EA042920B1 - INHIBITION OF CREB-BINDING PROTEIN (CBP) - Google Patents

Description

Cross-reference to related applications

This application claims priority over U.S. provisional application No. 62/692593 filed June 29, 2018, international application no. PCT/US 2018/051235 filed September 14, 2018, international application no. September 2018 and U.S. Provisional Application No. 62/819490, filed March 15, 2019, each of which is incorporated by reference in its entirety.

Technical field

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 the CBP/p300 family of bromodomains.

State of the art

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 CATZV) is a multi-domain protein that binds to various proteins, including many DNA-binding transcription factors. CREB (cyclic AMP response element binding protein) binding protein (CBP, also known as CATZA) 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 expression and activity of p300 has 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 the intrinsic enzymatic activity of acetyltransferase, is more feasible than blocking transcription factors with small molecules, since the study of chemical inhibitors of transcription factors has proven to be an extremely difficult task. 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

The first aspect of the present invention relates to compounds of formula (I)

or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein

R ¹ is -OR ⁵ ;

R ⁵ is -C ₁ -C ₆ alkyl;

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

R ¹⁰ is independently at each occurrence -C1-C6 alkyl, halogen, -OC1-C6 alkyl, or -OC3C6 cycloalkyl, where each alkyl or cycloalkyl is optionally substituted with one or more -R ¹² or where any two R ¹⁰ if present on non-adjacent atoms , may be combined to form a bridged C3- _C6 cycloalkyl or 5-membered heterocyclyl containing one or more ring atoms independently selected from O or N; or where any two R ¹⁰ , if present on adjacent atoms, can be combined to form a C ₃ -C ₆ cycloalkyl, a 5-membered heterocyclyl containing one or more ring atoms independently selected from O or N, or a 5-membered heteroaryl containing one or more ring atoms independently selected from O or N;

R ¹² is at each occurrence independently -C1- _C6 alkyl, -OH or halogen.

Preferably the compounds of formula (I) are compounds of formula (IV)

or a pharmaceutically acceptable salt thereof, where n is 0, 1, 2, 3, 4 or 5;

R ¹⁰ is at each occurrence independently -C ₁ -C ₆ alkyl, halogen, -OC ₁ -C ₆ alkyl, or -OC ₃ C ₆ cycloalkyl, where each alkyl or cycloalkyl is optionally substituted with one or more -R ¹² ; or where any two R ¹⁰ , if present on non-adjacent atoms, can be combined to form

- 1,042,920 bridged C3-C6 cycloalkyl or 5-membered heterocyclyl containing one or more ring atoms independently selected from O or N; or where any two R ¹⁰ , if present on adjacent atoms, can be combined to form a C ₃ -C ₆ cycloalkyl, a 5-membered heterocyclyl containing one or more ring atoms independently selected from O or N, or a 5-membered heteroaryl containing one or more ring atoms independently selected from O or N; And

R ¹² is at each occurrence independently -C ₁ -C ₆ alkyl, -OH or halogen.

Brief description of graphic materials

The drawing shows a table of connections in accordance with various embodiments of the invention.

Detailed description

The present invention relates to compounds that inhibit CBP, defined herein as compounds having one or more of the following characteristics when tested in accordance with the protocol of biochemical analysis by homogeneous time-resolved fluorescence (HTRF)) below in example 5: (1 ) the IC ₅₀ value for the CVR is less than 1 µm; and (2) and IC ₅₀ value for CVR from 0.001 to 1 µm.

Compounds according to the invention

In one aspect of the present invention, compounds of formula (I) are described.

or their pharmaceutically acceptable salts, enantiomers, stereoisomers and tautomers, where R ¹ and R ⁶ are described above.

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)

- 2 042920

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 Ri is methyl and R ₆ is phenyl optionally substituted with one or more R ¹⁰ ).

In some preferred embodiments, the compound of formula (I) is a compound of formula (IV), including its stereoisomers

or a pharmaceutically acceptable salt thereof, where n is an integer of 0, 1, 2, 3, 4 or 5 (preferably 0, 1 or 2) and R ₁₀ is as defined above. 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 R ₁₀ is as defined above.

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 is independently halogen or -OC ₁ -C ₆ alkyl, and wherein -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 -OC1 alkyl optionally substituted with one or more halogen (eg fluorine or chlorine) atoms. In some compounds of formula (IV-a) n is 2 and each R ₁₀ is independently halogen (eg fluorine or chlorine), OC1 alkyl substituted with 1, 2 or 3 halogens (eg fluorine or chlorine), or methoxy .

Another aspect of the present invention is the provision of pharmaceutical compositions containing therapeutically effective amounts of at least one compound of formula (I).

- 3 042920

An aspect of the present invention relates to compounds which are, or may be, inhibitors of one or more bromodomains of the CBP/p300 family (eg, compounds of formula (I)).

In some embodiments, the compounds of the invention have the formula (I)

R ⁶ RON Q No\ ^0H Po and O^R ¹ (I), or their pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer, where R ¹ represents-OR ⁵ ;

R ⁵ is -C _g C ₆ alkyl;

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

R ¹⁰ is at each occurrence independently -C1-C6 alkyl, halo, -OC1-C6 alkyl or -OC3C6 cycloalkyl, where each alkyl or cycloalkyl is optionally substituted with one or more -R ¹² ; or where any two R ¹⁰ , if present on non-adjacent atoms, can be combined to form a bridged C3-C ₆ cycloalkyl or a 5-membered heterocyclyl containing one or more ring atoms independently selected from O or N; or where any two R ¹⁰ , if present on adjacent atoms, can be combined to form a C ₃ -C ₆ cycloalkyl, a 5-membered heterocyclyl containing one or more ring atoms independently selected from O or N, or a 5-membered heteroaryl containing one or more ring atoms independently selected from O or N;

R ¹² is at each occurrence independently -C ₁ -C ₆ alkyl, -OH or halogen.

In some embodiments, the compounds of the invention have the formula (I)

^R6

Ron

P.T.Y.

O^R ¹ (I), or their pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer, where

R ¹ is -OR ⁵ ;

R ⁵ is -C _g C ₆ alkyl;

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

R ¹⁰ is at each occurrence independently -C1-C6 alkyl, halo, -OC1-C6 alkyl or -OC3C6 cycloalkyl, where each alkyl or cycloalkyl is optionally substituted with one or more -R ¹² ; or where any two R ¹⁰ , if present on non-adjacent atoms, can be combined to form a bridged C3-C ₆ cycloalkyl or a 5-membered heterocyclyl containing one or more ring atoms independently selected from O or N; or where any two R ₁₀ , if present on adjacent atoms, can be combined to form a C ₃ -C ₆ cycloalkyl, a 5-membered heterocyclyl containing one or more ring atoms independently selected from O or N, or a 5-membered heteroaryl containing one or more ring atoms independently selected from O or N; And

R ¹² is at each occurrence independently -C ₁ -C ₆ alkyl, -OH or halogen.

In some embodiments, the compounds of the invention have the formula (I)

or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein

R ¹ is -OR ⁵ ;

R ⁵ is -C1- _C3 alkyl;

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

R ¹⁰ at each occurrence is independently halogen or -OC ₁ -C ₆ alkyl, -OC ₃ -C ₆ cycloalkyl, where each alkyl or cycloalkyl is optionally substituted with one or more -R ¹² ;

R ¹² is halogen.

In some embodiments, the compounds of the invention have the formula (I)

- 4 042920

^R6

° R ¹ (I), or their pharmaceutically acceptable salt, where

R ¹ is -OR ⁵ ;

R ⁵ is -C ₁ -C ₆ alkyl and

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

R ¹⁰ is at each occurrence independently -C ₁ -C ₆ alkyl, halo, -OC _g C ₆ alkyl, or -OC 3 C ₆ cycloalkyl, where each alkyl or cycloalkyl is optionally substituted with one or more -R ¹² ; And

R ¹² is at each occurrence independently -C ₁ -C ₆ alkyl, -OH or halogen.

In some embodiments, the compounds of the invention have the formula (I)

^R6

or their pharmaceutically acceptable salt, where

R ¹ is -OR ⁵ ;

R ⁵ is -C ₁ -C3 alkyl;

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

R ¹⁰ is independently at each occurrence halogen, -OC ₁ -C ₆ alkyl, or -OC 3 -C ₆ cycloalkyl, where each alkyl or cycloalkyl is optionally substituted with one or more -R ¹² ; And

R ¹² is halogen.

In some embodiments, R ⁵ is methyl.

In some embodiments, R ¹⁰ is at each occurrence independently halogen or -OC ₁ -C ₆ alkyl, where -OC ₁ -C ₆ alkyl is optionally substituted with halogen.

In some embodiments, R ¹ is -OCH ₃ .

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.

In some embodiments, R ¹⁰ is -C1-C6 alkyl, halo, or -OC1C6 alkyl , where each alkyl is optionally substituted with one or more -R ¹² . In some embodiments, R ¹⁰ is -C1-C ₆ alkyl, where R ¹⁰ is substituted with R ¹² . In some embodiments, R ¹⁰ is halogen. In some embodiments, R ¹⁰ is at each occurrence independently -C ₁ -C ₆ alkyl, halo, -OC _g C ₆ alkyl, or -OC ₃ -C ₆ cycloalkyl, where each alkyl or cycloalkyl is optionally substituted with one or more -R ¹² ; where any two R ¹⁰ if they are present on non-adjacent atoms, can be combined to form a bridged C3-C6 cycloalkyl or 5-membered heterocyclyl containing one or more ring atoms independently selected from O or N; or where any two R ¹⁰ , if present on adjacent atoms, can be combined to form a C3-C6 cycloalkyl, a 5-membered heterocyclyl containing one or more ring atoms independently selected from O or N, or a 5-membered heteroaryl containing one or more ring atoms independently selected from O or N.

In some embodiments, R ¹² is halogen.

In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

Preferably, the compound is a CBP-inhibiting compound of formula (I), wherein R ₁ is —OCH ₃ . In some embodiments, the CBP-inhibiting compound of formula (I) comprises R1 which is —OCH3 and R6 which is C ₆ phenyl optionally substituted with one or more R ₁₀ . In some embodiments, the CBP-inhibiting compound of formula (I) comprises R1 which is -OCH3 and R6 which is C ₆ phenyl optionally substituted with one or more R ₁₀ selected from the group consisting of halogen (e.g., fluorine) and methoxy, where methoxy is optionally substituted with one or more R ₁₂ . In some embodiments, the CBP inhibitory compound of formula (I) comprises R ₁ being —OCH3 and R6 being C6 phenyl optionally substituted with one or more R10 selected from the group consisting of halogen (e.g., fluoro) and methoxy, where methoxy is optionally substituted with one or more R ₁₂ , and R ₁₂ is halogen (preferably fluorine).

