compound is represented by formula (III-d):

or a pharmaceutically acceptable salt thereof, where:

R ⁵ represents -C ₁ -C ₃ alkyl;

R ⁶ is phenyl, optionally substituted with one or more R ¹⁰ ;

R ¹⁰ in each instance is independently halogen, -OC ₁ -C ₆ alkyl, -OC ₃ -C ₆ cycloalkyl, -Oaryl or -Heteroaryl, wherein each alkyl, cycloalkyl, aryl or heteroaryl is optionally substituted by one or more -R ¹² ; and R ¹² is halogen.

10. A compound according to any one of claims 1-7, wherein R ⁶ is aryl, optionally substituted with one or more R ¹⁰ .

11. A compound according to any one of claims 1 to 7, wherein R ⁶ is phenyl, optionally substituted with one or more R ¹⁰ .

12. The compound according to any of paragraphs 1-6, paragraph 8 or paragraphs 10-11, where R ⁵ represents -C ₁ -C ₃ alkyl.

13. The compound according to any of paragraphs 1-6 or paragraphs 8-12, where R ⁵ represents methyl.

14. A compound according to any one of claims 1-13, wherein R ¹⁰ is in each instance independently halogen or -OC ₁ -C ₆ alkyl, wherein -OC ₁ -C ₆ alkyl is optionally substituted with halogen.

15. A pharmaceutical composition containing a compound according to any of paragraphs 1 to 14 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

Claims (63)