- 5 042920

In some embodiments, the compound of the invention is the compound selected in the figure, or a pharmaceutically acceptable salt thereof.

Method for the synthesis of compounds

Compounds of the present invention can be obtained in various ways, including standard chemical methods. Suitable synthesis methods are shown in the examples below.

The compounds of the present invention, i.e. 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 art of organic synthesis, as indicated in part in the following synthesis schemes. 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. Protective 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 obvious 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 appropriate for the preparation of compounds of formula (I).

Those skilled in the art will appreciate 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 may 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).

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

The invention also includes pharmaceutical compositions containing one or more CBP-inhibiting compounds as described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 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, anti-adhesives 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, which is obtained by dry granulation. For example, a CBP inhibitory compound of the present invention may 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 if the subject is in need of CBP inhibition, and if the subject is determined to be in need of CBP inhibition, and then administering to the subject the composition described herein.

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 the 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 in capsule form (PSvK (DiC)), encapsulated by simple granular dry mixing and a lipid-based solution in a hard shell capsule. Capsules may contain pharmaceutically acceptable excipients, and encapsulated capsules may be packaged in induction-sealed HDPE bottles.

Examples

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

CAN - acetonitrile

Ac ₂ O - acetic anhydride (+)BINAP(±)-2,2'-bis(diphenylphosphino)-1,1'-binaphtalene

Vostret-butoxycarbonyl

- 6 042920 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

QPC (FCC) flash column chromatography h-clock

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 (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 K2CO3 - potassium carbonate MeOH - methanol ml - milliliter mmol - millimol mg - milligram MHz - megahertz

MS (MS) - mass spectrometry m/z - mass-to-charge ratio NBSN - bromosuccinimide nm - nanometer

NMM - 4-methylmorpholine

NMR - nuclear magnetic resonance

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

Ph ₃ P - triphenylphosphine PhCHO - benzaldehyde Ph - Metoluene ppm - parts per million k.t. - room temperature RT - retention time SLC (SFC) supercritical liquid chromatography STAB - sodium triacetoxyborohydride p-TSA - p-toluenesulfonic anhydride p-TsOH - p-toluenesulfonic acid TFA - trifluoroacetic acid TFAA - trifluoroacetic anhydride THF - tetrahydrofuran

UV - ultraviolet radiation

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

materials

Unless otherwise noted, all materials were obtained from commercial suppliers and used without further purification. Anhydrous solvents were obtained from Sigma-Aldrich (Milwaukee, WI) and used directly. All reactions involving reagents sensitive to

- 7 042920 air or moisture were carried out under a nitrogen atmosphere, and all reactions using microwave radiation were carried out on a Biotage Initiator EXP EU instrument.

Unless otherwise noted, mass-launched HPLC purification and/or purity and low resolution mass spectral data were measured using the following: (1) Ultra High Performance Liquid Chromatography (UPLC) system from Waters Acquity (UPLC from Waters Acquity with sampler and Waters Micromass ZQ mass spectrometer) with UV detection at 220 nm and low-resonance positive electrospray ionization (ESI) mode (column: Acquity UPLC BEN 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 ammonium formate/acetonitrile/formic acid) over 2.2 min, then 100-5% Solvent B in Solvent A for 0.01 min, then hold at 5% Solvent B in Solvent A for 0.29 min), or (2) High Performance Liquid Chromatography (HPLC) (HPLC)) Waters HT2790 Alliance (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, 4.6x50 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 minutes, then hold at 95% solvent B in solvent A for 1 min (purity and low resolution MS only).

General Methods for the Preparation of Compounds

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

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 description and claims

^R6

R ² = OH

o ^R3= \° ⁿ

Scheme 1 shows methods applicable to the synthesis of compounds of formula I.

Scheme 1

Scheme 2 shows methods applicable to the synthesis of compounds of formula I.

Scheme 2

Alternatively, Scheme 3 provides methods applicable to the synthesis of certain compounds of formula I.

- 8 042920

Scheme 3

Alternatively, Scheme 4 presents methods applicable to the synthesis of certain compounds of formula I.

Scheme 4

compound 1: Methyl-(S)-5-amino-6-bromo-2-methyl-3,4-dihydro Obtaining intermediate quinoline-1 (2H)-carboxylate

About me

OHC^^ chloranil HCl (aq.) n-BuOH 100 *C

honh ₂ hci NaOAc. Me O Η rd^dbaj CHCI (+) BINAP, CsjCOj PhMe, 100°C

Stage 7

CICOjCHj pyridine. CHjCIj

Stage 8

o^o' Stage 9 o'^o'

Intermediate 1

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

In a 5 L 4-necked round bottom flask 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). Then hydrochloric acid (aq., 36.5%, 526.5 ml) and chloranil (456.5 g, 1.86 mol) were added. The resulting mixture was stirred for 1 hour at 100° C. under a nitrogen atmosphere. Then a solution of (E)-but-2-enal (169 ml, 2.06 mol) in 1-butanol (300 ml) was added dropwise. The resulting solution was stirred for 1 hour at 100° C. under a nitrogen atmosphere. The oil bath was cooled to 70° C. and tetrahydrofuran (1500 ml) was added. The resulting mixture was then 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: (ESI, m/z): 208, 210 [M+H] ⁺ . Then dried in an oven to give 8-chloro-5-methoxy-2-methylquinoline hydrochloride (83.0 g, 74%) as a yellow solid. MS (ESI, m/z): 208 [M+H] ⁺ .

Stage 2. 5-Methoxy-2-methylquinoline

In a 1000 ml 3-necked round bottom flask, 8-chloro-5-methoxy-2-methylquinoline hydrochloride (50 g, 204.82 mmol) was dissolved in methanol (300 ml). Then sodium hydroxide (3 M, 205 ml) was added and

- 9 042920

10% palladium on charcoal (25 g). 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 CPC (FCC) eluting with ethyl acetate/petroleum ether (1:5). This provided the title compound (28.5 g, 80%) as a yellow oil. MS: (ESI, m/z): 174 [M+H]+.

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

In a 30 ml (50 atm) 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-(αmino-κN)-l,2-diphenylethyl]-4-methylbenzenesulfonamide-αto-κN ][(1,2,3,4,5,6η)-1,2,3,4,5,6-hexamethylbenzene](1,1,1-trifluoromethanesulfonato-koO)-ruthenium obtained according to the 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 CPC (FCC) eluting with ethyl acetate/petroleum ether (1:4). This provided the title compound (3.0 g, 73%) as a yellow oil. MS: (ESI, m/z): 178 [M+H] ⁺ .

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

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 3x200 ml of water. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by CPC (FCC) eluting with ethyl acetate/petroleum ether (1:3). This provided the title compound (21 g, 89%) as a yellow oil. MS: (ESI, m/z): 236 [M+H] ⁺ .

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

In a 500 ml 3-necked round bottom flask, methyl-(2S)-5-methoxy-2-methyl-1,2,3,4tetrahydroquinoline-1-carboxylate (21 g, 89.36 mmol) was dissolved in dichloromethane (150 ml) . Boron tribromide (150 ml, 0.15 mol, 1M 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 3x300 ml dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by CPC (FCC) eluting with ethyl acetate/petroleum ether (1:2). This provided the title compound (13.5 g, 68%) as a yellow solid. MS: (ESI, m/z): 222 [M+H] ⁺ .

Step 6. Methyl-(S)-2-methyl-5-(((trifluoromethyl)sulfonyl)oxy)-3,4-dihydroquinoline-1(2H)-carboxylate

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 3x100 ml of water. The organic layers were combined, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by CPC (FCC) eluting with ethyl acetate/petroleum ether (1:3). This provided the title compound (5.5 g, 86%) as a yellow oil. MS: (ESI, m/z): 354 [M+H] ⁺ .

Step 7. Methyl-(S)-5-((diphenylmethylene)amino)-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate

In a 500 ml round bottom flask purged with nitrogen and maintained under an inert nitrogen atmosphere, methyl (2S)-2-methyl-5-[(trifluoromethane)sulfonyloxy]-1,2,3,4-tetrahydroquinoline-1-carboxylate (23.5 g, 65.18 mmol) was dissolved in toluene (100 ml). Then diphenylmethanimine (17.9 g, 97.78 mmol), tris(dibenzylideneacetone)dipalladium-chloroform adduct (1.19 g, 1.30 mmol), (+/-)-2,2'-bis(diphenylphosphino) was 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 nitrogen. The reaction mixture was cooled and the solids were filtered off. The residue was purified by CPC (FCC) eluting with ethyl acetate/petroleum ether (1:3). This provided the title compound (33 g, 80%) as a yellow oil. MS: (ESI, m/z): 385 [M+H] ⁺ .

Step 8. Methyl-(S)-5-amino-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate

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) was 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.

- 10 042920

The resulting mixture was concentrated in vacuo. The residue was purified by CPC (FCC) eluting with ethyl acetate/petroleum ether (1:2). This provided the title compound (12.5 g, 66%) as a yellow solid. MS: (ESI, m/z): 221 [M+H]+.

Step 9 Methyl-(S)-5-amino-6-bromo-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (intermediate 1)

In a 100 ml 3-necked round bottom flask, methyl-(28)-5-amino-2-methyl-1,2,3,4tetrahydroquinoline-1-carboxylate (1 g, 4.09 mmol) was dissolved in acetonitrile (20 ml) . Then N-bromosuccinimide (730 mg, 4.10 mmol) was added. The resulting solution was stirred for 30 min at room temperature. The resulting mixture was concentrated in vacuo. The residue was purified by CPC (FCC) eluting with ethyl acetate/petroleum ether (1:1). This provided the title compound (1.1 g, 90%) as a yellow solid. MS: (ESI, 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).

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

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-( 1 H-pyrazol-1 -yl)ethyl)-7-methyl-3 -(2-((( 1 -methyl-1 H-pyrazol-3 - yl)methyl)amino)ethyl)-3,7,8,9-tetrahydro-6H-imidazo[4,5-Dquinoline-6-carboxylate

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

A solution of trifluoromethanesulfonic acid (82.0 ml, 0.923 mol) in HNO3 (19.6 ml, 0.437 mol) was stirred for 20 min 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 value of the solution was adjusted to 8 with sodium bicarbonate (saturated aqueous solution). The resulting solution was extracted with dichloromethane (3x300 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 1:4 ethyl acetate/petroleum ether) 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. (28)-6-Fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline

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) under nitrogen atmosphere. This was followed by the addition of I ₂ (410 mg, 1.62 mmol) and 6-fluoro-2-methyl-5

- 11 042920 nitroquinoline (33.0 g, 0.160 mol) in toluene (100 ml). The resulting mixture was stirred for 20 h at room temperature (25° C.) under a hydrogen atmosphere (50 atm). The resulting mixture was concentrated in vacuo and purified by silica gel chromatography (eluting with 1:1 ethyl acetate/petroleum ether) 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 value of the solution was adjusted to 8 with sodium bicarbonate (saturated aqueous solution). The resulting solution was extracted with ethyl acetate (3x120 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 d, 76%). LC-MS (ESI, m/z): 211 [M+H]+.

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

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., 2x70 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-nitro1,2,3,4-tetrahydroquinoline-1-carboxylate as a yellow solid (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-1,2,3,4tetrahydroquinoline-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 for 15 h at 90°C and then cooled to room temperature. The reaction mixture was quenched with water (200 ml) and extracted with ethyl acetate (3x300 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography (eluting with 1:1 ethyl acetate/petroleum ether) to give methyl-(2S)-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino] -2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate as a red oil (32 g, 72%). LC-MS (ESI, m/z): 406 [M+H] ⁺ .

Step 5. Methyl-(2S)-5-amino-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl1,2,3,4-tetrahydroquinoline-1-carboxylate

A solution of methyl-(2S)-2-methyl-5-nitro-6-[[(1R,3R)-4-(methoxycarbonyl)cyclohexyl]amino]-1,2,3,4tetrahydroquinoline-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 h at 80°C and then cooled to room temperature. Solids were filtered off by filtration. The resulting solution was diluted with water (300 ml) and extracted with ethyl acetate (3x400 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

2-(4-chlorophenyl)-2-hydroxyacetic acid solution (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,Ndimethylformamide (2 ml) was stirred for 15 h at room temperature (25°C). The resulting solution was diluted with water (30 ml) and extracted with ethyl acetate (3x50 ml). The organic layers were combined and washed with brine (2x25 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography (eluting with 1:1 ethyl acetate/petroleum ether) to give methyl-(2S)-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, 8Н,9Н-imidazo[4,5-£]quinoline-6-carboxylate

Methyl-(2S)-5-[2-(4-chlorophenyl)-2-hydroxyacetamido]-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-1,2 solution ,3,4-tetrahydroquinoline-1-carboxylate (60.0 mg, 0.11 mmol) in AcOH (2 ml) was stirred for 15 h at 40°C and then cooled to room temperature. reactionary

- 12 042920 the mixture was diluted with water (10 ml). The pH value of the solution was adjusted to 8 with sodium bicarbonate (saturated aqueous solution). The resulting solution was extracted with ethyl acetate (3x15 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 1:1 ethyl acetate/petroleum ether) to give methyl-(7S)2-[(4-chlorophenyl)(hydroxy)methyl]-3-[(1R, 3R)-3-(methoxycarbonyl)cyclohexyl]-7-methyl-3H,6H,7H,8H,9Nimidazo[4,5-(]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-methyl3H,6H,7H,8H, 9H-imidazo[4,5-(]quinolin-3-yl]cyclohexane-1-carboxylic acid;(1R,3R)-3-[(7S)-2-[(S)(4-chlorophenyl)(hydroxy) methyl]-6-(methoxycarbonyl)-7-methyl-3Н,6Н,7Н,8Н,9Н-imidazo[4,5-(]quinolin3-yl]cyclohexane-1-carboxylic acid

A solution of methyl-(7S)-2-[(4-chlorophenyl)(hydroxy)methyl]-3-[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]-7-methyl-3H,6H,7H,8H, 9H-imidazo[4,5-(]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 h 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, 19x150 mm; mobile phase, A: water (containing 10 mmol/ l NH4HCO3) and B: ACN (10 to 37% over 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-3Н,6Н,7Н,8Н,9Н-imidazo[4,5-(]quinolin-3-yl]cyclohexan-1- carboxylic acid (413) as a white solid (10.5 mg, 43%) and (1R,3R)-3-[(7S)-2-[(S)-(4chlorophenyl)(hydroxy)methyl]-6 -(methoxycarbonyl)-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-(]quinolin-3yl]cyclohexane-1-carboxylic acid (501) as white solid (7.0 mg , 29%).

First eluted isomer (413): ¹ H-NMR (CD3OD, 400 MHz) δ (ppm): 7.49 (d, J=9.0 Hz, 1H), 7.42-7.33 (m, 5H) , 6.19 (s, 1H), 4.92-4.90 (m, 1H), 4.82-4.72 (m, 1H), 3.79 (s, 3H), 3.34-3 .20 (m, 1H), 3.02.94 (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 (CD3OD, 400 MHz) δ (ppm): 7.52-7.33 (m, 6H), 6.22 (s, 1H), 4.84-4, 73 (m, 2H), 3.78 (s, 3H), 3.27-3.16 (m, 1H), 3.04-2.92 (m, 1H), 2.90-2.88 ( m, 1H), 2.46-2.35 (m, 2H), 2.30-2.22 (m, 1H), 2.15-2.02 (m, 2H), 1.82-1, 71 (m, 1H), 1.63-1.55 (m, 2H), 1.40-1.28 (m, 1H), 1.15 (d, J=6.6 Hz, 4H). LC-MS (ESI, m/z): 512 [M+H] ⁺ .

The compounds listed in FIG. 1 were obtained using standard chemical manipulations and procedures similar to those described in this document. In FIG. The 1 eluted isomer refers to the order in which the 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-(]quinolin-3-yl]cyclohexane-1-carboxylic acid (424);(1R,3R)-3-[(7S)-2 -[(S)-(5-fluoro-2-methoxyphenyl)(hydroxy)methyl]-6-(methoxycarbonyl)-7methyl-3H,6H,7H,8H,9H-imidazo[4,5-(]quinoline-3 -yl]cyclohexane-1-carboxylic acid (660)

- 13 042920

424 660

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

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 h at room temperature. 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-(5-fluoro-2-methoxyphenyl)-2-[(trimethylsilyl)oxy]acetonitrile as a white solid substances (2.0 g, 79%).

Stage 2. 2-(5-Fluoro-2-methoxyphenyl)-2-hydroxyacetic acid

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 h 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

A solution of trifluoromethanesulfonic acid (82.0 ml, 0.923 mol) in HNO3 (19.6 ml, 0.437 mol) was stirred for 20 min 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 value of the solution was adjusted to 8 with sodium bicarbonate (saturated aqueous solution). The resulting solution was extracted with dichloromethane (3x300 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 1:4 ethyl acetate/petroleum ether) 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

Solution of (S)-(-)-MeO-BIPHEP (1.03 g, 1.77 mmol), chloro(1,5-cyclooctadiene)iridium(!) dimer (538 mg, 0.80 mmol) in toluene (100 ml) was stirred for 30 min at room temperature (25°C) under 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 h at room temperature (25° C.) under a hydrogen atmosphere (50 atm). The resulting mixture was concentrated in vacuo and purified by silica gel chromatography (eluting with 1:1 ethyl acetate/petroleum ether) 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 h at 60°C and then cooled to room temperature.

- 14 042920 temperature. The solids were collected by filtration and washed with ethyl acetate (120 ml). The solids were dissolved in water (50 ml). The pH value of the solution was adjusted to 8 with sodium bicarbonate (saturated aqueous solution). The resulting solution was extracted with ethyl acetate (3x120 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 d, 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

A solution of (2S)-6-fluoro-2-methyl-5-nitro-1,2,3,4-tetrahygroquinoline (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 (2x70 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-nitro1,2,3,4-tetrahydroquinoline-1-carboxylate as a yellow solid (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-1,2,3,4tetrahydroquinoline-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), methyl-(1R,3R)-3-aminocyclohexane-1-carboxylate (25.6 g, 162.84 mmol) in DMSO (270 ml) was stirred for 15 h at 90°C and then cooled to room temperature. The reaction mixture was quenched with water (200 ml) and extracted with ethyl acetate (3x300 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography (eluting with 1:1 ethyl acetate/petroleum ether) to give methyl-(2S)-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino] -2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate as a red oil (32 g, 72%). LC-MS (ESI, m/z): 406 [M+H] ⁺ .

Step 7. Methyl-(2S)-5-amino-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl1,2,3,4-tetrahydroquinoline-1-carboxylate

A solution of methyl-(2S)-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-5-nitro-1,2,3,4tetrahydroquinoline-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) was stirred for 1 h at 80°C and then cooled to room temperature. Solids were filtered off by filtration. The resulting solution was diluted with water (300 ml) and extracted with ethyl acetate (3x400 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

2-(5-fluoro-2-methoxyphenyl)-2-hydroxyacetic acid solution (240 mg, 1.20 mmol), HATU (228 mg, 0.60 mmol), methyl-(2S)-5-amino-6- [[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl1,2,3,4-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 h at 25°C. The resulting solution was diluted with H ₂ O (10 ml). The resulting solution was extracted with ethyl acetate (3x15 ml) and the organic layers were combined. The resulting mixture was washed with brine (2x20 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 3:2 ethyl acetate/petroleum ether) to give methyl-(2S)-5-[2-(5-fluoro-2-methoxyphenyl)-2-hydroxyacetamido]-6 -[[(1R,3R)-3(methoxycarbonyl)cyclohexyl]amino]-2-methyl-1,2,3,4-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[4,5-1]quinoline-6-carboxylate.

Methyl-(2S)-5-[2-(5-fluoro-2-methoxyphenyl)-2-hydroxyacetamido]-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl solution -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 1:1 ethyl acetate/petroleum ether) to give methyl-(7S)-2[(5-fluoro-2-methoxyphenyl)(hydroxy)methyl]-3- [(1R,3R)-3-(methoxycarbonyl)cyclohexyl]-7-methyl3H,6H,7H,8H,9H-imidazo[4,5-1]quinoline-6-carboxylate as a yellow solid (120 mg, 69 %). LC-MS (ESI, m/z): 540 [M+H] ⁺ .