1. Compound of formula (I) or a pharmaceutically acceptable salt, enantiomer or stereoisomer thereof, where R ¹ represents -OR ⁵ ; R ⁵ represents -C ₁ -C ₆ alkyl; R ⁶ is phenyl, optionally substituted with one or more R ¹⁰ ; R ¹⁰ in each instance is independently -C ₁ -C ₆ alkyl, halogen, -OC ₁ -C ₆ alkyl or -OC ₃ -C ₆ cycloalkyl, wherein each alkyl or cycloalkyl is optionally substituted by one or more -R ¹² ; or where any two R ¹⁰ , if present on non-adjacent atoms, can be combined to form a bridged C ₃ -C ₈ cycloalkyl; or wherein any two R ¹⁰ , if present on adjacent atoms, can be combined to form a C ₃ -C ₈ cycloalkyl or heterocyclyl or heteroaryl selected from dihydrofuranyl, furanyl, oxazolyl, methyloxazolyl, pyrrolyl, N-methylpyrrolyl and pyrazolyl; And R ¹² in each case is independently -C ₁ -C ₆ alkyl, -OH or halogen. 2. A compound according to claim 1 or a pharmaceutically acceptable salt, enantiomer or stereoisomer thereof, where R ⁵ represents -C ₁ -C ₃ alkyl; R ¹⁰ in each instance is independently halogen, -OC ₁ -C ₆ alkyl or -OC ₃ -C ₆ cycloalkyl, wherein each alkyl or cycloalkyl is optionally substituted by one or more -R ¹² ; And R ¹² represents halogen. 3. Connection according to any one of paragraphs. 1, 2 or a pharmaceutically acceptable salt thereof, wherein R ⁵ represents methyl. 4. Connection according to any one of paragraphs. 1-3 or a pharmaceutically acceptable salt thereof, wherein at least one R ¹⁰ represents a halogen. 5. Connection according to any one of paragraphs. 1-4 or a pharmaceutically acceptable salt thereof, wherein at least one R ¹⁰ is -OC ₁ -C ₆ alkyl. 6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein any two R ¹⁰ , if present on non-adjacent atoms, can be combined to form a C ₃ -C ₈ bridged cycloalkyl. 7. A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein any two ^R10 , if present on adjacent atoms, can be combined to form a _C3 - _C8 cycloalkyl or heterocyclyl or heteroaryl selected from dihydrofuranyl, furanyl, oxazolyl, methyloxazolyl, pyrrolyl, N-methylpyrrolyl and pyrazolyl. 8. Connection according to any one of paragraphs. 1-3 or a pharmaceutically acceptable salt thereof, wherein R ⁶ is phenyl, optionally substituted with one or two R ¹⁰ , and each R ¹⁰ in each instance is independently halogen or -OC ₁ -C ₆ alkyl, where -OC ₁ -C _{The 6} alkyl is optionally substituted with halogen. 9. Connection according to any one of paragraphs. 1-3 or a pharmaceutically acceptable salt thereof, wherein each R ¹⁰ in each instance is independently halogen or -OC ₁ alkyl, optionally substituted by one or more R ¹² , wherein R ¹² is halogen. 10. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, wherein each R ¹² in each case independently represents fluorine. 11. A compound according to claim 1, wherein the compound is a compound of formula (IV-a) or a pharmaceutically acceptable salt thereof, where n is an integer of 0, 1, 2, 3, 4 or 5; And each R ¹⁰ in each instance is independently selected from the group consisting of -C ₁ -C ₆ alkyl, halogen, -OC ₁ -C ₆ alkyl and -OC ₃ -C ₆ cycloalkyl, wherein each alkyl or cycloalkyl is optionally substituted by one or more halogen or C ₁ -C ₆ alkyl; or any two R ¹⁰ if present on non-adjacent atoms can be combined to form a bridged C ₃ -C ₈ cycloalkyl; or any two R ¹⁰ if present on adjacent atoms can be combined to form a C ₃ -C ₈ cycloalkyl or heterocyclyl or heteroaryl selected from dihydrofuranyl, furanyl, oxazolyl, methyloxazolyl, pyrrolyl, N-methylpyrrolyl and pyrazolyl. 12. The connection according to claim 11, where n is 0, 1 or 2. 13. The compound of claim 11 or 12, wherein each R ¹⁰ is in each case independently selected from the group consisting of -C ₁ -C ₆ alkyl, halogen, -OC ₁ -C ₆ alkyl and -OC ₃ -C ₆ cycloalkyl, wherein each alkyl or cycloalkyl is optionally substituted with one or more halogen or methyl. 14. Connection according to any one of paragraphs. 11-13, wherein each halogen is independently selected from the group consisting of fluorine and chlorine. 15. Connection according to any one of paragraphs. 11-14, where each -OC ₃ -C ₆ cycloalkyl is -O-cyclopropyl, and each -C ₁ -C ₆ alkyl is methyl, and each -OC ₁ -C ₆ alkyl is methoxy. 16. A compound or a pharmaceutically acceptable salt thereof selected from 17. A compound according to claim 1 or 11 or a pharmaceutically acceptable salt thereof, where the compound is selected from 18. A compound according to claim 1 or 11 or a pharmaceutically acceptable salt thereof, where the compound is selected from 19. A compound according to claim 1 or 11 or a pharmaceutically acceptable salt thereof, where the compound is selected from 20. A compound according to claim 1 or 11 or a pharmaceutically acceptable salt thereof, where the compound is selected from 21. A compound according to claim 1 or 11 or a pharmaceutically acceptable salt thereof, where the compound is selected from 22. A compound according to claim 1 or 11 or a pharmaceutically acceptable salt thereof, where the compound has the structure 23. A compound according to claim 1 or 11 or a pharmaceutically acceptable salt thereof, where the compound has the structure 24. A compound according to claim 1 or 11 or a pharmaceutically acceptable salt thereof, where the compound has the structure 25. A compound according to claim 1 or 11 or a pharmaceutically acceptable salt thereof, where the compound has the structure 26. A compound according to claim 1 or 11 or a pharmaceutically acceptable salt thereof, where the compound has the structure 27. Pharmaceutical composition for inhibiting CREB-binding protein (CBP) and/or p300, containing a therapeutically effective amount of a compound according to any one of paragraphs. 1-26 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

Images