- 15 042920

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,9Nimidazo[4,5-f]quinolin-3-yl]cyclohexane-1-carboxylic acid

A solution of methyl-(7S)-2-[(5-fluoro-2-methoxyphenyl)(hydroxy)methyl]-3-[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]-7-methyl-3H,6H, 7H,8H,9H-imidazo[4,5-f]quinoline-6-carboxylate (120 mg, 0.22 mmol) and LiOH (16 mg, 0.67 mmol) in tetrahydrofuran (2.0 ml), methanol ( 2.0 ml) and water (2.0 ml) was stirred overnight at 25°C. The resulting mixture was concentrated in vacuo. The crude product was purified by preparative HPLC (column, XBridge Prep C18 OBD column, 19x150 mm, 5 µm; mobile phase, A: water (containing 10 mmol/l NH4HCO3) and B: ACN (from 15.0% to 29.0 % within 14 min); detector, UV 220/254 nm). The product was separated by chiral preparative HPLC (column, CHIRALPAK IE, 2x25 cm, 5 μm; mobile phase, A: Hex (containing 0.1% FA) and B: ethanol (hold 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 (23.6mg, 20%) and (1R,3R)- 3-[(7S)-2-[(S)-(5-fluoro-2methoxyphenyl)(hydroxy)methyl]-6-(methoxycarbonyl)-7-methyl-3Н,6Н,7Н,8Н,9Н-imidazo[4 ,5-f]quinolin3-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: 0.46x5 cm; 3 µm; mobile phase: Hex (0.1% FA) : EtOH = 50 : 50, flow rate: 1.0 ml/min.

First eluted isomer (424): ¹ H-NMR (CD3OD, 400 MHz) δ (ppm): 7.56-7.47 (m, 1H), 7.477.31 (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), 7.447.29 (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] ⁺ .

In a preferred embodiment, the invention provides for 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:

I (Compound 424) or a pharmaceutically acceptable salt, hydrate, solvate or tautomer thereof.

In some embodiments, the invention provides a pharmaceutical composition comprising compound 424 of the above structure, or a pharmaceutically acceptable salt thereof, in a purity of at least 90%, such as greater than 90%, 91%, 92%, 93%, 94%, 95%, 96 %, 97%, 98% or 99% with respect to one or more of its related stereoisomers. For example, the description suggests compound 424 of the above structure or a pharmaceutically acceptable salt thereof with a purity of at least 90%, for example, a purity of more than 90%, 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 a compound 424 of the above structure, or a pharmaceutically acceptable salt thereof, in a purity of at least 95%.

The composition of formula (I) may contain a compound of one or more formulas (I-a), (I-b), (I-c), (Id), (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 comprising compound 424 of the above structure, or a pharmaceutically acceptable salt thereof, in a purity of at least 90%, wherein the composition contains less than 10%, such as 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 total of one or more of the following stereoisomers of compound 424 represented by formulas (II-a) to (II-o) below:

- 16 042920

In any of the above embodiments, said percent purity can be determined by HPLC. In some embodiments, the percent purity is determined using the following HPLC method.

Sample preparation:

Prepare 0.2mg/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: lOmM Ammonium acetate

Mobile Phase B: Acetonitrile

Column: Waters XSelect Phenyl-Hexyl, 3.5pm, 4.6x150mm

ColumnTemperature: 35'C

LC Gradient:

Runtime: 25 min

LC Flow Rate: 1 mL/min

UV Wavelength: 238 nm

Ionization Mode: Electrospray Ionization +ive

Injection Volume: 8pL

For example, the invention provides a pharmaceutical composition containing compound 424, or a pharmaceutically acceptable salt thereof, in 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 using the above HPLC method.

The invention provides a compound of formula II, obtained by the above method given in example 2

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

- 17 042920

It will be apparent to the experienced reader that each of the stereoisomers of the compound of formula (II) can be obtained by changing the stereochemistry of the respective 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 driving methyl-(1S,3R)-3-aminocyclohexane-1-carboxylate can be used in place 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 (P-a)-(P-o) depicted above can be synthesized.

Example 3 (1 R,3R)-3-[(7S)-2-[(R)-H-hydroxy(phenyl)methyl]-6-(methoxycarbonyl)-7-methyl3H,6H,7H,8H,9H -imidazo[4,5-f]quinolin-3-yl]cyclohexane-1-carboxylic acid (462)

Compositions containing compound 462 can be prepared as shown in the scheme below.

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

A solution of trifluoromethanesulfonic acid (82.0 ml, 0.923 mol) in HNO ₃ (19.6 ml, 0.437 mol) was stirred for 20 min 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 value of the solution was adjusted to 8 with sodium bicarbonate (saturated aqueous solution). The resulting solution was extracted with dichloromethane (3x300 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 1:4 ethyl acetate/petroleum ether) 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

Solution of (S)-(-)-MeO-BIPHEP (1.03 g, 1.77 mmol), chloro(1,5-cyclooctadiene)iridium(!) dimer (538 mg, 0.80 mmol) in toluene (100 ml) was stirred for 30 min at room temperature (25°C) under 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.) under a hydrogen atmosphere (50 atm.). The resulting mixture was concentrated in vacuo and purified by silica gel chromatography (eluting with 1:1 ethyl acetate/petroleum ether) 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 value of the solution was adjusted to 8 with sodium bicarbonate (saturated aqueous solution). The resulting solution was extracted with ethyl acetate (3x120 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 d, 76%). LC-MS (ESI, m/z): 211 [M+H] ⁺ .

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

Solution of (2S)-6-fluoro-2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline (25.3 g, 0.120 mol), pyridine

- 18 042920 (39.0 ml, 0.484 mol), methyl chloroformate (18.7 ml, 0.242 mol) in dichloromethane (150 ml) was stirred for 3 h at room temperature (25°C). The reaction mixture was washed with 1 M hydrogen chloride (2x70 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 a yellow solid (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-1,2,3,4tetrahydroquinoline-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), methyl-(1R,3R)-3-aminocyclohexane-1-carboxylate (25.6 g, 162.84 mmol) in DMSO (270 ml) was stirred for 15 h at 90°C and then cooled to room temperature. The reaction mixture was quenched with water (200 ml) and extracted with ethyl acetate (3x300 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography (eluting with 1:1 ethyl acetate/petroleum ether) to give methyl-(2S)-6-[[(1R,3R)-3(methoxycarbonyl)cyclohexyl]amino]- 2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate as a red oil (32 g, 72%). LC-MS (ESI, m/z): 406 [M+H] ⁺ .

Step 5. Methyl-(2S)-5-amino-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl1,2,3,4-tetrahydroquinoline-1-carboxylate

A 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 h at 80°C and then cooled to room temperature. Solids were filtered off by filtration. The resulting solution was diluted with water (300 ml) and extracted with ethyl acetate (3x400 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-methyl1, 2,3,4-tetrahydroquinoline-1-carboxylate as a dark green solid (27.5 g, 92%). LCMS (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

(R)-2-hydroxy-2-phenylacetic acid solution (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-1,2,3,4tetrahydroquinoline-1-carboxylate (800 mg, 2.13 mmol), DIEA (1.08 ml, 6, 20 mmol) in N,N-dimethylformamide (10 ml) was stirred for 5 h at room temperature (25°C). The resulting solution was diluted with water (30 ml) and extracted with ethyl acetate (3x50 ml). The organic layers were combined and washed with brine (2x25 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography (eluting with 1:1 ethyl acetate/petroleum ether) to give methyl-(2S)-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 (60θ 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[4,5-1]quinoline-6-carboxylate

Methyl-(2S)-5-((R)-2-hydroxy-2-phenylacetamido)-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-1,2 solution ,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 value of the solution was adjusted to 8 with sodium bicarbonate (saturated aqueous solution). The resulting solution was extracted with ethyl acetate (3x15 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 1:1 ethyl acetate/petroleum ether) to give methyl-(7S)-2-[(R)-hydroxy(phenyl)methyl]-3-[(1R ,3R)-3-(methoxycarbonyl)cyclohexyl]-7-methyl-3H,6H,7H,8H,9H-imidazo[4,5-1]quinoline-6-carboxylate (400 mg, 69%) as a colorless oil . LC-MS (ESI, m/z): 492 [M+H] ⁺ .

Step 8. (1R,3R)-3-[(7S)-2-[(R)-Hydroxy(phenyl)methyl]-6-(methoxycarbonyl)-7-methyl3H,6H,7H,8H,9H-imidazo[ 4,5-1]quinolin-3-yl]cyclohexane-1-carboxylic acid

A solution of methyl-(7S)-2-[(R)-hydroxy(phenyl)methyl]-3-[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]-7methyl-3H,6H,7H,8H,9H- imidazo[4,5-1]quinoline-6-carboxylate (400 mg, 0.81 mmol), LiOH (100 mg, 4.17 mmol) in tetrahydrofuran (5 ml) and water (2 ml) were stirred overnight at room temperature (25°C). The resulting mixture was concentrated in vacuo. The crude product was purified with

- 19 042920 preparative HPLC (column: XBridge Shield RP18 OBD column, 5 µm, 19x150 mm; mobile phase, A: water (containing 10 mmol/l NH4HCO3) and B: ACN (3 to 30% in 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[4,5-1]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 x 5 cm; 3 µm; mobile phase: Hex (0.1% FA): EtOH = 85:15, flow rate: 1.0 ml/min.

¹ H-NMR (CD3OD, 400 MHz) δ (ppm): 7.47-7.28 (m, 7H), 6.12 (s, 1H), 4.84-4.74 (m, 2H), 3.79 (s, 3H), 3.33-3.25 (m, 1H), 3.03-2.96 (m, 1H), 2.86-2.82 (m, 1H), 2, 38-2.25 (m, 2H), 2.25-2.07 (m, 3H), 1.79-1.72 (m, 1H), 1.64-1.57 (m, 2H), 1.40-1.29 (m, 2H), 1.16 (d, J=6.8 Hz, 3H). 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- 3Н,6Н,7Н,8Н,9Н-imidazo[4,5-1]quinolin-3-yl]cyclohexane-1-carboxylic acid (452), (1R,3R)-3-[(7S)-2-[ (R)-[2-(difluoromethoxy)-5-fluorophenyl](hydroxy)methyl]-6-(methoxycarbonyl)-7methyl-3H,6H,7H,8H,9H-imidazo[4,5-1]quinoline-3 -yl]cyclohexane-1-carboxylic acid (515)

3 4 5

2-(2-(difluoromethoxy)-5fluorophenyl)-2-hydroxyacetic acid

i. H ₂ (50 atm), l ₂

515 452

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

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) were stirred for 1 h at -30°C. The reaction mixture was diluted with water (20 ml). The resulting solution was extracted with ethyl acetate (3x100 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 1:1 ethyl acetate/petroleum ether) to give 2-(difluoromethoxy)-5fluorobenzaldehyde 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

2-(difluoromethoxy)-5-fluorobenzaldehyde solution (1.46 g, 7.68 mmol), TMSCN (760 mg, 7.66 mmol),

- 20 042920

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

A 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 h 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] ⁺ .

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

A solution of trifluoromethanesulfonic acid (82.0 ml, 0.923 mol) in HNO3 (19.6 ml, 0.437 mol) was stirred for 20 min 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 value of the solution was adjusted to 8 with sodium bicarbonate (saturated aqueous solution). The resulting solution was extracted with dichloromethane (3x300 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 1:4 ethyl acetate/petroleum ether) 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

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) under 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 h at room temperature (25° C.) under a hydrogen atmosphere (50 atm). The resulting mixture was concentrated in vacuo and purified by silica gel chromatography (eluting with 1:1 ethyl acetate/petroleum ether) 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 value of the solution was adjusted to 8 with sodium bicarbonate (saturated aqueous solution). The resulting solution was extracted with ethyl acetate (3x120 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 d, 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

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 (2x70 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 a yellow solid (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-1,2,3,4tetrahydroquinoline-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), methyl-(1R,3R)-3-aminocyclohexane-1-carboxylate (25.6 g, 162.84 mmol) in DMSO (270 ml) was stirred for 15 h at 90°C and then cooled to room temperature. The reaction mixture was quenched with water (200 ml) and extracted with ethyl acetate (3x300 ml). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The resulting crude product was purified by silica gel chromatography (eluting with 1:1 ethyl acetate/petroleum ether) to give methyl-(2S)-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino] -2-methyl-5-nitro-1,2,3,4-tetrahydroquinoline-1-carboxylate as a red oil (32 g, 72%). LC-MS (ESI, m/z): 406 [M+H] ⁺ .

Step 8. Methyl-(2S)-5-amino-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl1,2,3,4-tetrahydroquinoline-1-carboxylate

- 21 042920

A solution of methyl-(2S)-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-5-nitro-1,2,3,4tetrahydroquinoline-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 h at 80°C and then cooled to room temperature. Solids were filtered off by filtration. The resulting solution was diluted with water (300 ml) and extracted with ethyl acetate (3x400 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]-2methyl-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

Solution of methyl-(2S)-5-amino-6-[[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]amino]-2-methyl-1,2,3,4tetrahydroquinoline-1-carboxylate (200 mg, 0.53 mmol), 2-[2-(difluoromethoxy)-5-fluorophenyl]-2hydroxyacetic acid (220 mg, 0.93 mmol), DMTMM (350 mg, 1.26 mmol) in dichloromethane (5 ml) was stirred in for 1 h at room temperature (25°C). The resulting solution was concentrated in vacuo. The resulting crude product was purified by silica gel chromatography (eluting with 1:1 ethyl acetate/petroleum ether) to give methyl-(2S)-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 ,6Н,7Н,8Н,9Н-imidazo[4,5-£]quinoline-6-carboxylate

A solution of methyl-(2S)-5-[2-[2-(difluoromethoxy)-5-fluorophenyl]-2-hydroxyacetamido]-6-[[(1R,3R)-3(methoxycarbonyl)cyclohexyl]amino]-2- methyl 1,2,3,4-tetrahydroquinoline-1-carboxylate (70.0 mg, 0.12 mmol) in glacial acetic acid (2.0 ml) was stirred 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 (eluting with 1:2 ethyl acetate/petroleum ether) to give methyl-(7S)-2-[[2-(difluoromethoxy)-5fluorophenyl](hydroxy)methyl]-3-[ (1R,3R)-3-(methoxycarbonyl)cyclohexyl]-7-methyl-3H,6H,7H,8H,9Nimidazo[4,5-G|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-H|quinolin-3-yl]cyclohexane-1-carboxylic acid; (1R,3R)-3-[(7S)-2-[(R)-[2-(difluoromethoxy)-5-fluorophenyl](hydroxy)methyl]-6-(methoxycarbonyl)-7methyl-3H,6H,7H ,8H,9H-imidazo[4,5-L]quinolin-3-yl]cyclohexane-1-carboxylic acid

Methyl-(7S)-2-[[2-(difluoromethoxy)-5-fluorophenyl](hydroxy)methyl]-3-[(1R,3R)-3-(methoxycarbonyl)cyclohexyl]-7-methyl-3H solution, 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) was 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, 30x150 mm, 5 µm; mobile phase, A: water (containing 10 mmol/l NH4HCO3) 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-methyl3H ,6H,7H,8H,9H-imidazo[4,5-L]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-L]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: 0.46x5 cm; 3 µm; co-solvent: IPA (20 mM NH3), gradient (V%) : 10 to 50% in 4.0 min, retention 2.0 min at 50%.

First eluted isomer (452): ¹ H-NMR (CD3OD, 400 MHz) δ (ppm): 7.63-7.61 (m, 1H), 7.53 (d, J=8.8 Hz, 1H) , 7.41(d, J= 9.2 Hz,, 1H) 7.20-7.13(m, 2H), 6.67-6.30(m, 2H), 4.98-4.95 (m, 1H), 4.76-4.71 (m, 1H), 3.78 (s, 3H), 3.15-2.86 (m, 3H), 2.46-2.20 (m , 5H), 1.81-1.53 (m, 5H), 1.13 (d, J=6.8 Hz, 3H). LC-MS (ESI, m/z): 562 [M+H] ⁺ .

Second eluted isomer (515): 1H-NMR (CD3OD, 400 MHz) δ (ppm): 7.55-7.53 (m, 1H), 7.477.42 (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), 3.222.84 (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%.

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

- 22 042920 in example 4.

Example 5 HTRF Biochemical Assay for CBP and BRD4 Activity

The ability of compounds of formula I to selectively inhibit CBP was determined using the following HTRF biochemical assay 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 amounts of 10-point 3-fold serial dilution in DMSO were prefilled 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 Resonant Energy Transfer) was measured on a PHERAstar plate reader (BMG equipped with an HPRF optical module (HTRF) [337/520/490]) or 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 percent inhibition compared to control wells based on the following equation: %inh=1-((TR-FRET-AveLow ratio)/(AveHigh-AveLow)) where TR-FRET ratio=(fluorescence at 520 nm /fluorescence at 490 nm) * 10000), AveLow=average TR-FRET ratio of non-enzymatic control (n=32), and AveHigh=average TR-FRET ratio of DMSO control (n=32). IC ₅₀ values were determined by fitting the standard 4 parameter logistic fitting algorithm included in the Activity Base software package: IDBS XE Designer Model205. 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*((FLUAveLow)/(AveHigh-AveLow)) control (n=32) and AveHigh=average fluorescence value of DMSO control (n=32). IC ₅₀ values were determined by fitting the standard 4 parameter logistic fitting algorithm included in the Activity Base software package: IDBS XE Designer Model205. 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 indicated as +++; a value that is greater than 0.1 μM and less than or equal to 1 μM is indicated as ++; and values that are greater than 1 μM are indicated as +. Compounds that were not tested in a particular assay are labeled NT.

In some embodiments, the CBP inhibitory compound is also selective for CBP activity over BRD4 activity, as determined by obtaining an IC ₅₀ value for CBP inhibition in a HTRF biochemical assay for CBP that is lower than the corresponding value. IC ₅₀ obtained for HTRF biochemical analysis of BRD4 activity according to Example 5. The CBP inhibiting 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 retain sufficient CBP inhibition activity of the composition and selectivity for CBP over BRD4. Using the methods provided herein, CVR-inhibiting compositions may contain 95% by HPLC or more of a compound of the present disclosure or a pharmaceutically acceptable salt thereof, and up to 5% by HPLC of one or more stereoisomers of the compound.

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

In some embodiments, the present invention relates to 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 ₅₀ value that 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 HTRF biochemical analysis relative to the activity of CBP and BRD4, described in this document in example 5.

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

- 23 042920

1. Compound of formula (III)

or a pharmaceutically acceptable salt thereof, wherein

R ¹ is -OR ⁵ ;

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

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

R ⁶ is H or -C ₁ -C ₆ alkyl;

R ⁷ is -H, halogen, -OH, -CN, -OC ₁ -C ₆ alkyl, -NH2 -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 ^{1 0} is at each occurrence independently -C ₁ -C ₆ alkyl, -C ₂ -C ₆ alkenyl, -C ₂ -C ₆ alkynyl, -C3C8 cycloalkyl, -C4-C8 cycloalkenyl, heterocyclyl, heteroaryl, aryl, -OH, halogen, oxo, -NO2, -CN, -NH2, -OC1-C ₆ alkyl, -OC3-C ₆ cycloalkyl, -Oaryl, -Oheteroaryl, -NHC ₁ -C ₆ alkyl, -N (C ₁ -C ₆ alkyl ) ₂ , -S(O) ₂ NH(C ₁ C6alkyl), -S(O)2N(C1-C6alkyl)2, -S(O)2C1-C6alkyl, -C(O)C1-C6alkyl, -C( O)NH2, -C(O)NH(C1-C6alkyl), -NHC(O)C1-C6alkyl, -C(O)N(C1-C6alkyl)2, -C(O)OC _g C6alkyl, -N( C1-C6alkyl)SO2C1-C6alkyl, -S(O)(CiC 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 ;

R ^{1 2} 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 , -OC1-C6alkyl, -NHC1-C6alkyl, -N(C1-C6alkyl)2, -S(0)2NH(C1- C6alkyl), -S(0)2N(C1-C6alkyl)2, -S(O) ₂ C ₁ C6alkyl, -C(O)C1-C6alkyl, -C(O)NH2, -C(0)NH(C1 -C6alkyl), -C(0)N(C1-C6alkyl)2, -C(O)OC _g C6alkyl, -N(C1-C6alkyl)SO2C1-C6alkyl, -S(O)(C1-C6alkyl), -S (O)N(C1-C6alkyl)2 or -N(C1-C6alkyl)S(O)( _C1C6alkyl );

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

2. A compound according to claim 1, wherein R ¹² is halogen.

3. A compound according to any one of claims 1-2, where m is 3.

4. A compound according to any one of claims 1 to 3, wherein R ⁶ is H.

5. A compound according to any one of claims 1 to 4, wherein R ⁶ is aryl.

6. A compound according to any one of claims 1 to 5, wherein R ⁷ is -C(O)OH.

7. A compound according to any one of claims 1 to 6, wherein R ⁵ is methyl.

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

^R6

Mon Q

N=\ ^he

X ΤΎ

O^R ¹ (SH-s), or a pharmaceutically acceptable salt thereof, where 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, wherein

R ⁵ is -C1- _C3 alkyl;

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

R ¹⁰ is independently at each occurrence halogen, -OC ₁ -C ₆ alkyl, -OC ₃ -C ₆ cycloalkyl, -Oaryl or -Oheteroaryl, where each alkyl, cycloalkyl, aryl or heteroaryl is optionally substituted

- 24 042920 one or more -R ¹² ; And

R ¹² is halogen.

10. A compound according to any one of claims 1 to 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. A compound according to any one of claims 1-6, claims 8 or claims 10-11, wherein R ⁵ is -C ₁ -C ₃ alkyl.

13. A compound according to any one of claims 1-6 or claims 8-12, wherein R ⁵ is methyl.

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

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

Connection No. Structure Name Eluted isomer SVR 1C ₅ o (µM sr.geom.) BRD4 1C ₅ o (µM sr.geom.) 413 h. ? O (lR,3R)-3-((S)-2-((R)-(4chlorophenyl)(hydroxy)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8,9tetrahydro-3H-imidazo [4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 1st ++++ ++ 414 D' ° ^he (lR,3R)-3-((S)-2-((R)-(3-^op-4methylphenyl) (hydroxy)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8, 9tetrahydro-3H-imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 1st ++++ ++ 415 % HCU'O A st ^he O ^ O (lR,3R)-3-((S)-2-((S)-(3-^op-4methylphenyl) (hydroxy)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8, 9tetrahydro-3H-imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid acid 2nd ++++ ++ 416 GPU And ^he o^o (lR,3R)-3-((S)-2-((S)-(3-xflop-4methoxyphenyl)(hydroxy)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8,9tetrahydro- 3 H-imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 2nd ++++ ++ 417 0^0 (lR,3R)-3 -((S)-2-((R)-(3-fluoro-5methoxyphenyl)(hydroxy)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8,9tetrahydro- 3 H-imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 1st ++++ ++ 418 '2nW D ? ° (lR,3R)-3-((S)-2-((S)-(3-^op-5methoxyphenyl)(hydroxy)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8,9tetrahydro -3 H-imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 2nd ++++ ++ 419 b Uyun %?.- (lR,3R)-3-((S)-2-((S)-(2,3dihydrobenzofuran-5 yl) (hydroxy)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8,9tetrahydro -3 H-imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 2nd ++++ ++

- 25 042920

420 )-on A + ^he (lR,3R)-3-((S)-2-((S)-(3-φτop-4methoxyphenyl)(hydroxy)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8,9tetrahydro- 3 H-imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 2nd ++++ ++ 421 A· (lR,3R)-3-((S)-2-((S)-(3-chloro-5methoxyphenyl)(hydroxy)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8,9tetrahydro- 3 H-imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 2nd ++++ ++ 423 С—С/ won SG^O (lR,3R)-3-((S)-2-((S)-(3- chlorophenyl)(hydroxy)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8,9tetrahydro-3H-imidazo [4,5-f| quinolin3-yl)cyclohexane-1-carboxylic acid 2nd ++++ ++ 424 \-he _o A _o °^ ^he (lR,3R)-3-((S)-2-((R)-(5-φτop-2methoxyphenyl)(hydroxy)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8,9tetrahydro- 3 H-imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 1st ++++ + 426 □ / ^C| U-on f Ύ Ύ </ L~O _H oAe ⁰ (lR,3R)-3-((S)-2-((S)-(7-xflop-2,3dihydrobenzofuran-5 yl)(hydroxy)methyl)-6(methoxycarbonyl)-7-methyl-6.7 ,8,9tetrahydro-3H-imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 2nd ++++ ++ 427 A /XxV/N''/ \ to _L1 . ∆0 (lR,3R)-3-((S)-2-((R)-(7-φτop-2,3dihydrobenzofuran-5 yl) (hydroxy)methyl)-6(methoxycarbonyl)-7-methyl-6.7 ,8,9tetrahydro-3H-imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 1st ++++ ++ 428 RCGN F \-ΌΗ (lR,3R)-3-((S)-2-((R)-(2,3-diφτop-6methoxyphenyl)(hydroxy)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8, 9tetrahydro-3H-imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid acid 1st ++++ ++

- 26 042920

429 Υ ΌΗ 0^0 (lR,ЗR)-3-((S)-2-((S)-(5-φτop-lH- indazol-7-yl)(hydroxy)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8,9tetrahydro-3 H-imidazo [4,5 -f| quinolin3-yl)cyclohexane-1-carboxylic acid 2nd ++++ ++ 430 b-° to λ AU (lR,3R)-3-((S)-2-((R)-(2-xnop-4methoxyphenyl)(hydroxy)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8,9tetrahydro- 3 H-imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 1st ++++ ++ 431 y rYQ _Ο ^ΟΗ 1 (lR,3R)-3-((S)-2-((S)-(2-xnop-4methoxyphenyl)(hydroxy)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8,9tetrahydro- 3 H-imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 2nd ++++ ++ 432 V (lR,3R)-3-((S)-2-((S)-(3,4difluorophenyl) (hydroxy)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8,9tetrahydro-3H -imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 2nd ++++ ++ 433 Υο (lR,3R)-3-((S)-2-((R)-(3-xnop-5methoxyphenyl)(hydroxy)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8,9tetrahydro- 3 H-imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 1st ++++ ++ 434 Chr Στ ° Γ Ύ Ύ '-γ A 0^0 1 (lR,ЗR)-3-((S)-2-((R)-(5-φτop-lH- indol-7-yl)(hydroxy)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8,9tetrahydro-3 H-imidazo [4,5-f| quinolin3-yl)cyclohexane-1-carboxylic acid 1st ++++ ++ 436 HQ, Ν- ¹ nYQ Λ <λ ^0Η ? ⁰ (lR,3R)-3-((S)-2-((R)-2-(4-xnop-lHpyrazol-1 -yl)-1-hydroxyethyl)-6(methoxycarbonyl)-7-methyl-6, 7,8,9tetrahydro-3H-imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 1st ++++ ++

- 27 042920

437 ^C| -b A ° ⁿ A ^ ^0H (lR,3R)-3-((S)-2-((R)-(3-xnop-4methoxyphenyl)(hydroxy)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8,9tetrahydro- 3 H-imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 1st ++++ ++ 438 (lR,3R)-3-((S)-2-((R)-(3-φτop-4methoxyphenyl)(hydroxy)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8,9tetrahydro- 3 H-imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 1st ++++ ++ 440 2° ^H (lR,3R)-3-((S)-2-((S)-(2,3dihydrobenzofuran-7 yl) (hydroxy)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8,9tetrahydro -3 H-imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 2nd ++++ ++ 442 ci^Qo ⁷ Y-OH to nyo (lR,3R)-3-((S)-2-((R)-(5-xnop-2methoxyphenyl)(hydroxy)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8,9tetrahydro- 3 H-imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 1st ++++ ++ 444 D XD L ₀ A ₀ (lR,3R)-3-((S)-2-((S)-(2(difluoromethyl)-5 fluorophenyl)(hydroxy)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8, 9tetrahydro-3H-imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 2nd ++++ ++ 445 d/< (lR,ЗR)-3-((S)-2-((S)-(5-φτop-2isopropoxyphenyl)(hydroxy)methyl)6 -(methoxycarbonyl) -7 -methyl-6,7,8,9tetrahydro- 3 H-imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 2nd ++++ ++ 448 4: nYQ A^ ^0H 1 (lR,3R)-3-((S)-2-((S)-(5-φτop-lHindol-7-yl)(hydroxy)methyl)-6(methoxycarbonyl)-7-methyl-6.7, 8,9tetrahydro-3H-imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 2nd ++++ ++

- 28 042920

449 U-'ON (lR,3R)-3-((S)-2-((S)-(2,5difluorophenyl) (hydroxy)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8,9tetrahydro-3H -imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 2nd ++++ + 451 Τ >=\ ν-% # \-0Η ηΥΌ% 1 (lR,3R)-3-((S)-2-((R)-nwp _O KCH(2methoxybenzo[d]oxazol-5-yl)methyl)6-(methoxycarbonyl)-7-methyl-6,7, 8,9tetrahydro-3H-imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 1st ++++ ++ 452 \0Η Η /> z6 ^N Q ₀ Α ₀ Ά ^Η (lR,3R)-3-((S)-2-((S)-(2(difluoromethoxy)-5fluorophenyl)(hydroxy)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8,9tetrahydro -3 H-imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid ++++ ++ 453 Ά Qv νό Ό Ο X (lR,3R)-3-((S)-2-((R)-2-nwpoKCH-lphenylpropan-2-yl)-6(methoxycarbonyl)-7-methyl-6,7,8,9tetrahydro-3H -imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 2nd ++++ +++ 454 n. 0 Η/-, ^Q ϊ cA ? ⁰ (1K,3K)-3-((8)-2-((K)-2-cyclopentyl-1hydroxyethyl)-6-(methoxycarbonyl)-7methyl-6,7,8,9-tetrahydro-3 Nimidazo [4, 5-f|quinolin-3 yl)cyclohexane-1-carboxylic acid 1st ++++ ++ 458 a. Ο^Ο (!R,3R)-3-((S)-2-((R)-6eH30[d]0Kca30fl5 -yl(hydroxy)methyl) -6(methoxycarbonyl) -7 -methyl-6,7,8,9tetrahydro -3 H-imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 1st ++++ ++ 460 %α ^ν ό Α ^ ^0Η (lR,3R)-3-((S)-2-((R)-(2,3dihydrobenzofuran-5 yl) (hydroxy)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8,9tetrahydro -3 H-imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 1st ++++ ++

- 29 042920

461 A" (lR,3R)-3-((S)-2-((R)-(7-xnop-2,3dihydrobenzofuran-5 yl) (hydroxy)methyl)-6(methoxycarbonyl)-7-methyl-6.7 ,8,9tetrahydro-3H-imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 1st ++++ ++ 462 χάΡ \X °^ ^oh 1 (lR,3R)-3-((S)-2-((R)hydroxy(phenyl)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8,9tetrahydro-3H-imidazo [4, 5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 1st ++++ + 464 —0 \OH dr X c/ ^0H 0^0 1 (lR,3R)-3-((S)-2-((S)-(3-φτop-2,6dimethoxyphenyl)(hydroxy)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8, 9tetrahydro-3H-imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 2nd ++++ ++ 467 1 __ \OH nyo A 7-» (lR,3R)-3-((S)-2-((S)-nwp _O KCH(l-methyl-1 H-indo l-5 -yl)methyl) -6(methoxycarbonyl) -7 -methyl- 6,7,8,9tetrahydro-3H-imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 2nd ++++ ++ 470 /h (lR,3R)-3-((S)-2-((R)-rmipoKCH(4methoxyphenyl)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8,9tetrahydro-3H-imidazo [4 ,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 1st ++++ ++ 472 ΓΎΎ V d ^ ^0H 1 (lR,3R)-3-((S)-2-((S)-nwp _O KCH(3methoxyphenyl)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8,9tetrahydro-3H-imidazo [4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 2nd ++++ ++ 474 \OH /-L 5? (lR,3R)-3-((S)-2-((S)-(7-φτop-2,3dihydrobenzofuran-5 yl) (hydroxy)methyl)-6(methoxycarbonyl)-7-methyl-6.7 ,8,9tetrahydro-3H-imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 2nd ++++ ++

- 30 042920

478 Ά ^η XL q» X (lR,3R)-3-((S)-2-((R)-(5-φτop-lHindazol-7-yl)(hydroxy)methyl)-6(methoxycarbonyl)-7-methyl-6.7, 8,9tetrahydro-3H-imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 1st ++++ ++ 479 o § 0 ⁴ ° (lR,3R)-3-((S)-2-((R)-(3,4difluorophenyl)(hydroxy)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8,9tetrahydro-3 H -imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 1st ++++ + 480 % AND I (lR,3R)-3-((S)-2-((R)-ri^poKCH(l Hindazol-5-yl)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8,9tetrahydro -3 H-imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 1st ++++ ++ 482 Won N=\ X ^he 0^0 1 (lR,3R)-3-((S)-2-((S)-(2cyclopropoxy-5 fluorophenyl)(hydroxy)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8,9tetrahydro-3 H-imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 2nd ++++ ++ 488 (lR,3R)-3-((S)-2-((R)-(3,5difluorophenyl) (hydroxy)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8,9tetrahydro-3H -imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 1st ++++ ++ 491 A X (lR,3R)-3-((S)-2-((R)cycloheptyl(hydroxy)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8,9tetrahydro-3H-imidazo [4, 5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 1st ++++ ++ 493 wuyun gao yv (lR,3R)-3-((S)-2-((S)-(3,5difluorophenyl) (hydroxy)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8,9tetrahydro-3 H -imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 2nd ++++ ++

- 31 042920

499 Υ'ΌΗ Aq "A, Η 1 (1C,3C)-3-((8)-2-((8)-benzo[c1]oxazol5-yl(hydroxy)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8,9tetrahydro- 3 H-imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 2nd ++++ ++ 501 Cl Won N=<__ xty-Q 7-v X” (lR,3R)-3-((S)-2-((S)-(4chlorophenyl)(hydroxy)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8,9tetrahydro-3H-imidazo [4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 2nd ++++ ++ 503 but oh A X (lR,3R)-3-((S)-2-((S)-l-ri^poKCH-2phenylethyl) -6 -(methoxycarbonyl) -7 methyl-6,7,8,9-tetrahydro-3 Nimidazo [4,5-f|quinolin-3 yl)cyclohexane-1-carboxylic acid 2nd ++++ ++ 515 άά (lR,3R)-3-((S)-2-((R)-(2(difluoromethoxy)-5fluorophenyl)(hydroxy)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8,9tetrahydro -3 H-imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid ++++ + 523 ^ci A7 U-on K Ζ-1 rWO a» 1 (lR,3R)-3-((S)-2-((R)-(3- chlorophenyl)(hydroxy)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8,9tetrahydro-3H-imidazo [4,5-f| quinolin3-yl)cyclohexane-1-carboxylic acid 1st ++++ ++ 528 i /•oh v. οΧ ° (lR,3R)-3-((S)-2-((S)hydroxy(phenyl)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8,9tetrahydro-3H-imidazo [4, 5-f|quinolin3-yl)cyclohexane-1-carboxylic acid ++++ ++ 534 /3(-, nY'Q A σ ^on O^O 1 (lR,3R)-3-((7S)-2-(l-nwp _O KCH-l-phenylpropyl)-6-(methoxycarbonyl)-7methyl-6,7,8,9-tetrahydro-3 Nimidazo [4, 5-f|quinolin-3 yl)cyclohexane-1-carboxylic acid ++++ +

- 32 042920

537 F ^on A'X (1K,3K)-3-((8)-2-((8)-(3,5-difluoro-2methoxyphenyl)(hydroxy)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8, 9tetrahydro-3H-imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 2nd ++++ ++ 538 / ^he O \-OH x/o X < R ° ⁿ 0 ^ 0 1 (lR,3R)-3-((S)-2-((R)-nwp _O KCH(3methoxyphenyl)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8,9tetrahydro-3H-imidazo [4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 1st ++++ + 542 XX/^ ^OH (lR,3R)-3-((S)-2-((R)-l-nwp _O KCH-lphenylethyl) -6 -(methoxycarbonyl) -7 methyl-6,7,8,9-tetrahydro-3nimidazo [ 4,5-f|quinolin-3 yl)cyclohexane-1-carboxylic acid 1st ++++ + 564 \-OH xZo X /оН 0^0 1 (lR,3R)-3-((S)-2-((R)-(2(difluoromethyl)-5fluorophenyl)(hydroxy)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8,9tetrahydro -3 H-imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 1st ++++ + 565 rgyo X /~° ⁿ (1C,3k)-3-((8)-2-((8)-hydroxy(2methylbenzo[c!]oxazol-5-yl)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8 ,9tetrahydro-3H-imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 2nd ++++ + 566 I (lR,3R)-3-((S)-2-((S)^ypo[2,3c]pyridin-5-yl(hydroxy)methyl)-6(methoxycarbonyl)-7-methyl-6.7, 8,9tetrahydro-3H-imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 2nd ++++ ++ 569 AO 'o 0^0 1 (18.4 g)-4-((8)-2-((8)-1-hydroxy-2phenylethyl) -6 -(methoxycarbonyl) -7 methyl-6,7,8,9-tetrahydro-3 Nimidazo [4 ,5-f|quinolin-3 yl)cyclohexane-1-carboxylic acid 2nd ++++ ++

- 33 042920

631 Md 'n Mon ΪqMh 0^0 1 (lR,3R)-3-((S)-2-((R)hydroxy(isoquinolin-3-yl)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8,9tetrahydro-3 H- imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 1st +++ + 636 X (lR,3R)-3-((S)-2-((R)-(2,3dihydrofuro[2,3-c]pyridin-5yl)(hydroxy)methyl)-6(methoxycarbonyl)-7-methyl -6,7,8,9tetrahydro-3H-imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 1st +++ + 637 S-”L^ ^he (lR,3R)-3-((S)-2-((R)- cyclohexyl(hydroxy)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8,9tetrahydro-3H-imidazo [4,5-f| quinolin3-yl)cyclohexane-1-carboxylic acid 1st +++ + 638 ^p I° XA X <L° ⁿ 0^0 1 (lR,3R)-3-((S)-2-((S)-(2,3-diφτop-6methoxyphenyl)(hydroxy)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8, 9tetrahydro-3H-imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 2nd +++ + 649 nYQ οΆ 1 (lR,3R)-3-((S)-2-((R)-(3,5-diφτop-2methoxyphenyl)(hydroxy)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8, 9tetrahydro-3H-imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 1st +++ + 654 % Won χό“Ό (lR,3R)-3-((S)-2-((S)-(2,3dihydrofuro[2,3-c]pyridin-5yl)(hydroxy)methyl)-6(methoxycarbonyl)-7-methyl -6,7,8,9tetrahydro-3H-imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 2nd +++ + 660 DUs/ (lR,3R)-3-((S)-2-((S)-(5-φτop-2methoxyphenyl)(hydroxy)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8,9tetrahydro- 3 H-imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 2nd +++ +

- 34 042920

662 \-He A 7° 1 (1Ε,3Ε)-3-((8)-2-((Κ)-(5-φτορ-2isopropoxyphenyl)(hydroxy)methyl)6 -(methoxycarbonyl) -7-methyl-6,7,8,9tetrahydro- 3 H-imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 1st +++ ++ 674 but u—' №=( ___ Lo 7" 1 (1E,3E)-3-((8)-2-((8)-2-cyclopentyl-1hydroxyethyl)-6-(methoxycarbonyl)-7methyl-6,7,8,9-tetrahydro-3 Nimidazo [4, 5-f|quinolin-3 yl)cyclohexane-1-carboxylic acid 2nd +++ + 678 >b l .—to o o. νθ ¹ o t (lR,3R)-3-((S)-2-((R)-(2cyclopropoxy-5 fluorophenyl)(hydroxy)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8,9tetrahydro-3 H-imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 1st +++ ++ 682 U'YUN Ν=\ rngo D 7- (1K,3K)-3-((8)-2-((8)-hydroxy(4methoxyphenyl)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8,9tetrahydro-3H-imidazo [4 ,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 2nd +++ + 699 A (lR,3R)-3-((S)-2-((R)-(4,4difluorocyclohexyl)(hydroxy)methyl)6-(methoxycarbonyl)-7-methyl-6,7,8,9tetrahydro-3H -imidazo[4,5-f|quinolin-3-yl)cyclohexane-1 carboxylic acid 1st +++ + 701 X, ηΛΓ'Ό TV 7" (lR,3R)-3-((S)-2-((S)-(l,3- dihydroisobenzofuran-4yl) (hydroxy) methyl) -6(methoxycarbonyl) -7 -methyl-6,7,8,9tetrahydro-3 H-imidazo[4,5-1]quinolin3 -yl)cyclohexane-1-carboxylic acid 2nd +++ + 708 % Hee O^o 1 (lS,4r)-4-((S)-2-((S)- hydroxy(phenyl)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8,9tetrahydro-3H-imidazo [4,5-f| quinolin3-yl)cyclohexane-1-carboxylic acid 1st +++ +

- 35 042920

712 ^H 4 / - o% ^0H (lR,3R)-3-((S)-2-((R)-2-(4,4difluorocyclohexyl)-1-hydroxyethyl)6-(methoxycarbonyl)-7-methyl-6,7,8,9tetrahydro- 3 H-imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 1st +++ + 730 NO N- ⁷ /¾¾ A θ^ ^ΟΗ 0^0 1 (!R,3R)-3-((S)-2-((S)-2-(4-xflop-lHpyrazol-1 -yl) -1-hydroxyethyl)-6(methoxycarbonyl)-7-methyl-6 ,7,8,9tetrahydro-3H-imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 2nd +++ + 731 4 u t (1H,3H)-3-((8)-2-((H)-(5-chloropyridin2-yl) (hydroxy)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8,9tetrahydro- 3 H-imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 1st +++ + 735 U-on ν=< AV (lR,4r)-4-((S)-2-((R)hydroxy(phenyl)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8,9tetrahydro-3H-imidazo [4, 5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 2nd +++ + 747 A 77 0^0 1 (lR,3R)-3-((S)-2-((S)-(4,4difluorocyclohexyl)(hydroxy)methyl)6 -(methoxycarbonyl) -7-methyl-6,7,8,9tetrahydro-3 H -imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 2nd +++ + 749 -A O °</^ / X (lR,3R)-3-((S)-2-((R)-l-nwp _O KCH-l(pyridin-2-yl)ethyl)-6(methoxycarbonyl)-7-methyl-6.7, 8,9tetrahydro-3H-imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 1st +++ + 762 y Don N=( rAO X <λ ^0Η 0^0 (lR,3R)-3-((S)-2-((R)- cyclopentyl(hydroxy)methyl)-6(methoxycarbonyl)-7-methyl-6,7,8,9tetrahydro-3H-imidazo [4,5-f| quinolin3-yl)cyclohexane-1-carboxylic acid 1st +++ +

- 36 042920

770 AA -Q \-OH No \ ___ rijfQ A ° ^ ^he O X) 1 (1Κ,3Κ)-3-((8)-2-((Κ)-(3-φτορ-2,6dimethoxyphenyl) (hydroxy)methyl) -6 (methox and carbonyl) -7 -methyl-6,7,8 ,9tetrahydro-3H-imidazo[4,5-f]quinolin3-yl)cyclohexane-1-carboxylic acid 1st +++ + 774 Oh oh about ΞΕ (lR,3R)-3-((S)-2-((S)cyclopentyl(hydroxy)methyl)-6(methox and carbonyl l)-7-methyl-6,7,8,9tetrahydro-3H-imidazo [ 4,5 -f] quinolin3 -yl) cyclohexane-1-carboxylic acid 2nd +++ + 781 ABOUT \LON AA /A A X X° O^O 1 (lR,3R)-3 -((8)-2-((8)-1-hydroxy-1(pyridin-2-yl)ethyl)-6(methox and carbonyl)-7-methyl-6.7, 8,9tetrahydro-3H-imidazo[4,5-f]quinolin3-yl)cyclohexane-1-carboxylic acid 2nd +++ + 817 It. №( __ JSC about O^O 1 (1H,4d)-4-((8)-2-(H)-1-hydroxy-2phenylethyl) -6 -(methoxycarbonyl) -7 methyl-6,7,8,9-tetrahydro-3nimidazo [4.5 -f]quinolin-3 yl)cyclohexane-1-carboxylic acid 1st +++ ++ 822 O HQ A/ ^Ν =\ nUH Ζ" 1 (1R,3R)-3-((S)-2-((R)-1-th^okch-2phenylethyl) -6 -(methoxycarbonyl) -7 methyl-6,7,8,9-tetrahydro-3Nimidazo [ 4,5-f]quinolin-3 yl)cyclohexane-1-carboxylic acid 1st +++ + 826 X U-on aUCH A <λ ^ΟΗ 0^0 1 (lR,3R)-3-((S)-2-((R)-(l,3- dihydroisobenzofuran-4yl) (hydroxy)methyl) -6 (methox and carbonyl l) -7 -methyl-6,7,8,9tetrahydro-3 H-imidazo [4,5 -f]quinolin3 -yl)cyclohexane-1-carboxylic acid 1st +++ ++ 957 A A Ah Ch O ΞΕ (lR,3R)-3-((S)-2-((S)-l-(5-φτop-2methoxyphenyl)-1-hydroxyethyl)-6(methox and carbonyl l)-7-methyl-6.7, 8,9tetrahydro-3H-imidazo[4,5-f]quinolin3-yl)cyclohexane-1-carboxylic acid 2nd + + 960 F— ^λ= ΑθΗ nA '' _ - A Nn./y jfYj A cA ^he ΟΆ 1 (lR,3R)-3-((S)-2-((R)-l-(5-φτop-2methoxyphenyl)-1-hydroxyethyl)-6(methoxycarbonyl)-7-methyl-6,7,8, 9tetrahydro-3H-imidazo[4,5-f]quinolin3-yl)cyclohexane-1-carboxylic acid 1st + + 962 (1R, 3R)-3 -((8)-2-((H)-hydroxy(1methyl-1 H-indol-5 -yl)methyl) -6 (methoxycarbonyl) -7 -methyl-6,7,8 ,9tetrahydro-3H-imidazo[4,5-f|quinolin3-yl)cyclohexane-1-carboxylic acid 1st + +++

CLAIM

Claims (27)

1. Compound of formula (I) or a pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer thereof, wherein R ¹ is -OR ⁵ ; R ⁵ is -C ₁ -C ₆ alkyl; R ⁶ is phenyl optionally substituted with one or more R ¹⁰ ; R ¹⁰ is at each occurrence independently -C ₁ -C ₆ alkyl, halogen, -OC ₁ -C ₆ alkyl or -OC3- 37 042920 C6cycloalkyl, where each alkyl or cycloalkyl is optionally substituted with 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 6 cycloalkyl or 5-membered heterocyclyl containing one or more ring atoms independently selected from O or N; or where any two R ¹⁰ , if present on adjacent atoms, can be combined to form a C ₃ -C 6 cycloalkyl, a 5-membered heterocyclyl containing one or more ring atoms independently selected from O and N, or a 5-membered heteroaryl containing one or more ring atoms independently selected from O and N; R ¹² is at each occurrence independently -C ₁ -C ₆ lkyl, -OH or halogen. 2. The compound according to claim 1 or its pharmaceutically acceptable salt, enantiomer, stereoisomer or tautomer, where R ⁵ is -C ₁ -C ₃ alkyl; R ¹⁰ is at each occurrence independently halogen, -OC ₁ -C ₆ alkyl, or -OC ₃ C ₆ cycloalkyl, where each alkyl or cycloalkyl is optionally substituted with one or more -R ¹² ; And R ¹² is halogen. 3. A compound according to any one of claims 1 to 2, or a pharmaceutically acceptable salt thereof, wherein R ⁵ is methyl. 4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein at least one R ¹⁰ is halogen. 5. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein at least one R ¹⁰ is -OC ₁ -C ₆ alkyl. 6. A compound according to 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 bridged C ₃ -C ₆ cycloalkyl or a 5-membered heterocyclyl containing one or more ring atoms , independently selected from O and N. 7. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein any two R ¹⁰ , if present on adjacent atoms, can be combined to form C3-C6 cycloalkyl, a 5-membered heterocyclyl containing one or more ring atoms independently selected from O and N, or a 5-membered heteroaryl containing one or more ring atoms independently selected from O and N. 8. A compound according to any one of claims 1 to 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 occurrence is independently halogen or -OC ₁ -C ₆ alkyl, where -OC ₁ -C ₆ llkyl is optionally substituted with halogen. 9. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein each R ¹⁰ is independently halogen at each occurrence, or -OC ₁ alkyl optionally substituted with one or more R ¹² , where R ¹² is halogen. 10. A compound according to claim 9, or a pharmaceutically acceptable salt thereof, wherein each R ¹² in each occurrence independently represents fluoro. 11. The compound according to claim 1, where the compound is a compound of formula (IV-a) I 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 case 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, where each alkyl or cycloalkyl is optionally substituted with one or more halo or C ₁ -C ₆ alkyl; or any two R ¹⁰ , if present on non-adjacent atoms, may be combined to form a bridged C ₃ -C ₆ cycloalkyl or 5-membered heterocyclyl containing one or more ring atoms independently selected from O and N; or any two R ¹⁰ , if present on adjacent atoms, may be combined to form a C ₃ -C ₆ cycloalkyl, a 5-membered heterocyclyl containing one or more ring atoms independently selected from O and N, or a 5-membered heteroaryl, containing one or more ring atoms independently selected from O and N. 12. The connection according to claim 11, where n is 0, 1 or 2. 13. The compound according to claim 11 or 12, where each R ¹⁰ in each case 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, where each alkyl or cycloalkyl is optionally substituted with one or more halo or methyl. - 38 042920 14. A compound according to any one of claims 11-13, wherein each halogen is independently selected from the group consisting of fluorine and chlorine. 15. A compound according to any one of claims 10-13, wherein each -OC ₃ -C6 cycloalkyl is -Ocyclopropyl 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 - 39 042920 from from from from from 17. The compound according to claim 1 or 11, or a pharmaceutically acceptable salt thereof, where the compound is selected 18. The compound according to claim 1 or 11, or a pharmaceutically acceptable salt thereof, where the compound is selected 19. The compound according to claim 1 or 11, or a pharmaceutically acceptable salt thereof, where the compound is selected 20. The compound according to claim 1 or 11, or a pharmaceutically acceptable salt thereof, where the compound is selected 21. The compound according to claim 1 or 11, or a pharmaceutically acceptable salt thereof, where the compound is selected - 40 042920 22. The compound according to claim 1 or And or its pharmaceutically acceptable salt, where the compound has the structure 23. The compound according to claim 1 or And or its pharmaceutically acceptable salt, where the compound has the structure I 24. The compound according to claim 1 or And or its pharmaceutically acceptable salt, where the compound has the structure 25. The compound according to claim 1 or And or its pharmaceutically acceptable salt, where the compound has the structure CI 26. The compound according to claim 1 or And or its pharmaceutically acceptable salt, where the compound has the structure 27. A pharmaceutical composition containing a compound according to any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.